New Zealand Guidelines

NEW ZEALAND REGULATORY GUIDELINES FOR MEDICINES

VOLUME 1

Guidance notes for applicants for consent to distribute new and changed medicines and related products

Fifth EditionOctober 2001

(Combining and updating previous Volumes 1 and 2)

New Zealand Regulatory Guidelines for Medicines, Volume 1, Fifth edition, 2001

Foreword

This document is the fifth edition of the Guidance Notes for Applicants for Consent to Distribute New and Changed Medicines and Related Products. It combines and replaces the fourth (March 1999) edition of Volume 1 and the second (March 1999) edition of Volume 2: Guidance Notes for Bioequivalence Testing.

This new combined edition includes a number of changes in both content and format. Some text has been revised to reflect changes in policy or processes. Some new sections and subsections have been added, some others have been rearranged or deleted, and the various forms previously included in the main text have been moved to appendices at the end of the document. A more detailed list of changes is provided below.

These Guidelines are designed to assist sponsors in the preparation and submission of applications for consent to distribute new or changed medicines and related products in New Zealand in accordance with the legislation. They will be revised as needed and published on Medsafe’s web site (http://www.medsafe.govt.nz). Copies of the individual forms given in this volume are also provided as separate documents on the web site.

Clare Van der LemManagerMedsafe

DisclaimerWhile every care has been taken in the preparation of the information contained in these guidelines, Medsafe is not responsible for the results of any act or omission, done or omitted in reliance, in whole or in part, on the basis of that information, nor for any error in or omission from the guidelines. The information in the guidelines is of a general nature and should be used as a guide only to the provisions in the Medicines Act 1981, Medicines Regulations 1984, Misuse of Drugs Act 1975, Misuse of Drugs Regulations 1977, subsequent amendments and other relevant legislation.

Published with the permission of the Director-General of HealthISBN 0-478-26214-0 (Internet publication)ISBN 0-478-26211-6 (Book)

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Significant Changes in this Edition

1. Volume 2 has been amalgamated with Volume 1 to become Sections 15 and 16.

2. The fees schedule has been moved to an appendix at the end of the document.

3. Several of the forms and checklists have been revised and all have been moved out of the main text and into appendices at the end of the document.

4. The requirements of the Hazardous Substances and New Organisms legislation and the Environmental Risk Management Authority (ERMA) have been updated and expanded (Section 2.11.2).

5. The requirements for recording and reporting the supply of unapproved medicines have been updated (section 2.13).

6. A section dealing with Medical Advertisements has been added (Section 2.14).

7. Processing times for applications and notifications have been clarified (Section 5.7).

8. Web site addresses for overseas guidelines have been updated (Section 6.9).

9. A new section detailing requirements for proprietary names of therapeutic products has been added (Section 6.10).

10. The requirements for Certificates of Suitability have been updated and expanded (Section 7.2).

11. The ICH Common Technical Document has been added as a preferred format for dossiers (Section 8.1).

12. The list of individual German GMP inspectorates has been added (Section 11.5).

13. Labelling requirements for transdermal patches have been added (Section 12.8).

14. Labelling requirements for OTC hydrocortisone topical products have been added (Section 12.10.9).

15. A recommendation that the labelling for topical medicines should include a list of all of the ingredients has been added (Section 12.10.16).

16. The requirements for Consumer Medicine Information have been updated and clarified (Section 12.12).

17. The requirements and procedures for data sheets have been updated (Section 13).

18. The policies and processes for compiling and maintaining the List of Interchangeable Multi-source Medicines have been updated (Section 14.4).

19. Some changes have been made to requirements for batch sizes of test products used in bioequivalence studies (Section 15.5.6) and the requirement to re-analyse 15% of samples has been removed (Section 15.7.3).

20. New NRPA and CRPN forms have been created (Appendices 3 and 7) and reference to related products has been removed from the NMA and CMN forms (Appendices 2, 5 and 6).

21. A new checklist for completeness of data for new multi-source prescription medicines has been created (Appendix 4).

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Abbreviations

AAN Australian Approved Name

ADEC Australian Drug Evaluation Committee

ADR Adverse drug reaction

Ae Cumulative urinary recovery

ANOVA Analysis of variance

API Active pharmaceutical ingredient

ARTG Australian Register of Therapeutic Goods

AUC Area under the concentration vs. time curve

AUC AUC up to the last quantifiable concentration plus additional area extrapolated to

infinity, calculated using kel

AUCt Area under the concentration vs. time curve (AUC) measured to the last quantifiable

concentration

AUCTCSS AUC measured over one dose interval (T) at steady state

AUCTS AUC over the dosing interval (T) following a single dose of the MR product

AUCTS/AUC Ratio of AUC over the dosing interval to the total AUC

BAN British Approved Name

BNF British National Formulary

BP British Pharmacopoeia

CARM Centre for Adverse Reactions Monitoring

Cav Average concentration

CFC Chlorofluorocarbon

Cmax Maximum observed concentration

CMI Consumer Medicine Information

Cmin Minimum observed concentration

CMN Changed Medicine Notification

CoS Certificate of Suitability (European Pharmacopoeial Commission)

Cpd Pre-dose concentration determined immediately pre-dose

CPMP Committee for Proprietary Medicinal Products [Europe]

CPP Certificate of a Pharmaceutical Product

CRPN Changed Related Product Notification

Ct The last quantifiable concentration

CTD Common Technical Document (ICH format)

DF Degree of fluctuation = (Cmax - Cmin)/ (AUCT/T) x 100%

DMF Drug Master File

EC European Community; or European Commission; or Enteric-coated

EMEA European Medicines Evaluation Agency

EP [See Ph Eur]

ERMA Environmental Risk Management Authority

EU European Union

FDA Food and Drug Administration [USA]

FEV1 Forced expiry volume in 1 second

GC Gas chromatography

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GCRP Good Clinical Research Practice

GMP Good Manufacturing Practice

GSC Generics Subcommittee of MAAC

HPLC High pressure (or performance) liquid chromatography

HRC Health Research Council

HSNO Hazardous Substances and New Organisms Act

ICH International Conference on Harmonisation

IMM Interchangeable Multi-source Medicine

IMMP Intensive Medicines Monitoring Programme

INN International Non-proprietary Name

kel Terminal elimination rate constant

MAAC Medicines Assessment Advisory Committee

MARC Medicines Adverse Reactions Committee

MCA Medicines Control Agency [UK]; or Medicines Control Advisor

MCC Medicines Classification Committee

MOH Medical Officer of Health

MoH Ministry of Health

MoU Memorandum of Understanding

MQC Minimum quantifiable concentration

MR Modified release

MRC Medicines Review Committee

MRT Mean residence time

NBE New Biological Entity

NCE New Chemical Entity

NF National Formulary [USA]

NMA New Medicine Application

NMA-H New higher-risk medicine application

NMA-I New intermediate-risk medicine application

NMA-L New lower-risk medicine application

NRL National Radiation Laboratory

NRPA New Related Product Application

NZ New Zealand

NZRGM New Zealand Regulatory Guidelines for Medicines

NZRP New Zealand Reference Product

OIA Official Information Act

OTC Over The Counter [i.e. non- prescription products]

Part I Administrative/summary section of European dossier

Part II Chemistry & pharmaceutical section of European dossier

Part III Pharmaco-toxicological section of European dossier

Part IV Clinical section of European dossier

Ph Eur European Pharmacopoeia

PHARMAC Pharmaceutical Management Agency Ltd

PMF Plasma Master File

PU Prescriber Update

r Correlation coefficient

r2Coefficient of determination

RP Related Product

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SACN Self-assessable Change Notification

SCOTT Standing Committee on Therapeutic Trials [an HRC committee]

SMARTI System for the Management of Activities, Risks and Therapeutic Information [Medsafe database]

SPC Summary of Product Characteristics

t½ Elimination half-life

TGA Therapeutic Goods Administration [Australia]

Tmax Observed time at which Cmax occurred

TPDR Therapeutic Product Database Report [from SMARTI]

TSE Transmissible spongiform encephalopathy

USAN United States Approved Name

USNF [see NF]

USP United States Pharmacopoeia

VSC Vaccines Subcommittee [of MAAC]

WHO World Health Organisation

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Contents

Page

Section 1: Introduction............................................................................................................1

1.1 Introducing Medsafe.................................................................................................11.1.1 Statutory responsibilities and accountabilities...........................................................11.1.2 Regulatory framework..............................................................................................21.1.3 Internal structure of Medsafe.....................................................................................21.2 Contacting Medsafe..................................................................................................31.3 Medsafe’s Web Site..................................................................................................51.4 Obtaining Copies of New Zealand Legislation..........................................................6

Section 2: Therapeutic Products Controlled under New Zealand Legislation......................7

2.1 Medicines.................................................................................................................72.2 Related Products.......................................................................................................82.3 Herbal Remedies......................................................................................................82.4 Homeopathic Remedies............................................................................................82.5 Medical Devices.......................................................................................................9

2.5.1 Clinical trials involving medical devices...................................................................92.6 Cosmetics with a Therapeutic Purpose....................................................................102.7 Radiopharmaceuticals.............................................................................................102.8 Dietary Supplements...............................................................................................112.9 Categorisation by Substance or Product Type..........................................................112.10 Therapeutic Purpose and Claims.............................................................................112.11 Requirements to Comply with Other Legislation and Standards..............................13

2.11.1 Consumer legislation..............................................................................................132.11.2 Hazardous Substances and New Organisms legislation...........................................132.11.3 Standards and pharmacopoeia................................................................................14

2.12 Consent not to be used for Promotional Purposes....................................................152.13 Supplying Unapproved Medicines..........................................................................152.14 Medical Advertisements.........................................................................................15

Section 3: Application Types.................................................................................................17

3.1 When is a Medicine a “New Medicine”?.................................................................173.1.1 Evidence that a medicine has been generally available............................................173.1.2 Previously approved medicine that has not been generally available.......................183.1.3 Combination packs of currently approved medicines...............................................18

3.2 What is a New Active Substance ?..........................................................................183.3 New Medicine Applications....................................................................................18

3.3.1 New higher-risk medicine applications....................................................................193.3.2 New intermediate-risk medicine applications..........................................................193.3.3 New lower-risk medicine applications.....................................................................19

3.4 Referrals under Section 24(5) of the Medicines Act 1981........................................203.5 Changed Medicine Notifications and Changed Related Product Notifications..........20

3.5.1 Material changes to medicines and related products...............................................21

Section 4: Fees........................................................................................................................22

4.1 Evaluation Fees......................................................................................................224.1.1 New medicine or related product applications........................................................224.1.2 Changed medicine/related product notifications......................................................234.1.4 Self-assessable change notifications........................................................................23

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4.2 Administration........................................................................................................234.3 Fee Waivers............................................................................................................24

Section 5: Administrative Procedures...................................................................................25

5.1 Evaluation Processes for Applications and Notifications.........................................255.1.1 New higher-risk medicine applications....................................................................255.1.2 New intermediate- and lower-risk medicine and related product applications.........265.1.3 Changed medicine notifications and changed related product notifications.............26

5.2 Priority Assessment of New Medicine Applications................................................275.2.1 Criteria for priority assessment..............................................................................275.2.2 Processing of priority assessment applications.......................................................27

5.3 Phases of the Evaluation Process.............................................................................285.3.1 New higher-risk medicine applications....................................................................285.3.2 New intermediate- and lower-risk medicine and related product applications.........315.3.3 Changed medicine or related product notifications.................................................32

5.4 Requests for Further Information............................................................................335.5 Outcomes of the Evaluation Process........................................................................33

5.5.1 Full consent............................................................................................................335.5.2 Provisional consent................................................................................................335.5.3 Decline...................................................................................................................345.5.4 Withdrawal.............................................................................................................345.5.5 Revocation of consent or withdrawal from the market.............................................35

5.6 Database Report......................................................................................................355.7 Processing Times for Applications and Notifications...............................................355.8 Protection of Confidential Supporting Information..................................................37

5.8.1 Period of protection................................................................................................375.8.2 Disclosure of data..................................................................................................375.8.3 Relationship with the Official Information Act 1982................................................383.8.4 Effect on the evaluation process..............................................................................38

5.9 Certificate of Pharmaceutical Product.....................................................................385.10 Short Supply and Discontinued Medicines..............................................................39

Section 6: General Requirements for Applications and Notifications..................................40

6.1 Eligibility...............................................................................................................406.2 Language................................................................................................................416.3 Format....................................................................................................................416.4 Individual Patient Data...........................................................................................426.5 Covering Letter.......................................................................................................426.6 Submitting an Application or Notification...............................................................426.7 Updating the Data Package.....................................................................................436.8 Sponsors’ Responsibility to Retain Copies of All Documents..................................446.9 Technical Guidelines to be Followed......................................................................44

6.9.1 ICH guidelines........................................................................................................466.9.2 CPMP guidelines....................................................................................................466.9.3 FDA guidelines.......................................................................................................47

6.10 Proprietary Names..................................................................................................476.11 Description of Dosage Form...................................................................................486.12 Routes of Administration........................................................................................506.13 Shelf Life and Storage Conditions...........................................................................50

Section 7: Ingredients in Medicines and Related Products.................................................51

7.1 Drug Master Files...................................................................................................517.1.1 When is a DMF not required?.................................................................................527.1.2 Format for a DMF..................................................................................................52

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7.2 Certificate of Suitability..........................................................................................537.3 Ingredients of Human or Animal Origin..................................................................537.4 Colouring Agents...................................................................................................54

Section 8: New Medicine Applications..................................................................................55

8.1 Formats for New Medicine Applications.................................................................558.1.1 Format for a new innovative medicine application..................................................558.1.2 Format for an abridged new medicine application dossier......................................568.1.3 ICH and EU formats for abridged dossiers.............................................................58

8.2 Data Requirements for New Medicine Applications................................................608.3 Standard Requirements for New Multi-source (Generic) Prescription Medicines.... .61

Section 9: Changed Medicine Notifications.................................................................................68

9.1 Format for Changed Medicine and Related Product Notifications............................689.2 Data Requirements for Changed Medicine or Related Product Notifications............699.3 Self-assessable Changes..........................................................................................729.4 Changes Not Requiring a CMN or CRPN...............................................................73

9.4.1 Changes in Pharmacopoeial Specifications.............................................................739.4.2 Changes in names of manufacturers or packers......................................................739.4.3 Updates to Drug Master Files.................................................................................739.4.4 Updates to Plasma Master Files.............................................................................73

Section 10: New and Changed Related Products....................................................................74

10.1 Data Requirements for New Related Product Applications......................................7410.2 Data Requirements for Changed Related Product Notifications...............................76

Section 11: Good Manufacturing Practice Documentation....................................................77

11.1 When is GMP Documentation Required?................................................................7711.2 Recognised Documentation.....................................................................................7811.3 Classes of Medicine................................................................................................7911.4 Sites which Manufacture Bulk Active Pharmaceutical Ingredients...........................7911.5 Recognised Authorities...........................................................................................80

Section 12: Labelling and Patient Information......................................................................84

12.1 Labelling of Medicines and Related Products..........................................................8412.2 Submitting New and Changed Medicine Labels......................................................8412.3 Labelling Checklists and Declarations.....................................................................8512.4 Labelling Exemptions.............................................................................................8612.5 Overlabelling or Oversticking Labels......................................................................8712.6 Physician’s Sample Packs.......................................................................................8712.7 Small Containers....................................................................................................88

12.7.1 OTC medicines.......................................................................................................8812.7.2 Small volume medicines and related products.........................................................88

12.8 Transdermal Patches in Pouches or Sachets.............................................................8812.9 Safety Containers....................................................................................................89

12.9.1 Definition and use of safety containers....................................................................8912.9.2 Labelling of safety containers.................................................................................89

12.10 Specific Packaging and Labelling Requirements for Certain Medicines...................9012.10.1 Anti-anxiety or anti-insomnia medicines.................................................................9012.10.2 Antihistamines........................................................................................................9112.10.3 Blood products......................................................................................................9112.10.4 Contact lens solutions.............................................................................................9112.10.5 Controlled Drugs....................................................................................................9212.10.6 Corticosteroids as aqueous solutions for nasal inhalation.......................................9212.10.7 Fluoride tablets......................................................................................................93

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12.10.8 Hexachlorophane....................................................................................................9412.10.9 Hydrocortisone topical medicines...........................................................................9412.10.10 H2-Antagonists......................................................................................................9412.10.11 Ibuprofen liquid......................................................................................................9412.10.11 Iodine.....................................................................................................................9512.10.12 Paracetamol...........................................................................................................9512.10.13 Pholcodine.............................................................................................................9612.10.14 Pregnancy test kits..................................................................................................9612.10.15 Sodium phosphate in oral bowel preparations.........................................................9712.10.16 Topical medicines...................................................................................................9712.10.17 Topical medicines likely to be used in the genital area............................................97

12.11 Product Information Leaflets...................................................................................9712.12 Consumer Medicine Information.............................................................................98

Section 13: Data Sheets............................................................................................................99

13.1 Introduction............................................................................................................9913.2 Preparing a Data Sheet for Approval....................................................................10013.2.1 Format.................................................................................................................10013.2.2 Content.................................................................................................................10013.2.3 Preparing a new data sheet for which there is an acceptable source document......10113.2.4 Preparing a data sheet for which there is no acceptable source document.............102

13.3 Submitting Data Sheets for Approval and Publication...........................................10713.3.1 NMA for a new chemical or biological entity medicine or a new vaccine...............10813.3.2 NMA for a new multi-source medicine..................................................................10913.3.3 New dose form of an approved medicine...............................................................11013.3.4 CMN for a new indication and/or new dosage instructions....................................11013.3.5 New or updated safety data...................................................................................11113.3.6 Miscellaneous changes to data sheets...................................................................112

13.4 Helpful Hints for Preparing Data Sheets for Publication........................................11213.5 Changes to Published Data Sheets.........................................................................11413.6 Additional Safety Information Required in New Zealand Data Sheets....................115

13.6.1 Individual medicines.............................................................................................11513.6.2 Therapeutic Groups..............................................................................................121

Section 14: Bioequivalence and Interchangeability..............................................................125

14.1 Introduction..........................................................................................................12514.2 Choice of Reference Product.................................................................................12614.3 Bioavailability Data Requirements........................................................................126

14.3.1 Product types that require comparative bioavailability data..................................12614.3.2 Justifying not submitting comparative bioavailability data....................................12714.3.3 Medicines not requiring comparative bioavailability data.....................................12814.3.4 Changes not requiring further bioequivalence testing............................................129

14.4 Interchangeability of Multi-source Medicines........................................................13114.4.1 Style and content of the Interchangeable Multi-source Medicine List.....................13114.4.2 New Zealand reference product............................................................................13414.4.3 Maintenance of the Interchangeable Multi-source Medicine List...........................134

Section 15: Bioequivalence Testing of Oral Medicines........................................................136

15.1 Introduction..........................................................................................................13615.2 Important Overseas Bioequivalence Guidelines.....................................................13615.3 Definitions............................................................................................................13715.4 Variables in a Comparative Bioavailability Study..................................................138

15.4.1 Extent of absorption..............................................................................................13815.4.2 Rate of absorption................................................................................................139

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15.4.3 Pharmacodynamic responses................................................................................13915.4.4 Comparative in vitro dissolution rate....................................................................140

15.5 Designing a Comparative Bioavailability Study....................................................14015.5.1 Single dose versus steady-state studies..................................................................14115.5.2 Parameters...........................................................................................................14115.5.3 Choice of subjects.................................................................................................14115.5.4 Standardisation of experimental conditions...........................................................14215.5.5 Number of subjects...............................................................................................14215.5.6 Formulation and quality control data requirements..............................................14315.5.7 Number and timing of samples..............................................................................14315.5.8 Fasting and non-fasting studies............................................................................14415.5.9 Medicine administration.......................................................................................144

15.6 Modified-release Products.....................................................................................14515.6.1 Characteristics.....................................................................................................14515.6.2 Parameters...........................................................................................................14615.6.3 Study design.........................................................................................................14615.6.4 Requirements for modified release formulations unlikely to accumulate................14715.6.5 Requirements for modified release formulations likely to accumulate....................147

15.7 Analytical Methods...............................................................................................14815.7.1 Chromatographic assay validation........................................................................14815.7.2 Radioimmunoassays..............................................................................................14915.7.3 Assay of study samples..........................................................................................150

15.8 Reporting Data.....................................................................................................15115.9 Presentation of Summarised Data..........................................................................15215.10 Statistical Analysis...............................................................................................152

15.10.1 Number of subjects...............................................................................................15215.10.2 Analysis of variance (ANOVA)..............................................................................15315.10.3 Confidence intervals.............................................................................................15415.10.4 Power of ANOVA..................................................................................................154

15.11 Data Requirements................................................................................................154

Section 16: Equivalence Testing of Inhaled Medicines.........................................................156

16.1 Introduction..........................................................................................................15616.2 Physical equivalence.............................................................................................157

16.2.1 Measuring particle size distribution......................................................................15716.2.2 Particle size..........................................................................................................158

16.3 Clinical Equivalence.............................................................................................15816.3.1 Statistical analysis................................................................................................15916.3.2 -Sympathomimetic medicines..............................................................................15916.3.3 Anticholinergic medicines.....................................................................................16016.3.4 Non-steroidal prophylactic medicines...................................................................16016.3.5 Glucocorticoids....................................................................................................161

16.4 Powders for Inhalers.............................................................................................16216.5 Nasal Inhalation Products......................................................................................16216.6 Changes to Currently Marketed Products..............................................................162

16.6.1 Rubber or plastic components...............................................................................16216.6.2 Replacement of chlorofluorocarbons.....................................................................16316.6.3 Changes to powders for inhalation.......................................................................163

Section 17: Classification and Reclassification of Medicines................................................164

17.1 Medicines Classification Committee.....................................................................16417.2 Classification categories........................................................................................16417.3 First Schedule to the Medicines Regulations 1984.................................................16517.4 Classification of Controlled Drugs........................................................................165

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17.5 Classification of Medicines...................................................................................16517.6 Classification Criteria...........................................................................................16617.7 Classification Process...........................................................................................16717.8 Submissions for Reclassification...........................................................................168

Section 18: Clinical Trials of Medicines..............................................................................170

18.1 Introduction..........................................................................................................17018.2 Application for Approval of a Clinical Trial..........................................................171

Section 19: Pharmacovigilance..............................................................................................173

19.1 Spontaneous Adverse Medicine Reaction Reporting Scheme.................................17319.2 Intensive Medicines Monitoring Programme.........................................................17419.3 Responsibility of Companies to Report Adverse Medicine Reactions....................175

19.3.1 Reporting adverse reactions to CARM..................................................................17519.3.2 Reporting substantial untoward effects of medicines.............................................17519.3.3 Media interest in medicine safety issues................................................................176

19.4 Centre for Adverse Reactions Monitoring (CARM)...............................................17619.5 Medicines Adverse Reactions Committee..............................................................176

Appendix 1: Schedule of Fees..................................................................................................177

Appendix 2: NMA Form..........................................................................................................179

Appendix 3: NRPA Form........................................................................................................187

Appendix 4: Checklist for New Multi-source Medicine Data.................................................187

Appendix 5: CMN Form A......................................................................................................187

Appendix 6: CMN Form B......................................................................................................187

Appendix 7: CRPN Form........................................................................................................187

Appendix 8: Labelling Declaration.........................................................................................187

Appendix 9: Labelling Checklist for Medicines......................................................................187

Appendix 10: Labelling Checklist for Contact Lens Solutions................................................187

Appendix 11: Labelling Checklist for Related Products..........................................................187

Appendix 12: Data Sheet Declaration.......................................................................................187

Appendix 13: Checklist for NZ Format Data Sheet..................................................................187

Appendix 14: Form for Reporting Supply of Unapproved Medicine.......................................187

Appendix 15: Form for Reporting Adverse Reaction to Medicines, Vaccines, Medical Devices and IMMP...........................................................................................................187

Appendix 16: Form for Reporting Adverse Reaction to Fractionated Blood Products..................187

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Section 1: Introduction

1.1 Introducing Medsafe

Medsafe is the regulatory authority for therapeutic products in New Zealand.

The mission statement of Medsafe is -

Healthy New Zealanders by:

regulating medicines and medical devices to maximise safety and benefit

1.1.1 Statutory responsibilities and accountabilities

The regulatory responsibility of Medsafe is to administer the Medicines Act 1981 and parts of the Misuse of Drugs Act 1975, and their accompanying Regulations.

The objective of the medicines legislation is to manage the risk of avoidable harm associated with the use of medicines. The legislation is designed to ensure that:

medicines conform to acceptable standards of safety, quality and efficacy personnel, premises and practices used to manufacture, store and distribute medicines comply

with requirements to ensure the continued conformity of the products to those standards until they are delivered to the end-user

information about the selection and safe use of medicines is provided to consumers and prescribers of medicines.

In carrying out its functions, Medsafe is accountable to:

the Minister of Health through delegations and the Purchase Agreement between the Ministry of Health and the Minister of Health

the Ministry of Health for regulatory activities and for policy advice or public good activities funded by the Crown

the pharmaceutical industry for those activities which are funded by fees collected from the industry.

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1.1.2 Regulatory framework

Medsafe’s mission is accomplished by applying a framework that ensures benefits in the use of therapeutic products while managing the potential risks.

Ensuring that the therapeutic products available in New Zealand are those which can be expected to have greater benefits than risks, if used appropriately, is achieved through a pre-marketing approval system and post-marketing surveillance.

The pre-marketing approval system is outlined in this publication. New medicines and related products cannot be marketed in New Zealand without the consent of the Minister of Health (or delegated authority). Changed medicines and related products cannot be marketed without the consent of the Director-General of Health (or delegate). Data that satisfactorily establish the quality, safety and efficacy of the product, for the purposes for which it is to be used, must be submitted to Medsafe for evaluation before consent can be granted.

The approval system is independent of the Government’s subsidisation of medicines managed by PHARMAC, except that PHARMAC may request fast-tracking of evaluation of certain new medicine applications where significant cost savings may result from availability of the medicines concerned on the New Zealand market.

Post-marketing surveillance monitors the safety of medicines and medical devices in use. Products shown to be unsafe are removed from use, and prescribers are advised about new safety information for other products. Post-marketing surveillance is achieved through:

pharmacovigilance - the spontaneous reporting of adverse effects of medicines and the Intensive Medicines Monitoring Programme, and through monitoring the international literature and other international sources

routine monitoring, such as testing marketed medicines against product quality standards auditing and licensing of medicine manufacturers, pharmacies etc.

1.1.3 Internal structure of Medsafe

Medsafe consists of three operational teams and operates out of four sites nation-wide, with centralised administrative functions and product approval and standard setting based at the Wellington office.

The Evaluation Team provides advice to the Minister and Director-General of Health on the quality, safety and efficacy of medicines and related products which are proposed for distribution in New Zealand.

The Compliance Team ensures that therapeutic products and persons involved in their manufacture, distribution and use comply with legislative requirements.

The Business Development and Support Team develops policy, strategic direction and business opportunities for Medsafe, oversees medicine classification and pharmacovigilance, and provides prescribers, pharmacists and consumers with information about the safe use of medicines and medical devices.

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1.2 Contacting Medsafe

Medsafe may be contacted at the following addresses:

Postal Address: MedsafePO Box 5013Wellington

Street/Courier Address: MedsafeLevel 18 Grand Plimmer Tower2-6 Gilmer TerraceWellington

Telephone: (04) 496 2000

Fax: (04) 496 2229

Internet address: http://www.medsafe.govt.nz

Individual staff members can be contacted by e-mail using the following Internet address: first [email protected].

Medicine evaluation enquiries Administrative enquiries should be directed to the Workflow Co-ordinator, Evaluation Team

(at the above address). Complaints and feedback should be directed to the Evaluation Team Leader. Technical issues (following receipt of a query letter) should be directed to the evaluator.

Applications and submissions New Medicine and Related Product Applications, Changed Medicine and Related Product

Notifications and ‘Section 29’ reports should be forwarded to the Manager, Medsafe (at the above address).Note: When a large application dossier is delivered to Medsafe, the courier should be advised not to deliver the boxes to the reception desk on the 18th floor of Grand Plimmer Tower. The courier should contact reception to notify their arrival and arrange access to the locked storage area on a lower floor of the building.

Requests for a Certificate of Pharmaceutical Product should be forwarded to the Support Officer, Evaluation Team.

Submissions to reclassify a medicine should be forwarded to the Secretary, Medicines Classification Committee, Medsafe.

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Clinical trial applications and queriesForward 1 copy of the application to the Manager, Medsafe and 4 copies to the Chairperson of the Standing Committee on Therapeutic Trials (SCOTT):

Postal Address: Courier Address:

Assoc. Prof. R Robson Assoc. Prof. R RobsonPO Box 2856 c/- The Pegasus CentreChristchurch 31 Tuam Street

Christchurch(Attention: The Secretary)

Queries about applications for clinical trials should be made to the Support Officer, Evaluation Team, Medsafe.

Medicine control and compliance enquiries Medicine control issues (e.g. licences to pack, wholesale, hawk medicines) should be directed

to Medicine Control advisors at the local Medicine Control Offices. Contact details are as follows:

Northern Medicines Control OfficeASB Bank, Level 18-12 Link DriveWairau ParkPO Box 100 166AucklandTelephone (09) 441 3670Fax (09) 441 3689

Central Medicines Control Office18th Floor, Grand Plimmer Tower2-6 Gilmer TerracePO Box 5013WellingtonTelephone (04) 496 2437Fax (04) 496 2229

Southern Medicines Control Office - ChristchurchNational Radiation Laboratory108 Victoria StPO Box 25 177ChristchurchTelephone (03) 366 7394Fax (03) 366 1156

Southern Medicines Control Office - Dunedin9th Floor, John Wickliffe HousePrinces StPO Box 384DunedinTelephone (03) 479 2561Fax (03) 477 6338

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Other compliance issues should be directed to the Compliance Team, Medsafe, at the Wellington address given above. These may include: recalling of a medicine, advertising of medicines, audits of medicine manufacturers etc.

1.3 Medsafe’s Web Site

Medsafe’s web site http://www.medsafe.govt.nz includes the information listed below and sponsors and applicants are encouraged to visit the site regularly and take note of any new information or changes to requirements and guidelines published there.

About Medsafe Who we are What we do Vision and values Legislation (sources) Contacting us (contact addresses) Mail order (for Medsafe publications) Links (to relevant New Zealand and overseas health and pharmaceutical web sites) Vacancies (any vacancies in Medsafe)

Information for Consumers How medicines are regulated Safe use of medicines Consumer Medicine Information Information about medicines Information about complementary healthcare products Pharmacist Only medicines Medical devices Reporting a side-effect Making a complaint Support groups

Information for Health Professionals Prescriber Update articles Regulatory issues Clinical trials Recent changes to medicines Medicine Data Sheets Consumer Medicine Information Interchangeable Medicines Unapproved Medicines Classification of Medicines Medicine supply issues Medical device issues Reporting an adverse reaction Reporting a defect Drug abuse issues

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1.4 Obtaining Copies of New Zealand Legislation

Copies of the New Zealand legislation referred to in these guidelines may be purchased from any of the following:

Bennetts Government Bookshop360 Queen StreetPO Box 5513AucklandTelephone (09) 377 3496Fax (09) 377 3497

Bennetts Government BookshopBowen HouseCorner of Bowen St and Lambton QuayPO Box 5334WellingtonTelephone (04) 499 3433Fax (04) 499 3375

Brooker’s LtdPO Box 43WellingtonTelephone (04) 499 8178Fax (04) 499 8173

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Section 2: Therapeutic Products Controlled under New Zealand Legislation

Section summaryThe medicines legislation controls products used in humans for a therapeutic purpose.Products used for a therapeutic purpose can be categorised as medicines, related products, herbal remedies or medical devices. These terms are explained in this section.A product is considered to be intended for a therapeutic purpose if a therapeutic claim is stated or implied in the product labelling or promotional material, or where the active ingredient(s) clearly has a pharmacological action. This section describes the sorts of statements considered to be therapeutic claims.

Legislation to read in conjunction with this sectionMedicines Act 1981

Section 2: Interpretation and meaning of ‘medical device’ Section 3: Meaning of ‘medicine’, ‘new medicine’, ‘prescription medicine’

and ‘restricted medicine’Section 4: Meaning of ‘therapeutic purpose’Section 28: Exemptions in respect of herbal remediesSection 94: Meaning of ‘related product’Part IV: Medical advertisements

Dietary Supplement Regulations 1985Regulation 2: InterpretationRegulation 11: Therapeutic claims

2.1 Medicines

The term “medicine” is defined in section 3 of the Medicines Act 1981. In practical terms, a product is a medicine if it is administered to humans primarily for a therapeutic purpose. Most, but not all, medicines have a pharmacological effect. Therapeutic purpose is defined in section 4 of the Act, and includes the treatment, diagnosis and prevention of disease or the modification of a physiological function. It also includes cleaning, soaking or lubricating contact lenses, inducing anaesthesia, or effecting contraception. Spermicidal condoms and intrauterine devices (IUDs) containing copper or a hormone are medicines whereas non-spermicidal condoms and other barrier-type contraceptives (e.g. diaphragms) are devices. In vivo diagnostic agents are medicines while in vitro diagnostic products are devices (with the exception of pregnancy test kits which are medicines). The only products that are regulated as medicines, but are not actually administered to humans, are pregnancy test kits. The consent of the Minister is required before a new medicine can legally be distributed in New Zealand (except in the case of certain specified exemptions, as explained later in this document).

Medicines that are also Controlled Drugs are controlled under the Medicines Act 1981 and associated Medicines Regulations and also the Misuse of Drugs Act 1975 and associated Misuse of Drugs Regulations.

In accordance with section 109(4) of the Medicines Act, where a product is controlled under both sets of legislation, the Misuse of Drugs legislation takes precedence in the event of any inconsistency.

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The following are not medicines and the Minister’s consent is not required for their distribution in New Zealand:

Substances used in dental surgery for filling dental cavities (these are medical devices) Non-medicated bandages and other surgical dressings (these are medical devices). [Medicated

dressings where the medication has a curative function that is not limited to sterilising the dressing are medicines by legislation.]

Radioactive materials used for a therapeutic purpose. (These are specifically excluded from the Medicines legislation, but are subject to other controls. See Section 2.7 below.)

2.2 Related Products

A related product is a product that is primarily a food, dentifrice or cosmetic, but has a secondary therapeutic use. This term is defined in section 94 of the Medicines Act. The consent of the Minister is required before a new related product can legally be distributed in New Zealand. The legislation does not require a related product to be manufactured in a factory licensed to manufacture medicines, but the manufacturer must comply with an appropriate standard of GMP (see section 11).

Examples of related products include the following:

Fluoride toothpastes containing not more than 0.1% elemental fluorine (Toothpastes containing more than 0.1% elemental fluorine are classified as pharmacy-only medicines.) Note that fluoride mouthwashes intended to be swallowed as a supplement are medicines.

Antidandruff shampoos

In addition, the following have traditionally been treated as elated products:

Antiseptic throat lozenges (Fungicidal lozenges are restricted medicines.) Antiseptics used for cleaning wounds, cuts, abrasions, stings, insect bites and superficial

burns.

2.3 Herbal Remedies

A herbal remedy is a special sub-category of medicine, defined in section 2 of the Medicines Act. A herbal remedy is a medicine that does not contain a prescription, restricted or pharmacy-only medicine, and consists of a substance derived from plant material that has been dried or crushed (or derived through any other similar process). It may also be an aqueous or alcoholic extract of the dried or crushed plant material, or a mixture of that material with another inert substance.

Ministerial consent is not required for the distribution of a herbal remedy which is sold or supplied without any recommendation as to its use and the labelling complies with the requirements of section 28 of the Medicines Act, whereas Ministerial consent is required for the distribution of a herbal remedy which is sold with a recommendation for use for a therapeutic purpose.

2.4 Homeopathic Remedies

A homeopathic remedy which is prepared under the principle of homeopathy in which the active ingredient to be administered is in a concentration not more than 20 parts per million, and the remedy is labelled only with the name of the active ingredient, trade name (if any) and a statement that it is a homeopathic remedy does not normally require Ministerial consent before distribution. The product label or associated advertising material must not contain therapeutic claims or indications for use.

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A homeopathic remedy which is labelled or advertised with claims as to its therapeutic purpose is a medicine and subject to the full control of the Medicines legislation.

Sterile homeopathic preparations intended for injection or for administration to the eyes are regarded as medicines and therefore subject to the full control of the Medicines legislation

2.5 Medical Devices

The term medical device is defined in section 2 of the Medicines Act 1981. A medical device is any device, instrument, apparatus etc. used primarily by humans for a therapeutic purpose. This includes bandages and surgical dressings provided they are not medicated with a therapeutic agent (if medicated, they are medicines).

Under current legislation, ministerial consent is not required for the distribution of medical devices. However, some medical devices are subject to specific legal requirements:

All condoms distributed in New Zealand are required by law to comply with either the International Standard ISO 4074-1:1996(E) Rubber Condoms or the New Zealand Standard NZS 7106:1998 Polyurethane Condoms as applicable.

All intra-uterine contraceptive devices are required to comply with the New Zealand Standard NZS 7102:1980 Specification for Intra-uterine Contraceptive Devices.

Note: New Zealand legislation classifies a number of products as medicines while overseas these are classified as medical devices (e.g. pregnancy test kits).

Registration of medical devices is expected to become a legal requirement in the future under proposed legislation.

Medsafe is working closely with the Australian TGA on harmonising New Zealand and Australian controls on medical devices. Medsafe is currently developing regulations which will require a register of medical devices so that device tracking in New Zealand can be maintained until new legislation is developed. Further details can be obtained from Medsafe.

New Zealand and Australia have a joint reporting system for adverse reactions to medical devices. A medical device incident reporting form is on Medsafe’s web site. Any concerns with the safety of a medical device distributed in New Zealand should be reported to Medsafe. Any alerts or recalls overseas should also be reported if the device is distributed in New Zealand.

2.5.1 Clinical trials involving medical devices

Medsafe is working towards aligning the requirements for conducting clinical trials on medical devices with the Australian Therapeutic Goods Administration. When a trial is intended, Medsafe should be informed of the name of the device under trial and details of the trial, the company co-ordinating the trial, and the hospitals or clinics involved in the trial. Progress reports should be submitted to Medsafe.

A company wishing to conduct a clinical trial on a medical device must:

label the device to show that it is to be used only in a clinical trial, and

source the device from a factory operating suitable good manufacturing practices, and

ensure that the clinical trial complies with the New Zealand Regulatory Guidelines for Medicines, Volume 3: Interim New Zealand Guide to Good Clinical Research Practice, and

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obtain approval from the appropriate institutional ethics committee(s), and

advise all patients who will receive the device of the international status of the device. They must also be informed that they are part of a clinical trial and must be informed of any risks associated with the device.

2.6 Cosmetics with a Therapeutic Purpose

Section 2 of the Medicines Act 1981 defines a cosmetic. In general terms, a cosmetic is a product used to cleanse, protect or beautify the hair or skin. The following types of products, when sold without any therapeutic claims and not containing any substance listed in the First Schedule of the Medicines Regulations 1984 (and amendments) are considered to be cosmetics, and the Minister’s consent for distribution is not required for their distribution:

Antiperspirants Deodorants Insect repellents Dusting powders Sunscreen and suntan preparations Cleansers for normal or blemished skin Moisturisers for normal, sunburnt or wind burnt skin Hair conditioners Astringents and skin toners Agents to assist in the fading of spots, pimples and blemishes Antiseptics for generalised, all-over use, on the body and not on broken skin Solutions which are bathed in to relax the body Anti-wrinkle and anti-ageing products which have a superficial cosmetic effect and not a

physiological effect.

Cosmetics must not be advertised as making basic underlying changes to the skin such as cellular changes.

Sunscreens are currently categorised as cosmetics and do not require approval or Ministerial consent before marketing. Companies are encouraged to market only sunscreens that comply with the Australian/New Zealand Standard AS/NZS 2604:1998 Sunscreen Products - Evaluation and Classification. Companies marketing sunscreens should have evidence to support the SPF and broad spectrum protection claimed. Future legislation may control sunscreens as therapeutic products.

2.7 Radiopharmaceuticals

Radiopharmaceuticals are not controlled under the Medicines Act or Medicine Regulations administered by Medsafe. Control of the import and use of radiopharmaceuticals in New Zealand is the responsibility of the National Radiation Laboratory (NRL).

Anyone intending to import radioactive materials into New Zealand must have the consent of the Director of the NRL. Any hospital, clinic or medical practitioner intending to administer radiopharmaceuticals to a patient or patients for the purpose of diagnosis or treatment must be licensed to do so by the NRL. Further information may be obtained from:

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The General ManagerNational Radiation Laboratory108 Victoria StreetPO Box 25177ChristchurchNew ZealandTelephone: (03) 366 5059Fax: (03) 366 1156

2.8 Dietary Supplements

Dietary supplements are controlled under the Dietary Supplements Regulations 1985. Regulation 2 of these Regulations defines a dietary supplement. In practical terms, a dietary supplement is an edible substance, in a controlled dosage form, which is intended to supplement the intake of substances normally derived from food. A product marketed as a dietary supplement may not be promoted for a therapeutic purpose. Companies wishing to make therapeutic claims for such products must apply for consent to distribute the product as a medicine or related product.

2.9 Categorisation by Substance or Product Type

If a product is administered to humans and contains a substance that exerts a therapeutic effect, that product is considered to be a medicine, irrespective of whether therapeutic claims are made on the label or in advertising material. For example, a product containing a hormone is a medicine, regardless of the purpose for which it is being promoted.

The First Schedule of the Medicines Regulations 1984 contains a list of Prescription, Restricted and Pharmacy-Only Medicines. It also contains some “class” classifications (e.g. anorexiants). The First Schedule is therefore a useful guide to determining whether or not a product is considered to be a medicine. However, please note that listing of a particular medicine in the First Schedule does not necessarily mean that it is currently approved for distribution in New Zealand, but rather, that it would be classified as indicated if it was approved for distribution.

2.10 Therapeutic Purpose and Claims

There may be several indicators that a product has a therapeutic purpose. These may include:

the trade name of the product conveying an intended purpose use of the words remedy, medicated or therapeutic statements of historical therapeutic use, or use by ethnic groups for a therapeutic purpose directions for use, such as Spread on affected area use of statements to the effect that the manufacturers are prohibited from making specific

claims about the product.

A therapeutic claim can be direct, implied, or suggested. Statements that a product will/can/may/is intended to give relief from a disease, pain, or symptoms associated with a disease are therapeutic claims.

Nutritional statements, or statements relating to the normal biochemical or physiological function of a substance, are not considered to be therapeutic claims.

The following is a guide to the sorts of claims made for products.

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Gastro-intestinal systemA claim such as Beneficial for the digestive tract. Good for abdominal cramps is regarded as a therapeutic claim, since it implies or indicates treatment for an adverse physiological condition. If Good for abdominal cramps were removed, the product would not be considered a therapeutic product.

A claim such as Supports the healthy function of kidneys, liver and digestive tract is regarded as a broad statement relating to normal biochemical function, hence the product would not be considered a therapeutic product. A claim such as Beneficial for digestion and intestinal complaints. Use for cholesterol control is regarded as a therapeutic claim, both because the product is implied/intended for the alleviation or treatment of intestinal complaints, and because it is intended to reduce cholesterol.

A claim such as For the formation of a number of important biological substances required for many vital cellular functions would be regarded as a broad statement relating to nutritional needs, and not a therapeutic claim.

Urinary systemA claim such as Helps maintain the healthy function of urinary organs. Has anti-inflammatory properties is considered to be a therapeutic claim since it implies that maintenance is by means of the anti-inflammatory properties of the product.

A claim such as Beneficial for the genito-urinary system. Use for fluid retention is regarded as a therapeutic claim since it is implied the product treats fluid retention. If the sentence Use for fluid retention is removed, the claim would fall into the category of a statement relating to normal biochemical or physiological function.

Cardiovascular systemA claim such as Anti-thrombotic, cholesterol-suppressive for an edible product is regarded as a therapeutic claim because the product would be marketed for these purposes, rather than for its nutritional purpose.

Respiratory systemA claim such as Beneficial and soothing for the respiratory system. Alleviates mucous congestion is regarded as a therapeutic claim, since the product is implied or intended to relieve a particular symptom of an adverse physiological condition.

Central nervous systemA claim such as Temporary relief of sleeplessness and excitability is considered to be a therapeutic claim since the product is principally intended to act as a sedative, and would not have a nutritional purpose.

Musculoskeletal systemA claim such as Beneficial for the temporary relief of pain due to arthritis, rheumatism, menstruation and muscular pain is regarded as a therapeutic claim. Generally, all products intended to be analgesics, or acting by means of an analgesic effect, are therapeutic products.

Obstetrics and gynaecologyA claim such as Apply for nappy rash or Apply to cracked nipples is regarded as a therapeutic claim since the product would purport to relieve these physiological conditions.

Eye, ear, nose, mouth and throat

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A claim such as Removes problem-causing bacteria which cause bad breath or Removes plaque would not normally be considered to be a therapeutic claim unless the product is also intended to treat conditions such as gingivitis.

A claim such as Relieves sore throats or Soothes sore throats for a lozenge is regarded as a therapeutic claim because an anaesthetic action is involved.

SkinA claim such as Disinfection of hands and skin would not be regarded as a therapeutic claim. Conversely, a claim such as For the prevention of infection in wounds, cuts and abrasions is a therapeutic claim because the product would be applied to broken skin.

A claim such as Keeps skin smooth and resilient would not be regarded as a therapeutic claim.

A claim such as Removes oil, make-up and dirt without over-drying. Medicated to kill problem-causing bacteria would not generally be regarded as a therapeutic claim in spite of the use of the word ‘medicated’, unless the product is intended to be used or has an implied use on a specific skin condition.

A claim such as Promoting hair growth or Increasing nutrient supplies for follicles would be regarded as a therapeutic claim, since baldness and its associated physiological condition is listed in the First Schedule to the Medicines Act 1981.

2.11 Requirements to Comply with Other Legislation and Standards

2.11.1 Consumer legislation

Medicines, related products and medical devices are regulated by the Ministry of Health in accordance with the Medicines and Misuse of Drugs legislation. Sponsors should also be aware that, as these products are articles of commerce, they also need to comply with any other relevant consumer legislation (e.g. the Fair Trading Act 1986) administered by the Ministry of Economic Development.

2.11.2 Hazardous Substances and New Organisms legislation

Certain medicines must comply, not only with the Medicines legislation, but also with the requirements of the Hazardous Substances and New Organisms Act 1996 (HSNO), its amendments and its associated regulations as administered by the Environmental Risk Management Authority New Zealand (ERMA).

Most human medicines in finished dose form are exempt from the HSNO legislation even when they cross the HSNO thresholds for hazardous properties. However, the following types of new human medicines are not exempt and must comply with the HSNO legislation:

Substances that are gases (e.g. medical gases) contained in pressure containers of more than 100 mls and at pressures of more than 170 kPa, up until the time they are administered to one or more human beings for a therapeutic purpose.

New medicines (e.g. vaccines or gene therapy products) that contain live or attenuated viruses or bacteria and are “new organisms” as defined in section 2(A) of the HSNO Act 1996. To be a new organism it must be “a species of any organism which was not present in New Zealand on the date of commencement of this Act” (i.e. 29 July 1998). For the purposes of the HSNO

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legislation, genetic modification of a previously present species of a micro-organism produces a new organism.

Medicines covered by the exemption applying to human medicines are not exempt from the HSNO legislation when used as veterinary medicines.

Substances used in the manufacture of medicines in New Zealand by licensed medicine manufacturers are not exempt and importers and manufacturers must comply with the HSNO legislation.

The web site http:///www.hsno.govt.nz is dedicated to the HSNO legislation and its application.

The web site http://www.ermanz.govt.nz includes information on ERMA procedures together with a searchable register of applications and approvals under the HSNO Act.

Where a sponsor wishes to distribute a new medicine that is a medical gas or new organism as defined above, the sponsor must apply separately to both Medsafe and ERMA for consent using their respective application forms and procedures. Details of the date and status of the application to ERMA must be provided on the New Medicine Application form (see Appendix 2 of these Guidelines). The medicine concerned may not be distributed in New Zealand until consent from both agencies has been granted.

In the event of such an application to Medsafe and ERMA, the two agencies will work together (subject to any confidentiality limitations imposed by the applicant), sharing relevant information and evaluation reports as appropriate, and co-ordinating their activities as far as is practical to ensure the efficient and effective administration of the requirements of the Medicines and HSNO legislation.

For further information about the HSNO and ERMA requirements for obtaining consent to import and or release products controlled under the HSNO legislation, contact:

The Manager, OperationsEnvironmental Risk Management Authority New ZealandLevel 1, BP House20 Customhouse QuayPO Box 131WellingtonTelephone: (04) 473 8426Fax: (04) 473 8433Web site: http://www.ermanz.govt.nz

2.11.3 Standards and pharmacopoeia

Where a product is required to conform (or is claimed to conform) to any particular “standard” or pharmacopoeial monograph, it must comply with all of the requirements (including test methods, unless otherwise justified) of the current version of that standard or pharmacopoeial monograph. Where a pharmacopoeial monograph exists for an ingredient, this is considered to be the minimum requirements.

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http://www.ermanz.govt.nz/


2.12 Consent not to be used for Promotional Purposes

Ministerial consent for the distribution of a new or changed medicine, or related product is not to be construed as an endorsement of any claim made for the product. No reference may be made to this consent in any label or advertising, promotional or other published material about the product.

2.13 Supplying Unapproved Medicines

An “unapproved medicine” is a medicine for which full or provisional consent for distribution has not been granted. A general exemption from the consent provisions for new and changed medicines is provided in section 29 of the Medicines Act, permitting the supply of any medicine (including an unapproved medicine) to a medical practitioner at his/her request, to treat a particular patient under his/her care. The supply must be initiated by the medical practitioner and the supplier may not advertise the availability of the medicine.

Medsafe’s web site lists unapproved medicines reported to Medsafe as being supplied in New Zealand, and includes further information about the responsibilities of the supplier and the medical practitioner and the rights of the patient involved in the supply of an unapproved medicine under the provisions of section 2.

The supplier (i.e. the New Zealand importer or manufacturer) must have a licence issued under the Medicines Act 1981 which allows the supply of the medicine, or be exempt from this requirement under section 26, and must also maintain complete and accurate records of the information listed below. The records must be stored in a secure and confidential manner in the supplier’s New Zealand office and be available for audit by Medsafe if required. The information to be recorded and stored is:

name(s) of the medical practitioner(s) who requested supply of the medicine name(s) of the patient(s) the medicine was required for dose form(s) and strength(s) of the medicine supplied date(s) on which the medicine was supplied name(s) of the place(s) the medicine was supplied to.

Suppliers of unapproved medicines must also notify the Team Leader, Compliance, Medsafe, PO Box 5013, Wellington, as soon as practicable after the end of every month in which the medicine has been supplied, of the following:

international non-proprietary name (INN) of the medicine trade name of the medicine pharmaceutical form month and year of supply

The form for reporting to Medsafe the supply of unapproved medicines is provided at the end of these guidelines in Appendix 14.

2.14 Medical Advertisements

The Medicines Act 1981 and the Medicines Regulations 1984 control the advertising of therapeutic products including medicines, related products, herbal medicines, medical devices, and methods of treatment. Medical advertisements must comply with the legislative requirements. In addition, such advertisements need to comply with the “Advertising Code of ethics” and the “Code for Therapeutic

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Advertising” in Advertising Codes of Practice published by the Advertising Standards Authority Inc., PO Box 10-675, Wellington Tel. (04)472 7852, Fax (04)471 1785.

Advertisers intending to publish a medical advertisement in the media (including radio, television, newspapers, magazines, etc.) are strongly advised first to have the advertisement vetted on behalf of the Advertising Standards Authority by:

Therapeutic Advertising Pre-vetting Service (TAPS)43 Tirohunga DriveHendersonAucklandTel. (09)836 2680Fax (09)837 5057

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Section 3: Application Types

Section summaryTo obtain Ministerial consent to distribute a new medicine or related product, the distributor must submit to Medsafe a “New Medicine Application” (NMA) or “New Related Product Application” (NRPA), together with supporting data.When a material change to a previously approved medicine or related product is planned, the distributor or New Zealand manufacturer must notify the Director-General of Health of the change by submitting a “Changed Medicine Notification” (CMN) or “Changed Related Product notification” (CRPN).


Section 3: Meaning of ‘medicine’, ‘new medicine’, ‘prescription medicine’ and ‘restricted medicine’

Section 20: Restrictions on sale or supply of new medicinesSection 23: Minister may give provisional consentSection 24: Distribution of changed medicine restricted

3.1 When is a Medicine a “New Medicine”?

The term “new medicine” is defined in section 3 of the Medicines Act. In practical terms, a new medicine is:

a medicine for which Ministerial consent for distribution in New Zealand has not previously been granted, or

an approved medicine that has undergone a material change that has resulted in its referral to the Minister under section 24(5) of the Act, or

a medicine that has previously been approved but has not been generally available in New Zealand during the five years immediately preceding the date on which it is proposed to become available.

A medicine is considered to have been “generally available” if, during the relevant five year period:

the product has been sold or offered for sale in New Zealand on one or more occasions, or the product has been advertised in New Zealand as available for sale, or

the regulatory file for the approved medicine has been updated through either a Changed Medicine Notification (CMN) or an application for a labelling exemption, or

the product has been the subject of a submission made to PHARMAC for a tender.

3.1.1 Evidence that a medicine has been generally available

An applicant wishing to show that a product is not a new medicine because it has been “generally available” must support that claim by providing:

evidence of one or more sales during the relevant period (e.g. invoice), or evidence of importation (e.g. customs clearance form), or evidence of listing in a sales catalogue or price list from the relevant period, or a statement identifying regulatory activity for the product, such as a CMN.

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The claim must be supported by a declaration from a person in New Zealand that the evidence is genuine, and that any documents provided are true copies of the original documents. The original documents must be made available on request.

3.1.2 Previously approved medicine that has not been generally available

When a sponsor wishes to commence or re-commence distribution of a previously approved product that has not been generally available in New Zealand in the last five years a New Medicine Application must be submitted, otherwise, the medicine may only be supplied as an unapproved medicine under section 29 of the Medicines Act (see Section 2.13 of these Guidelines for details). An appropriate application fee will be required based on the amount of evaluation and administrative work required, as determined by the Evaluation Team Leader.

The data must include the elements described in section 21 of the Medicines Act. However, where the details are the same as those submitted in the original application for consent, or in any subsequent CMN, it will be sufficient to submit a declaration to that effect.

Where the details differ, the difference should be detailed and supporting data provided in the same way as is required for a CMN. If the change(s) is such that the safety profile of the product may have been altered, the data package should include a report of post-marketing surveillance from other countries in which the product has been marketed.

3.1.3 Combination packs of currently approved medicines

A new combination pack containing two or more currently approved medicines packaged together constitutes a new medicine and the Minister’s consent for its distribution must be obtained before it may be distributed. Section 2 of the Medicines Act 1981 provides a definition of package.

3.2 What is a New Active Substance ?

A chemical or biological active substance (also known as an active pharmaceutical ingredient, API) is a new active substance, in line with the European Union definition, when it is :

a chemical, biological or biotechnological substance for which Ministerial consent for distribution as a medicine in New Zealand has not previously been granted, or

an isomer, mixture of isomers, an ester, a complex or other derivative, or a salt, of a chemical substance with Ministerial consent for distribution as a medicine in New Zealand but differing in properties with regard to safety and efficacy, or

a biological or biotechnological substance for which Ministerial consent for distribution as a medicine in New Zealand has been granted, but differing in molecular structure, nature of the source material or manufacturing process.

3.3 New Medicine Applications

A New Medicine Application (NMA) is an application under section 20 or 23 of the Medicines Act seeking the Minister’s consent to distribute a new medicine.

In practice, the power to approve medicines is delegated to a senior Ministry of Health officer, referred to as the Minister’s delegate.

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To facilitate administrative processing of applications, NMAs are divided into three types as detailed in Subsections 3.3.1 to 3.3.3.

3.3.1 New higher-risk medicine applications

A New Higher-risk Medicine Application (NMA-H) is an application for Ministerial consent to distribute a:

new medicine containing a new active substance (i.e. a new chemical, biological or biotechnological entity)

new medicine with provisional consent under section 23 of the Medicines Act (the data requirements are different for these applications)

medicine (with full Ministerial consent under section 20) for which provisional consent for distribution under section 23 has previously been granted

new fixed combination product containing a prescription medicine new medicine with a new route of administration or novel pharmaceutical form new inhaled prescription medicine which acts locally at the bronchial site prescription medicine with a new indication (see Section 3 for further explanation) new vaccine new blood product new multi-source biological or biotechnological medicine.

3.3.2 New intermediate-risk medicine applications

A New Intermediate-risk Medicine Application (NMA-I) is an application for consent to distribute a new medicine that does not contain a new active substance and is a:

multi-source prescription medicine. [Note that a multi-source biological or biotechnological medicine is a higher-risk medicine. The term “multi-source medicine” is now used in place of the term “generic medicine”.]

Controlled Drug for which a prescription is required medicine with a new (but not novel) pharmaceutical form or a new strength or additional

flavour of an approved prescription medicine prescription medicine with an extended indication (see Section 3 for further explanation) injectable medicine irrigation solution dialysis solution medical gas.

3.3.3 New lower-risk medicine applications

A New Lower-risk Medicine Application (NMA-L) is an application for consent to distribute a new medicine that:

is not defined above as a Higher-risk or Intermediate-risk Medicine, and may be supplied without a prescription (i.e. an OTC product), and is recommended for indications that are already well documented for the active ingredient(s),

and is presented in a pharmaceutical form that is monographed in a pharmacopoeia, andeither contains active ingredients that are the subject of a pharmacopoeial monograph or contains active ingredients that have a well documented history of use in OTC products (e.g.

as evidenced by entries in Martindale etc.) or

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has active ingredients that are contained in one or more other products marketed OTC in New Zealand.

Lower-risk medicines may include products required to be sterile (e.g. eye drops).

A product containing a Controlled Drug for which a prescription is not required (e.g. pholcodine linctus or a codeine-containing combination analgesic) is evaluated using the New Lower-risk Medicine assessment procedure, provided it meets the criteria listed above.

New Intermediate- and Lower-risk Medicine Applications are sometimes referred to as “abridged” applications, because they do not contain the clinical and toxicological data required in a New Higher-risk Medicine Application. New Lower-risk Medicine Applications require less data as the medicine poses a lower-risk and can, therefore, safely be subjected to a lower level of regulatory control.

Each unique product is the subject of a separate product approval and has its own separate entry in Medsafe’s Therapeutic Products Database (SMARTI). A unique product is defined by its name, dose form, active ingredient(s), strength, flavour (if applicable) and classification. When an application is made for consent to distribute a new unique product, a New Medicine Application must be submitted. Reduced data requirements and evaluation fees apply to New Medicine Applications for products that are closely related to an existing approved product.

3.4 Referrals under Section 24(5) of the Medicines Act 1981

Section 24 of the Medicines Act sets out restrictions on the distribution of changed medicines. Subsection 5 permits the Director-General of Health to refer a medicine (that is the subject of a CMN) to the Minister in certain circumstances. Such a referral occurs when a CMN is so large or complex that the changed product should not be allowed to be distributed until the changes have been fully evaluated. An example of such a change would be a major new indication. Once the CMN has been referred to the Minister under section 24(5) of the Medicines Act, the application becomes an NMA.

3.5 Changed Medicine Notifications and Changed Related Product Notifications

A Changed Medicine Notification (CMN) or Changed Related Product Notification (CRPN) is a notification to the Director-General of Health by the sponsor of a product, under section 24 of the Medicines Act, of a planned material change to an approved product (this includes prescription and non-prescription medicines and related products), and the reasons for the change.

Where a medicine or related product is distributed as a complete finished product by one (primary) sponsor and the same finished product is also distributed by a second sponsor in a combination pack together with another product(s), both sponsors are responsible to ensure that the second sponsor is informed and the Director-General of Health is notified (via a CMN or CRPN) of any material changes affecting the medicine or related product in each of its presentations. There should be a commercial agreement between the two sponsors ensuring that the necessary information is exchanged between them and the necessary CMNs or CRPNs are lodged with Medsafe. The primary sponsor may lodge the appropriate CMNs or CRPNs for both presentations. A CMN or CRPN is required for each presentation of the product as a consent must be issued for each presentation.

If any change to a product results in a new active ingredient, new combination of active ingredients, new strength, new dose form, new flavour or new trade name an NMA or NRPA (not a CMN or

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CRPN) is required. The NMA or NRPA must be kept separate from and will be processed separately from any other CMN or CRPN. The “new product” cannot legally be distributed until consent has been granted and published in the New Zealand Gazette.

3.5.1 Material changes to medicines and related products

A material change to a medicine or related product may require evaluation (in which case an evaluation fee is payable) or be self-assessable (in which case an administrative fee is payable). Assessable changes are notified through a CMN or CRPN and consent must be obtained before the change is made. Ask Medsafe for advice if there is doubt about whether a proposed change is notifiable or not.

Often one change in a product leads automatically to other changes (e.g. a change in formulation will often result in changes in manufacture, quality control and stability). Details of the various types of assessable and self-assessable changes and the applicable fees are given in the CMN and CRPN forms (see Appendices 5 - 7). The forms include common material changes (and changes consequent to these) and are designed to be as comprehensive as possible. If an intended change is not included in the relevant form, seek advice from Medsafe.

For a self-assessable change, there is no requirement to obtain consent prior to making the change. However, the notification must precede the change. The onus is on the applicant to ensure that data to support the change are held and could be made available on request. Such changes are to be notified using the same CMN or CRPN form as used for notifying assessable changes.

Medsafe carries out random audits of self-assessable changes and, where any significant problems are identified, the sponsor is required to rectify these. Where a CMN or CRPN rather than a SACN should have been submitted, the sponsor is asked to submit this.

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Section 4: Fees

Section summaryThis section sets out the fees applied to applications and notifications for new and changed products.

Legislation to read in conjunction with this sectionMedicines Regulations 1984, Amendment No. 4 (Fees)

4.1 Evaluation Fees

Amendment 4 to the Medicines Regulations 1984 sets out the fees for evaluation of New Medicine or Related Product Applications and Changed Medicine or Related Product Notifications. Fees are GST-inclusive.

The fees schedule applying to applications and notifications is given in Appendix 1 and guidance for calculating the fees for specific types of new and changed products are given in the relevant new medicine and related product application forms (see Appendices 2-3) and changed medicine and changed related product notification forms (see Appendices 5-7)

4.1.1 New medicine or related product applications

The fee for evaluation of a New Medicine Application is based on the amount of effort involved in evaluating the application. The fee is therefore greater for a medicine containing a new active substance than for a new multi-source medicine. The fee is further reduced in the case of an application for consent to market a new dose form, strength or flavour of a product.

A product is considered to be a separate product and, therefore, a new medicine or new related product if it has a different name, active ingredient, strength, dose form, flavour or classification from a previously approved product. Each product is the subject of a separate product approval, has a separate file number and has its regulatory details recorded in a separate entry in Medsafe’s Therapeutic Product Database (SMARTI). Note that, in this context, a different pack size does not constitute a different strength.

When consent is sought for the distribution of a new or additional product that is substantially the same as a previously approved product (such as an additional name or strength), a reduced data package is required to be evaluated. The fee for evaluation is based on the amount of evaluation effort required to assess the differences between the old and new products.

When simultaneous applications are lodged for two or more dose forms of a product, the “parent” dose form will be that which would on its own attract the greatest fee and the “additional” dose forms will be those that would attract the lower fees. For example, if an application was for a tablet and an injection of a particular medicine, then the tablet would be the parent dose form and the injection would be the additional dose form. If an application was for more than one dose form and it would make no difference to the fees which dose form was chosen as parent, then any one of them could be selected as the parent dose form for the purpose of the application.

4.1.2 Changed medicine/related product notifications

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The fees for evaluation of Changed Medicine/Related Product Notifications reflect the average amount of evaluation effort involved in assessment of the data. The amount of evaluation effort depends on the number of changes being made, the nature of the changes, and the number of separate products to which the changes apply. The fees also cover the administrative work involved in updating and maintaining Medsafe records.

Same change(s) to multiple productsWhen an identical change or set of changes is made to two or more products at the same time, the evaluation effort involved in assessing the change usually does not have to be repeated for each product. There is, however, a cost associated with the administrative processing of each application received. This administrative cost is incurred regardless of the amount of evaluation effort involved. To cover this cost, an “administration only” fee applies to applications for which no evaluation effort is required.

In no case can the total fee for changes to a product exceed the fee for an NMA or NRPA for the same type of product.

4.1.4 Self-assessable change notifications

An “administration only” fee applies to self-assessable changes. When the same self-assessable change is made to multiple products, the “administration only” fee applies to each product affected by the change. No fee is payable for self-assessable changes notified along with a CMN or CRPN for which evaluation of data is required and a fee is payable, except in the case of a data sheet for which the changes are not consequential to any other change included in the CMN or CRPN. (In this case an additional SACN fee is required for the changes to the data sheet.)

If a SACN is audited and a proper CMN or CRPN is required to be submitted the full CMN or CRPN fee for the change(s) must be paid. The SACN fee already paid is used to cover the administration and auditing of the SACN and is not treated as part of the CMN or CRPN fee.

4.2 Administration

Payment to cover the fee (or evidence that the fee has been paid) must accompany every application or notification.

Fees for NMAs, NRPAs, CMNs and CRPNs, clinical trial approvals and Certificates of Pharmaceutical Products may be paid either by cheque or by direct credit to the Ministry of Health bank account. Until further notice, all other Medsafe fees must be paid by cheque. Credit card payments are not accepted for any Medsafe fees.

If payment is by cheque, the cheque should be made out to the Ministry of Health.

The Ministry’s GST number for accounting purposes is 14-290-389.

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For direct credit payments, the Ministry’s bank account details are as follows:

Bank name and address:Westpac Trust, NZ Government BranchWellington, New Zealand

Bank account name:Ministry of Health

Bank account number:03-0049-0001805-08

To enable easy identification of payments the following information should appear on Medsafe’s bank statements:

Particulars Code Reference

(Company name, abbreviated or coded if necessary to fit available boxes)

(TT50 number for CMNs and CPPs) (*Code and medicine name)

*Codes: NMA for new medicine applicationNRPA for new related product applicationCMN for changed medicine notificationCRPN for changed related product notificationCT for clinical trial applicationCPP for Certificates of Pharmaceutical Product (Free Sales Certificate)

Important Notes:1. The full amount in $NZ exclusive of bank charges must be paid.2. Separate transactions are required for each application or notification. Where a group of two or

more dose forms is involved, one transaction covering the grouped applications or notifications is required.

3. A remittance slip (or a covering letter) with full payment details must be included with the application or notification

4. No liability can be accepted by the Ministry of Health for payments that do not reach our bank account. It is the payer’s responsibility to follow up any payments that have not been received by the Ministry. The Ministry will only be able to confirm whether or not a payment has been received.

Medsafe’s letter acknowledging receipt of an application or notification includes confirmation of receipt of the fee. If an application is not accompanied by the appropriate fee, the applicant is informed that an additional payment is required. Processing of an application does not commence until the appropriate fee has been paid in full. When an applicant pays a fee greater than required, the surplus will be refunded by cheque as soon as this can be arranged.

4.3 Fee Waivers

The legislation allows for the fee to be waived, either partially or completely, after taking into consideration the complexity of the application and the amount of time required to complete the evaluation. Fees may also be waived in the interests of public health.

In certain circumstances (e.g. in the case of very low volume/value sales) a partial or complete waiver of fees may be appropriate. Such fee waivers will be considered on their merits on a case-by-case basis. An applicant who considers a waiver appropriate should submit a written request and explanation to the Evaluation Team Leader for consideration.

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Section 5: Administrative Procedures

Section summaryThis section: explains who evaluates different types of applications describes the various phases in the evaluation process sets out Medsafe’s performance targets for the evaluation of new and changed medicine and related

product applications


Section 3: Meaning of ‘medicine’, ‘new medicine’, ‘prescription medicine’ and ‘restricted medicine’Section 8: Advisory and technical committeesSection 9: Medicines Classification CommitteeSection 10: Medicines Review Committee establishedSection 20: Restrictions on sale or supply of new medicinesSection 21: Applications for Minister’s consentSection 23: Minister may give provisional consentSection 29: Exemption for medicine required by medical practitionerSection 109: Relationship with Misuse of Drugs Act 1975

Medicines Amendment Act 1994First Schedule to the Medicines Regulations 1984 & Amendments (Medicines Classification)Misuse of Drugs Act 1975 & Regulations

5.1 Evaluation Processes for Applications and Notifications


Most New Higher-risk Medicine Applications are evaluated by members of the Medicines Assessment Advisory Committee (MAAC). Where appropriate, some may, instead, be evaluated by external evaluators contracted by Medsafe, or by Medsafe’s own evaluation staff. Following this evaluation, the full MAAC reviews and discusses the evaluation reports and makes a recommendation to the Minister of Health’s delegate to grant or decline consent, or the Committee defers a decision pending satisfactory responses to any questions raised. The MAAC may recommend provisional consent to distribute a medicine under section 23 of the Medicines Act where it believes that the medicine should be available but there is insufficient evidence of safety and/or efficacy to allow full consent.

Most applications for provisional consent under section 23 and most new indications for currently distributed higher-risk medicines are also considered by the MAAC. A “new indication” usually is an extension of indications to the treatment of a condition not consequential to the indications already approved, or the treatment of a condition affecting another system of the body.

All extended indications for already approved products (including extensions of currently approved indications to include special populations, e.g. paediatric, geriatric, etc.) are considered to be “new indications”.

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As a general rule, all new and extended indications will be referred under section 24(5) as a new medicine application.

Members of the MAAC are appointed by the Minister of Health. The terms of reference of the Committee are to:

assess and advise on the efficacy, safety and quality of new medicines recommend the classification of new medicines consider and advise the Minister on the suitability of medicines for distribution in New

Zealand consider and advise the Minister on any matters regarding new medicines or the distribution

of medicines.

The MAAC normally meets four times per year, usually early in March, June and September, and in late November or early December.

Evaluation of the labelling and data sheet of medicines considered by the MAAC is usually carried out by Medsafe evaluators in liaison with the Committee.

Any communication between the sponsor and the MAAC regarding any aspect of an application must be carried out through the MAAC Secretary.

5.1.2 New intermediate- and lower-risk medicine and related product applications

Medsafe evaluators (assisted by external evaluators where appropriate) assess New Intermediate- and Lower-risk Medicine and New Related Product Applications. These applications are allocated to one of the two evaluation “streams”.

One stream evaluates all applications for which there is an extended time-frame. These are:

New Intermediate-risk Medicine Applications NMAs for injectable medicines (even though these may be classified as pharmacy-only

medicines) Medical gases CMNs for Intermediate-risk medicines referred under section 24(5) of the Medicines Act. As

a general rule, all new and extended indications will be referred under section 24(5).

The other stream evaluates all applications for which there is a shortened time-frame. These are:

New Lower-risk Medicine Applications New Related Product Applications Injectable diluents (e.g. water for injection or normal saline) presented separately from

products containing active ingredients CMNs for prescription and non-prescription medicines and related products

5.1.3 Changed medicine notifications and changed related product notifications

CMNs, whether for prescription or non-prescription medicines, and CRPNs are usually assessed by Medsafe evaluators but may sometimes be sent to external evaluators. Following evaluation, a decision is made whether to accept the change, or request more information from the applicant.

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Self-assessable Change Notifications (SACNs) undergo administrative processing (e.g. filing and updating of Medsafe’s Therapeutic Product Database (SMARTI), but do not require evaluation.

5.2 Priority Assessment of New Medicine Applications

5.2.1 Criteria for priority assessment

The two criteria for eligibility for priority assessment of an NMA are significant clinical advantage or significant potential cost savings to the taxpayer.

(1) Significant clinical advantage

Requests for priority assessment on the basis of significant clinical advantage will be considered for New Higher-risk Medicine Applications for products containing new active substances. Vaccines for the prevention of diseases are treated in the same way as other agents for the treatment of diseases. Cost saving does not constitute a significant clinical advantage, hence will not be taken into account when deciding whether a product meets the clinical criteria for priority assessment.

The sponsor of a medicine may request priority assessment if:

the medicine is the subject of a New Higher-risk Medicine Application, and the active ingredient of the medicine is a new active substance, and the medicine is indicated for the treatment or diagnosis of a serious, life-threatening or

severely debilitating disease or condition for which other treatment options are limited, and data demonstrating the effect of the medicine on clinical outcomes is submitted with the

application.

Requests for priority assessment can only be made by the New Zealand sponsor or distributor of the product.

Sponsors are encouraged to provide support for claims of significant clinical advantage by submitting material such as letters of support from clinicians and consumer support groups.

The Evaluation Team Leader and Clinical Advisor(s) decide which applications are accepted for priority assessment on the basis of significant clinical advantage.

(2) Significant potential cost savings

A request for priority assessment of a medicine on the basis of potential cost savings can normally only be made by PHARMAC. Such requests are considered by the Minister’s delegate who, where appropriate, instructs Medsafe to undertake a priority assessment of the application.

5.2.2 Processing of priority assessment applications

Applications that have been accepted for priority assessment on clinical grounds, or are accompanied by an instruction from the Minister’s delegate directing that they be given priority on cost-saving grounds, will be processed earlier and faster than normal applications.

Once an application has been accepted for priority assessment on clinical grounds, the application is placed on the agenda for the next MAAC meeting provided there is sufficient time for the evaluation reports to be prepared and considered by members.

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Follow-up actions resulting from recommendations from MAAC are completed in the usual way. However, when a response to a request or query is received from the applicant, its assessment is also given priority. The internal assessment of the data sheet and labelling receives similar priority.

Most applications undergoing priority assessment on cost-saving grounds will be New Intermediate-risk Medicine Applications evaluated by Medsafe evaluators. Where a priority assessment on cost-saving grounds relates to a medicine that is reviewed by the MAAC, the process is as described above for priority assessment on clinical grounds.

For an internally-evaluated product given priority, the application is allocated to an evaluator and becomes that evaluator’s next piece of new work. In a similar way, when a response relating to a priority assessment is received from an applicant, that response becomes the next piece of follow-up work undertaken by the evaluator.

5.3 Phases of the Evaluation Process

The evaluation process for new and changed medicine and related product applications and notifications is divided into phases, each with a specific performance target.

Administrative processing of an application cannot commence until a valid application has been lodged. A valid application is an application submitted in an appropriate format, with an appropriate data package, and accompanied by the appropriate fee.


The administrative process for New higher-risk medicine applications is divided into three phases as follows:

Phase 1: Receipt and acknowledgement of the applicationThis phase consists of the following processes.

1. Medsafe receives the application and appropriate fee.2. The Support Officer creates a new file and Therapeutic Product Database (SMARTI) entry, and

sends an acknowledgement letter to the applicant.3. The Support Officer forwards the application to the Workflow Co-ordinator.4. The Workflow Co-ordinator assigns the application to the MAAC and forwards the file to the

MAAC Secretary.

Completion of Phase 1 is marked by the MAAC Secretary receiving the application for processing by the MAAC.

Phase 2: Evaluation The products to be considered at an MAAC meeting are determined about 3 months before the meeting. A typical agenda includes about 12 new medicines (including new chemical or biological entities and new dose forms or combinations of previously approved medicines), a number of new or extended indications for previously approved medicines, and reconsideration of several medicines for which approval was previously deferred and sponsors have provided responses to the issues raised by the MAAC.

The new medicines typically include one or two products for which priority assessment has been granted, several products for which overseas evaluation reports are or will be available for the Committee’s use, and several products for which no overseas reports are available. The actual mix of applications is arranged to ensure that maximum use can be made of overseas reports and that all

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applications can flow smoothly through the queue without unnecessary delays and that they can reach the MAAC not more than 18 months after submission.

A tentative agenda is set about 13 weeks before the meeting. Usually one place on the agenda is saved for any late-coming “fast-tracked” application. The agenda is closed 10 weeks before the meeting.

The MAAC Secretary advises the applicant about 12-13 weeks before the Committee meeting that the application is scheduled for consideration by the MAAC at the forthcoming meeting. Usually at the same time, further copies of the Part I (sufficient for each MAAC member expected to be at the meeting to have a copy) and the pivotal clinical trial reports from Part IV of the application dossier are requested for the Committee’s use. The amount of additional data requested from the sponsor depends upon the availability or otherwise of suitable overseas evaluation reports. Where the Committee or individual members evaluating the data find it necessary to access data not provided at this time, the Secretary may request the additional volumes from the applicant.

Note: If the extra copies of data supplied for Committee use at this time (or later in response to queries raised by the MAAC) include material not previously supplied with the original application, an extra copy of this material should also be supplied (and clearly identified) for addition to Medsafe’s copy of the application and supporting data.

Whenever possible, to reduce unnecessary duplication of effort, an evaluation report is obtained from another regulatory agency with whom New Zealand has a Memorandum of Understanding (MoU) or similar agreement. Reports are only obtained from agencies that approach medicine regulation in such a manner that New Zealand regulators can have confidence in the quality of their evaluation process. The MAAC seeks to obtain copies of suitable overseas evaluation reports (and company responses to any issues raised in those reports) to assist it in its own assessment of the medicines it considers. If overseas reports are used by the MAAC, the Committee does not simply adopt the conclusions of the overseas evaluators but examines the reports and sufficient raw data together with any additional information provided by the sponsor to enable it to form its own independent assessment of the product.

There is a MoU currently in place with the Therapeutic Goods Administration (TGA) in Australia. The TGA routinely provides Medsafe with copies of its evaluation reports prepared for the Australian Drug Evaluation Committee (ADEC), and Medsafe routinely supplies the TGA with copies of evaluation reports prepared for the MAAC. This exchange does not include copies of additional data submitted by companies in response to issues raised during the evaluation.

Medsafe also has access to the reports produced by European authorities for the European Medicines Evaluation Agency (EMEA) and its Committee for Proprietary Medicinal Products (CPMP). Under a special agreement with the EMEA, where a product has been considered by the EMEA/CPMP for distribution in the European Union under its centralised procedure, the company responsible for the product is free to release a copy of the full CPMP evaluation report(s) to regulatory authorities in PER member countries outside of the European Union as soon as the CPMP has given a recommendation for approval of the product. Sponsors of products to be considered by the MAAC should arrange for a copy of these CPMP reports to be forwarded to the MAAC Secretary as soon as the CPMP recommendation is made.

Please note that European Public Assessment Reports (EPARs) are only summaries of the EMEA evaluation and approval process and are not suitable for use by Medsafe or the MAAC.

While TGA reports are obtained directly from the TGA, the applicant is normally asked to supply (along with additional copies of data from the application dossier) several extra copies of any available TGA and/or European evaluation report along with copies of any additional data submitted

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to the overseas agency(ies) concerned to satisfy that agency’s requirements for further information or changes to the product or supporting data.

Where no suitable overseas evaluation report is available, or likely to be available within a reasonable time, the application and dossier of supporting data are evaluated in full by MAAC members or contracted evaluators for the MAAC.

The MAAC Secretary receives the overseas and/or New Zealand evaluation report(s) and distributes them to Committee members.

The MAAC then reviews the evaluation report(s) at a Committee meeting and makes a recommendation to the Minister of Health’s delegate to grant or decline consent, or it defers making a recommendation until additional information has been received and reviewed.

Following the Committee’s consideration of the application, a summary briefing of the outcome is forwarded to the Minister’s delegate. The briefing will also indicate whether Medsafe supports the recommendation of the Committee. In the rare event that Medsafe disagrees with the MAAC recommendation, the Minister’s delegate will consider the conflicting recommendations before making a final decision.

The MAAC Secretary informs the applicant in writing of the MAAC recommendation, normally within 2 weeks of the meeting. Verbal information about the outcome of the MAAC’s deliberations will not be given (and should not be sought) prior to receipt of the Secretary’s letter.

If the MAAC has recommended that consent be declined, the applicant is given the option of either withdrawing the application or submitting arguments and/or additional data for consideration by the MAAC before a final decision is made. If the application is not withdrawn and no additional information is submitted, and the Minister’s delegate accepts the MAAC’s recommendation, the applicant then has 28 days from receipt of the formal notification that the application has been declined in which to lodge an appeal and pay the requisite fee.

Such appeals are referred to the Medicines Review Committee (MRC). The MRC does not review the technical data related to the product concerned, but reviews the process followed, to ensure that the application has been considered fairly and adequately.

For products for which consent has been recommended, the MAAC Secretary evaluates the draft label(s) and data sheet and ensures that any recommendations by the MAAC are agreed with the applicant and incorporated. The Secretary then sends a copy of the evaluation reports and the draft Therapeutic Product Database Report to the applicant. The applicant should check the details on the database report carefully for accuracy and advise the MAAC Secretary immediately if any changes are required before the report becomes the “officially agreed particulars” about the product concerned.

Completion of Phase 2 is marked by the finalising of the labels, data sheet and details in Medsafe’s Therapeutic Product Database (SMARTI).

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Phase 3: Consent process Phase 3 applies only to medicines for which consent is to be granted and consists of the following processes:

1. The Secretary forwards the product file to the Support Officer who drafts the New Zealand Gazette notice of Ministerial consent. Note that gazettal applies to new medicines, new presentations of medicines, and approvals of CMNs for new indications for medicines referred as NMAs under section 24(5) of the Medicines Act.

2. The Minister’s delegate signs the draft New Zealand Gazette notice, thus formally consenting to the distribution of the product in New Zealand

3. The Support Officer submits the New Zealand Gazette notice for publication and completes the Therapeutic Product Database (SMARTI) entry showing the date of consent (following publication of the notice in the Gazette) and forwards copies of the New Zealand Gazette notice and the finalised database report to the applicant.

The distributor may legally distribute and promote the product from the date of publication of the New Zealand Gazette notice. The date of consent is the date of publication of the notice, not the date on which the notice was signed by the Minister’s delegate.

Completion of Phase 3 is marked by dispatch of copies of the New Zealand Gazette notice and finalised database report to the applicant.

5.3.2 New intermediate- and lower-risk medicine and related product applications

The administrative process for New Intermediate- and Lower-risk Medicine Applications and New Related Product Applications is divided into three phases as follows:

Phase 1: Receipt and acknowledgement of the applicationThis phase consists of the following processes:

1. Medsafe receives the application and appropriate fee2. The Support Officer creates a new file and database entry and sends an acknowledgement letter to

the applicant3. The Support Officer forwards the application to the Workflow Co-ordinator4. The Workflow Co-ordinator assigns the application to the appropriate evaluation stream and

forwards the file to an evaluator.

Completion of Phase 1 is marked by the forwarding of the application to an evaluator for assessment.

Phase 2: EvaluationThe evaluator assesses the application and supporting data and completes an evaluation report. If there are no outstanding issues the application moves directly to Phase 3.

If, on the other hand, additional information needs to be supplied or changes need to be made to the product or data, the evaluator will inform the applicant. The applicant may also be sent a copy of the draft evaluation report at this stage. The applicant then collates and forwards to the evaluator a response to any request for additional information or changes. The evaluator evaluates the additional information when supplied and prepares a final report on the product.

There can be several cycles of additional information being requested, provided and evaluated. However, the performance target for this phase relates to the time from receipt of the first response from the applicant to completion of the evaluation of that response.

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The evaluator completes the final evaluation report and forwards this to the evaluation stream Senior Advisor for review.

The evaluation stream Senior Advisor reviews the evaluator’s report and, if necessary, the report is amended. If the product is a multi-source medicine in a solid oral dose form or another form that makes it a potential candidate for specific inclusion in the list of Interchangeable Multi-source Medicines, the final evaluation report is forwarded to the Generics Subcommittee of the MAAC for review before a final decision is made to recommend consent.

In the case of an intermediate-risk medicine (but not a lower-risk medicine or a related product) the evaluator sends a copy of the completed evaluation report, the draft Therapeutic Product Database Report, and a letter stating, if appropriate, that all issues are resolved (or indicating any requirements to be fulfilled or data to be submitted after approval of the product) and that the product will be recommended for consent. If a labelling exemption has been granted this will be indicated in the letter. The applicant should check the details on the database report carefully for accuracy and advise the evaluator immediately if any changes are required before the report becomes the “officially agreed particulars” about the product concerned.

If there are significant obstacles to approval of the product, the applicant may withdraw the application or Medsafe may forward the application and report to the MAAC for advice on whether the application should be declined.

Completion of Phase 2 is marked by the finalising of the recommendation for consent or decline and (for products to be approved for distribution in New Zealand) forwarding of the product file to the Support Officer for drafting of the New Zealand Gazette notice.

Phase 3: Consent processThis phase consists of the following processes:

1. The Support Officer drafts the New Zealand Gazette notice. 2. The Minister’s delegate signs the draft New Zealand Gazette notice, thus formally consenting to

the distribution of the product in New Zealand.3. The Support Officer submits the New Zealand Gazette notice for publication4. The Support Officer submits the New Zealand Gazette notice for publication and completes the

database entry showing the date of consent (following publication of the notice in the New Zealand Gazette) and forwards a copy of both the New Zealand Gazette notice and the finalised database report to the applicant.

The distributor may legally commence distribution and promotion of the product as from the date of publication of the New Zealand Gazette notice.

Completion of Phase 3 is marked by dispatch of the New Zealand Gazette notice and finalised database report to the applicant.

5.3.3 Changed medicine or related product notifications

Changed Medicine and Related Product Notifications proceed through a process similar to the first two phases of the process as described for NMA-Is and NMA-Ls in Section 5.3.2 (above) but completion of Phase 2 is marked by the issue of a consent letter by the evaluator (rather than publication of a Gazette notice) and an updated database report.

5.4 Requests for Further Information

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At completion of the initial evaluation of an application the applicant may receive a request for additional information arising from the evaluation. A response to the request should be sent as quickly as possible. If a full response is likely to take longer than any deadline given in the letter requesting the information, the applicant should send an interim response indicating when the information will be available and requesting an extension of the deadline.

Applicants should ensure that each issue requiring further information has been responded to, even if it is necessary to provide only an interim response and an undertaking to supply additional data by a specified date.

Evaluation of additional information will not normally commence until a full response has been received.

5.5 Outcomes of the Evaluation Process

5.5.1 Full consent

Full consent is Ministerial consent for the distribution of a medicine or related product in New Zealand without any special conditions. Full consent takes effect from the day the consent is published in the New Zealand Gazette.

5.5.2 Provisional consent

Provisional consent for distribution of a new medicine may be granted under section 23 of the Medicines Act where there is insufficient safety or efficacy information to justify full consent but the MAAC accepts that there is a clinical need for the medicine to be available in New Zealand. This allows limited access to a medicine where the potential benefit is considered greater than the risk of non-treatment. For example, a medicine that does not have long-term safety data available may show potential in treating a rare fatal condition for which there is no alternative treatment.

Where only provisional consent is granted for the distribution of a medicine, this fact, along with any conditions imposed upon its distribution, should be included in the data sheet for the product.

There are two situations where provisional consent may be granted:

(1) Original application is for provisional consent

If an NMA is only for provisional consent at the time of lodging the NMA and the MAAC considers that the data support only provisional consent, provisional consent only will be granted. The applicant may later submit additional or updated data and an application for upgrading of the approval to full consent.

If this second application and supporting data are submitted within 2 years of the provisional consent being granted, an additional fee to bring the total up to that applying to an NMA for full consent will be payable before full consent is considered. If the application for upgrading of the approval to full consent is received after expiry of the provisional consent, an additional fee equivalent to that applying to a fresh NMA for full consent will be required.

Alternatively, if the MAAC considers that the data submitted with the first application support full consent, such consent will be offered to the applicant but an additional fee to bring the total up to that applying to an NMA for full consent will be payable before full consent is granted.

(2) Original application is for full consent

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If an NMA is for full consent and is supported by a full dossier of data and accompanied by a full NMA fee but, after reviewing the data, the MAAC or Medsafe concludes that the data only support provisional consent, only such consent will be granted. No part of the fee will be refunded. However, if the applicant later submits additional data required to support full consent and requests upgrading of the approval to full consent, this application will be considered without an additional fee if submitted prior to the expiry of the provisional consent. If the application for upgrading of the approval to full consent is received after expiry of the provisional consent, an additional fee equivalent to that applying to an NMA for full consent will be required.

Provisional consent may be granted for a period of up to two years, and the availability of the medicine is usually restricted to certain prescribers or target patient populations. An application for renewal of the consent can be made (and a renewal fee paid) prior to the expiry of the two-year period. However, an application for full consent can be made at any time if the required data become available. The MAAC assesses all applications for provisional consent.

A recommendation to decline an application for provisional consent may be due to:

lack of evidence of adequate therapeutic efficacy unjustifiable safety risk due to known problems with the manufacturing process or

formulation inadequate information on which to assess risk risk of non-treatment of the condition being less than the risks involved in use of the product,

or alternative preferred treatments of known risk and efficacy are available.

5.5.3 Decline

For all NMAs and NRPAs it is usual practice for Medsafe evaluators or the MAAC to keep requesting information from the applicant, or changes to the product, until all issues are satisfactorily resolved. If, after exhaustive requests, the applicant refuses or is unable to provide the required information (or an assurance that any required changes to the product will be made), then a recommendation is normally made by the MAAC to the Minister’s delegate to decline the application.

The applicant is notified of the terms of the recommendation to decline and the reasons. The applicant is given 28 calendar days after receiving the notice, to lodge a written objection to the recommendation. Such objections are considered by the Medicines Review Committee, constituted under sections 10 - 13 of the Medicines Act 1981. This Committee can recommend that the application be declined, accepted, or referred back to the MAAC.

There is no provision in the legislation for Medsafe to decline a CMN. However, if the change notification is not satisfactory, and the applicant is unable to satisfactorily answer the questions raised during evaluation, the applicant may be asked to withdraw the notification, or it may be referred to the Minister’s delegate under section 24(5) of the Medicines Act, thus making it an NMA. In either case, the applicant may not distribute the changed medicine.

5.5.4 Withdrawal

The applicant is encouraged to withdraw an application or notification when there is no longer a desire to obtain consent to distribute the medicine, or the applicant is unable to satisfactorily answer questions raised in the evaluation process. In these instances, the applicant should request in writing that the application or notification be withdrawn. There is no refund of the application fee and no return of the data submitted.

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5.5.5 Revocation of consent or withdrawal from the market

Revocation of consent for the distribution of a medicine or related product may be initiated by Medsafe or by the sponsor. This may be for safety reasons or for issues affecting intellectual property of information used in the evaluation process. Such revocation must be notified in the New Zealand Gazette.

If a sponsor wishes to have consent revoked, the sponsor should inform the Manager, Medsafe accordingly in writing giving reasons for the decision.

Alternatively, a sponsor may wish to withdraw a product from the market without having consent for distribution formally revoked. In this case the sponsor should inform the Manager, Medsafe accordingly prior to the withdrawal taking effect. The withdrawal will then be recorded in Medsafe’s database. The sponsor may subsequently resume distribution of the product at any time up to 5 years after the withdrawal. Medsafe must be informed of the resumption of distribution before it takes place. If a product remains off the market for more than 5 years consent lapses and can only be reactivated through submission of a new medicine application.

5.6 Database Report

Once consent is granted, an updated Therapeutic Product Database Report (TPDR) will be forwarded to the applicant. This report provides a record of the approved particulars of the product. It should be retained and used as a reference for subsequent regulatory activities.

5.7 Processing Times for Applications and Notifications

Processing times taken by Medsafe for the different phases of the evaluation and consent process are shown in the following table. The times stated are those taken (in calendar days) to complete the processes concerned for the majority (80%) of applications and notifications during the 12-month period July 1999 to June 2000. These times are given to provide applicants with a general guide to the times that Medsafe’s processing of the different types of applications and notifications can be expected to take. No data are given for processes over which Medsafe has no control.

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Processing times for 80% of applications and notifications

Phase Higher-risk New Medicine

Applications and S24.5 CMNs

Intermediate-risk New Medicine

Applications and S24.5 CMNs

Lower-risk New Medicine & New Related Product Applications and

S24.5 CMNs

Changed Medicine & Related Product Notifications (but not S24.5 CMNs)

Receipt and acknowledgement

Application or notification acknowledged within 5 days of receipt

Initial evaluation Initial evaluation and consideration by the MAAC within

440 days of acknowledgement

of application (See Note 1)

Initial evaluation completed within


of application(See Note 2)



of application



of application

Evaluation of additional data

Applicant’s first response considered

by the MAAC within 180 days

of receipt

Applicant’s first response evaluated

within 65 days of receipt

Applicants’ first response evaluated

within 21 daysof receipt

Applicant’s first response evaluated

within 16 daysof receipt

Ongoing requests for additional information and evaluation of responses, if applicable

Gazettal of consent

Consent notice published in Gazette

within 15 days of sponsor being notified of Ministry’s decision to recommend consent



(See Note 3)



(See Note 2)

N/A

Total time application under Medsafe action (excluding the evaluation of additional data)

460 days (approx. 15 months)

110 days(approx. 4 months)

55 days(approx. 2 months)

26 days(approx. 1 month)

Notes: 1. Fast-tracked new higher-risk medicine applications are normally considered by the MAAC within 120-180

days of the decision to grant priority.2. Fast-tracked new intermediate-risk medicine applications are normally evaluated within 30 days of the decision

to grant priority.3. The Ministry’s decision to recommend approval is normally made within 3 days of completion of the evaluation

report and peer review process.

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5.8 Protection of Confidential Supporting Information

5.8.1 Period of protection

The Medicines Amendment Act 1994 provides a period of protection for confidential supporting information supplied with an application for consent to distribute a medicine containing a new active substance. The provisions are designed to protect data from “unfair commercial use” or disclosure.

The requirement to protect confidential supporting information applies only to data submitted with an NMA. It does not apply to data submitted subsequently (e.g. to support new indications for approved products).

“Confidential information” includes trade secrets and information that has commercial value that would be, or would likely be, diminished by disclosure. “Confidential supporting information” means confidential information contained in, or relating to, an application for consent to distribute an innovative medicine, or confidential information about that medicine.

As applications for multi-source medicines do not usually contain clinical or toxicological data, reference may be made to data supplied by the innovator to prove safety and efficacy. As a result of the Medicines Amendment Act 1994 No. 128, data relating to an innovative medicine containing a new active substance should not be used in the evaluation of a multi-source product within the protected period - usually 5 years from the date of consent or the date of the decision to decline the application for consent to distribute the innovator product. Data in applications that have been withdrawn by the applicant are protected for a period of 5 years from the date of receipt of the application.

This procedure applies to all applications under section 20 and section 23 of the Medicines Act received after 1 January 1995. The Medicines Amendment Act 1994 also gives retrospective protection to confidential information. However, disclosure of such information may be made at any stage if it is in the interests of public health and safety, even if such information could be subject to ‘unfair commercial use’.

5.8.2 Disclosure of data

The Minister may disclose data during the five year “protected period” to the following:

an advisory or technical committee appointed under section 8 of the Medicines Act 1981 the Medicines Classification Committee the Medicines Review Committee a Government department or statutory body, for the purposes of that Government department

or statutory body, or an advisor, for the purpose of the Minister obtaining advice about the medicine to which the

data relates.

Data will only be disclosed to a Government department, statutory body, or advisor where the Minister considers steps will be taken to keep the data confidential.

Disclosure may also be made to the WHO, the Food and Agricultural Organisation, a regulatory agency of a World Trade Organisation member or a person/organisation approved by regulation.

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The grounds for disclosure to these groups are not limited to the protection of health and safety. This is not considered to contravene the GATT “TRIPS” agreement, because these organisations are either not involved in the regulation of medicines or, where they are involved, there are safeguards in place against ‘unfair commercial use’ of the data. Usually only part of the data will be released, and will be insufficient to support a New Medicine Application from another company.

Medsafe can disclose data to other regulatory authorities on two grounds. Firstly, to protect health and safety (e.g. where a question of safety, quality or efficacy has arisen) in which case it is usual for only that specific part of the data to be released. Secondly, data can be disclosed to facilitate approval of the same product by another regulatory agency. This relates to the exchange of information under the PER Scheme or the MoU with Australia. In this case, only the evaluation report is released (not the actual data). The evaluation report can only be used to approve the identical product in an overseas market, and not to approve multi-source versions of the product.

5.8.3 Relationship with the Official Information Act 1982

When responding to a request made under the Official Information Act 1982 (OIA) for release of information on an application or notification, Medsafe must consider the requirements of both the OIA and the Medicines Amendment Act 1994. Data that may be used for commercial advantage (e.g. details of formulations, manufacturing processes, assay and other test procedures) are protected from release under the OIA.

3.8.4 Effect on the evaluation process

Before a New Intermediate-risk Medicine Application for consent to market a multi-source medicine is evaluated, a check will be made to determine whether the “protected period” for the innovator product is still in force. Evaluation of the multi-source medicine application can commence during the protected period, but no reference can be made to the innovator data without the consent of the innovator company and consent to distribute the multi-source product cannot be granted until after the end of the protected period.

When this situation arises, the evaluator will notify the applicant that the protected period is still in force, and outline the consequences for the assessment and approval of the product. The applicant may then choose to submit the additional data required to enable the evaluation of the application to be completed without the need to refer to the innovator data. If the additional data are provided, the evaluation can be completed and consent granted prior to expiration of the protected period.

5.9 Certificate of Pharmaceutical Product

Pharmaceutical companies requiring formal certification of Ministerial consent having been granted for distribution of a medicine in New Zealand may request a Certificate of Pharmaceutical Product suitable for submission to overseas regulatory authorities. This certificate meets the requirements of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. It is referred to as a “Free Sales Certificate” in some jurisdictions.

A separate certificate is issued for each name, dose form, strength and flavour of each product and each country for which the certificate is required.

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Requests accompanied by the appropriate fee should be addressed to:

The Support Officer, Evaluation TeamMedsafePO Box 5013WELLINGTON

5.10 Short Supply and Discontinued Medicines

When the distribution of a medicine is likely to be affected by a problem of short supply or its distribution is to be discontinued (either temporarily or permanently) the sponsor should advise Medsafe as soon as possible, preferably well in advance, so that Medsafe can consider the likely clinical implications and take any action required.

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Section 6: General Requirements for Applications and Notifications

Section summaryThis section outlines the general requirements for applications for Ministerial consent to distribute new and changed medicines and related products.

6.1 Eligibility

The Medicines legislation requires that a New Medicine or Related Product Application (NMA or NRPA) or a Changed Medicine or Related Product Notification (CMN or CRPN) is lodged by or in the name of a manufacturer, importer or proprietor resident in New Zealand. The New Zealand resident manufacturer, importer or proprietor may be an individual or a company and is designated the “sponsor” (or “licence holder”) for the product concerned. The sponsor is legally responsible for all aspects of the product in New Zealand, including any regulatory action relating to it. The sponsor is responsible to ensure the accuracy of any information submitted to Medsafe in support of any NMA, NRPA, CMN or CRPN.

An overseas pharmaceutical company wishing to market a medicine or related product in New Zealand therefore needs to have a New Zealand-based subsidiary or appoint a local individual or company as New Zealand agent to act for them in New Zealand as sponsor for the product concerned. The New Zealand subsidiary or agent is the sponsor responsible for the product, including any supply of the product under section 2 of the Medicines Act and any recall of the product from the market.

An NMA or NRPA or CMN or CRPN is submitted to Medsafe in the name of the sponsor. An overseas branch of the company or a local or overseas regulatory affairs consultant may act on the sponsor’s behalf and prepare the paperwork for an application and submit it to Medsafe. For administrative purposes, the identity of the “applicant” depends upon the circumstances:

1. Many applications and notifications are prepared, signed and forwarded to Medsafe by an employee of the sponsor (e.g. a regulatory affairs manager or associate). In this case the applicant is the sponsor.

2. Some applications and notifications are prepared and submitted on the sponsor’s behalf by an independent regulatory affairs consultant who signs the documentation as if he or she was an employee of the sponsor. In this case the applicant is the sponsor.

3. Some applications and notifications are prepared and submitted on the sponsor’s behalf by a local or oversees consultant who signs the documentation, not as an employee, but in his or her own right as a contracted agent of the sponsor. In this case the consultant (not the sponsor) is the applicant.

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4. Some applications and notifications are prepared and submitted on the sponsor’s behalf by an overseas branch of the company. An employee of the oversees company signs the documentation and forwards it to Medsafe. In this case the oversees branch of the company is the applicant while the New Zealand branch is the sponsor.

Where a local or overseas regulatory affairs consultant or an overseas branch of a company acts on behalf of the sponsor in submitting an NMA, NRPA, CMN or CRPN, a letter (or copy of a previous letter) from the sponsor confirming the consultant’s or oversees company’s authority to act on the sponsor’s behalf should be forwarded to Medsafe, either with the application/notification or separately.

All Medsafe correspondence relating to the application or notification will be sent to the applicant, irrespective of whether the applicant is also the sponsor, unless the applicant specifically requests otherwise.

Joint applications in which all or part of the data are shared, may be made by two or more sponsors. It should be clearly indicated in the application that each sponsor supports the shared use of the data. This may be indicated by the covering letter(s) being signed by all sponsors. The letter(s) must identify the person to whom questions and other correspondence relating to the application should be addressed.

Such joint applications commonly relate to one product to be distributed under two or more brand names. For administrative purposes, each brand name is treated as a separate product. However, the application fee is calculated as for one principal product attracting a full fee with each additional brand name attracting a smaller additional fee as if was for an “additional name” of the principal product.

6.2 Language

The medicines legislation requires applications and supporting data to be written in English. Documents in languages other than English (e.g. GMP certificates and manufacturer’s licences) may be included in the application dossier provided they are accompanied by a notarised English translation.

6.3 Format

The preferred format for NMAs and NRPAs is the ICH Common Technical Document (CTD) or the older “EU format” for applications submitted in the European Union. If an application dossier in ICH or EU format is available, this should be submitted unchanged except for Part IA (Administrative Data) which should be presented using the form given in Appendix 2 or 3. Where an application dossier in ICH or EU format is not available, Part IA should be submitted and the remainder of the data package supporting the NMA should preferably be assembled as far as reasonably possible to coincide with the ICH or EU format. Regardless of the format, a detailed Table of Contents must be provided to assist evaluators in their assessment.

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6.4 Individual Patient Data

Normally individual patient data from clinical trials need not be included in an application dossier (except in the case of bioequivalence studies where the individual plasma/serum concentrations and derived pharmacokinetic data are to be supplied). However, tabulated individual patient data may be included in clinical trial documentation if the applicant considers it appropriate.

Before an application is lodged, applicants should ensure that individual patient data (case report forms) are available in a format acceptable for submission in the EU or USA, and indicate in the application that these data are available. Individual patient data not already supplied may be requested during the evaluation period.

Where not already presented in the Clinical Expert Report, overall numbers of clinical trial patients and treatment subgroups should be tabulated and submitted with Part I of the application.

6.5 Covering Letter

All NMAs and NRPAs should be accompanied by a covering letter. A covering letter is not required for a CMN or CRPN unless the sponsor wishes to provide information additional to that given in the CMN or CRPN form. Section 4 of the relevant CMN or CRPN form must be completed in full with the currently approved details and the proposed changes described, whether or not a covering letter is included.

For higher-risk medicines, the covering letter should indicate whether there are any significant differences in the product, its indications, or the data submitted in New Zealand, Australia and Europe. An explanation for such differences should be given.

6.6 Submitting an Application or Notification

The applicant must ensure that the application dossier is complete. Medsafe does not carry out detailed checking of dossiers for completeness upon receipt. They are accepted in good faith and placed in the appropriate evaluation queue. There may be situations when some data (e.g. final stability data) may not be available until later. If this is the case, the situation should be explained and justified in a covering letter and an estimate of when the information can be expected to arrive at Medsafe should be given.

Once an evaluator commences the assessment of the application or notification and finds that the dossier is incomplete in critical information (e.g. an accompanying DMF or equivalent data, appropriate bioequivalence data, or stability data sufficient to support a reasonable shelf-life are missing) and no adequate explanation for the omission or indication of when the information can be expected to be supplied has been provided, the application may be rejected at this point and the application fee may not be refunded. Applicants, therefore, are strongly advised to check carefully all applications and dossiers of supporting data for completeness before submitting material to Medsafe.

All data, including supplementary data, must be submitted on A4 sized paper and should be bound in sturdy ring-binders (or other types of binders from which pages can be removed and replaced) that do not spill their contents when opened. Each part of the application should contain a detailed Table of Contents.

Applicants wishing to submit data in electronic form should discuss the requirements with the Evaluation Team Leader.

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One copy of all applications and supporting data should be submitted. For applications to be considered by the MAAC, additional copies of the dossier of supporting data will be requested by the MAAC Secretary when required (usually about 2 months before the MAAC meeting to which the application has been assigned).

Applications for approval of new or changed labels or data sheets must be accompanied by the appropriate notification form, checklist and a signed declaration. (See Sections 12 and 13 and Appendices 8 – 13 for details).

Send completed applications (with supporting data and the appropriate fee) to the Manager, Medsafe at the address given in section 1.2.

When an application is accompanied by cartons of supporting information, each carton should be labelled clearly with the product name and contents (including volume numbers).

Boxes containing volumes of data must be sturdy enough to provide adequate protection to their contents. They should also not exceed the weight that can be comfortably lifted.

The courier should be advised not to deliver the boxes to the reception desk on the 18th floor of Grand Plimmer Tower. Instead, the courier should contact reception to notify their arrival and arrange access to the locked data storage area on a lower floor of the building.

The fee cheque should not be enclosed in one of the cartons of data. It should accompany the covering letter and Part IA for an NMA or NRPA, and accompany the CMN or CRPN form for a change notification.

6.7 Updating the Data Package

While a product is being evaluated, applicants should notify Medsafe of:

any rejections or withdrawals of applications in other countries any serious adverse effects observed for the first time, or at a frequency which has become a

concern.

Applicants should consider withdrawing an application if, during the evaluation period, significant new data become available that are contrary to the use of the medicine.

Applicants are encouraged to update stability data for New Higher Risk Medicines during the evaluation process provided the additional data can be received by Medsafe no less than 2 months before the product is due for consideration by the MAAC. This will allow the data to be taken into account in determining the shelf-life at approval and so reduce the need for changes later.

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6.8 Sponsors’ Responsibility to Retain Copies of All Documents

Sponsors are expected to retain a copy of all documentation submitted to Medsafe and all correspondence relating to NMAs, NRPAs, CMNs and CRPNs, and data sheets. They are also expected to retain copies of product specifications and certificates of analysis for each batch of their products distributed in New Zealand.

In the event of a company merger or takeover, regulatory files should be transferred to the new sponsor.

6.9 Technical Guidelines to be Followed

The technical data requirements for applications for consent to distribute new and changed medicines in New Zealand are closely aligned with those currently applying in the European Union. The European requirements are published by the European Commission (EC) as the Rules Governing Medicinal Products in the European Union. Various other documents have been published as additions and amendments to these Rules by the Committee for Proprietary Medicinal Products (CPMP) Working Parties as ‘Notes for Guidance’. Medsafe also recognises the technical guidelines published by the United States Food and Drug Administration. These CPMP and FDA documents are listed on EMEA and FDA Internet web sites and may be downloaded from there (see Subsections 6.9.2 and 6.9.3).

The International Conference on Harmonisation (ICH) has also developed tripartite guidelines for use by regulatory authorities in the EU, USA and Japan. When these reach the final stage of adoption by the ICH they are normally adopted by the EC, USA and Japan as additions to, or replacements for, their guidelines.

Once ICH, CPMP or FDA guidelines are formally adopted and come into force in the EU or the USA they are recognised by Medsafe.

Medsafe also recognises relevant guidelines published in the British, European and United States Pharmacopoeia and, where relevant, the guidelines published by the World Health Organisation and the Australian Therapeutic Goods Administration (TGA).

While there are different administrative procedures applying in New Zealand and Australia, there is substantial harmonisation of the data requirements for evidence of quality, safety and efficacy of medicines and the grounds on which consent for distribution is granted in the two countries. Consequently, there are considerable similarities between the requirements of Medsafe and the Australian TGA. However, there are Australian-specific requirements for some aspects of the quality control and stability data that are not relevant to New Zealand. New Zealand has a cooler climate than Australia and, consequently, the same stability data may support a longer shelf life for room temperature storage in New Zealand (<25C) than in Australia (<30C).

It is recognised that, in some circumstances, a different approach from that described in a guideline may be appropriate. However, where an applicant chooses to submit a data package that does not meet the relevant guideline, that decision should be explained and justified in the dossier submitted in support of the application. The following situations are possible grounds for departing from current guidelines:

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scientific development circumstances unique to the product in question adoption by the company of an acceptable approach which had not previously been considered by

Medsafe sufficient alternative studies having been conducted which satisfy the criteria of quality, safety and

efficacy.

In assessing the chemical, pharmaceutical and biological data submitted with new medicine applications and changed medicine notifications, Medsafe generally follows the technical guidelines published by the International Conference on Harmonisation (ICH), the European Commission and its Committee for Proprietary Medicinal Products (CPMP), and the United States Food and Drug Administration (FDA), as well as the technical guidance provided by the British, European, and United States Pharmacopoeia (which Medsafe regards as essentially equivalent and equally acceptable standards). Where appropriate, Medsafe also takes notice of guidelines published by the World Health Organisation (WHO) and the Australian Therapeutic Goods Administration (TGA). Medsafe recognises these overseas guidelines from the dates on which they come into force internationally.

Medsafe expects toxico-pharmacological studies and clinical studies supplied in support of any new medicine application or changed medicine application to have been carried out in accordance with the internationally accepted standards of Good Laboratory Practice and Good Clinical Research Practice.

Where a product or ingredient is controlled according to a pharmacopoeial monograph, the specifications are to be updated to reflect any revisions to the monograph concerned. Where a pharmacopoeial monograph exists, this is considered to be the minimum requirements for the product or substance.

Guidelines and pharmacopoeia are constantly evolving as a result of scientific developments and harmonisation of the requirements of the major overseas regulatory authorities. Medsafe endeavours to keep abreast of such developments and keep its evaluation policies in line with “best international practice”.

Where an ICH guideline exists for a particular aspect of a medicine (e.g. impurity limits, validation of analytical procedures, stability) and has been adopted by the European, US and Japanese regulatory authorities, conformity to this guideline is the normal requirement for applications submitted to Medsafe. Applicants should ensure that the data in their application dossiers comply with these ICH guidelines. It is recognised, however, that older medicines may have been developed before publication of the ICH guidelines. The data packages for these products may not meet current ICH guidelines, but do meet earlier CPMP or FDA guidelines. In this situation, the available data should be submitted for evaluation. The data will be acceptable if they can be seen to be effectively equivalent, although not identical, to those which would meet the requirements of the ICH guidelines.

Where no ICH guideline exists for a particular aspect of a medicine, data will normally be acceptable if they comply with the requirements of the CPMP and/or FDA guidelines. These guidelines are generally equivalent in intent, if not always in their details.

The ICH, CPMP and FDA guidelines are listed on and available for downloading and printing from these organisations’ web sites (see below).

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6.9.1 ICH guidelines

The ICH has developed and published numerous guidelines relating to the quality, safety and efficacy of medicines. Copies of these guidelines may be obtained from:

ICH Secretariatc/o IFPMA30 rue de St-JeanPO. Box 9CH-1211 Geneva 18SwitzerlandFax: +41-22-345 8275

ICH guidelines may also be obtained in electronic form (printable pdf format) via the Internet from the following address: http://www.ifpma.org/ich5.html.

6.9.2 CPMP guidelines

The European Commission (EC) has issued various directives relating to medicinal products. The Commission’s CPMP and its veterinary equivalent (the CPVP) has applied these directives in developing a set of rules which have been published in series of volumes entitled Rules Governing Medicinal Products in the European Union. Volumes 2B, 3A, 3B and 3C are applicable to New Zealand as well.

Volume 1 details European Union pharmaceutical legislation and EC directives and, therefore, is generally not relevant to applications submitted in New Zealand.

Volume 2 is in 3 parts (A, B and C) and details the procedures for marketing authorisation in the European Union (Vol. 2A), the presentation and content of application dossiers, summaries of product characteristics and expert reports (Vol. 2B) and regulatory guidelines (Vol. 2C). Medsafe prefers that application dossiers submitted in New Zealand are in the EU format as described in Volume 2B.

Volume 3 is also in 3 parts (A, B and C) and contains technical guidelines relating to the various sections of the dossier, namely: Quality and Biotechnology (Vol. 3A), Safety, Environment and Information (Vol. 3B), and Efficacy (Vol. 3C). Numerous other specific guidelines have been drafted or finalised by the CPMP Working Parties and issued as separate ‘Notes for Guidance’.

Volume 4 details the EC requirements for good manufacturing practices (GMP) for medicinal products for human and veterinary use.

Volumes 5, 6, 7 and 8 detail European pharmaceutical legislation, regulatory procedures and technical guidelines for veterinary medicinal products.

Volume 9 details European requirements for pharmacovigilance of both human and veterinary medicinal product.

Printed copies of the European Commission’s Rules Governing Medicinal Products in the European Union and the individual ‘Notes for Guidance’ may be obtained from:

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Office for Official Publications of the European Communities2, rue MercierL-2985 LuxembourgFax +352-488573 or +352-486817

Printed copies of the Rules Governing Medicinal Products in the European Union may also be obtained from:

Hunter Publications58a Gipps Street CollingwoodVictoria 3066AustraliaFax: +61-3-9419-7154

Alternatively, the Rules may be downloaded in printable electronic form (pdf format) from the Internet site: http://dg3.eudra.org/F2/eudralex/index.htm.

Individual ‘Notes for Guidance’ may be obtained in printable electronic form (pdf format) from the following Internet site: http://www.emea.eu.int.

6.9.3 FDA guidelines

The US FDA has published numerous guidelines dealing with all aspects of medicines. Copies of FDA guidelines may be obtained from:

Office of Training and CommunicationsDivision of Communications ManagementDrug Information BranchFood and Drug Administration5600 Fishers LaneRockville, MD 20858USAFax: +1-301-827-4577

Most FDA guidelines relevant to New Zealand requirements may also be obtained in printable electronic form (pdf format) from the following Internet address: http://www.fda.gov/cder/guidance/index.htm.

FDA guidelines relating to biological and biotechnological products may be obtained from:http://www.fda.gov/cber/guidelines/htm.

6.10 Proprietary Names

The proposed proprietary name for a new medicine or related product must be clear, unambiguous, not unacceptably similar to, or likely to be confused in any way in print, handwriting or speech with, another medicine or related product currently registered in New Zealand, and not misleading in any way with regard to the nature, composition, purpose, uses or effects of the product.

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6.11 Description of Dosage Form

The dosage form description for a product should be selected from the following list:

Capsule, combinationCapsule, liquid filledCapsule, liquid filled, nasal inhalationCapsule, modified releaseCapsule, powder filledCapsule, powder filled, nasal inhalationCapsule, soft gelatinCement, boneCement, bone, liquid componentCement, bone, powder componentChewing gumChocolate, medicatedCombinationCondom with spermicideCream, topicalCream, vaginalCrystalsDiluentDressing, medicatedDrops, earDrops, ear/eyeDrops, ear/eye/noseDrops, eye, powder and diluentDrops, eye, solutionDrops, eye, suspensionDrops, nasalDrops, oralElixirEmulsion, oralEmulsion, topicalEnemaEye discEye strip, impregnatedFoamGargle, powder forGargle, solutionGargle, tablet forGasGel, ophthalmicGel, oralGel, oral topicalGel, topicalGel, vaginalGranules, effervescentGranules, modified releaseGranules, oral

Herb, driedImplant, subcutaneousImplant, urethralInfusion, concentrateInfusion, emulsionInfusion, powder forInfusion, solutionInhalation, capsule, liquid filledInhalation, capsule, powder filledInhalation, powderInhalation, solutionInhalation, solution, powder forInhalation, suspensionInhalation, volatile liquidInhaler, aerosol, meteredInhaler, aerosol, non-meteredInjection with diluentInjection, concentrateInjection, depotInjection, emulsionInjection, gelInjection, granules forInjection, powder forInjection, solutionInjection, suspensionIntrauterine contraceptive deviceIrrigationIrrigation, eyeIrrigation, powder for reconstitution.Lacquer, nailLinctusLinimentLotion, scalpLotion, skinLozengeMouthwash, solutionOilOil, bathOil, topicalOintment, earOintment, ear/eyeOintment, eyeOintment, rectalOintment, topicalOintment, vaginal

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Pad, skin wash impregnatedPaste, oralPaste, topicalPessaryPillPowderPowder, effervescentPowder, nasalPowder, topicalShampooSkin washSoapSolutionSolution, antisepticSolution, contact lensSolution, dialysisSolution, dialysis, powder forSolution, intratrachealSolution, oralSolution, oral, granules forSolution, oral, powder forSolution, topicalSolution, topical, powder forSolution, vaginal doucheSponge, vaginalSpray, contact lens solutionSpray, nasal solutionSpray, nasal suspensionSpray, oralSpray, topicalSpray, topical powderStick, topical

SuppositorySuppository, urethralSuspension, intratrachealSuspension, intratracheal, powder forSuspension, oralSuspension, oral, granules forSuspension, oral, powder forSuspension, rectal/oralSyrupSyrup, powder forTabletTablet for contact lens solutionTablet, chewableTablet, chewable/dispersibleTablet, coatedTablet, dispersibleTablet, effervescentTablet, enteric coatedTablet, film coatedTablet, modified releaseTablet, solubleTablet, sublingualTablet, uncoatedTablet, vaginalTest kitTest kit, pregnancyTest strip, diagnosticToothpasteTransdermal gelTransdermal patchVaginal ringWafer

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6.12 Routes of Administration

The description of the route of administration for a product should be selected from the following list:

ConjunctivalCutaneousDentalEndocervicalEndosinusialEpiduralExtra-amnioticGingivalHaemodialysisInhalationInsufflationIntra-amnioticIntra-arterialIntra-articularIntrabursalIntracardiacIntracavernousIntracervicalIntracoronaryIntradermalIntradiscalIntralesionalIntralymphaticIntramuscular

IntraocularIntraperitonealIntrapleuralIntrasternalIntrauterineIntrathecalIntratrachealIntravenousIntravesicalNasalNot ApplicableOralOromucosalOticPeriarticularPerineuralRectalSubconjunctivalSubcutaneousSublingualTransdermalUrethralVaginal

6.13 Shelf Life and Storage Conditions

The claimed shelf life must be supported by stability studies. Such studies should meet the requirements of the ICH guidelines for stability testing. If specific storage conditions are required, the storage conditions statement should be selected or compounded using elements from the following list (or words of similar meanings):

protect from light

protect from moisture

below -20°C (Deep freeze)



below -5°C (Freeze)

at 2° to 8°C (Refrigerate, do not freeze)

at 8° to 15°C (Cool)

at 15° to 25°C (Controlled room temperature)

below 20°C (Controlled room temperature)

at or below 25°C

below 25°C

below 30°C

Note that in New Zealand “below 25°C” means room temperature, whereas in Australia “below 25°C” refers to air-conditioned facilities and “below 30°C” refers to room temperature.

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Section 7: Ingredients in Medicines and Related Products

Section summaryThis section provides details of the format and content of Drug Master Files and Certificates of SuitabilityIt also details Medsafe requirements for ensuring the freedom of active ingredients and excipients from infective agents and other harmful substances.

Guidelines to read in conjunction with this section:CPMP: European drug master file procedure for active substances (EU Rules Vol. 3A)FDA: Guideline for Drug Master FilesTGA: Submission of Data for a Drug Master File (DMF) on an Active Raw Material, Appendix 7 in Australian Guidelines for the Registration of Drugs, Volume 1, July 1994.WHO: Guidelines for assuring the quality of pharmaceutical preparations made by recombinant DNA technology WHO/PHARM/89.542 BS/89.1609

7.1 Drug Master Files

Active pharmaceutical ingredients (APIs) are commonly manufactured by a company other than the manufacturer of the finished product. In such cases, the manufacture, quality control and stability of the active ingredient are usually described in a ‘Drug Master File’ (DMF), submitted to the regulatory authority by the manufacturer of the active ingredient.

Where the active and finished product are manufactured by the same company, information on the production, quality control and stability of the active substance may be submitted as part of the dossier for the finished product rather than in a separate DMF.

In order to refer to the DMF in an application, the applicant must have the written permission of the active ingredient manufacturer who submitted the DMF. A “letter of access” from the active ingredient manufacturer, addressed to Medsafe and indicating clearly the applicant to which it applies must be sent to Medsafe by the active ingredient manufacturer, either with the DMF or separately.

If an active substance manufacturer has supplied (or been asked to supply) a DMF to Medsafe for the registration of a medicine, it is not necessary for a further copy of the DMF (or part thereof) to be provided for the registration of another product sponsored by a different sponsor. However, the active substance manufacturer needs to provide Medsafe with a new letter of access, referring to the previously supplied DMF and the new applicant.

Finished product sponsors are responsible for the quality of their products and the raw materials used to manufacture them. Therefore, applicants should provide written assurance that there is a formal agreement between the active raw material manufacturer and the sponsor which ensures that information will be communicated to the sponsor, and to Medsafe, before any significant change is made to the method of manufacture or specifications of an active raw material used in a product distributed in New Zealand.

Quality control of the bulk active ingredient is carried out by both the manufacturer of the active ingredient and by the manufacturer of the finished product. Testing by the manufacturer of the bulk

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active ingredient is usually described in a DMF. Good Manufacturing Practice requires the finished product manufacturer to re-test the active ingredient’s identity, potency and purity before use in the manufacture of finished products. This testing is usually described in the application dossier for the finished product.

DMFs should be updated periodically to reflect any changes. The sponsor concerned should ensure that either the updated DMF (together with a detailed list of changes made), or details of any changes made, are forwarded to Medsafe. The changes made need to be described in sufficient detail to enable Medsafe to determine if any material changes have been made to the characteristics, manufacture or quality control of the substance concerned and what those changes are. Where formal evaluation of the changes is required, the sponsor will be required to submit a CMN and pay the appropriate fee.

7.1.1 When is a DMF not required?

A DMF is not required for:

any active substance that is controlled according to the relevant monograph in the European Pharmacopoeia and for which a valid (recently issued) European Pharmacopoeial Commission “Certificate of Suitability” is provided (see Section 7.2 for details)

any active substance predominantly used in a lower-risk medicine (e.g. paracetamol) or related product, but if the substance is also used in a higher- or intermediate risk medicine, a DMF or European Pharmacopoeial Certificate of Suitability may be required to support an NMA or CMN relating to that product.

common inorganic substances and simple organic compounds available commercially in high purity from chemical supply houses, e.g. sodium chloride, magnesium hydroxide, naturally occurring organic acids and their salts (such as ascorbic acid and sodium citrate), sugars (such as dextrose, mannitol), amino acids (even though they may be synthesised rather than being extracted and refined).

Simple, unrefined extracts from plant materials.

Although a DMF is not required for these active ingredients, evidence needs to be submitted by the finished product manufacturer that the substance is obtained from a reliable source and consistently complies with the applicable pharmacopoeial or non-pharmacopoeial specifications. Any non-pharmacopoeial specifications need to be assessed to determine their appropriateness and adequacy to ensure the quality of the substance.

7.1.2 Format for a DMF

DMFs compiled using the European or US format are acceptable in New Zealand. If a DMF has already been assessed and approved by an overseas regulatory authority, and the evaluation report is available to the manufacturer, a copy of the full report should be forwarded with the DMF. If the report is not available, the manufacturer should state when and by whom the DMF was assessed and approved.

The DMF may, if required, be presented in two sections, with the first (open) section containing information accessible to the finished dose form manufacturer and the second (closed) section containing information not accessible to the finished dose form manufacturer.

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7.2 Certificate of Suitability

Where an active ingredient is described in the European Pharmacopoeia, the manufacturer may submit the DMF (or equivalent documentation) to the European Pharmacopoeial Commission for assessment and issue of a ‘Certificate of Suitability’ (CoS). This certificate confirms that the purity of the substance, as produced by the manufacturer, is suitably controlled by the monograph in the European Pharmacopoeia. This certificate may then be submitted in lieu of a DMF, obviating the need for regulatory authorities to carry out their own detailed assessment of the data. For details of the certifications scheme, contact the secretariat of the European Pharmacopoeial Commission. Some information is available on the internet site: http://www.pheur.org.

Where a CoS is submitted in lieu of a DMF, the sponsor must also provide a written assurance that any conditions attached to the CoS by the European Pharmacopoeial Commission, as well as any agreed additional tests and limits (e.g. for polymorphic form, particle size distribution, impurities, etc.) are applied to each batch used in product intended for the New Zealand market.

The European Pharmacopoeial Commission also assesses and issues Certificates of Suitability for substances used as active ingredients or excipients in pharmaceutical products confirming that they comply with European Pharmacopoeial requirements for minimising the risk of transmission of animal spongiform encephalopathies. Medsafe accepts these certificates.

Where a CoS is submitted in lieu of a DMF, the applicant for consent to distribute a medicine in New Zealand must ensure that the CoS is submitted with the written permission of the manufacturer of the bulk active ingredient to be used in manufacture of the finished product for the New Zealand market. Submission of the CoS as part of the dossier of data supporting a new medicine application or changed medicine notification implies, but does not prove, that there is a commercial agreement between the applicant and the active ingredient manufacturer. This agreement between the parties must be confirmed to Medsafe by means of a formal “letter of access” from the active ingredient manufacturer, addressed to Medsafe and clearly indicating the applicant and, where possible, the products to which it applies. The letter of access should also confirm that the active ingredient manufacturer will, if requested, supply direct to Medsafe data relating to the manufacture, quality control and stability of the substance concerned.

7.3 Ingredients of Human or Animal Origin

Guidelines to read in conjunction with this subsection:

ICH Guidelines: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological

Products Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products

Derived from Cell Lines of Human or Animal Origin Quality of Biotechnological Products: Derivation and Characterisation of Cell Substrates

Used for Production of Biotechnological/Biological Products

CPMP Guidelines, etc: Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy

Agents via Medicinal Products (CPMP/BWP/1230/98) Position Paper on production of Tallow Derivatives for Use in Pharmaceuticals (CPMP/1163/97) Note for Guidance on Plasma-Derived Medicinal Products (CPMP/BW/269/95) Position Paper on Plasma-derived Medicinal Products: Alt Testing (CPMP/BWP/385/99)

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Note for Guidance: Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses (CPMP/BWP/268/95)

The Introduction of Nucleic Acid Amplification Technology (NAT) for the Detection of Hepatitis C Virus RNA in Plasma Pools (CPMP/BWP/390/97)

FDA Guidelines: Guidance Concerning Demonstration of Comparability of Human Biological Products,

Including Therapeutic Biotech-Derived Products Guidance for Industry: Donor Screening for Antibodies to HTLV-II Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls

Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use

Guidance for Industry: Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeld-Jacob Disease (CJD) and New Variant Creutzfeld-Jacob Disease (nvCJD) by Blood and Blood Products

New Zealand Guidelines: Minimum Standards for the Collection, Processing and Quality Assurance of Blood and

Medicines Derived from Human Blood and Plasma (New Zealand, 1998)

If a product contains an ingredient (active or excipient, e.g. magnesium or calcium stearate, stearic acid, gelatin) that is, or potentially is, of human or animal origin, or comes into contact with material of human or animal origin during manufacture, the source of the material (or contact) must be declared in the NMA or CMN. If it is of animal origin, evidence must be provided that the product is free from viruses, other micro-organisms and transmissible spongiform encephalopathy (TSE) agents. The guidelines listed above should be followed in preparing the documentation to provide this evidence.

A European Pharmacopoeial Commission Certificate of Suitability is acceptable as evidence of freedom from TSE agents.

7.4 Colouring Agents

Regulation 6 of the Medicines Regulations 1984 contains a list of acceptable colouring agents for use in medicines in New Zealand. However, other colouring agents will generally be acceptable provided they are acceptable colourings for use in foods or medicines in the EU, USA or Australia.

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Section 8: New Medicine Applications

Section Summary

This section outlines the format and data requirements for applications for Ministerial consent to distribute new and changed medicines and related products.

Legislation to read in conjunction with this section:Medicine Act 1981

Section 21: Applications for Minister’s consentSection 23: Minister may give provisional consentSection 24: Distribution of changed medicines restricted

8.1 Formats for New Medicine Applications

8.1.1 Format for a new innovative medicine application

A new medicine application for a new chemical entity or new biological entity is be presented in two sections, i.e. the administrative information and the dossier of supporting data to establish the quality, safety and efficacy of the product.

The administrative data consists of the following documents (as applicable for the particular type of product):

Covering letter and fee (cheque or evidence of electronic payment having been made) Completed NMA form(s) (see Appendix 2) Certificates of Suitability (See Section 7.2) GMP documentation (see Section 11) Labelling (see Section 12) Information leaflet/Package insert (See Section 12.11) Data sheet (see Section 13) Copies of overseas evaluation report(s)

An NMA form must be completed for all New Medicine Applications. A separate form should be completed for each name, dose form, strength and flavour.

Note: The NMA form in Appendix 2 has been revised. Applications received by Medsafe after 1 January 2002 must be made using the revised form. Applications made using previous formats published in earlier editions of these Guidelines received after 1 January 2002 will not be accepted for processing and will be returned to the applicant.

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The accompanying dossier of supporting quality, safety and efficacy data includes the following (as applicable for the type of application):

Summaries (ICH format dossier, Module 2) or EU format Expert Reports Chemical, Pharmaceutical and Biological documentation (including separate Drug Master File(s)

if applicable) Pre-clinical/Toxicology documentation Clinical documentation

The preferred format for the dossier of supporting data for NMAs and NRPAs is either:

1. The “ICH format” Common Technical Document (CTD) Modules 2 (Overviews and Summaries of the Quality, Non-clinical and Clinical data), 3 (Quality), 4 (Non-clinical Study Reports) and 5 (Clinical Study Reports) as detailed in the ICH Guideline Multidisciplinary Topic M4: The Common Technical Document and in the European Commission’s The Rules Governing Medicinal Products in the European Union. Volume2B: Notice to Applicants, 2001 edition, or

2. The “EC format” Parts IC (expert reports), Part II (Chemical, Pharmaceutical and Biological Documentation), Part III (Toxico-pharmacological Documentation) and Part IV (Clinical Documentation) as detailed in the European Commission’s Rules Governing Medicinal Products in the European Union, Volume2B: Notice to Applicants, 1998 edition.

From 1 July 2002 the ICH format will be the preferred format for all newly assembled application dossiers. However, the EU format will still be acceptable in cases where the dossier has previously been assembled and submitted in that format to a regulatory authority in Europe or Australia. Medsafe does not expect applicants to re-format such material to the ICH format. If an application dossier in EU format is available, this should be submitted unchanged except for “Part IA” (Administrative Data) which must be replaced with the NZ NMA form so that all information relevant to the NZ application is presented and that specific to EC administrative requirements is omitted. The accompanying “Part IB” documents (GMP documentation, data sheet, labelling, etc) should be submitted as they are or adapted to New Zealand requirements, as appropriate.

Where an application dossier in either “ICH format” or “EC format” is not available, Parts IA and IB should be submitted according to the New Zealand formats and requirements and the remainder of the data package supporting the NMA should preferably be assembled as far as reasonably possible to coincide with either the ICH format (Modules 2 – 5) or the EU format (Parts IC, II, III and IV).

A detailed Table of Contents must be provided with any dossier, regardless of the format, to assist evaluators in their assessment.

8.1.2 Format for an abridged new medicine application dossier

A new medicine application for an “Intermediate Risk” medicine (including multi-source medicines and new dose forms and strengths of innovative and multi-source medicines) or for a “Lower risk” medicine or related product is be presented in two sections, i.e. the administrative information and the dossier of supporting data purporting to establish the quality and, if relevant, the bioequivalence of the product and the corresponding innovator product.

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The administrative data consists of the following documents (as applicable for the particular type of product):

Covering letter and fee (cheque or evidence of electronic payment having been made) Completed NMA form(s) (see Appendix 2) Certificates of Suitability (See Section 7.2) GMP documentation (see Section 11) Labelling (see Section 12) Information leaflet/Package insert (See Section 12.11) Data sheet (see Section 13) Copies of overseas evaluation report(s)

The covering letter should indicate if one or more active ingredient manufacturers have been commissioned to submit direct to Medsafe Drug Master Files (DMFs) or Plasma Master Files (PMFs) as part of the application package

An NMA form must be completed for all New Medicine and New Related Product Applications (including those for additional names, dose forms and strengths or flavours). A separate form should be completed for each name, dose form, strength and flavour.

Note: The NMA form in Appendix 2 has been revised. Applications received by Medsafe after 1 January 2002 must be made using the revised form. Applications made using previous formats published in earlier editions of these Guidelines received after 1 January 2002 will not be accepted for processing and will be returned to the applicant.

The accompanying dossier of supporting data includes the following (as applicable for the type of application):

Summaries (ICH format dossier, Module 2) or Expert reports (pre-2002 EU format dossier, Part IB) (if available; not required for low risk medicines)

Chemical, Pharmaceutical and Biological data (including separate Drug or Plasma Master File(s) if applicable; not required for low risk medicines)

Bioavailability or bioequivalence data (if applicable; not required for low risk medicines) Pre-clinical/Toxicology data, e.g. for new excipients (if applicable) Clinical data (if applicable; not required for low risk medicines)

The preferred format for the dossier of supporting data for NMAs and NRPAs is either:

1. The “ICH format” Common Technical Document (CTD) Module 2 (Overviews and Summaries of the Quality, Non-clinical and Clinical data) and Module 3 (Quality) and, if relevant, Module 4 (Non-clinical Study Reports) and Module 5 (Clinical Study Reports) as detailed in the ICH Guideline Multidisciplinary Topic M4: The Common Technical Document and in the European Commission’s The Rules Governing Medicinal Products in the European Union. Volume2B: Notice to Applicants, 2001 edition, or

2. The “EC format” Part IC (expert reports) and Part II (Chemical, Pharmaceutical and Biological Documentation) and, if relevant, Part III (Toxico-pharmacological Documentation) and Part IV (Clinical Documentation) as detailed in the European Commission’s Rules Governing Medicinal Products in the European Union, Volume2B: Notice to Applicants, 1998 edition.

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From 1 July 2002 the ICH format will be the preferred format for all newly assembled application dossiers. However, the EU format will still be acceptable in cases where the dossier has previously been assembled and submitted in that format to a regulatory authority in Europe or Australia. Medsafe does not expect applicants to re-format such material to the ICH format. If an application dossier in EU format is available, this should be submitted unchanged except for “Part IA” (Administrative Data) which must be replaced with the NZ NMA form so that all information relevant to the NZ application is presented and that specific to EC administrative requirements is omitted. The accompanying “Part IB” documents (GMP documentation, data sheet, labelling, etc) should be submitted as they are or adapted to New Zealand requirements, as appropriate.

Where an application dossier in either “ICH format” or “EU format” is not available, Parts IA and IB should be submitted according to the New Zealand formats and requirements and the remainder of the data package supporting the NMA or NRPA should preferably be assembled as far as reasonably possible to coincide with either the ICH format (Modules 2 and 3) or the EU format(Parts IC and II).

A detailed Table of Contents must be provided with any dossier, regardless of the format, to assist evaluators in their assessment.

8.1.3 ICH and EU formats for abridged dossiers

ICH FormatThe ICH (Common Technical Document) format headings for Chemical, Pharmaceutical and Biological Documentation are presented below.

3.1 TABLE OF CONTENTS

3.2 BODY OF DATA

3.2.S DRUG SUBSTANCE3.2.S.1 General Information 3.2.S.1.1 Nomenclature 3.2.S.1.2 Structure 3.2.S.1.3 General Properties

3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s)3.2.S.2.2 Description of manufacturing process and process controls3.2.S.2.3 Control of materials 3.2.S.2.4 Controls of critical steps and intermediates 3.2.S.2.5 Process validation and/or evaluation 3.2.S.2.6 Manufacturing process development3.2.S.3 Characterisation3.2.S.3.1 Elucidation of structure and other characteristics 3.2.S.3.2 Impurities3.2.S.4 Control of drug substance3.2.S.4.1 Specification3.2.S.4.2 Analytical procedures3.2.S.4.3 Validation of analytical procedures 3.2.S.4.4 Batch analyses 3.2.S.4.5 Justification of specification3.2.S.5 Reference standards or materials3.2.S.6 Container closure system3.2.S.7 Stability

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3.2.P DRUG PRODUCT3.2.P.1 Description and composition of the drug product3.2.P.2 Pharmaceutical development3.2.P.3 Manufacture3.2.P.3.1 Manufacturer(s)3.2.P.3.2 Batch formula3.2.P.3.3 Description of manufacturing process and process controls3.2.P.3.4 Controls of critical steps and intermediates3.2.P.3.5 Process validation and / or evaluation3.2.P.4 Control of excipients3.2.P.4.1 Specifications3.2.P.4.2 Analytical procedures3.2.P.4.3 Validation of analytical procedures3.2.P.4.4 Justification of specifications3.2.P.4.5 Excipients of human or animal origin ---3.2.P.4.6 Novel excipients 3.2.P.5 Control of drug product 3.2.P.5.1 Specification(s)3.2.P.5.2 Analytical procedures3.2.P.5.3 Validation of analytical procedures 3.2.P.5.4 Batch analyses 3.2.P.5.5 Characterisation of impurities3.2.P.5.6 Justification of specification(s)3.2.P.6 Reference standards or materials3.2.P.7 Container closure system3.2.P.8 Stability

3.2.A APPENDICES3.2.A.1 Facilities and equipment3.2.A.2 Adventitious agents safety evaluation3.2.A.3 Novel excipients

3.2.R REGIONAL INFORMATION3.3 LITERATURE REFERENCES

EU FormatThe EU format headings for Chemical, Pharmaceutical and Biological Documentation for abridged applications are presented below.

PART II A: Composition and presentation of product1. Composition of the product2. Container3. Clinical trial formula(e) (if applicable)4. Development pharmaceutics

PART II B: Method of preparation1. Manufacturing formula, including details of batch size2. Manufacturing process for finished product (including in-process control)3. Validation of the process (where a non-standard method of manufacture is used or the

method of preparation is critical for the product)

PART II C: Control of starting materials1. Active pharmaceutical ingredients

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2. Other ingredients3. Packaging material (immediate packaging)

PART II D: Control tests on intermediate products

PART II E: Control tests on the finished product1. Specifications and routine tests2. Scientific data

PART II F: Stability

PART II G: Bioavailability / Bioequivalence (if applicable)

PART II Q: Other information

8.2 Data Requirements for New Medicine Applications

The requirements for the data supporting a new medicine application depend upon the category of product involved::

New Higher-risk Medicine (NMA-H) New Intermediate-risk Medicine (NMA-I) New Lower-risk Medicine (NMA-L) an application for provisional consent to distribute a new medicine

Please note that an OTC medicine does not automatically fall into the Lower-risk Medicine category.

New Intermediate-risk and Lower-risk medicines usually contain active ingredients that are listed in a pharmacopoeia and claim indications for which there is sufficient supportive published literature. Where this is not the case, a New Intermediate-or new Lower-risk Medicine Application may need to contain clinical documentation to support the proposed indications, and also possibly relevant toxicological and pharmacological documentation.

While an application for provisional consent need not contain the same detail of safety and efficacy data as that required for full consent, all available information should be included, along with an explanation of the type of data still being collected and when these data will be available.

When the product that is the subject of an NMA is closely related to an existing product, such as a new strength, the applicant is only required to submit data relevant to the introduction of the new product. The application must specify all differences between the new and existing products and provide data to support the safety, quality and efficacy of the new product. A complete dossier duplicating data already supplied for an existing product is not required.

Different pharmaceutical forms and strengths or flavours of a medicine require separate application forms, but may be supported by reference to the same dossier of information.

Where a medicine has been evaluated and approved in Australia, Europe, Canada or the USA and the overseas evaluation reports are available, sponsors should provide copies of those reports along with an indication as to whether the supporting data submitted overseas was identical or not to the data submitted with the New Zealand application.

Product Development Pharmaceutics are not normally required for lower risk medicines. They may be required for unusual dose forms or formulations.

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Where pharmacopoeial test methods are used to control a finished product, sufficient validation data should be provided to confirm that the test methods work satisfactorily for the product concerned.

8.3 Standard Requirements for New Multi-source (Generic) Prescription Medicines

Medsafe’s standard requirements for the data for new intermediate-risk medicines are as set out below. Dossiers are assessed for conformity with these requirements.

Note: A checklist is provided in Appendix 4 to assist applicants in ensuring that all of the required data are included in their application dossiers. Applicants are asked to complete this checklist and include it with the application.

Administrative Information The proposed proprietary name for the product must be clear, unambiguous, not unacceptably

similar to, or likely to be confused in any way in print, handwriting or speech with, another medicine currently registered in New Zealand, and not misleading in any way with regard to the nature, composition, purpose, uses or effects of the product.

Good Manufacturing Practice (GMP) certification or other evidence of GMP compliance must be provided for each finished product manufacturing and packing site and the certification: (a) relates to the product (or product class) concerned, (b) must be issued by authorities recognised by Medsafe, and (c) will not have expired or be more than 5 years old by the time the product is likely to be approved for distribution in New Zealand.

Appropriate evidence of GMP (in the form of a GMP certificate or a DMF) must be provided (or have been provided previously) for each active ingredient manufacturing site.

The labelling must comply with the NZ Medicines Regulations and Guidelines (See Section 12). Otherwise, the labelling must be revised or, if the criteria set out in Section 12.4 are met, a labelling exemption may be requested.

If applicable, the labels must allow easy discrimination between the different strengths of the product.

The draft data sheet must comply with the NZ Medicines Regulations and Guidelines (see, Section 13).

In the case of a multi-source medicine, the data sheet must be consistent with that of the corresponding innovator product.

If applicable, any package insert/information leaflet supplied with the product must be consistent with the New Zealand product details and the data sheet.

If any excipients in the product are unsuitable for particular patient populations, appropriate information or warnings must be included on the label (or, when space on the label does not permit, in an information leaflet/ package insert) and also in the data sheet.

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Chemical, Pharmaceutical and Biological Documentation

Composition

The dose form and formulation must be adequately justified, appropriate for the medicine concerned and all of the ingredients are acceptable for use in human medicines.

The ingredients must be compatible with each other.

Dose delivery must be consistent within clinically acceptable limits.

If relevant, any antioxidants and any chemical or anti-microbial preservatives included in the product must be adequately justified and their effectiveness must be established.

Adequate measures must be taken to ensure that any animal-derived ingredients (e.g. gelatin, magnesium or calcium stearate, stearic acid) used in the product are free from TSE contamination.

Different strengths of the product must be readily distinguished (e.g. by differences in size, colour, shape, markings, etc).

If tablets are scored, evidence that the tablets split evenly must be provided.

The primary (immediate) and secondary (outer) packaging and packaging materials, closures, induction or tamper-proof seals, pack sizes, any dosing device, and any desiccant or cotton wool contained in the package must be appropriate for the product.

If the NZ Medicines Regulations require the product to be in a safety container, it must be so packaged.

Manufacture of Active Ingredient(s)

Unless previously submitted and approved, a satisfactory Drug Master File(s) or equivalent information about the manufacture of the active ingredient(s) from each supplier of bulk active ingredient must be submitted.

The DMF must describe in detail: the “route of synthesis”, each step in the manufacturing and purification process, the reaction conditions and in process controls for each step, the quality control of starting materials, reagents, catalysts, solvents and any isolated intermediates, as well as any subsequent processing (e.g. milling) of the bulk substance.

The DMF must also provide proof of chemical and stereochemical structure of the substance (and of any significant impurities) using appropriate physical, chemical and spectroscopic methods.

Where relevant, adequate evidence of the crystalline form produced and control thereof must be provided.

Manufacture of Finished Product

The manufacturing, sterilisation (if any) and packaging processes, the equipment used, and batch sizes must be described in detail, appropriate and justified.

Any overages or ranges of quantities for the active ingredient(s) or any excipients must be appropriate and adequately justified.

If relevant, any sterilisation processes must be justified, and it must be established that harmful by-products are not formed during the sterilisation process.

Any overfill of the container(s) must be justified.

Any solvents or gases used in the manufacturing process must be of adequate quality.

If alternative processes are intended at some steps in the manufacture, these have been justified and shown to yield finished product of equivalent quality.

The in-process controls (incl. temperatures, mixing times and speeds, filter integrity), test methods and acceptance limits at each step in the manufacturing, sterilisation (if any) and packaging processes must be defined, appropriate and adequate to assure batch quality and unit-to-unit consistency.

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If relevant, any processing (e.g. neutralising, cleaning, washing, sterilisation) of the containers before filling must be adequately controlled.

If relevant, controls on sterility of the equipment, product and containers must be adequate throughout the process.

If sterilisation is by filtration, the bioburden of the product before filtration must be adequately controlled, the filter membrane pore size must be not more than 0.22 microns, and the integrity of the filter must be checked before and after use.

If sterilisation is by autoclaving or gamma irradiation, the equipment and procedures must be described in detail and adequately controlled.

If sterilisation of the product or container is by treatment with ethylene oxide, its use must be the only viable option and the residue level must be controlled to not more than 1 ppm in the product or 1 mcg/ml container volume, and any chlorohydrin residue must be controlled to not more than 50 ppm in the product or 50 mcg/ml container volume.

All critical steps in the manufacturing process (including any cleaning and/or sterilisation steps) must have been adequately developed and validated at each manufacturing site at either production scale or at pilot scale (10% of full scale or 100,000 solid dose units, whichever is the greater unless otherwise justified) using production scale equipment.

If only pilot scale validation has been completed, confirmation that full scale validation is scheduled for when commercial scale production commences must be provided.

Quality Control of Active Ingredient(s)

(a) Controls applied by manufacturer of bulk active ingredient

Unless previously submitted and approved, a satisfactory Drug Master File (or a Ph Eur Commission “Certificate of Suitability”) from each supplier of bulk active ingredient must be submitted.

The active ingredient specifications applied by the manufacturer of the bulk active ingredient must be in accordance with a recognised pharmacopoeia (e.g. Ph Eur, BP, USP) or, if non-pharmacopoeial specifications are applied, these must cover all of the relevant identity, organoleptic, physical (including crystalline form and particle size distribution, if applicable), chemical, stereochemical and microbiological quality parameters.

Justification must be given for the selection of any non-pharmacopoeial tests, test procedures, requirements and limits.

If certain tests are not carried out routinely, adequate justification must be provided.

Physical, chemical and microbiological test procedures (whether pharmacopoeial or not) must be self-validating or have been validated in accordance with pharmacopoeial standards or ICH guidelines.

All assay and related product/degradation product and residual solvent impurity level tests must have been validated (as appropriate) for specificity/selectivity, limit of detection, limit of quantitation, accuracy, precision, repeatability, linearity, stability of solutions, and robustness/ ruggedness.

Proof must be provided that the related substance assay procedure is adequate to detect and control all of the related substance impurities actually or potentially present in the bulk substance produced using the intended manufacturing process.

Satisfactory representative batch analytical data must be supplied for typical batches of bulk active substance.

Any certificates of analysis submitted must have been signed.

If a “house” reference standard is used in the assays, characterisation and analytical data confirming its suitability for use must be provided.

(b) Controls applied by manufacturer of finished product

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The active ingredient specifications applied by the finished product manufacturer in testing bulk active substance before use in manufacture of the finished product must be in accordance with a recognised pharmacopoeia (e.g. Ph Eur, BP, USP) or, if non-pharmacopoeial specifications are applied, these must cover all of the relevant identity, organoleptic, physical (including particle size distribution, if applicable), chemical, stereochemical and microbiological quality parameters.

Justification must be given for the selection of any non-pharmacopoeial tests, test procedures, requirements and limits.

If certain tests are not carried out routinely, adequate justification must be provided.

Physical, chemical and microbiological test procedures (whether pharmacopoeial or not) must be self-validating or have been validated in accordance with pharmacopoeial standards or ICH guidelines in the testing laboratory(ies) used by the finished product manufacturer for routine quality control of the bulk active(s).

All assay and related product/degradation product and residual solvent impurity level tests must have been validated (as appropriate) for specificity/selectivity, limit of detection, limit of quantitation, accuracy, precision, repeatability, linearity, stability of solutions, and robustness/ ruggedness.

Satisfactory representative batch analytical data generated by the finished product manufacturer(s) must have been supplied for typical batches of bulk active substance from each supplier.


If a “house” reference standard is used in the assays, characterisation and analytical data confirming its suitability for use must be provided.

Quality Control of Excipient(s)

The identity and quality of all excipients (including capsule shells and their constituents, and any gases used in filling vials or ampoules) must be controlled by either pharmacopoeial or appropriate in house specifications.

Any non-pharmacopoeial specifications must be appropriate and adequately control identity, and physical, chemical and microbiological quality of the material.

Adequate measures must be taken to ensure that any ingredients of animal origin (e.g. gelatin, magnesium or calcium stearate, stearic acid) used in the product are free from TSE contamination in accordance with EC and US guidelines.

Satisfactory representative batch analytical data must be provided for any excipients controlled by non-pharmacopoeial specifications.


Quality Control of Packaging Materials (Immediate Packaging)

The packaging materials used (polymers, types of glass, etc.), containers, seals, closures and any delivery device(s) supplied with the product must be clearly defined, suitable for pharmaceutical use, and adequately controlled for identity, dimensions, physical and chemical properties, manufacturing defects, and sterility, as applicable.

Any plastic or rubber packaging/closure materials in contact with the product must be free from any leachable toxic impurities and must comply with Ph Eur and USP requirements for polymeric materials used in packaging of medicines.

Satisfactory representative batch analytical data must be provided for any primary packaging materials, containers and closures in contact with the product.


Quality Control of Delivery Device(s)

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Any delivery device(s) supplied with the product must be clearly defined, suitable for pharmaceutical use and adequately controlled for identity, dimensions, physical and chemical properties, manufacturing defects, sterility, and dose delivery, as applicable.

Quality Control of Intermediate Products

If there is an intermediate product, it must controlled by separate, appropriate specifications that adequately control all relevant parameters.

Satisfactory representative batch analytical data must be provided.


Quality Control of the Finished Product

The complete identity and quality of the finished product must be adequately controlled at release and throughout its shelf-life by appropriate pharmacopoeial or in house specifications that cover all of the necessary organoleptic, physical, dissolution, chemical, microbiological and dose delivery parameters relevant to the dose form

It must be clear which requirements apply at release and which apply throughout the shelf-life.

If applicable, any non-pharmacopoeial test procedures used as replacements for, or in addition to, the procedures in a pharmacopoeial monograph must be appropriate and have been justified.

If all specified tests are not carried out routinely, justification must be provided.

The test procedures used must be self-validating or have been adequately validated in accordance with pharmacopoeial requirements or ICH guidelines at each of the testing sites intended for routine quality control of the product.

All assay and related product/degradation product and residual solvent impurity level tests must have been validated (as appropriate) at each testing laboratory involved in the quality control of the product for specificity/selectivity, limit of detection, limit of quantitation, accuracy, precision, linearity, repeatability, stability of solutions, and robustness/ ruggedness.

Satisfactory recent analytical reports must be provided for the final market formulation(s) of the product manufactured at least at pilot scale at each of the proposed manufacturing sites. Results must be included for each specified test and all of the reported test results must comply with the specifications. If not, an adequate explanation or justification must be provided.


Stability of the Active Ingredient(s)

The stability of the active ingredient(s) is normally described in the associated DMF(s).

The stability data submitted must have been produced in accordance with ICH guidelines and adequately establish that the bulk active substance packaged in the intended storage container and stored under the prescribed storage conditions will remain within specifications for the whole of the claimed shelf-life or retest period.

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Stability of the Finished product

The stability of the market formulations of the finished product (or formulations that may reasonably be expected to have the same stability) packaged as intended for marketing must have been tested in accordance with ICH guidelines (including the ICH requirements for the number and sizes of batches used) unless otherwise justified.

Preferably, more than one batch of active substance should have been used in the manufacture of the stability batches.

The stability trial protocol, packaging, packaging orientation (if relevant), storage conditions and test procedures must be described in detail.

All of the stability-indicating organoleptic, physical, chemical and microbiological quality parameters relevant to the dose form and type of packaging must have been included in the testing schedule and have been monitored using appropriate, clearly defined, validated (in the testing laboratory used for the stability samples), stability-indicating test procedures.

Any changes in test procedures during the stability trials must be justified and results correlated.

At least 12 months data for storage under the recommended storage conditions must be available and be submitted with the application (unless otherwise justified).

The stability data should be updated before submission.

Wherever relevant, results should be expressed quantitatively rather than as “complies” or “passes test”.

Any lack of mass balance between assays and degradation products must be explained or discussed.

If relevant, preservative levels or effectiveness must be monitored.

The results (and allowing for extrapolation within reasonable limits) must adequately support the proposed shelf-life under the recommended storage conditions (otherwise a shorter shelf-life may be granted until adequate stability data can be provided to support the proposed shelf-life).

If relevant, the stability of the product after first opening, reconstitution or dilution (as applicable) must have been investigated and shown to be adequate for the intended use of the product.

If relevant, adequate storage instructions and time-limits for use of the product after first opening or reconstitution or dilution must be stated on the draft product label, in any package insert, and in the Data Sheet.

Bioequivalence

If applicable, the bioequivalence (or, if more appropriate, clinical equivalence) of the product and that of the appropriate reference product marketed in New Zealand (or an acceptable alternative product) must have been established in accordance with the detailed requirements set out in Sections 14 - 16.

The batches of trial and reference medicine used in the study must have been of acceptable quality.

The batch(es) of trial medicine(s) used in the biostudy must have been of adequate scale and truly representative of the product intended for marketing with respect to: (a) formulation, (b) crystalline form/polymorph of active ingredient, and (c) particle size distribution of the active (especially if <1% soluble in water) [or any differences in any of these parameters must be unlikely to affect the product’s bioavailability].

If the batch of reference product used in the study was obtained from outside New Zealand, adequate evidence that its formulation was the same as that distributed in New Zealand must be provided.

The results (e.g. for Tmax, Cmax and mean plasma/serum concentrations after dosage) obtained in the biostudy must be consistent with the published pharmacokinetic properties of the medicine.

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The pharmacokinetic data must have been subjected to the correct statistical analyses as detailed in Section.15.10.

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Section 9: Changed Medicine Notifications

Section summaryThis section outlines the format and data requirements for applications for Ministerial consent to distribute changed medicines.

Legislation to read in conjunction with this section:Medicine Act 1981, Section 24: Distribution of changed medicines restricted

9.1 Format for Changed Medicine and Related Product Notifications

When submitting a CMN the relevant forms and fee schedules given in Appendices 5 and 6 should be used. CMN Form A should be used for type I and type II products while CMN Form B should be used for Type III products.

Notifications received by Medsafe after 1 January 2002 must be made using the forms and fee schedule below. Notifications using previous formats received after 1 January 2002 will not be accepted for processing and will be returned to the applicant.

Each CMN or CRPN involving a material change must be accompanied by a CMN or CRPN form and summary sheet, providing administrative details and outlining the changes being notified. A separate sheet should be completed for each product and all sections must be completed. Applicants should submit one copy of the form, summary sheet and any supporting documentation and the appropriate fee.

The fees applied depend upon the type of product and the amount of evaluation involved.

Type I: Lower-risk medicines and related products

Type II: Intermediate-risk or Higher-risk medicines other than biological or biotechnological products (but including antibiotics and like substances derived from micro-organisms)

Type III: Biological, or biotechnological products (i.e. vaccines, serums and allergens, medicinal products derived from human blood or plasma, immunological medicinal products, and products derived from biotechnology)

If the same change(s) has been approved by another regulatory authority in Australia, Europe or North America and that authority’s evaluation report is available, a copy should be included with the CMN.

Where an applicant applies for consent to distribute a new medicine or related product and notifies the Director-General of changes to a currently marketed product at the same time the documentation must be kept separate. It is not acceptable to combine a CMN or CRPN with an NMA or NRPA.

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Medsafe will not accept further changes to a CMN or CRPN after it has been submitted (except, perhaps, to indicate or clarify changes consequential to the changes notified in the original CMN or CRPN). If further (non-consequential) material changes are intended a new CMN or CRPN and fee are required.

Note that when Medsafe issues formal consent for a change to a medicine or related product, only those changes specifically identified and applied for in the CMN or CRPN form are covered by the consent. Material changes included in any accompanying documentation but not specifically identified in the CMN or CRPN form and consequently not assessed as changes, are not included in any consent that may be granted for the CMN or CRPN.

Consequential changes are grouped with some material changes for the purpose of fees calculations. However, these changes must be identified separately and supported by appropriate data or documentation, if relevant.

Each change included in a CMN or CRPN is assessed separately. In some cases, Medsafe may consider that only some of the proposed changes can be approved. This may be because the supporting data submitted with the CMN or CRPN do not justify the other changes proposed. In this situation, if the sponsor is unable to supply acceptable data to support the proposed change(s), a recommendation to withdraw those changes from the CMN or CRPN will be made to the sponsor. This will enable consent to be granted for the approvable changes. Partial consent for some of the changes, with other changes assessed later, is not Medsafe’s current practice. Any proposed changes withdrawn from a CMN or CRPN can be resubmitted as a new CMN or CRPN at a future date when the required supporting data are available. This new notification must be accompanied by a new fee applying to those particular changes

9.2 Data Requirements for Changed Medicine or Related Product Notifications

The data required to support a Changed Medicine Notification or Changed Related Product Notification is essentially the same as that required for the corresponding section of a New Medicine Application .

Except in the case of a changed label or data sheet, no data are required to be submitted with a Self-assessable Change Notification. The applicant must, however, hold the data required to show that the change is acceptable and must be able to supply the data to Medsafe on request.

In the case of other changes, the following data should be provided, and if not provided, may be requested by the evaluator:

Formulation Certificates of Analysis issued by the finished product manufacturer for 2 or 3 representative

batches of any new excipient if that excipient is not controlled in accordance with a recognised pharmacopoeial monograph.

Comparative dissolution data for the proposed new and currently approved finished products using a discriminatory test, must be supplied for tablets and capsules. The data need to establish that there are no significant differences between the new and original formulations.

Certificates of Analysis for the finished product manufactured using the proposed new formulation. At least one batch should be full production scale unless otherwise justified, while the other batches should be at least pilot scale manufactured using full production scale equipment.

Bioequivalence data if required (see note below)

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Stability data if required (see note below) If the formulation involves a change to the preservative system, then additional data may be

required such as:1. Proof of anti-microbial efficacy of the finished product at expiry.2. Test methods (and validation data) for the determination of preservative content at finished

product release.3. Stability data (including microbial quality).

Note: The following changes are considered unlikely to have an impact on the stability or bioavailability of an immediate release or modified release solid oral dose form:

1. Removal, replacement or reduction in the amount of a colouring or flavouring agent.

2. A change in the percentage content of any of the following excipients provided that:a. the change in the amount of an individual excipient does not exceed the maximum

allowable change for that excipient as shown in the table below, andb. the total additive change to all non release-controlling excipients is not more than 5% of the

total formulation, andc. the total additive change to all release-controlling excipients in a modified release dose form

is not more than 5% of the total formulation, andd. the total weight of the dosage form is still within the previously approved range.

Excipient Maximum allowable change (as percentage of total weight)

Filler 5%

Disintegrant: Starch

Other

3%

1%

Binder 0.5%

Lubricant: Calcium stearate

Magnesium stearate

Other

0.25%

0.25%

1%

Glidant: Talc

Other

1%

0.1%

Film coat 1%

If a product undergoes a series of stepwise formulation changes, bioavailability data will be required if the overall change exceeds the limits stated above.

When an application is made for approval of a change to the formulation of a solid oral dose form, and the change falls within the criteria above, a bioequivalence study and stability study are not required to be submitted with the change notification. For any formulation change that falls outside the criteria given above, the applicant must either provide stability and bioavailability data, or provide adequate justification for not doing so.

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Site of manufacture (Active ingredient) Either a Drug Master File with accompanying “letter of access”, or a European Pharmacopoeial

Certificate of Suitability with accompanying “letter of access”, or (if the finished product is “low risk”) Certificates of Analysis for representative batches of active ingredient issued by the finished product manufacturer.

Site of manufacture (Finished product). GMP certification for the new site, if available, or other acceptable evidence of GMP compliance

at the site (see Section 11). Appropriate validation of the process at the new site must be submitted to demonstrate that

product manufactured at this site meets the currently registered requirements for in process controls and the finished product specifications.

Description and validation of quality control test methods where there is a change in test procedures or the laboratory testing the product.

Certificates of Analysis for representative batches of finished product manufactured at the new site. At least one batch should be full production scale unless otherwise justified, while other batches should be at least pilot scale manufactured using full production scale equipment.

Comparative dissolution data using a discriminatory test, must be supplied for tablets and capsules. The data need to establish that there are no significant differences between product made at the old and new sites.

Relevant stability data must be generated for batches produced at the new site as required by GMP. Medsafe may request the Company to provide accelerated stability data for a particular medicine where stability is known to be a problem or where changes in stability could have clinical consequences. The relevant stability data need not necessarily be supplied prior to the issue of a consent for the change of site. However, if stability data are not supplied, the Company must provide written assurance that stability data will be generated and Medsafe notified immediately if there are any significant problems identified or if the data indicate that the stability of product from the new site is different from that made at the original site to the extent that the shelf life of the medicine would be affected.

If the application complies with the FDA’s Guidance for Industry on Scale-Up and Post-Approval Changes (SUPAC) requirements, this is also acceptable.

Manufacturing process (Active ingredient). Description of changed manufacturing process and in-process controls. Certificates of Analysis for representative batches of active ingredient manufactured using the new

process.

Manufacturing process (Finished product). Description of the changed manufacturing process including validation and in-process controls. Certificates of Analysis for representative batches of finished product manufactured using the

proposed process. At least one batch should be full production scale unless otherwise justified, while the other batches should be at least pilot scale manufactured using full production scale equipment.

Comparative dissolution data for representative batches of the finished product using a discriminatory test, must be supplied for tablets and capsules. The data need to establish that there are no significant differences between product manufactured using the new and original manufacturing processes.

Stability data or confirmation that stability data will be collected. Relevant stability data must be generated for batches produced using the new process as required by GMP. Medsafe may request the Company to provide accelerated stability data for a particular medicine where stability is known to be a problem or where changes in stability could have clinical consequences. The relevant stability data need not necessarily be supplied prior to the issue of a consent for the change of process. However, if the data are not supplied, the Company must provide written assurance that stability data will be generated and Medsafe notified immediately if there are any

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significant problems identified or if the data indicate that the stability of product from the new process is different from that made at the original process to the extent that the shelf life of the medicine would be affected.

Bioequivalence data if required.

Specifications/test methods (active ingredient and finished product) Justification for specification changes. Validation of any changed test methods. Certificates of Analysis for the active ingredient or finished product demonstrating the ability of

the company to meet specifications.

Packaging Packaging materials specifications. Stability data if the packaging may be expected to be less protective than the currently approved

packaging.

New and extended indications Justification or supporting clinical data (as appropriate) and a draft revised data sheet.

9.3 Self-assessable Changes

One copy of the CMN or CRPN form should be submitted, along with the appropriate fee, for a material change that is self-assessable.

Medsafe acknowledges but does not formally “approve” or issue a “consent notice” for self-assessable change notifications. SACNs are subject to audit and then, if a SACN is found to be unsatisfactory, Medsafe advises the sponsor and requests rectification of the unsatisfactory or inappropriate aspect(s) of the SACN (e.g. by submission of a formal CMN). Once the CMN is evaluated and found to be satisfactory, a consent notice is issued for that CMN.

Labels and data sheetsWhen a self-assessable change is made to a label or data sheet, the appropriate checklist and declaration must be completed by the applicant and submitted with the CMN or CRPN form, along with copies of the previously approved and new labels or data sheets. See Sections 12 and 13 for further details.

A CMN or CRPN is not required when the only change to a label is the classification statement (as long as no other changes to the label are required as a consequence of reclassification). In this case all that is required is a copy of the new label for inclusion in Medsafe’s product file.

Change of sponsorWhen a change in sponsor for a product(s) is to be made, a self assessable CMN or CRPN is required providing details of the change and all of the products involved. Letters or other documentary evidence from both the new and old sponsor (or the manufacturer, if that is more appropriate) confirming the arrangement should be submitted with the CMN or CRPN.

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9.4 Changes Not Requiring a CMN or CRPN

9.4.1 Changes in Pharmacopoeial Specifications

A CMN or CRPN is not required for updating of specifications for an active ingredient, excipient or finished product to conform to the most recent edition of the relevant pharmacopoeial monograph. Manufacturers are expected to keep their specifications in line with any revisions to those monographs. However, a CMN or CRPN is required if there is a change from the specifications of a monograph in one pharmacopoeia to that in another pharmacopoeia, or from in house specifications to a pharmacopoeial monograph (or vice versa).

9.4.2 Changes in names of manufacturers or packers

When the name of a manufacturer or packer is changed but there are no changes to the address or the manufacture or packing processes a CMN or CRPN is not required. Instead, the sponsor should advise Medsafe by letter so that Medsafe can update its records.

9.4.3 Updates to Drug Master Files

DMFs should be updated periodically to reflect any changes. Sponsors should ensure that such updated DMFs (together with a list of changes made), or (at least) details of any changes made, are forwarded to Medsafe. Medsafe considers the list of changes made and, if the changes are such that formal evaluation of them is required, the sponsor will be required to submit a formal CMN and pay the appropriate fee.

9.4.4 Updates to Plasma Master Files

Plasma master files should be updated annually to reflect any changes in the disease epidemiology of the donor group. The sponsor is required to forward a copy of the revised data to Medsafe which then considers the changes and, if action is required, advises the sponsor accordingly.

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Section 10: New and Changed Related Products

Section summaryThis section outlines the format and data requirements for applications for Ministerial consent to distribute new and changed related products.

Legislation to read in conjunction with this section:Medicine Act 1981, Part VII (sections 94-96: Related Products

10.1 Data Requirements for New Related Product Applications

An application for consent to distribute a new related product should be accompanied by the following data:

A. Related products other than dentifrices

I Summary of the DossierAdministrative data, including purpose and directions for use

Labelling, accompanied by a self-assessment checklist and declaration[Note that GMP certification need not be provided for related products.]

II Chemical, Pharmaceutical & Biological DocumentationComposition and presentation of product

(Note: Product Development Pharmaceutics are not required.)Method of preparationSpecifications for active ingredients

(Control tests on excipients need not be supplied.)Specifications for the finished product

(Validation data should be provided to confirm that the proposed test methods work satisfactorily for the characteristics that establish the therapeutic nature of the product concerned.)

Stability (Required only for products taken internally, or otherwise, if relevant.)

Other information (if relevant)

B. Dentifrices

Dentifrices can be either related products or medicines. The two factors that determine whether a dentifrice will be assessed as a related product or a medicine are (1) the fluoride content, or (2) the extent of the claims made for the product.

Any dentifrice containing more than 0.1% (1000 ppm) of elemental fluoride will be regarded as a medicine.

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Any mouthwash formulated so that it can be swallowed to supplement fluoride intake will be regarded as a medicine.

For dentifrices that are related products, sponsors should submit (and assessment will be restricted to) the following information:

Administrative data (as required in Section 1 of the NRPA form) Labels Therapeutic claims Therapeutic efficacy of the active ingredients (if an active ingredient other than fluoride is

used) Quality control of the active ingredient(s) (both as the raw material, and in the finished dose

form) and representative batch analytical data for the finished product.

Formulation details may be supplied, but will not be assessed in detail. Any future changes to formulations that are purely cosmetic in nature and do not affect the active ingredient(s) will not require the submission of a CRPN. However, the sponsor is responsible to ensure that compliance with regulatory requirements relating to colours, flavours, etc is maintained.

The following information need not be supplied for a dentifrice:

GMP certification Product development Manufacturing method and in process control Quality control of the excipients or the finished product (except for controls on active

ingredient identity and content) Stability data

The following claims for therapeutic efficacy for dentifrices containing fluoride are acceptable (any other claims or words of similar meaning will require assessment):

Gums: helps maintain healthy teeth and gums Plaque (tartar, calculus): removes, reduces, prevents, fights, loosens, helps neutralise plaque

acids Tooth decay: protects against, prevents, fights, complements brushing, reduces cavities Teeth and tooth enamel: protects, toughens, hardens, strengthens, cleans, shines, polishes,

brightens, whitens, maintains healthy teeth, remove stains Mouth: keeps mouth and breath fresh and clean, fights bad breath, helps relieve dry mouth

For junior formulations of fluoride toothpastes, the following warning statements, or words of similar meanings, must be included on the labels:

Children under the age of 5 should use no more than a smear (5mm) of fluoride toothpaste on a small brush.*

Children should be discouraged from swallowing or eating toothpaste.*

* Note: For further details, see Prescriber Update No. 10, October 1995, pages 13-16. (Copes of Prescriber Update are available on request from Medsafe.)

10.2 Data Requirements for Changed Related Product Notifications

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The procedure and data requirements for changed related product notifications are similar to those for Lower-risk medicines and should be submitted to Medsafe using the CRPN Form in Appendix 7.

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Section 11: Good Manufacturing Practice Documentation

Section summaryThis section explains when evidence of compliance with GMP is required and what evidence is acceptable.

11.1 When is GMP Documentation Required?

Medsafe requires evidence of Good Manufacturing Practice (GMP) compliance for each finished product manufacturing site and packaging site specified in a New Medicine Application or Changed Medicine Notification.

Evidence of GMP compliance is required for products regarded as medicines in New Zealand, whether or not they are considered medicines in the country of origin. For bone cement containing an antibiotic, condoms containing a spermicide, intrauterine contraceptive devices containing copper, and pregnancy tests, all of which are regarded as medical devices overseas but are medicines in New Zealand, evidence of compliance with the relevant medical device GMP requirements in the country of origin (e.g. Europe, USA, Australia) is required.

In the case of related products, evidence of compliance with GMP is required for NRPAs and CRPNs for products taken internally (e.g. throat lozenges, and vitamin and mineral tablets).

Evidence of GMP is not required for related products used externally such as fluoride toothpaste containing not more than 0.1% elemental fluorine, fluoride mouthwash and antidandruff shampoos categorised as related products. However, Medsafe expects the manufacturer to comply with a suitable GMP standard.

For bulk active pharmaceutical ingredients evidence that the material is manufactured consistently and produced with acceptable quality is required.

GMP certification, or equivalent documentary evidence, stating the products or product classes for which it has been granted is required for all:

manufacturers of the finished product (including manufacturers of intermediate products) sterilisers of the finished product packers of the finished product sites where products are overlabelled

A manufacturing site for a finished product is any site which contributes to a manufacturing operation which converts bulk raw materials to a finished dose form. This includes sterilising sites. A packing site means any site which contributes to a packing operation which places the final dose form into its labelled primary or secondary container.

Manufacturers and/or packers with premises in New Zealand must hold an appropriate current licence to manufacture and/or pack medicines. The licence must have been issued for the site for the manufacture and/or packaging of the type of product or packaging operation before manufacture or

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packaging of the product for distribution can commence. Provided they hold such current licences, certification need not be provided with each application or notification.

For overseas manufacturers and packers, Medsafe requires that certification be included with each NMA or CMN which relates to a change of site, even if the site already supplies product to New Zealand and certification has been supplied previously with an earlier application or notification. This reduces delays associated with locating other files, and because it is desirable for the certification to be product-specific and up-to-date.

Acceptable evidence of GMP compliance normally consists of copies of appropriate certificates, manufacturing licences or reports issued by a regulatory authority whose competence is recognised by Medsafe. Details of the documentation that is acceptable and a list of authorities whose competence to certify GMP compliance is recognised by Medsafe are given below in section 11.5.

The certificate, licence or report should be no more than 3 years old when the NMA or CMN is submitted, and must be no more than 5 years old at the time of approval of the new or changed product for distribution in New Zealand.

If the original documentation was in a language other than English then copies of both the original documents and a certified English translation must be submitted.

If acceptable evidence of GMP compliance is not available, an audit of the site by Medsafe auditors can be arranged at the applicant's request and expense.

11.2 Recognised Documentation

GMP certification recognised by Medsafe can be any document issued by a recognised authority which attests to GMP compliance. Legible photocopies of the documents are acceptable.

Documents should contain the following information:

the street address of the site concerned reference to the product or product class reference to GMP acceptability and/or to a GMP audit name and address of the issuing authority date and signature. date of expiry of the certification or licence

The following are examples of acceptable evidence of GMP certification:

licence to manufacture issued by a recognised authority where such a licence is issued only where the site is inspected and regularly re-inspected for GMP compliance

current registration and entry (for the product, product class or process concerned) of the site in the Australian Register of Licensed Manufacturers

United Kingdom Product Licence or Product Licence Variation where name and address of site is shown

certification of pharmaceutical product issued under the WHO scheme by a recognised authority which certifies the quality of pharmaceuticals moving in international commerce

Canadian Drug Plant Inspection Rating Report a letter or file note from a recognised authority which attests to GMP compliance. The most

usual example seen is an extract from FDA files obtained by the manufacturer under the US Freedom of Information Act. It usually states that an audit occurred on the given date and gives the outcome of the audit

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a certificate issued by the Australian TGA confirming that it has confirmed (e.g. with the US FDA) that GMP compliance at the particular site is satisfactory. Note that Medsafe also has access to the FDA’s electronic GMP database and can check the GMP status of manufacturing sites inspected by the FDA.

The following are NOT acceptable as evidence of GMP compliance:

a licence to manufacture which is not issued by a recognised authority certification issued by a pharmaceutical company - even if the company certifying is not the

same as the manufacturer or packer Annual Registration of Drug Establishment (USA). This document is not indicative of GMP

compliance.

11.3 Classes of Medicine

Certification should preferably be product-specific. Certification in the WHO format or a manufacturing or product licence listing the product are the most easily obtained examples of this type.

If product-specific certification cannot be obtained, the certification must relate to a medicine or medicines of the same class(es) (see below) as the one which is the subject of the application or notification. A medicine may belong to more than one class. In such cases, the certification should be for a product belonging to the same classes.

I Medicines containing penicillinII Medicines containing cephalosporinIII Vaccines or seraIV Sterile medicinesV Hormones and steroidsVI Microdose preparations (other than vitamins), i.e. containing 5 mg or less per unit doseVII Antineoplastic agents and immunosuppressant agents (other than steroids)VIII Solid dose formsIX Recombinant DNA medicinesX Metered dose aerosol preparationsXI Liquids, creams, ointmentsXII Non-metered dose aerosolsXIII PowdersXIV Wound dressingsXV Transdermal patches

11.4 Sites which Manufacture Bulk Active Pharmaceutical Ingredients

Evidence of GMP (or at least evidence that a bulk active pharmaceutical ingredient is manufactured consistently and to acceptable quality standards) is required for all sites which manufacture bulk active pharmaceutical ingredients. Such evidence should be included with each application or notification which relates to a change of site.

Applications and notifications must include the name and address of the actual site of manufacture and applicants should ensure that there is no confusion between sites of manufacture and addresses of

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company head offices or brokers. Any documentary evidence of GMP must refer to the actual site of manufacture.

Any of the following are acceptable as evidence for manufacturers of bulk active pharmaceutical ingredients:

A GMP certificate or inspection report issued by a recognised authority. Note that not all authorities issue certification for sites manufacturing bulk active substances.

A Drug Master File or equivalent data submitted as part of the dossier for a new chemical entity or new biological entity medicine.

A European Pharmacopoeial “Certificate of Suitability” for a substance controlled according to the European Pharmacopoeia.

Batch analytical data demonstrating consistent quality of the substance produced (accepted as adequate evidence only for lower risk medicines and related products).

Note: A GMP certificate alone is not acceptable as a substitute for a DMF, Certificate of Suitability or batch analytical data where these are normally required.

11.5 Recognised Authorities

GMP certification issued by the authorities listed below is recognised by Medsafe. The authorities listed include the competent authorities in the European Community, member authorities of the PIC and/or PIC/S organisations, and other authorities where Medsafe has information that GMP assessment systems that are compatible with New Zealand expectations exist. The inclusion of all the European Community competent authorities is a consequence of the Mutual Recognition Agreement in Relation to Conformity Assessment that became effective between New Zealand and the European Community on 1 January 1999. Omission of an authority from the list generally indicates that Medsafe has not assessed that authority’s systems, and should not be construed in any way as an adverse reflection on the competence of the authority itself. The inspectorates recognised by Medsafe are listed below.

AustraliaTherapeutic Goods Administration, Commonwealth Department of Health and Family Services

AustriaPharmaceutical Division, Federal Ministry of Health, Sports and Consumer Protection (Bundesministerium fur Gesundheit und Konsumentenshutz)

BelgiumInspection general de la Pharmacie, Ministere de la Sante Publique et de la Famille

CanadaTherapeutic Products Directorate, Health Product and Food Branch, Health Canada

Czech RepublicState Institute for Drug Control

DenmarkMedicines Division, Danish Medicines Agency (Sundhedsstyrelsen)

FinlandNational Agency for Medicines

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FranceAgence du Medicament, Ministere de la Sante

GermanyBundesministerium fur Gesundheit(The individual medicine inspectorates for the different German states and cities, as listed in the Pharmaceutical Inspection Convention List of Inspectors Employed by the PIC/S Competent Authorities, [State, Name of Authority (City)] are as follows:

Baden-Württemberg Regierungspräsidium Tübingen, Leitstelle Arzneimittel-überwachung Baden-Württemberg (Tübingen)

BayernRegierung von Mittelfranken (Ansbach)Regierung von Niederbayern (Landshut)Regierung von Oberbayern (München)Regierung von Oberfranken (Bayreuth)Regierung der Oberpfalz (Regensburg)Regierung von Schwaben (Augsburg)Regierung von Unterfranken (Würzburg)

Berlin Landesamt für Gesundheitsschutz, Arbeitsschutz und technische Sicherheit (Berlin)

BrandenburgLandesamt für Soziales und Versorgung (Wünsdorf )

Bremen Senator für Gesundheit, Jugend, Soziales und Umwelt-schutz (Bremen)

Hamburg Behörde für Arbeit, Gesundheit und Soziales (Hamburg)

Hessen Regierungspräsidium Darmstadt (Darmstadt)

Mecklenburg-Vorpommern Arzneimittelüberwachungs- und –prüfstelle Mecklenburg-Vorpommern (Schwerin)

NiedersachsenBezirksregierung Braunschweig (Braunschweig)Bezirksregierung Hannover (Hannover)Bezirksregierung Lüneburg (Lüneburg) Bezirksregierung Weser-Ems (Oldenburg)Bezirksregierung Arnsberg (Arnsberg)Bezirksregierung Detmold (Detmold)Bezirksregierung Düsseldorf (Düsseldorf)Bezirksregeirung Köln (Köln)

Nordrhein-WestfalenBezirksregierung Münster (Münster)

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Rheinland-Pfalz Landesamt für Soziales, Jugend und Versorgung (Koblenz)

Saarland Ministerium für Frauen, Arbeit, Gesundheit und Soziales (Saarbrücken)Regierungspräsidium Chemnitz (Chemnitz)Regierungspräsidium Dresden (Sachsen)Regierungspräsidium Leipzig (Leipzig)

Sachsen-Anhalt Landesamt für Versorgung und Soziales Sachsen-Anhalt (Halle a.d. Saale)

Schleswig-Holstein Landesamt für Gesundheit und Arbeitssicherheit des Lan-des Schleswig-Holstein (Kiel)

Thüringen Thüringer Landesverwaltungsamt (Weimar)

For immunologicals: Paul-Ehrlich-Institut, Federal Agency for Sera and Vaccines

GreeceNational Drug Organisation (E.O.F.)

HungaryDrug Inspectorate, National Institute of Pharmacy

IcelandState Drug Inspectorate

IrelandIrish Medicines Board

ItalyPharmaceutical Division, Ministry of Health (Ministero della Sanita, Direzione Generale del Servicio Farmaceutico)

JapanPharmaceutical Affairs Bureau, Ministry of Health and Welfare

LiechtensteinKontrollstelle fur Arzneimittel, Amt fur Lebensmittelkontrlle

LuxembourgDivision de la Pharmacie et des Medicaments

NetherlandsPharmaceutical Inspectorate, Section Pharmaceutical Industry and Trade (Ministerie van Volksgezondheid, Welzijn en Sport, Inspectie voor de Gezonheidszorg)

NorwayPharmaceutical Inspectorate, Pharmaceutical Department, (Helsedirektoratet Legemiddelavdelingen)

Portugal

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Pharmacies and Pharmaceutical Inspections Department (Instituto Nacional da Farmacia e do Medicamento - INFARMED)

RomaniaState Institute for Drug Control and Pharmaceutical Research

SingaporeMinistry of Health, National Pharmaceutical Administration

Slovak RepublicState Institute for Control of Drugs

SpainMinisterio de Sandidad y Consumo, Subdireccion General de Farmaceutico

SwedenPharmaceutical Inspectorate, Medical Products Agency (Lakemedelsverket)

SwitzerlandFor sera and vaccines:Office Federal de la Sante PubliqueFor other pharmaceutical products:Office Intercantonal de Controle des Medicaments

United KingdomMedicines Control Agency, Department of Health

USAFood and Drug Administration

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Section 12: Labelling and Patient Information

Section summaryThis section: provides guidance on the labelling requirements for products explains how to submit new and changed labels for approval explains how and when to apply for a labelling exemption

Legislation to read in conjunction with this sectionMedicines Regulations 1984:

Part IV: LabellingRegulation 2: InterpretationRegulation 37: Safety Containers

Amendment No 6 Medicines Regulations 1984Medicines Amendment Regulations 2000Misuse of Drugs Regulations 1977

Regulation 25: Labelling of Containers

12.1 Labelling of Medicines and Related Products

The Medicines Regulations Part IV and subsequent Amendments thereto set out the requirements for the labelling of medicines and related products. Sponsors must ensure labels include all the information required by legislation, and that the appearance and layout of the label are designed to maximise the safe use of the medicine. Medicines Amendment Regulations 2000 have removed some of the requirements in the original Regulations to provide greater flexibility, bring the requirements into better harmony with those applying in Australia, and remove trade barriers.

Rx as a Classification StatementIn addition to the changes to the legislation indicated above, Medsafe accepts “Rx” as a symbol meaning “prescription medicine” where it is clearly used as a classification statement on a medicine label. Note that Rx printed as a blue symbol on a yellow cross centred on a blue square with rounded corners is a protected brand mark owned by the Pharmacy Guild of New Zealand (Inc.) and is not to be confused with Rx used as a classification statement.

12.2 Submitting New and Changed Medicine Labels

Copies of artwork for labels and packaging material, including actual size copies and an indication of the intended colours must be submitted with any NMA or NRPA and with any CMN or CRPN involving any change to the labelling. If colour samples of the actual label are not available at the time of application or notification, these must be submitted to Medsafe as soon as possible once the label is printed.

When submitting a label for a new medicine or a notification of a change to a previously approved label, the applicant must complete the appropriate Labelling Checklist (see Appendices 9 - 11) designed to ensure that the label is in compliance with the legislation. The applicant must then also

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sign a declaration stating that the label complies with the legislation or identify those aspects in which the label is non-compliant. If the label is non-compliant, the applicant should first investigate the possibility of a compliant label (e.g. by overlabelling), or determine whether the criteria for requesting a labelling exemption could be met.

Prior assessment, through a CMN, is required for any labelling change that changes the actual information (not merely the colour or print style) relating to the name, strength of active ingredient, dosage instructions or warning statements, or results in the label becoming non-compliant, or is the result of the medicine being re-classified as a Controlled Drug. Note that changing the location of some information on the label could make the label non-compliant.

Any other change to a label may be self-assessed by the applicant and notified through a Self-assessable Change Notification. Such changes do not require prior approval and may be implemented immediately. Sponsors should note that Medsafe carries out random audits of self-assessable changes and, where any significant problem is identified, the sponsor is asked to rectify it.

Note that a SACN cannot be submitted for consent for a label that has been the subject of a labelling exemption and is now compliant with the requirements. This requires, instead, a CMN for a labelling change Grade 2.

When a CMN is submitted for a change to a label, a copy of the current label and the artwork for the new label must be included with the checklist and declaration.

12.3 Labelling Checklists and Declarations

A completed Labelling Checklist and signed declaration (see Appendices 8-11) must accompany every application for approval of a new or changed medicine or related product label. Three versions of the checklist are provided.

If the product is a medicine (including a Controlled Drug) but is not a contact lens solution) use the Medicine Labelling Checklist. If the product is a contact lens solution use the Contact Lens Solution Labelling Checklist.If the product is a related product use the Related Product Labelling Checklist.

Where a product has both a primary container (e.g. bottle, vial) label and an outer package (e.g. carton) label, both labels must be checked for compliance with the legislation.

Each section of the checklist must be completed: If the section is not relevant to the product label being assessed, tick the “N/A” (not

applicable) box. If the product label meets all the requirements listed in a section, tick the “Yes” box for that

section. If the product label does not meet one or more of the requirements listed in the relevant

section, tick the “No” box and highlight the particular requirement(s) that are not met. If appropriate, the non-compliance of the label may be explained in a covering letter.

If there is any doubt about the compliance of a label with the requirements, Medsafe’s advice should be obtained.

An applicant wishing to market a medicine with a non-compliant label must either amend the label to make it compliant or apply for a labelling exemption. See also Section 12.4 and Medicines Regulation 12(5). A labelling exemption cannot be granted for a Related Product or a Controlled Drug.

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It is acceptable for a New Zealand label to include the Australian Register of Therapeutic Goods registration number (R xxxxxx). It is also acceptable for a label to include a barcode.

A single checklist is used to assess the primary container and secondary package labels where the product is packaged in a strip pack inside a carton. In any other situation where the primary container is enclosed in a secondary container (e.g. a bottle or vial enclosed in a cardboard box) the primary container and the secondary package labels must each be assessed for compliance with the requirements in the legislation. In this case, a separate checklist should be completed and submitted for the container and outer package labels.

Normally only one declaration form covering both labels needs to be signed and submitted with the labels and checklists. However, if one label is compliant and the other is non-compliant, separate declarations should be completed for each label.

In signing the declaration, the applicant accepts legal responsibility for the compliance of the label(s) with the legislation. The product may have to be recalled from the market if non-compliance is later identified.

12.4 Labelling Exemptions

Regulation 12(5) of the Medicines Regulations 1984 makes provision for a labelling exemption to be granted to allow a medicine to be marketed with a label that does not meet the labelling requirements of the Medicines Regulations. A labelling exemption may be requested using the CMN form. A completed labelling self-assessment checklist highlighting the areas of non-compliance should accompany the CMN.

A labelling exemption is not required when oversticking of labels occurs in order to bring them into compliance with the regulations, but the oversticking must be carried out in premises licensed for labelling or overlabelling and complying with GMP requirements.

Where a product is manufactured, packed and labelled overseas it is not necessary for the label concerned to include the name and address of the New Zealand sponsor or distributor [see regulations 13(1)(k), 13(2)(b), 14(1)(h), and 14(2)(b) of the Medicines Regulations 1984].

Labelling exemptions cannot be granted for related products or controlled drugs, or when any non-compliant aspects of a label create a safety problem for New Zealand prescribers, dispensers or consumers.

Labelling exemptions are considered on a case-by-case basis and may be granted when:

low sales volume for the product (i.e. 3000 or less units per year, or the sponsor can justify a higher limit) mean that the cost of amending the label would not be recoverable or

temporary, unforeseen stock shortfalls occur requiring the importation of product with non-compliant labels

and the aspect in which the label is non-compliant is considered immaterial to the safe use of the

product and is unlikely to cause confusion or misuse of the product.

When a labelling exemption is granted, the approval letter will indicate the period (up to a maximum of 2 years) for which the exemption applies. If any change is made to a label that is the subject of a labelling exemption, a new labelling exemption must be requested or, if applicable, a request must be made for approval of the new label through a CMN for labelling change Grade 2. Such label changes are not self-assessable.

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A labelling checklist must be completed and submitted along with any request for a renewal of a labelling exemption. The applicant should check that the labelling exemption is still needed and that an exemption has not become redundant because of changes in labelling requirements. A labelling exemption will not be granted in any situation where use of the non-compliant label could be unsafe or cause confusion. Labelling exemptions cannot be granted for Related Products or Controlled Drugs.

Note: Inclusion of a product information leaflet or CMI leaflet that is inconsistent with the approved New Zealand data sheet is not permissible, even when a labelling exemption has been granted for use of a non-compliant label. Also, it is not permissible for the consumer information panel (CIP) to be printed on the inside of a container and a labelling exemption will not be granted for such placement of the CIP.

12.5 Overlabelling or Oversticking Labels

Oversticking of labels to make them compliant with New Zealand legislation is permitted. However, the overlabelling must be carried out either at a site that is currently approved for packaging of the product concerned, or at another site whose current packing licence allows overlabelling of the product or overlabelling in general (in this case a CMN or CRPN is required to register the overlabelling site for the product concerned and overlabelling must not commence until the Director-General’s consent has been granted).

Where a product is wholly manufactured and packed overseas it is not necessary for the label to bear the name and address of the New Zealand distributor. If it becomes necessary to overstick the label in New Zealand to make it compliant with New Zealand regulations (e.g. by adding the required classification statement) then it is not also necessary to add the name and address of the New Zealand distributor to the label. Overlabelling under these circumstances is not considered to be a manufacturing or packing process in terms of regulations 13(k)(2)(b) and 14(h)(2)(b) of the Medicines Regulations 1984.

Where a sponsor has any questions relating to the suitability of a site for overlabelling (or re-packing) of a product, such questions should be addressed to the local Medicines Control office.

12.6 Physician’s Sample Packs

A medicine label must include dosage instructions if the product is intended to be supplied as a gift or sample for the purposes of promoting a sale. This requirement applies regardless of whether the product is a prescription or an OTC product. Thus all physician’s sample packs must, in addition to meeting other labelling requirements, be labelled with the dosage instructions for the product.

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12.7 Small Containers

12.7.1 OTC medicines

Regulation 20 of the Medicines Regulations 1984 describes the information that must be presented on the Consumer Information Panel (CIP) of the label of a medicine intended for OTC sale. If it is not possible to print all the necessary information on the CIP, then a separate information sheet is permitted for OTC medicines. Such information sheets are considered to be part of the labelling of the medicine, and as such are assessed and approved in the same way as the label. In this case, reference to where the information can be located must be made on the container label.

It is not acceptable to have any part of the CIP printed anywhere on the inside of a container or package.

Information sheets produced under regulation 20 differ from Consumer Medicine Information leaflets or product information leaflets provided for consumers or prescribers (see Sections 12.11 and 12.12).

12.7.2 Small volume medicines and related products

Regulation 16(1)(a)(iii) of the Medicines Regulations 1984 as amended in the Medicine Amendment Regulations 2000 describes the information that must be presented on the labels on small primary containers (ampoules, vials, dental cartridges, etc.) of sterile medicines where (1) the containers are too small to bear all of the information normally required on the label and (2) the containers are not intended for separate sale and (3) they are contained in a fully labelled secondary package. The labels on the individual primary containers need only include the product’s trade name (if any) and the active ingredient(s), but the label on the secondary package (e.g. carton) must include all of the information described in regulation 13 (medicines) or regulation 14 (related products). For safety reasons, it is strongly recommended that the strength of the active ingredient(s) is also indicated on the primary container(s).

12.8 Transdermal Patches in Pouches or Sachets

Transdermal patches that do not contain a Controlled Drug and are packaged in pouches (or sachets) of any size need only bear the following information on the pouch or sachet:

product trade name name and strength of each active ingredient batch number expiry date

provided all of the following conditions are met:

the pouches are contained in an outer package (e.g. carton) that is fully labelled in accordance with the Medicines Regulations

the pouches are not for individual sale the product is not a Controlled Drug

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12.9 Safety Containers

12.9.1 Definition and use of safety containers

A safety container is defined in the Medicines Regulations [see regulation 2(1)] as a container, such as a strip container composed of aluminium foil or blister trays of metal or plastic laminates, which is reasonably resistant to attempts by young children to open it.

Where plastic is used, it need not be opaque. Transparent plastic is permitted by Amendment 6 to the Medicines Regulations.

Regulation 37 of the Medicines Regulations 1984 require that solid dose forms of oral medicines containing any of the following substances are required to be supplied in a safety container:

Aspirin and its salts Iron, where the medicine contains more than 24 mg elemental iron per dose Paracetamol Barbiturates Phenothiazine and derivatives of phenothiazine and their salts except dimethothiazine,

methdilazine, promethazine, trimeprazine, and their salts and molecular compounds Tricyclic, tetracyclic and analogous antidepressants

Paracetamol tablets or capsules may be distributed to pharmacies in bulk quantities in bottles rather than in safety packaging for unit dose dispensing provided the bulk containers have the following warning prominently displayed on the label: NOT FOR GENERAL DISPENSING OR RETAIL SALE. FOR UNIT DOSE DISPENSING ONLY.

There is no legal requirement for manufacturers to supply any liquid medicines with child resistant closures, however, manufacturers of these medicines are strongly encouraged to do so.

12.9.2 Labelling of safety containers

Regulation 37(3) of the Medicines Regulations 1984 defines the requirements for the labelling of safety containers for the medicines listed above in Section 12.9.1. If the medicine is packaged in strip-packs, each strip must state the batch code and each individual unit container (e.g. blister) must be labelled with the medicine’s trade name, active ingredient(s) and strength. If there is insufficient space on the safety container for this information, only the trade name of the medicine is necessary.

It is strongly recommended that the expiry date should also be marked on each strip.

Regulation 16 defines the requirements for the labelling of safety packages for medicines other than those listed above in Section 12.9.1 and related products. If the medicine is packaged in strip-packs, each strip (rather than each individual blister) must state the batch code, the medicine’s trade name and active ingredient(s).

If a related product is packaged in strip-packs, each strip must state the product’s trade name and batch code. If a strip-pack strip is perforated and likely to be sold or dispensed in portions, it is required that each perforated portion should state the trade name of the product.

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In all cases, the outer packaging that encloses the safety containers must be labelled with all information required for a medicine label.

12.10 Specific Packaging and Labelling Requirements for Certain Medicines

Certain requirements, in addition to the usual labelling requirements for medicines, apply to a number of products and types of products. Regulation 22 of the Medicines Regulations 1984 require special warnings on the labels of the following types of product:

Antihistamines must bear a warning about the danger of impairment of ability to drive a vehicle or operate machinery.

Products containing aspirin, salicylamide and other salicylates must bear a warning against prolonged use or administration to children under 2 years of age without medical advice.

Products containing paracetamol must bear a warning against prolonged use or administration to children under 2 years of age without medical advice.

Topical medicines, related products and cosmetics containing hexachlorophane must bear a warning against use on infants or on burnt or damaged skin.

Medicines containing hydrocortisone or hydrocortisone acetate must bear a warning against use of the product for more than 7 days without medical advice if the ailment does not respond to treatment. Additional requirements are given in Section 12.10.9.

Medicines and related products for internal use that contain more than 3% ethyl alcohol must bear a warning that they contain alcohol.

In addition, certain prescription medicines may also be sold without a prescription provided they are in packs that meet specific packaging and labelling requirements.

Specific requirements for particular medicines are detailed in the following subsections. Note that words of similar meaning are acceptable.

12.10.1 Anti-anxiety or anti-insomnia medicines

Sedating antihistamines and any other OTC medicines indicated for insomnia or anxiety may be sold as Restricted Medicines when the following conditions apply. Those medicines which are for insomnia or anxiety and which do not fulfil these conditions must be sold as prescription medicines.

Pack size: Not more than 10 doses

Use: For short-term use onlyNot for children under 12 yearsDo not exceed maximum stated dose

Warning statements: Consult a doctor if sleeplessness (or anxiety) persists.

Note: Normal sedation warnings apply for sedating antihistamines.(See Medicines Regulations 1984, regulation 22)

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12.10.2 Antihistamines

Regulation 22 of the Medicines Regulations 1984 requires antihistamines to be labelled with a warning:

“Be cautious about driving a vehicle or operating machinery within 8 hours of taking this medicine.”

The same regulation also provides for the Director-General of Health to grant an exemption from this requirement. Non-sedating (“second generation”) antihistamines, while not having a sedating effect on most people, may still have a sedating effect on some individuals, and are required to carry the following warning on their labels:

“Although the medicine is unlikely to affect your ability to drive or operate machinery, a few people may be impaired and care should be taken.”

12.10.3 Blood products

Labels for blood components distributed by the New Zealand Blood Service are not required to comply with the Medicines Regulations. These labels must comply with the requirements stated in the Minimum Standards for the Collection, Processing and Quality Assurance of Blood and Medicines Derived from Human Blood and Plasma published by the New Zealand Blood Service.

12.10.4 Contact lens solutions

Contact lens solutions (or tablets for the preparation of solutions), must have the following information on the label: Trade name and a description of the preparation (e.g. sterile cleaning solution) on the

principal display panel Instructions for use. Specify the minimum volume required for use, whether suitable for

boiling, time for procedures etc. The label may refer to the product information leaflet. Net contents Name and address of manufacturer or distributor Expiry date Batch number Name(s) and strength(s) of preservatives and any other materials critical to the biological

performance of the solution e.g. wetting agents. A minimal disclosure of ingredients is permissible provided written assurance is given that a full disclosure of composition is available on request.

Name(s) of the lens or lens type with which the solution may be used, or a statement that the solution should not be used with a particular type of lens.

Precautions for use. Actions which must be taken to avoid or minimise hazards. Include warnings against direct application of the solution to the eye, if applicable, and against mixing or dilution of the solution with another, transferring it to another container other than the lens case, or re-using it.

Expiry date of solutions applied directly to the eye once the container is opened.

In addition to the above label requirements, product information should indicate the tonicity, pH and buffering properties of the solution.

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12.10.5 Controlled Drugs

Regulation 25 of the Misuse of Drugs Regulations 1977, and subsequent amendments, outline the requirements for labelling of Controlled Drugs. The labelling requirements of the Medicines Regulations must also be met for Controlled Drugs, except where the requirements of the two pieces of legislation are in conflict, in which case the Misuse of Drugs legislation takes precedence.

Any controlled drug named in Part VI of the Third Schedule to the Misuse of Drugs Act and fulfilling the specified requirements is by definition a pharmacy-only medicine and can be labelled as such in accordance with the Medicines legislation. The label is not required to include the words CONTROLLED DRUG. All other controlled drugs must be labelled in accordance with the Misuse of Drugs Regulations.

12.10.6 Corticosteroids as aqueous solutions for nasal inhalation

Low dose beclomethasone, budesonide, flunisolide, fluticasone and mometasone aqueous nasal preparations may be sold as Restricted Medicines for use in the prophylaxis and treatment of seasonal allergic rhinitis when the following conditions apply:

Type of preparation Non CFC aqueous formulations

Strength Beclomethasone not more than 50 mcg per actuationBudesonide not more than 50 mcg per actuationFlunisolide not more than 25 mcg per actuationFluticasone not more than 50 mcg per actuationMometasone not more than 50 mcg per actuation

Pack Size Not more than 200 doses

Indications Short term (3-6 months) prophylaxis or treatment of seasonal allergic rhinitis (hay fever) in adults and children aged 12 years and over.

Dosage Beclomethasone Maximum of 400 mcg (200 mcg in each nostril) per day in divided doses.

BudesonideMaximum 400 mcg (200 mcg in each nostril) per day in divided doses.

FlunisolideMaximum daily dose as a single dose or in divided doses:

Adults 200 mcg (100 mcg in each nostril)Children (12 to 16 years) 150 mcg (75mcg in each nostril)

FluticasoneMaximum daily dose 200 mcg as a single dose

Mometasone

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Maximum daily dose 200 mcg as a single dose

Use Do not exceed maximum stated dose.Dose should be reduced for maintenance treatment once full effect obtained.Do not use for more than 6 months except on medical advice.

Warning Statements Seek medical advice before using (product name) if you are already taking another steroid product, e.g. tablets, asthma or nasal inhaler or eye/nose drops.

Seek medical advice before using (product name) if you have infection in the nasal passages or sinuses.

Seek medical advice before using (product name) if you have recently had an injury or surgery to your nose, or problems with ulceration in your nose.

Seek medical advice if nasal symptoms are not relieved after 7 days of treatment.

While using (product name) seek medical attention if you develop:signs or symptoms of infection such as:- fever, nasal or facial pain or swelling - purulent [i.e. pus-containing] or discolored nasal discharge- bleeding from the nose- acute eye pain or visual disturbance.

Contraindications As per data sheet

Adverse effects As per data sheet

Additional Warningsand Precautions

As per data sheet

12.10.7 Fluoride tablets

Labels for fluoride tablets should include dosage instructions that are consistent with the Ministry of Health’s recommendations that:

tablets should not be used during pregnancy (because there is no firm evidence of benefit from use of fluoride tablets by pregnant women and in line with the general policy that unnecessary medicines should be avoided during gestation).

fluoride tablets should only be used in areas where there is less than 0.3 part per million fluoride in the water supply

the dosages for different age groups should be:3 to 5 years: 0.25 mg elemental fluoride per day6 to 8 years: 0.5 mg elemental fluoride per day9 years and over: 1.0 mg elemental fluoride per day [Note that 0.25 mg elemental fluoride is equivalent to 0.55 mg sodium fluoride.]

fluoride tablets should be either chewed thoroughly or dissolved in drinking liquid before swallowing.

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12.10.8 Hexachlorophane

All OTC products containing hexachlorophane must carry a warning that the product should not be used on infants without the advice of a registered medical practitioner.

12.10.9 Hydrocortisone topical medicines

All OTC topical products containing hydrocortisone should bear the following warnings:

CAUTION – Do not use for children under 2 years unless a doctor has told you to. Do not use for more than 7 days unless a doctor has told you to. Do not use under waterproof bandages unless a doctor has told you to. Do not use in eyes. Do not use for acne.

12.10.10 H2-Antagonists

Low dose presentations of cimetidine or nizatidine may be sold as restricted medicines, and low dose presentations of famotidine or ranitidine may be sold as pharmacy-only medicines, when the following conditions apply:

Pack size Not more than 14 days’ supply when used at the recommended dose.

Indications Symptomatic relief of heartburn, dyspepsia and hyperacidity OR on the recommendation of a medical practitioner.

Warning statements Do not use the medicine for any purpose other than that specified on the pack unless under the supervision of a doctor.Consult a doctor if symptoms persist, recur or worsen.Consult a doctor if new or additional symptoms occur.Do not use with non-steroidal anti-inflammatory medicines unless under the supervision of a doctor.Use with caution if over 40 years of age.In the case of cimetidine, do not use without medical supervision if taking warfarin, phenytoin or theophylline.

12.10.11 Ibuprofen liquid

Liquid ibuprofen may be sold as a Pharmacy-Only medicine when the following conditions apply:

Strength Must not exceed 100 mg ibuprofen per 5ml.

Pack size Not more than 200 ml

Indications Relief of pain and reduction of fever and inflammation. Note that juvenile rheumatoid arthritis is not an approved indication for the OTC sale of ibuprofen liquid.

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Dosage Dose is of the order of 20 mg/kg/day and generally meets the following recommendations:

Age Single dose1-2 years 50 mg3-7 years 100 mg8-12 years 200 mg

The dose should be given 3 to 4 times a day, if necessary. For children weighing less than 30 kg the total dose given in 24 hours should not exceed 500 mg.

Warning statements Use of the medicine without a doctor’s advice is contraindicated in: children aged less than 12 months children weighing less than 7 kg children suffering dehydration through diarrhoea and/or

vomiting children with gastric ulceration, indigestion, stomach pain, or

bleeding children who have previously shown hypersensitivity to

aspirin, ibuprofen, or other NSAIAs.

Precautions This medicine should NOT be taken without medical supervision by: children who have impaired renal function children who are taking other medicines children suffering from asthma, urticaria or rhinitis.

Consult a doctor if symptoms persist for more than 3 days.

12.10.11 Iodine

The labels of OTC products for internal use that contain iodine should bear the following statements:

Caution - total iodine intake may exceed recommended level when taking this preparation Warning - contains iodine - do not take when pregnant except on a physician’s advice.

12.10.12 Paracetamol

The Ministry of Health’s guidelines for paracetamol dosage are as follows:

Age Single dose

3-12 months 60-120 mg

1-5 years 120-250 mg

6-12 years 250-500 mg

>12 years 500-1000 mg

Where these doses do not coincide with standard dose form, doses should be recommended to the nearest half tablet or 2.5 ml.

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Liquid dose forms should be consistent in strength, i.e., 120 mg/5 ml or 250 mg/5 ml. Reserve the 250 mg/5 ml concentration for adults (250 mg is accepted, rather than 240 mg, as it is equivalent to half of a standard tablet).

Solid dose forms for adults should be multiples of 250 mg or 500 mg only, whereas solid dose forms for children should be multiples of 60 mg to be consistent with liquid dose forms for children.

Dosages for tablets should be expressed as the appropriate number of whole tablets or half tablets using the above table, instead of specifying the milligram dose.

Tablets should preferably be scored to allow accurate breaking in half, but smaller fractions are not recommended. Capsules are not readily or accurately divisible into halves. Therefore, doses of less than whole capsules should not be recommended.

Use of paracetamol with other medicines in the one product

For adults, combination products which contain paracetamol, should normally contain standard doses of paracetamol, although there may be exceptions.

For children 12 years of age or less, the medicines in combination, particularly analgesics, should be in lower doses than the approved standard doses administered separately.

12.10.13 Pholcodine

Pholcodine, when compounded in a liquid preparation as a linctus is considered by the Ministry of Health to be a Pharmacy Only Medicine (Controlled Drug Class C6).

12.10.14 Pregnancy test kits

In New Zealand pregnancy test kits are classed as general sales medicines, whereas in most other countries they are classed as medical devices. The following guidelines have been developed to ensure general harmony between the labelling requirements for these products in New Zealand and Australia.

1. Outer carton

The requirements for the labelling of outer carton are that the following detail must be included:

Trade Name The words “Pregnancy Test Kit”, unless these are included in the Trade name The number of pregnancy test kits in the carton The name and address of the manufacturer or sponsor The batch number The expiry date

Recommended storage conditions are not required if the kits are to be stored at room temperature in New Zealand

2. Inner pouch containing actual test kit

The recommendations for the labelling of the pouch(es) containing the actual test kit(s) are that, as a minimum, the following detail should be included:

The batch number The expiry date

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3. Instructions for use

At least one copy of the instructions for use must be included. These instructions may be printed on the carton or pouch or be supplied as a package insert. The instructions must include:

Directions for use of the reaction device and the urine dropper (if any) Direction to allow the device to return to room temperature before use if it has been stored in a

refrigerator Directions (with a clear diagram) for applying urine to the reaction device Information on minimum and maximum times to wait before reading the result A diagrammatic example of a positive result Information on false positive/negative results

12.10.15 Sodium phosphate in oral bowel preparations

Sodium phosphate is classified as a restricted medicine when contained in oral preparations for bowel cleansing prior to diagnostic, medical or surgical procedures, but it is classified as a prescription medicine when used as a laxative.

No sodium phosphate product marketed as a restricted medicine may contain any reference to use as a laxative in the package information, data sheet or CMI.

12.10.16 Topical medicines

Some patients may have allergies to certain ingredients (e.g. peanut oil) used in some topical medicines. To assist such patients in avoiding contact with these allergens, it would be helpful for ingredients of topical medicines to be listed on the label or in product information leaflets. At its meeting on 14 June 2001, the Medicines Adverse Reactions Committee recommended that all ingredients, including preservatives, of topical medicines be required to be listed in the labelling.

12.10.17 Topical medicines likely to be used in the genital area

Some ingredients (e.g. mineral oils and paraffin waxes) used in the formulation of topical creams, ointments, foams and pessaries rapidly degrade latex rubber on contact. In order for doctors and pharmacists to be adequately informed, the distributors of topical medicines likely to be applied to the male or female genital area must make available information about the compatibility of their products with latex rubber. This information should be included in the data sheet for prescription medicines and on the product label or package insert for OTC medicines.

Latex rubber condoms marketed in New Zealand are required by law to conform to the International Standard ISO 4074-1:1996(E) - Rubber Condoms. In accordance with this standard the packaging is required to include advice to consult a doctor or pharmacist about the compatibility of condoms with prescription or over-the-counter topical medicines that are applied to the penis or vagina.

12.11 Product Information Leaflets

Applicants must indicate when a product is to be marketed with an enclosed product information leaflet, and must declare that the information contained in the leaflet is consistent with the approved New Zealand data sheet or the New Zealand approved details for the product, unless some of the content is considered to be an extension to the labelling, in which case this section only will be evaluated. Where there are inconsistencies, the company must either amend the leaflet or remove it from the packs to be sold in New Zealand.

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These leaflets are neither evaluated nor approved. The onus is on the applicant to ensure and confirm to Medsafe that the information is consistent with the approved data sheet and details approved by Medsafe. As these product information leaflets do not form part of the label, labelling exemptions cannot be granted to allow the inclusion of a leaflet that is inconsistent with the New Zealand approved details for the product.

12.12 Consumer Medicine Information

Consumer Medicine Information (CMI) is accessible and understandable information about medicines written for consumers in accordance with the current edition of New Zealand Regulatory Guidelines for Medicines Volume 4: Consumer Medicine Information. This can be downloaded from the Medsafe web site. A Microsoft Word template for preparing CMI is also available on the web site.

While producing CMI is not mandatory (New Zealand currently has no legislation regarding CMI), sponsors are encouraged to do so. The provision of CMI will help consumers use medicines safely and effectively.

CMI should not be submitted with an NMA or CMN. It should, instead, be sent direct to the CMI Co-ordinator at Medsafe.

Note: If a product information leaflet has the content or intent of Consumer Medicine Information and the sponsor would like it published on the Medsafe web site, then it must be submitted as CMI in accordance with New Zealand Regulatory Guidelines for Medicines Volume 4: Consumer Medicine Information.

CMI for Prescription and Restricted medicines must be based on the approved New Zealand data sheet.

For Pharmacy Only and General Sales medicines, CMI is to be based on the approved New Zealand data sheet. If there is no such data sheet, CMI for Pharmacy Only and General Sales medicines can be based on any of the following approved source documents:

Australian Prescribing Information or CMI UK data sheet or CMI USPDR document Canadian Product Monograph European Summary of Product Characteristics Company international prescribing information.

For all CMI the sponsor must ensure that:

the safety information in the New Zealand CMI is consistent with that in the approved source document; and

any requirements in Section 13.6 of these Guidelines are also included in the CMI; and the content of the CMI is consistent with the terms of New Zealand approval for the product.

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Section 13: Data Sheets

Section summaryThis section: provides detailed guidance on the preparation and submission of data sheets explains the process for approving and publishing new and updated data sheets

Legislation to read in conjunction with this sectionMedicines Regulations 1984

Part X (Regulations 51-54): Data SheetsThird Schedule: Data sheet requirements

13.1 Introduction

Part X of the Medicines Regulations requires sponsors to submit for approval data sheets for new and changed prescription or restricted medicines. Data sheets are not required for pharmacy-only or general sale medicines or for related products. When a material change is made to an approved medicine, and that change affects the information in the data sheet, the data sheet must be amended and submitted for approval. The approval of the Director-General of Health is required before a new or updated data sheet can be published.

The legislation relating to data sheets is prescriptive and somewhat outdated. It was written for a paper-based system and does not take account of the efficiencies and opportunities offered by the electronic storage and publication of information. Therefore, Medsafe has implemented a modified approach to the preparation, submission, approval and publication of data sheets that will be efficient and resource-sparing for all concerned, and will move data sheets into the electronic era. Once processed and approved, data sheets will be electronically stored and published on Medsafe’s web site.

Data sheets are not legally required for pharmacy-only and general sales medicines. However, it may be appropriate for data sheets to be prepared and submitted for such medicines that are commonly prescribed. The onus is on sponsors to determine if this would be appropriate and submit a data sheet for approval and publication on Medsafe’s web site. The data sheet may be based on any of the overseas approved documents listed in Section 13.2 and the content of the data sheet must be consistent with the terms of New Zealand approval for the product and must include any required safety warnings.

Data sheets are not required for related products and, if submitted, will not be processed or published on Medsafe’s web site.

Note, also, that if a product is marketed under two or more names, separate data sheets are required for each name of the product concerned.

The following sub-section provides detail on how to prepare a data sheet for a prescription or restricted medicine, either by amending an overseas-approved document, or by starting from scratch where there is no such ‘source’ document available.

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Note that, in addition to the limited checking of data sheets that takes place during the approval and publication processes, Medsafe also carries out random audits of published data sheets from time to time. If problems are identified, these are brought to the attention of the sponsor concerned and the appropriate corrective action is requested.

13.2 Preparing a Data Sheet for Approval

13.2.1 Format

Data sheets will be accepted in any of the following formats (including section headings):

NZ-format data sheet, as described in the Medicines Regulations 1984 UK data sheet EU Summary of Product Characteristics Product information published in the USA Physicians Desk Reference (PDR) Canadian Product Monograph (English version) Australian Product Information (PI), or Pharmaceutical company international prescribing information document.

The paper cop(ies) should be headed with the words “Data Sheet”, but this should be omitted from the electronic copy. The template used to format data sheets for the web site automatically adds the heading.

The data sheet (both paper and electronic copies) must also include the “Date of Preparation”, which is the date (day, month and year) that particular version of the data sheet was prepared for submission. The date of preparation must be changed each time an updated version is prepared, so that only one date of preparation appears on each data sheet. This date will be used to identify that particular version of the data sheet as it progresses through the stages of being proposed, approved or superseded.

13.2.2 Content

The data sheet must contain all the information required in a New Zealand data sheet, but the information does not have to be presented in the particular order or under the exact headings specified in the New Zealand legislation. A data sheet submitted for approval in New Zealand can have the same content as any of the following documents for the same medicine:

Medsafe-approved data sheet (any data sheet published on Medsafe’s web site) UK-approved data sheet EU-approved Summary of Product Characteristics Product information published in the USA Physicians Desk Reference (PDR) Canadian Product Monograph (English version) Australian-approved Product Information (PI), or Internationally approved pharmaceutical company prescribing information document,

provided it has been amended where necessary to include:

information on presentation, indications, dosage, medicine classification, package quantities and name and address of distributor that is specific to the product as approved in New Zealand. This information must be amended carefully so that the data sheet accurately describes the product approved in New Zealand. It is not permissible for a data sheet to show indications or dosages, or to list strengths or dose forms, that are not approved in New Zealand. The indications, dosages

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and other New Zealand-specific information such as product presentation must be checked for consistency with the New Zealand approval and amended where necessary.

any additional NZ-specific safety information requested by Medsafe, often on the recommendation of an advisory committee. The term “safety information” refers to all the information about: actions, pharmacokinetics, contraindications, warnings and precautions, adverse effects, interactions, overdosage, pharmaceutical precautions, and any “further information” to be included in a data sheet. Where an overseas-approved source document is used, the safety information from that source document should be reproduced unchanged in the data sheet except where there are specific New Zealand requirements. Apart from any New Zealand-specific safety information, the safety information in the data sheet should be the same as that contained in the source document. It is not necessary to re-format the document or to change the headings.

If only provisional consent for distribution of the medicine under section 23 of the Medicines Act has been granted, this fact should be included in the data sheet, along with any gazetted conditions applying to its distribution. Any conditions should be detailed using the wording in the New Zealand Gazette notice.

Regulation 53(4) and 54(6) of the Medicines regulations 1984 require that a New Zealand data sheet must not contain comparative data or any other reference to any medicine or brand of medicine other than the product that is the subject of the data sheet.

13.2.3 Preparing a new data sheet for which there is an acceptable source document

The source document used in preparing a data sheet must be either the prescribing information document currently approved overseas as described above or a Medsafe-approved data sheet. When a company’s international prescribing information document is used, the document must be current. It is helpful if the document shows the date on which it was approved for use by the company’s international head office. Whatever document is used, it must be amended to include New Zealand-specific product, indications and dosage, and safety information.

The source document for a multi-source medicine is the data sheet for the innovator product, amended where necessary to reflect the approved details of the multi-source product (e.g. product name, description, approved indications, and sponsor details). If it is not appropriate to include all of the innovator’s indications, this should be explained and justified in a covering letter. The data sheet for a multi-source medicine must contain the same indications, dosage and safety information as the Medsafe approved data sheet for the innovator product (except where all of the indications approved for the innovator product have not been approved for the multi-source product because they were not applied for in the original multi-source NMA or in a subsequent CMN, or there is still patent protection of one or more of the indications approved for the innovator’s product). The indications approved for the corresponding innovative product are not automatically approved for a multi-source medicine. Each must be applied for as part of the original NMA or a subsequent CMN.

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13.2.4 Preparing a data sheet for which there is no acceptable source document

Where there is no Medsafe approved data sheet and no overseas-approved source document, the data sheet should be prepared in the New Zealand format set out in the New Zealand Medicines Regulation 1984.

Before submission to Medsafe, the data sheet must be assessed by the applicant for compliance with the requirements of the legislation and these guidelines. A self-assessment checklist is provided at the end of this subsection to assist applicants in checking data sheet drafts.

A. Content and layout for New Zealand-format data sheets

The following general principles should be taken into account when preparing a New Zealand format data sheet:

Where practicable, all dose forms marketed under the same trade name should be included in a single data sheet.

It may be appropriate for some information to be repeated under different headings. Promotional statements are not permitted in data sheets. Reference to another medicine is not allowed unless it aids the understanding of the proper

use of the medicine described in the data sheet. The word "medicine" is used to indicate a therapeutic substance. In New Zealand, the word

"drug" indicates a substance of abuse. Bibliographic references are not to be included in the data sheet.

Data sheets should contain information under the following section headings, in the order given below. Where no relevant information is available, the word "Nil" should appear under the heading.

Name of medicine Presentation (includes dose form and strength, and flavour if applicable) Uses - Actions, Pharmacokinetics, Indications Dosage and administration Contraindications Warnings and precautions Adverse effects Interactions Overdosage Pharmaceutical precautions Medicine classification Package quantities Further information Name and address Date of preparation

Name of MedicineThe proprietary name, the name of each active ingredient and the strength(s) should be included. If there is no trade name, the sponsor’s name should be included. A quality reference to the Ph Eur, BP or USP for the dose form can be also included in this section. There is no need to include headings for the "Trade name", "Multi-source name", “INN” etc.

Presentation

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The colour, dimensions and other physical characteristics of the product(s). A new paragraph should be used for each dose form.

UsesThe subheadings “Actions”, “Pharmacokinetics” and “Indications” appear under this heading.

ActionsThe pharmacological/pharmacodynamic properties that are relevant to the therapeutic purpose, including:

pharmacotherapeutic group mechanism of action (if known) pharmacodynamic effects for which there is evidence of a relationship with the therapeutic

effect, or which may induce adverse reactions. The onset and duration of action should also be included.

For anti-bacterial agents the following format is recommended:

General properties of the agent, e.g. class, nature and mode of action, information on concentration-dependent bactericidal activity

Susceptibility data based on in vitro tests using no less than 100 strains of each species recently isolated. New Zealand-specific data should be presented when available.

A list of susceptible, intermediate and resistant organisms, indicating the MIC range for each susceptibility category.

In vitro data where clinical efficacy has been demonstrated and is reflected in the approved indications. In vitro data should also be included where clinical efficacy is unknown but susceptibility of the organism may be relevant to the approved indications. A statement should be included to indicate that there is a risk of therapeutic failure and this risk must be weighed against the potential benefit.

A list of species where many strains show intermediate susceptibility, with an indication of whether and how clinical successes have been obtained for such strains. The information could refer to the occurrence of resistance in special areas of the South Pacific and describe the therapeutic implications of that situation.

Susceptibility data should be tabulated as follows:

Species Resistance group A or B or C

MIC range for organisms without known resistance mechanisms

The species should be listed alphabetically in the following categories:

aerobic gram positive organisms

aerobic gram negative organisms

anaerobic organisms other micro-organisms

Where A = resistance not yet described B = resistance occurs in 10-50% C = inherent resistance or resistance frequently occurring (>50%)

The MIC range is necessary only for antibiotic/species combinations for which there is clinical relevance

Further detail, including the in vitro methods (inoculum size, source of strains and number of strains), should appear in the “Further Information” section.

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PharmacokineticsGeneral characteristics:

absorption - bioavailability of each dosage form and information on whether oral dose forms are affected by liver first pass effect, incomplete absorption, or the presence of food

distribution - plasma protein binding, volume of distribution, tissue and/or plasma concentrations

biotransformation - to active metabolites or inactive metabolites, and in the case of prodrugs, to the active substance

elimination - elimination half-lives, total clearance, excretion route(s) for unchanged substance and metabolites.

Characteristics in patients:

any known relationship between plasma/blood concentrations and therapeutic activity or adverse reactions

variations with respect to confounding factors - age, polymorphic metabolism, concomitant pathological situations (renal failure, hepatic insufficiency).

Indications The indication(s) approved by Medsafe, related as precisely as possible to the results of clinical trials. A description of the purpose of the medicine.

Dosage and AdministrationThis should include:

dose, dose interval and duration of treatment timing in relation to food dosage adjustment with renal or liver insufficiency, dialysis, or concomitant disease maximum tolerated daily dose (if relevant) advice on monitoring any procedural steps critical to safe administration of the medicine with reference, where

appropriate, to each age category (neonates, children, adults and the elderly).

ContraindicationsSituations where patients should never be treated with the medicine, or generally should not be treated. In cases where the medicine should never be given, these must be specifically stated.

Warnings and PrecautionsInformation intended to:

warn prescribers of the possibility of adverse reactions, including habituation, occurring under normal conditions of use or in particular situations such as renal, hepatic or cardiac failure

inform prescribers of the recommended ways to prevent the occurrence or the worsening of these adverse reactions by patient monitoring, dose reduction or discontinuation of treatment, and

describe the conditions under which the medicine may be recommended for use in sub-groups of patients at risk, provided that the special conditions of use are fulfilled.

Pregnancy and LactationSuitability for use in pregnancy and lactation.

For medicines where there is extensive therapeutic experience, the Australian (or US or Swedish) categorisation system for safety in pregnancy should be used. One of the seven class statements from the Australian Therapeutic Goods Administration (TGA) publication Prescribing medicines in

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pregnancy, 4th edition (previously called Medicines in Pregnancy) should be included where possible. Copies of this publication can be obtained from the TGA web site: http:www.health.gov.au/tga.

For medicines with limited therapeutic experience this section should include:

conclusions from animal reproduction/fertility studies and the human experience the risk in humans during each trimester, as assessed from the above the risk of using the medicine in fertile and pregnant women.

If the active substance or any of its metabolites is excreted in human milk, a recommendation to stop or continue breast feeding, and the likelihood and degree of adverse reactions in the infant.

Effects on ability to drive and use machinesWhether the medicine is:

a) presumed to be safe or unlikely to produce an effect, or b) likely to produce minor or moderate adverse effects, orc) likely to produce severe adverse effects or presumed to be potentially dangerous, andd) any relevant warnings or precautions.

OtherSignificant preclinical safety findings (including those from in vitro mutagenicity or carcinogenicity studies). Where further explanation is warranted the detail can be inserted under Further Information.

Adverse EffectsInformation on:

significant adverse effects observed, or the most predictable adverse effects on the basis of toxicology, especially findings from repeated dose toxicity studies

frequency of these effects and their seriousness previous clinical experience with medicines of the same class, where relevant.

The data should identify whether a causal association is likely or unlikely.

Reactions should be listed according to frequency. A tabular presentation is preferred. All adverse reactions with a prevalence of 1% or more should be included. Any serious adverse reactions, and any others specified by the Medicines Adverse Reaction Committee, should also be included.

If a narrative description of adverse reactions is used, the following words should be used to describe prevalence:

“common/frequent” = 1%“uncommon/infrequent” = < 1% but 0.1% “rare” = < 0.1 %

InteractionsInformation on:

interactions with other medicines or other substances abnormal laboratory test results associated with the medicine the effect of concomitant use of medicines, including herbals the effect of daily activities e.g. meals and consumption of alcohol.

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Only interactions that have been observed, or for which there is potential based on clinically meaningful experience with medicines of the same pharmacotherapeutic group, need to be included.

The following information should be given for each interaction:

mechanism of action (if known) effect on plasma levels of other medicines and/or effect on laboratory and clinical parameters recommendations such as dose adjustment, contraindication, precautions for use etc.

OverdosageThe symptoms and treatment of overdosage, including:

human experience management of overdose in human acute experience in animals

Pharmaceutical Precautions

Instructions for Use/HandlingWhere appropriate:

a direction that the product, as presented, is not intended for immediate use and has, for instance, to be suspended or diluted before administration. There may be circumstances where this advice should be included under ‘Dosage and Administration’. Details on compatibility should be included here

instructions on using/handling the medicine advice that a particular dosing device is needed to administer the medicine

IncompatibilitiesWhere appropriate information on:

physical and chemical incompatibilities with other medicines with which it is likely to be mixed or co-administered. This is particularly important for medicines requiring dilution before parenteral administration

significant problems of absorption or adsorption to syringes, large volume parenteral containers etc.

Shelf LifeThe shelf life of the medicine:

packaged for sale after first opening the container (where appropriate) following dilution or reconstitution according to the directions (where appropriate)

Special Precautions for StorageThe maximum (or minimum) storage temperatures stated in C. If the medicine is stable at temperatures up to 30C, special storage instructions are not needed. State any special precautions regarding humidity and light (see Section 6.12 for permitted terms).

Medicine ClassificationThe classification of the medicine - Prescription Medicine or Restricted Medicine.

Package QuantitiesPack sizes and strengths of each dose form available in New Zealand. The ‘Package Quantities’ could, alternatively, appear under the heading ‘Presentation’.

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Further InformationOther data, if any, not included in previous sections, such as:

summary information describing clinical trial results information on preclinical test results that could be relevant in assessing the risk/benefit of

using the medicine. If the results of preclinical studies do not add to the information needed by the prescriber, then the results, either positive or negative, need not be included in the data sheet

laboratory details relating to antibacterial agents chemical structure a qualitative list of excipients warnings about the presence of lactose, gluten or particular colourings, if appropriate

Note: If only provisional consent for distribution of the medicine under section 23 of the Medicines Act has been granted, this fact should be included in this section, along with any gazetted conditions applying to its distribution. Any conditions should be detailed using the wording in the New Zealand Gazette notice.

Name and AddressThe name, business address in New Zealand and telephone number of the holder of the consent to distribute. Fax and e-mail addresses may also be included.

Date of PreparationThe date of preparation (day/month/year) of that version of the data sheet.

B. Data sheet checklist

The Data Sheet Checklist in Appendix 13 is to be used by applicants when preparing and checking a New Zealand-format data sheet for compliance with the Medicines legislation and the Guidelines. Where the data sheet does not include information that would normally be required, a brief comment should be included on the checklist to indicate why the information was omitted. An example would be “No data available on excretion in breast milk”.

The checklist should be forwarded to Medsafe along with the draft data sheet.

A checklist is not required for data sheets prepared using an overseas-approved source document.

13.3 Submitting Data Sheets for Approval and Publication

The processes for preparation, submission, approval and publication of draft and final data sheets depends upon the circumstances.

For an NMA a draft document is to be submitted along with the NMA for review along with the data supporting the NMA. The sponsor may be required to modify the text before it can be approved. Once the NMA has been approved and the Minister’s or Director General’s consent has been gazetted or conveyed by letter to the sponsor, the sponsor must submit the final version of the data sheet in both paper and electronic copy for formal approval and publication on Medsafe’s web site.

Note that dose forms and strengths and flavours of a medicine that have been approved for distribution but are not being marketed may be left off the data sheet. However, it may be desirable to print all of the approved dose forms and strengths and flavours but have a qualifier [e.g. (not marketed)] next to the relevant dose form/strength/flavour.

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When a sponsor subsequently commences marketing one or more of these products and wishes to remove the words “not marketed”, this can be arranged by submitting a self-assessable change notification (SACN) and fee together with a paper and an electronic copy of the final version of the data sheet for publication on the web site.

Similarly, if a sponsor wishes to update the safety information in a data sheet the sponsor must submit a SACN and fee together with a paper and an electronic copy of the final version of the data sheet for publication on the web site.

When a data sheet is updated as a result of a CMN or SACN, the date of preparation must also be updated. The sponsor should, if relevant, also consider revising any information leaflet/package insert and any CMI

The steps involved in the various circumstances are given in the subsections below.

13.3.1 NMA for a new chemical or biological entity medicine or a new vaccine

Step 1The sponsor drafts a data sheet (normally using an overseas-approved source document or company head office-approved basic text).

Step 2The draft and a copy of the ‘source document’ (if applicable) are submitted to Medsafe along with the NMA and dossier of supporting data.

Step 3The draft data sheet is assessed along with the NMA and supporting data. Any required changes are communicated to the sponsor by the MAAC Secretary or Vaccines Sub-committee Secretary processing the NMA. There may be additional correspondence between the sponsor and the Secretary or evaluator before the final wording is agreed. Once the NMA is ready for recommendation for Ministerial consent, the sponsor is asked to submit the final text of the data sheet to the Data Sheet Co-ordinator for processing and publication (see step 5 below).

Step 4Ministerial consent for the distribution of the new medicine in New Zealand is gazetted.

Step 5Within 14 days after gazettal of consent, the sponsor forwards to the Data Sheet Co-ordinator the following:

1. The final data sheet on A4 paper2. The final data sheet in electronic form in MS Word for Windows or Rich Text Format on

computer disk3. The completed Data Sheet Declaration Form (see Appendix 12)4. The source document (if applicable). [Note: Although a copy may already have been supplied with

the NMA, a second copy is required to ensure that it can easily be located and perused with the final version of the data sheet.]

Step 6Medsafe processes the data sheet and publishes it on the web site and advises the sponsor that the data sheet has been approved and published. (Publication of the data sheet on the web site is part of

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the approval process.) The sponsor should check the published data sheet to ensure that it is correct. Once the data sheet has been approved, the sponsor may distribute it.

13.3.2 NMA for a new multi-source medicine

Step 1The sponsor drafts a data sheet (normally using as the source document the innovator’s data sheet as published on Medsafe’s web site). The onus is on the sponsor to ensure that any patent protections of particular indications approved for the innovator’s product are taken into account.

Step 2The draft and a copy of the ‘source document’ are submitted to Medsafe along with the NMA and dossier of supporting data.

Step 3The essentials of the draft data sheet are assessed along with the NMA and supporting data. Any required changes are communicated to the sponsor by the Medsafe evaluator processing the NMA and, once the NMA is ready for recommendation for Ministerial consent, the sponsor is asked to submit the final text of the data sheet to the Data Sheet Co-ordinator for processing and publication (see step 5 below).


Step 5Within 14 days after gazettal of consent, the sponsor forwards to Medsafe’s Data Sheet Co-ordinator the following:




[Note: If the final text is not submitted within 14 days of gazettal consent, the sponsor will be reminded to do so. If the data sheet is then not received within 1 month of gazettal, an additional SACN fee will be charged. In the meantime, if the medicine is being marketed, the trade name of the medicine will be published on the web site with the comment “data sheet not supplied by (company name)’ against it.]

Step 6Medsafe processes the data sheet and publishes it on the web site and advises the sponsor that the data sheet has been approved and published. (Publication of the data sheet on the web site is part of the approval process.) The sponsor may then distribute the data sheet.

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13.3.3 New dose form of an approved medicine

Step 1The sponsor drafts a data sheet (normally using as the source document the data sheet for the previously approved dose form(s) of the same medicine as published on Medsafe’s web site). The data sheet may be dose form-specific or it may cover the currently approved and the new dose forms.

Step 2The draft and a copy of the ‘source document’ are submitted to Medsafe along with the NMA and dossier of supporting data.

Step 3The essentials of the draft data sheet are assessed along with the NMA and supporting data. Any required changes are communicated to the sponsor by the MAAC Secretary or Medsafe evaluator processing the NMA and, once the NMA is ready for recommendation for Ministerial consent the sponsor is asked to submit the final text of the data sheet to the Data Sheet Co-ordinator for processing and publication (see step 5 below).


Step 5Within 14 days after gazettal of consent, the sponsor forwards to the Data Sheet Co-ordinator the following:




[Note: If the final text is not submitted within 14 days of consent, the sponsor will be reminded to do so. If the data sheet is then not received within 1 month of gazettal, an additional SACN fee will be charged. In the meantime, if the new dose form of the medicine is being marketed, its trade name will be published on the web site with the comment that a data sheet for the particular dose form(s) of the medicine has not supplied by the sponsor.]

Step 6Medsafe processes the data sheet and publishes it on the web site and advises the sponsor that the data sheet has been approved and published. (Publication of the data sheet on the web site is part of the approval process.) The sponsor may then publish the data sheet.

13.3.4 CMN for a new indication and/or new dosage instructions

Step 1The sponsor drafts a revised data sheet (normally using as the source document the previously approved data sheet as published on Medsafe’s web site). In the case of a multi-source medicine, the source document will be the innovator’s data sheet including the new indication/dosage. The onus is on the multi-source medicine sponsor to ensure that the new indication/dosage is not subject to patent protection. If a new indication not approved for the innovator’s product is being sought, this will have to be supported by clinical data.

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Step 2The draft and a copy of the ‘source document’ are submitted to Medsafe along with the CMN and any required dossier of supporting data for the new indication and/or dosage instructions.

Step 3The CMN may be processed as a CMN or referred to the Minister under section 24(5) of the Medicines Act and thereafter processed as an NMA, either by a Medsafe evaluator or by the MAAC. The revisions to the data sheet are assessed along with the CMN/S24(5) NMA and supporting data. Any required changes are communicated to the sponsor by the MAAC Secretary or Medsafe evaluator processing the CMN/NMA. Once the new indication is ready for recommendation for the Director General’s or the Minister’s consent, the sponsor is asked to submit the final text of the data sheet to the Data Sheet Co-ordinator for processing and publication. The sponsor is also asked to notify Medsafe when the product is to be marketed for the new indication/dosage.


Step 5Within 14 days after consent is given or gazetted, the sponsor forwards to Medsafe’s Data Sheet Co-ordinator the following:




[Note: If the final text is not submitted within 14 days of consent, the sponsor will be reminded to do so. If the data sheet is then not received within 1 month of gazettal, an additional SACN fee will be charged.]

Step 6Medsafe processes the data sheet, publishes it on the web site and advises the sponsor that the data sheet has been approved and published. (Publication of the data sheet on the web site is part of the approval process.) The sponsor may then distribute the data sheet.

13.3.5 New or updated safety data

Step 1The sponsor prepares a final version of the data sheet incorporating the new information (normally using as the source document a revised company prescribing information). In the case of a multi-source medicine, the source document will be the innovator’s data sheet including the new information published on Medsafe’s web site.

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Step 2The sponsor submits to Medsafe a self-assessable change notification (SACN) together with the required fee and:


computer disk3. The completed Data Sheet Declaration Form (see Appendix 12)4. The source document (if applicable).

Step 3Medsafe acknowledges the SACN. [Note that the document is not routinely assessed by Medsafe. Approval is granted on the basis of the applicant’s signed declaration that either the safety information is the same as that approved overseas or the safety information meets the requirements in the legislation and guidelines and has been approved by Medsafe and any NZ-specific additional safety information required by Medsafe is included.]

Step 4Medsafe processes the data sheet and publishes it on the web site and advises the sponsor that the data sheet has been published.

13.3.6 Miscellaneous changes to data sheets

Where a sponsor wishes to make minor changes to one or more data sheets (e.g. change in name or address of the sponsor, or changes in the pharmacokinetic or pharmacodynamic data) such changes should be submitted through a self-assessable change notification (SACN) listing all of the products concerned. It is necessary to submit both a paper copy and an electronic copy of the actual data sheet(s) concerned. Medsafe will then make the necessary changes to the data sheet text(s) on its web site. It is important that the changes are clearly indicated (e.g. by highlighting) on the paper copy.

Where a significant number of data sheets are involved the Evaluation Team Leader may grant a fee discount for bulk. Sponsors should discuss this option with the Team Leader.

13.4 Helpful Hints for Preparing Data Sheets for Publication

File FormatData sheets should be submitted on a 1.4Mb 3.5 inch IBM PC diskette, either as a Microsoft Word for Windows document or in Rich Text Format (RTF). The text must be clean and not include changes highlighted or struck out. The disk must be accompanied by a clean A4 paper copy of the data sheet. A separate paper copy highlighting any changes should also be supplied to assist identification and checking of the changes.

Text FormattingDo not include the heading “Data Sheet” on the electronic copy. This will be added during Medsafe’s formatting of the document for publication on the Medsafe web site.

For efficient processing and publication on the web site, it is essential that data sheets are prepared using standard “styles”. This will result in a standardised format for documents on the web site. Data sheets submitted without using these standard styles will not be processed and published, and will be returned to the applicant for re-submission in the required style.

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The document must use standard styles as follows:

‘Title’ for trade name of the product ‘Subtitle’ for the active ingredient, dose form and strength ‘Heading 1’for main section headings (such as “Uses” in the NZ format) ‘Heading 2’ for sub-section headings (such as “Actions” in the NZ format) ‘Heading 3’ for lower level headings ‘Heading 4’ for lowest level headings ‘Normal’ for all other text. ‘Normal Indent’ may also be used. Any dot points in the data sheet should be in the ‘List Bullet’ style. Any numbered lists should be in the ‘List Number’ style.

Note: No other styles should be used.

There is no special requirement for font type or size. Provided all the main headings use the style “Heading 1”, it does not matter what font size this is, or whether it is bold, underlined or in italics. When publishing data sheets on the web site, Medsafe will apply a macro and use a style sheet to convert the different fonts and font sizes to a single standard style, giving the published data sheets a uniform appearance.

To put a document into the required styles, simply highlight a heading and select the appropriate style from the style box in your word processing program. If the specified style does not appear in the style box, type it in. Normal text does not require highlighting as it is a default style.

More detailed instructions on using styles can be found in the Regulatory Information section of Medsafe’s web site (www.medsafe.govt.nz).

The name of the product should be in the style ‘Title’. The generic name, strength and dosage form should be in the style ‘Subtitle’. All main headings should be in Heading 1 style and then descending order to Heading 4.

The main words in the headings should be a capital letter followed by lowercase letters, e.g., ‘Dosage and Administration’ not ‘DOSAGE AND ADMINISTRATION’ or ‘Dosage and administration’.

All lines in company addresses should end with a Shift+Enter. This removes the spaces between lines.

All numbered lists should be in the style ‘List Number’ and bulleted lists under the style ‘List Bullet’.

Some graphics have been of a poor standard. Be prepared for requests for better diagrams. Note: graphics should be as “.gif” or “.jpg” files.

Tables require a significant amount of formatting. The easiest way of managing this is to have each piece of data in its own cell. Data separated by use of the Enter key is difficult to line up with corresponding data in other columns. Do not use tabs or spaces to align text

Text Emphasis should not be made by underlining the relevant word(s) as it

can be mistaken for a hyperlink on the web site. Instead “bold” the relevant word(s).

Any symbols used in the data sheet should be inserted from the Character Map. To insert a symbol, open “Accessories”, select “Character Map”, then choose the appropriate symbol from the available options.

All µg symbols should be written out as mcg or micrograms, µL should be microlitres, and µmol should be micromol or micromoles.

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Liquid measurements should be in millilitres, not teaspoons. The expressions “b.i.d” and “t.i.d.” should preferably be spelt out in full The degree (°) symbol should be in Arial font and the easiest way of doing

this is to hold down the ‘Alt’ key and then key in 0176. The ½ symbol is also found in the Arial character map (‘alt’ 0189).

Update the ‘Date of Preparation’ each time you make a change.

Content It is vital that all product details, indications and dosages are correct. If in

doubt, contact Medsafe to determine the approved indications. Generic companies must have all indications approved (either at the time

of initial approval of the generic or later through a CMN) - they cannot just adopt the innovator’s indications without notifying Medsafe.

Generic data sheets must be essentially similar to the innovator product data sheet but need not necessarily have identical wording.

Make sure all sentences make sense. Medsafe has found many sentences in draft data sheets that are ambiguous or simply incomprehensible.

Administrative Indicate if the data sheet is for a marketed or non-marketed

product. This saves Medsafe from having to contact the sponsor to clarify if the data sheet is to be published or not. Non-marketed products are not published on the web site.

If a product is withdrawn from the New Zealand market, ensure that Medsafe is advised. Unless the sponsor requests otherwise, the data sheet will normally remain on the web site for 2 years from the time of withdrawal of the product.

If you have an update, please indicate clearly the changes made. However, do not use revision lines on the electronic copy. If the changes are small, it is sometimes easier to amend the existing web copy rather than reformat the whole document. However, Medsafe still requires an electronic copy.

Note that: It is the sponsor’s/applicant’s responsibility to format the data sheet as

described above, but there is no special requirement to use any particular font or font size. The font and font size will be formatted by Medsafe when preparing the document for publication on the web site.

If the document is incorrectly formatted, it will be returned and the administration fee will not be refunded. If in doubt, contact Medsafe before submitting the electronic version.

If any minor changes (such as punctuation or spelling) have been made to the data sheet by Medsafe, these will be indicated on the approval letter. All other changes will be discussed with the sponsor before publication.

13.5 Changes to Published Data Sheets

For a CMN where the intended changes are to indications or dosage and require amendment of the data sheet, a draft document is to be submitted with the CMN along with any data supporting the change.

For all other CMN changes affecting the data sheet, a copy of the revised document should not be submitted until consent has been received for the change. Once the CMN has been approved the

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sponsor must submit the amended data sheet in both paper and electronic form together with the declaration and a copy of the CMN consent letter.

13.6 Additional Safety Information Required in New Zealand Data Sheets

The following safety information relating to specific medicines and therapeutic groups, must be included in the New Zealand data sheet irrespective of how the data sheet is prepared.

13.6.1 Individual medicines

Anistreplase Warning: antibody persists for at least 4 years and re-administration carries a risk of allergic reactions and reduced efficacy.

Astemizole Sedation warning - see entry for non-sedating antihistamines.QT-prolongation and arrhythmias warning: Risk factors - more than recommended dose, liver disease and interacting medicines.

Benzydamine Systemic allergic reactions may occur with topical use of benzydamine e.g. lozenges, gargle, oral gel.

CarbamazepineIf pregnancy occurs, or if considering starting treatment during pregnancy, the potential benefits must be carefully weighed against the possible hazards particularly in the first 3 months of pregnancy.

CarbimazoleAdverse effects: agranulocytosis and granulocytopenia.

CilazaprilAdverse effects: drop in haemoglobin.

CisaprideContraindications: Concomitant administration of azole antifungals; macrolide antibiotics such as erythromycin, clarithromycin or troleandomycin; HIV protease inhibitors; nefazodone.Adverse effects: Rare cases of cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT-prolongation have been reported. Most patients were receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias.Interactions: The main metabolic pathway of cisapride is through CYP3A4. The concomitant oral parenteral use of drugs that significantly inhibit these enzymes may result in increased plasma levels of cisapride and could increase the risk of QT-prolongation. Hence the concomitant use of the following medicines is contraindicated: azole antifungals; macrolide antibiotics such as erythromycin, clarithromycin or troleandomycin; HIV protease inhibitors; nefazodone.

Clarithromycin Interaction with cisapride: prolongation of the QT interval and cardiac arrhythmias.

Clozapine

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Warnings and precautions: Clozapine use has been associated with varying degrees of impairment of intestinal peristalsis ranging from constipation to intestinal obstruction, faecal impaction and paralytic ileus. On rare occasions these cases have been fatal. Patients should be warned and questioned about bowel function.Adverse effects: Constipation and ileus.

Note that access to prescribing clozapine is limited to medical practitioners who are vocationally registered under the Medical Practitioners Act 1995 in the branches of psychological medicine or psychiatry and medical practitioners employed as registrars in psychological medicine or psychiatry who are under the supervision of vocationally registered specialists in these fields. Practitioners prescribing clozapine must also comply with a minimum set of standards such as those contained in the New Zealand Guidelines for the use of Atypical Anti-psychotic Drugs (2nd edition, September 1998) or the requirements of local Hospital Health Service Protocols for the use of Clozapine.

ColchicinePharmacokinetics: The elimination half life is 10-31 hours. It increases with renal and hepatic impairment, and in overdose situations.Dosage and administration: For acute gouty arthritis: It is usual to start with a dose of 1.2mg (two 0.6mg tablets). This dose may be followed by 1 tablet 2-hourly until the pain is relieved or diarrhoea, or other gastrointestinal symptoms, develop. The total dose in an acute attack should not exceed 6mg (10 tablets total). It is important to observe this maximum because of the toxicity of colchicine, and the risk of serious prolonged diarrhoea. In elderly patients, those who are small and slight (<50kg) and those with renal or hepatic impairment, other treatments should be considered. If colchicine is used in these patients a lower maximum dose (3mg) should be observed.Such an intensive regimen of colchicine therapy should not be repeated until an interval of at least three days has elapsed between courses, but maintenance therapy with one tablet could be taken the day following treatment for an acute attack.Overdosage: Patients with a suspected overdose of colchicine require close hospital monitoring.

Erythromycin Interaction with cisapride: cardiac arrhythmias.

Fluconazole Interaction with cisapride: cardiac arrhythmias from prolongation of QT interval.

Fluoxetine Use with other serotonergic agents may lead to serotonin syndrome. Interaction with warfarin: haemorrhageWarning: withdrawal effects may occur and the dosage may need to be tapered on withdrawal in some patients.

Itraconazole Interaction with cisapride: prolongation of the QT interval and cardiac arrhythmias.

Ketoconazole Interaction with cisapride: prolongation of the QT interval and cardiac arrhythmias.

MetforminContraindications: significant renal impairment (serum creatinine > 0.16 mmol/L), chronic hepatic disease, conditions associated with hypoxia (e.g. recent myocardial infarction, cardiac failure, pulmonary disease and surgery), alcoholism.Warnings and precautions: because of the increased risk of lactic acidosis, metformin should be ceased at least 48 hours prior to a procedure (or on admission for an emergency procedure)

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predisposing to dehydration and not restarted until the patient is eating and drinking normally. The glucose levels of patients in catabolic states, e.g. sepsis or in the post-operative period should be monitored. Short term insulin therapy is advised.Other risk factors for lactic acidosis include sepsis, high dosage of metformin, increasing age and dehydration.

MetoclopramideAdverse effects: galactorrhoea (nonpuerperal lactation) and elevation of serum prolactin levels may occur.

Miconazole Interaction with cisapride: prolongation of the QT interval and cardiac arrhythmias.

Moclobemide Use with other serotonergic agents may lead to serotonin syndrome.

NefazodoneWarnings and precautions: Although there is no evidence that pre-existing liver disease increases the risk of an idiosyncratic hepatic adverse drug reaction, any patient with compromised liver function who experiences an additional hepatic insult may be at greater risk for a severe outcome. Therefore, in patients with pre-existing liver disease, the extent of hepatic impairment should be assessed when considering initiating nefazodone treatment.

Nefopam Actions: include pharmacological actions, particularly anticholinergic and sympathomimetic action.

Nystatin, oralSystemic absorption and systemic adverse reactions, including hypersensitivity reactions may occur.

Oestriol (systemic, not topical)Delete any statements about endometrial proliferation not occurring.Warnings and Precautions: A population-based case control study has shown that oral oestriol 1-2mg daily is associated with an increase in the risk of endometrial cancer in postmenopausal women. The overall risk associated with recent use (< 1 year previously) compared with no use was 2.4 (95% confidence interval 1.8-3.0). The risk increased with duration of use and declined rapidly after discontinuation of hormone use. The study provided no information on the relative risk of endometrial cancer between oestriol and standard potency oestrogens, nor did it investigate a possible dose relationship.Since endometrial proliferation may occur in some women, cyclic administration of a progestogen may be appropriate. (This advice could be included in another section.)

Oestrogens - low potency (systemic, not topical)(Adapt the information under oestriol.)

OmeprazoleAdverse effects: hyponatraemia

Paroxetine Warning: some patients will experience withdrawal effects, and dosage may need to be tapered during withdrawal.

Phenylbutazone Indication: use in acute flare-ups of ankylosing spondylitis only, because of the risk of aplastic anaemia.

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PropofolDosage and Administration (sedation during intensive care): There are limited data on propofol safety at high dosage (> 4 mg/kg/h) for extended periods of greater than 48 hours (see Warnings and Precautions).Warnings and Precautions: Special caution should be exercised of infusion rates in prolonged sedation (>48 hours) exceed 4 mg/kg/h. In severely head injured patients also receiving incremental inotropic support, fatal metabolic acidosis or cardiac failure have been reported in association with propofol infusion rates >5 mg/kg/h for >58 hours. Review of the sedation regime should be conducted in the presence of unexplained acidosis or cardiovascular compromise.Adverse Effects: very rarely with prolonged sedation, metabolic acidosis and cardiac failure.

RisperidoneAdverse effects: hepatic reactions.

Roxithromycin Adverse effects: neuropsychiatric reactions may occur including agitation, anxiety, confusion, depression, sleep disorder, hallucination.

Sertraline Warning: some patients will experience withdrawal effects, and dosage may need to be tapered during withdrawal.

Spironolactone Should not be prescribed for hirsutism in women contemplating pregnancy and should be considered only after other possible measures have been explored.

Streptokinase Warning: antibody persists for at least 4 years, and re-administration carries a risk of allergic reactions and reduced efficacy.

TamoxifenAdverse effects: There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism during tamoxifen therapy. When tamoxifen is used in combination with cytotoxic agents, there is a further increase in the risk of thromboembolic events occurring.Precaution: According to one study, women who have taken unopposed oestrogen therapy, who are obese, or who are continuing to take tamoxifen after therapy for 5 years may be at greater risk for endometrial cancer and consideration should be given to closer monitoring of these groups.

Terbinafine Adverse effects: neuropsychiatric (dizziness, agitation, paraesthesia), haematological, skin and hepatic adverse effects.

Terfenadine Sedation warning -see entry for non-sedating antihistamines.Adverse effects: QT prolongation and cardiac arrhythmias. Risk factors: more than recommended dose, liver disease and concomitant interacting medicines or grapefruit juice.

ThioridazineUnder Therapeutic indications add as the preamble: Thioridazine therapy should be initiated only by a specialist and only after the patient has failed to respond adequately to treatment with appropriate courses of at least two other suitable medicines.

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Under Dosage and Method of Administration add as the preamble: Treatment should be initiated only after the patient has been assessed for risk factors for QT-prolongation and undergone a check of the QTc-interval and serum potassium (see Warnings and Precautions for further details).Dosage and timing of thioridazine intake should be individually adjusted according to the nature and severity of symptoms. It is recommended that the initial dose be at the lower end of the ranges mentioned below and be gradually increased until the fully effective level or a maximum of 200mg daily is reached. The total daily amount is usually given in 2 to 4 divided doses. Dosages of more than 200mg daily should be prescribed only in exceptional circumstances and only under the supervision of a specialist. If dosages above 200mg are used, a maximum of 600mg daily should be observed and after every increase in dose the QTc-interval should be measured. The ECG should be recorded 2 weeks after the increase in dosage and the measurement taken 12 hours after a dose or immediately prior to a dose. The dosage should be adjusted downwards if the QT c-interval is 500ms and the patient should be assessed for risk factors (see Warnings and Precautions). For patients on a maintenance dose of greater than 200mg daily, the ECG should be checked if the patient develops a disease state or commences medication that may increase the risk of QT-prolongation either directly or indirectly (e.g. by causing hypokalaemia).Paediatric indications: As for adults, thioridazine should be prescribed for children only under specialist supervision (paediatrician or child psychiatrist). The maximum dose of 4 mg/kg/day should be observed (upper limit 200mg). Doses above 200mg daily should be used only in exceptional circumstances and only under specialist supervision, and the contraindications, precautions and monitoring advice should be followed.The dosage instructions for some of the indications will need to be adjusted for consistency.

Under Contraindications add: History of QT-prolongation, ventricular arrhythmia, torsade de pointes, and those with risk factors for arrhythmia, such as second or third degree atrioventricular block, clinically significant heart disease and congenital long QT-syndrome.Baseline QTc-interval 500ms.Abnormal serum potassium.Concomitant use of medicines which inhibit CYP 2D6 (e.g. cimetidine, fluoxetine, paroxetine, moclobemide, tricyclic antidepressants) or inhibit metabolism by another mechanism (e.g. fluvoxamine, pindolol, propranolol) or cause prolongation of the QTc-interval (see Interactions).

Under Warnings and Precautions add:QT-prolongation: Because of the risk of QT-prolongation, thioridazine should be initiated only after the patient has been assessed for risk factors for QT-prolongation and undergone baseline ECG and serum potassium. Patients with a baseline QTc-interval 500ms should not receive thioridazine. Abnormal serum potassium should be corrected prior to prescribing thioridazine. Concomitant medication should also be assessed for substances that inhibit CYP 2D6, inhibit metabolism of thioridazine by another pathway or cause QT-prolongation (see Interactions). Use of thioridazine is contraindicated with such medicines. Caution should be exercised if the patient is taking a medicine which may predispose to hypokalaemia.Because thioridazine is metabolised by CYP 2D6, patients who are slow metabolisers by this enzyme are also at increased risk of QT-prolongation with thioridazine. For some patients slow metaboliser status may be suspected, because of experience with other agents metabolised by CYP 2D6. A procedure for checking for slow metaboliser status is not widely available. Those patients known to be slow metabolisers should not be prescribed thioridazine.Patients taking thioridazine who have a QTc-interval 500ms during treatment should have the dosage adjusted downwards and an assessment conducted for risk factors. The continuing prescription of thioridazine should be evaluated in these patients. If the QTc-interval is persistently 500ms, or if the patient develops a contraindication (disease state or medicine), thioridazine should be discontinued by gradual dosage reduction over a period of a month and concurrent introduction of alternative medication.

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Elderly patients: Elderly patients are more likely to have identified or unidentified cardiovascular disease and special care should be taken with regard to the risk of arrhythmias from QT-prolongation in these patients.

Under Interactions add:Cytochrome P450 2D6 metabolismThioridazine is metabolised by CYP 2D6 and is itself an inhibitor of metabolism by this pathway. The effects of thioridazine may therefore be increased and prolonged by medicines which inhibit this enzyme, such as cimetidine, fluoxetine, paroxetine, tricyclic antidepressants and moclobemide. Concomitant use is contraindicated.

Metabolism by other pathwaysCertain other agents, such as fluvoxamine, pindolol and propranolol, inhibit the metabolism of thioridazine by other pathways. Concomitant use is contraindicated.

Tricyclic antidepressants Both tricyclic antidepressants (e.g. amitriptyline, dothiepin, doxepin, nortriptyline, clomipramine) and thioridazine may cause QTc-prolongation. In addition, most tricyclic antidepressants, like thioridazine inhibit CYP 2D6, resulting in possible increases in plasma concentrations of both medicines. Concomitant use is contraindicated.

Agents causing QTc-prolongation: Thioridazine is contraindicated with agents which may cause QTc-prolongation including quinine, terfenadine, astemizole, cisapride, some antiarrhythmic medicines (e.g. amiodarone, quinidine, flecainide, sotalol), tricyclic antidepressants and some other antipsychotic agents (e.g. droperidol, haloperidol, risperidone).

Tiaprofenic acid Adverse effects: cystitis, which may progress to renal failure if tiaprofenic acid is not discontinued.Warning: use with caution in patients with recurrent urinary tract infections or cystitis, or urinary symptoms from any cause, since the symptoms of urinary problems with tiaprofenic acid may be masked. Before starting treatment with tiaprofenic acid all patients should be advised to contact their doctor if any urinary symptoms develop.

VigabatrinWarnings and Precautions: Visual field defects may develop with vigabatrin. Asymptomatic effects are common (about 30%) but symptomatic effects occur infrequently (<1%). It is not clear whether the rate may continue to increase with duration of use. Visual field defects with vigabatrin appear to be irreversible after discontinuation of vigabatrin. Available data suggest that the pattern of visual field defects is a concentric constriction of the visual field of both eyes, which is generally more marked nasally than temporally. In the central visual field (within 30 degrees of eccentricity) frequently an annular nasal defect is seen. Central visual acuity is not impaired. Most patients with defects confirmed by perimetry have not previously noticed any symptoms, even in cases where a severe defect was observed in perimetry. Signs such as blurred vision, diplopia, peripheral vision disturbances (bumping into furniture, difficulty in locating objects in the home or while shopping) may be an indication of visual field constriction. The risk of visual field defects should be considered and the benefit to be expected from vigabatrin weighed against the risks and benefits of other treatment options before prescribing vigabatrin. If seizures are better controlled with vigabatrin than with other agents it may be acceptable to risk some visual field constriction, especially if it may be asymptomatic. Special consideration should be given to the use of vigabatrin in children, since it is not possible to conduct adequate visual field testing in those under a developmental age of 12-13 years.Appropriate visual field testing should be performed at baseline and six-monthly thereafter. Patients should be instructed to report any new vision problems. If visual symptoms develop, then the patient should be referred to an ophthalmologist for further evaluation.

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If visual field defects are identified, the decision to continue or discontinue vigabatrin should be based on an individual benefit-risk assessment. In patients where visual field testing cannot be adequately performed (e.g., commonly in young children), the decision to start vigabatrin should similarly be based on an individual benefit-risk judgement.Adverse effects: Visual field defects have been reported in patients receiving vigabatrin. Asymptomatic visual field defects are frequent whereas symptomatic visual field constriction of various degrees is uncommon (see Warnings and Precautions).

Warfarin Interaction with oral miconazole gel to produce an increase in INR and bleeding problems.

13.6.2 Therapeutic Groups

ACE inhibitorsNot for use in pregnancy. Embryopathy can occur in second or third trimester. May cause pancreatitis.

Beta-blockers, including alpha/beta blockersContraindicated in asthma or other obstructive lung disorders, uncontrolled heart failure, cardiogenic shock, sick sinus syndrome, grade 2 and 3 A-V block or severe bradycardia.

BenzodiazepinesMay impair driving. Will exacerbate the effects of alcohol. Can cause blurred vision/dizziness and impair concentration. Rebound effects may occur, especially with short-acting agents. Can cause dependency even in short term use. Courses should be as brief as possible - up to one week for insomnia or three weeks for anxiety. Intermittent use may be acceptable. After chronic use, tolerance will occur and doses should be tapered off in withdrawal.

CephalosporinsShould not ordinarily be given to those allergic to cephalosporins or to penicillins, especially where an allergic or urticarial reaction has occurred.

Dermal corticosteroids Contraindicated where there is coexisting infection, otherwise concurrent antimicrobial therapy required. Not for use in the eye. Use in pregnancy to be limited because of possible teratogenic effects. Systemic absorption and hypothalamic-pituitary axis suppression may occur. Use for longer than 4 weeks can cause atrophic striae, prolonged use on flexures and in intertriginous areas is undesirable.

FluoroquinolonesMay cause tendinitis, hypoglycaemia.

H2-receptor antagonistsWhen indicated for the eradication of H pylori in patients with peptic ulcer disease:The data sheet should reflect the importance of H Pylori in the pathophysiology of peptic ulcer disease and emphasise that eradication of the infection is the single most important therapeutic intervention in patients positive for H. Pylori.

Hormone replacement therapyProlonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in post-menopausal women. Studies have found that protection from this effect is achieved with 10 days progestagen therapy per month.

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There is a small risk of breast cancer with the use of hormone replacement therapy. The risk increases with duration of use, but drops to the normal level within five years of discontinuation of use. Women using hormone replacement therapy have less advanced breast cancer at diagnosis. The role of progestogens in the risk of breast cancer is unclear.Contraindicated in cerebrovascular or coronary artery disease, cancer, pregnancy, undiagnosed abnormal vaginal bleeding, thrombophlebitis or thromboembolic processes or a history of these; hereditary or acquired predisposition to venous thrombosis (e.g. antithrombin III deficiency). Relatively contraindicated in gall bladder disease, hypertension, decreased glucose tolerance, hypercalcaemia or where there is an hepatic adenoma.Warnings should include: The risk of venous thromboembolism is increased with a positive family history, obesity (body mass index >30kg/m2), prolonged immobilisation, surgery, trauma or severe varicose veins. If any signs of thromboembolic processes occur, treatment should be discontinued immediately. Any statements about monitoring patients with a history of thromboembolic disorders or other inadequate precautions should be deleted.Adverse effects: skin rash.

Hormone replacement therapy products with the following indication: “For a reduction in the risk of coronary heart disease (CHD) in women with no current or prior evidence of CHD.”The following warning statement: “In the Heart and Oestrogen-progestin Replacement Study (HERS), 2763 postmenopausal women with documented coronary heart disease (CHD) who were taking their usual cardiac medications were randomised to conjugated oestrogen’s (CE) 0.625mg plus medroxyprogesterone acetate (MPA) 2.5mg daily or placebo. Documented CHD was defined as the presence of one or more of the following: previous myocardial infarction, previous percutaneous mechanical revascularisation, previous coronary artery bypass graft surgery, or angiographic evidence of greater than 50% occlusion of one or more major coronary arteries. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of recurrent coronary heart disease events, defined as CHD death or nonfatal myocardial infarctions, in this elderly population (average age 66.7 years) with established coronary disease. There was an early increase in recurrent CHD events in the first year in the CE plus MPA group, but after two years of treatment with CE plus MPA, a decrease in recurrent CHD events was reported.”

Inhaled and intranasal corticosteroidsWarnings and Precautions: advice about systemic effects and about growth retardation occurring in children.

Non-sedating antihistamines Sedation warning - “Although this medicine is unlikely to affect the ability to drive or operate machinery, a few people may be impaired and care should be taken.”

Non-steroidal anti-inflammatory agentsParenteral:Contraindicated in patients taking anticoagulants or on intensive antidiuretic therapy.Oral or parenteral:Contraindicated in patients with gastrointestinal ulceration, haemorrhagic diasthesis, asthma. Relatively contraindicated in liver dysfunction. Dosage should be minimised in the elderly and in patients with renal impairment.

Oestrogen-containing contraceptive pillContraindicated in women with cancer, liver disease, disturbed lipometabolism, a history of thromboemboli, hemiplegic migraine, undiagnosed vaginal bleeding. Ischaemic or haemorrhagic stroke is more likely in women of 35 years of age and older who smoke.

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Relatively contraindicated in women with hypertension, cardiac or renal dysfunction, diabetes, migraine, epilepsy, depression. Unsuitable for use in lactating women.

Opioid analgesics Warnings: This medicine should not be used for the treatment of chronic pain of non-malignant origin unless:all other conservative methods of analgesia have been tried and have failedthere is no psychological contraindication, drug-seeking behaviour or history of drug misuse.Therapy should only be initiated by a specialist with experience in chronic pain management and in accordance with guidelines approved by the New Zealand Medical Association.

Oral contraceptives containing desogestrel or gestodeneContraindications: A history of venous thromboembolism or hereditary thrombophilia.Warnings and precautions: If any signs of thromboembolic processes occur, treatment should be discontinued immediately. The risk of venous thromboembolism increases with a positive family history, obesity, extensive varicose veins, immobilisation, malignancy, haemolytic uraemic syndrome and systemic lupus erythematosus. The risk is temporarily increased with major surgery, trauma, injury or temporary immobilisation. Four published studies have suggested a higher risk of venous thromboembolism with combined oral contraceptives containing desogestrel or gestodene than with those containing levonorgestrel. The absolute risk of venous thromboembolism appears to be approximately 2 per 10,000 woman years for the oral contraceptives containing desogestrel or gestodene and 1 in 10,000 woman years for those containing levonorgestrel. For comparison, the risk associated with pregnancy is 6 cases per 10,000 pregnant woman years. The figures in the four studies point to a higher risk with the oral contraceptives containing desogestrel or gestodene. Bias and confounding factors may partially explain the difference in risk.

Progestogen-only oral contraceptivesContraindications: Current thromboembolic process.Contraindicated in women with a history of ectopic pregnancy, cancer of breast or genitals.Contraindicated in liver disease, disturbed lipometabolism, severe arterial disease, undiagnosed vaginal bleeding.Relatively contraindicated in patients with hypertension, diabetes, migraine, cardiac dysfunction, ovarian cysts, malabsorption syndrome, depression. Use with caution in lactating women since progestogens are found in milk. Possible loss of effect through interaction with antibiotics, anticonvulsants or diminished absorption through diarrhoea or vomiting. Action to be taken in the event of a suspected pregnancy. May enlarge uterine fibroids.May cause certain liver function tests to be unreliable.Warnings and precautions: There is evidence that doses of progestogen higher than those used for contraception (5-30mg daily vs. 0.5mg daily) may be associated with an increased risk of venous thromboembolism. Progestogens at doses used for contraception do not appear to be associated with an increase in risk of venous thromboembolism. Progestogen-only contraceptive pills may be considered as an option for contraception in women who have experienced DVT or PE with a combined oral contraceptive, provided the thromboembolic process has resolved. In most cases a progestogen-only contraceptive pill need not be discontinued for major surgery involving immobilisation.

Protease inhibitorsWarnings and precautions: There have been reports of new onset diabetes mellitus or hyperglycaemia, or exacerbation of pre-existing diabetes mellitus or hyperglycaemia. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred.

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In the majority of cases, treatment with protease inhibitors was continued while in some cases treatment was either discontinued or interrupted. In some patients, hyperglycaemia persisted after the protease inhibitor was withdrawn, whether or not diabetes was reported at baseline.Adverse effects: new onset of diabetes mellitus or hyperglycaemia, or exacerbation of pre-existing diabetes mellitus.

Proton pump inhibitorsWhen indicated for the eradication of H pylori in patients with peptic ulcer disease:The data sheet should reflect the importance of H Pylori in the pathophysiology of PUD and emphasise that eradication of the infection is the single most important therapeutic intervention in patients positive for H. Pylori.

Products derived from or purified using human blood componentsThe data sheet should include the fact that the product is derived from or purified using human blood components and that the risk of transmission of some infectious agents cannot be excluded completely.

Topical medicines likely to be used in the male or female genital areaInformation about the compatibility of these products with latex rubber condoms should be included in the data sheet.

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Section 14: Bioequivalence and Interchangeability

Section summaryThis section: defines the choice of reference product for a bioequivalence study lists the products for which comparative bioavailability is required discusses interchangeability and the list of interchangeable multi-source medicines

14.1 Introduction

To be approved for distribution in New Zealand, a multi-source prescription medicine must usually be bioequivalent to the appropriate New Zealand Reference Product (NZRP). Similarly, evidence of bioequivalence will usually be required for changes in products where bioavailability or clinical efficacy may be significantly altered as a result of the change. Evidence of bioequivalence with a reference product is the surrogate used, instead of clinical trial data, to demonstrate safety and efficacy.

Oral dose forms are considered bioequivalent when 90% confidence intervals for the ratios of their geometric mean Cmax and AUC (from zero time to infinity for single doses or within a dosing interval at steady state) are within the range 0.8 - 1.25 (wider limits, e.g. 0.75 – 1.33, may be appropriate for Cmax in certain circumstances where this can be justified on clinical grounds), and any difference between their Tmax’s is within clinically acceptable limits.

The above range is the maximum permitted for medicines that present a known or theoretical bioequivalence problem requiring an in vivo bioequivalence study. It may be tightened for medicines that have:

a narrow therapeutic index known serious dose-related toxicity a steep dose/effect curve non-linear pharmacokinetics within the therapeutic dosage range.

Bioequivalence of metered dose inhalers and other inhaler devices may be established from data establishing physical and clinical equivalence.

Procedures for establishing the bioequivalence of oral does forms and inhaled products are outlined in Sections 15 and 16 respectively.

There is no New Zealand specific guideline for bioequivalence of topical corticosteroid preparations. The US FDA has published a guideline for establishing the bioequivalence of this type of product entitled Topical Dermatological Corticosteroids: in vivo bioequivalence.

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Note: Where there is any doubt about the appropriateness of a bioequivalence study age, design, choice of reference product, formulation of the reference product, or the formulation of the test product, the applicant is strongly advised to seek Medsafe’s advice before submitting the data in support of an NMA or CMN.

14.2 Choice of Reference Product

To establish bioequivalence, the applicant must provide evidence that a multi-source product is bioequivalent to the New Zealand Reference Product (NZRP). In most circumstances, the NZRP is either the innovator product marketed in New Zealand or another product for which Medsafe holds clinical trial and pharmacology data.

There may be more than one reference product, especially where two products have entered the market with clinical trial and pharmacology data. Where there is no obvious innovator or where the innovator product is discontinued, the reference product is the New Zealand market leader.

It is not essential for the batch of reference product used in the bioequivalence study to be sourced in New Zealand. However, when it is sourced outside New Zealand, evidence is required that the foreign-sourced batch has an identical formulation to the New Zealand market product. Such evidence usually includes most or all of the following:

appearance dimensions (mean and individual data for 10 dosage units) mean weight and weight uniformity for 20 dosage units dissolution profiles (mean and individual data for 6 dosage units) at 3 different pHs across the

gastro-intestinal range 1 to 7.5 Fourier transform infra-red (FTIR) spectra of samples, recorded either as KBr pellets or as

pressed powders in a diamond cell, scaled so that the strongest band in each spectrum is the same height and the spectra can be overlaid for comparison

powder X-ray diffraction (XRD) spectra results (where practicable) of qualitative and quantitative analyses of the excipients.

For changed innovative medicines the reference product will be the formulation previously approved and marketed.

14.3 Bioavailability Data Requirements

14.3.1 Product types that require comparative bioavailability data

If a new prescription medicine is intended to be substituted for a product already on the market, bioequivalence with this product should be shown or justified. Comparative bioavailability studies should be carried out when lack of bioequivalence may be therapeutically significant. Therefore, comparative bioavailability studies are carried out if there is a risk of lack of bioequivalence and/or a risk of therapeutic failure or diminished clinical safety.

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Comparative bioavailability studies are required for the following types of product:

1. Systemically-acting oral immediate release products with any of the following characteristics: indicated for serious conditions requiring an assured therapeutic response narrow therapeutic index steep dose-response curve pharmacokinetics complicated by:

- variable absorption- absorption less than 70% - non-linear pharmacokinetics- pre-systemic elimination/first pass metabolism greater than 70%

high ratio of excipients to active ingredients unfavourable physico-chemical properties (e.g. low solubility, poor permeability, metastable

crystalline form, instability) documented evidence of bioavailability problems either for the particular medicine or other

medicines with similar formulations or whose active ingredient(s) have similar chemical structures

no relevant data available, unless justification by the applicant that an in vivo study is not necessary

2. Non-oral and non-parenteral immediate release products designed to act systemically3. Modified release products with a systemic action4. Fixed combination products with systemic action

14.3.2 Justifying not submitting comparative bioavailability data

Where comparative bioavailability data are normally required in an application but the sponsor wishes to omit the data, justification for the omission is required.

The following issues should be addressed in the justification (copies should be provided of any literature cited):

What is the water solubility of the medicine? What is the nature of the dosage form? For reformulations and applications for approval of a new strength or flavour of an already

approved product, how similar are the formulations of the various products? For different strengths, are the formulations direct scales?

For reformulations and applications for approval of a new strength of an already approved product, how do dissolution profiles of the various products compare? For multi-source products, this may include a dissolution comparison of each strength with the corresponding strength of a market leader. If the multi-source and the market leader are supplied in different strengths, a comparison is still possible in terms of percent label strength dissolved against time, but the justification will be less powerful.

Is there a first pass effect and is it significant? Are the pharmacokinetics linear? How wide is the margin between the minimum effective and minimum toxic plasma

concentrations? What are the clinical consequences of lack of bioequivalence or variable bioavailability (e.g.

increased dose leading to toxicity or decreased dose leading to inefficacy)? Are any special claims made in labelling or prescribing information about the absorption

profile?

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14.3.3 Medicines not requiring comparative bioavailability data

New Medicine Applications for the following dose forms or product types do not usually need to include comparative bioavailability data or a justification as to why the data are not required.

Over-the-counter (OTC) medicines. Simple aqueous solutions intended for intravenous injection. Micellar or liposomal solutions

are not regarded as ‘simple’ solutions. Solutions, complex or simple, which do not contain pharmacologically active ingredients ,

e.g. artificial tears, contact lens solutions, lubricants, irrigation solutions and cleansing solutions. Aqueous injections containing the same active ingredients and excipients in the same

concentrations, and administered by the same route(s), as an already approved product. Oral solutions containing the same active ingredients in the same concentration as an oral

solution already approved, and where the excipients do not significantly affect gastric passage or absorption of the active ingredients.

Powders for reconstitution where the resultant solution meets the criteria for one of the five solution groups above.

Topical or locally acting solutions that have the same formulation. Products containing therapeutic substances which are not systemically or locally absorbed

(e.g. antacids, anthelmintics, barium sulphate enemas or oral suspensions, non-biodegradable ion exchange resins or other non-biodegradable long chain polymers, powders in which no ingredient is absorbed). If there is doubt as to whether absorption occurs, a study or justification may be required.

Vaccines (clinical trial data are always required for vaccines) Nebuliser solutions Nasal sprays intended for local action Medicinal gases Monoclonal antibodies Dialysis solutions Products for which an acceptable correlation has been shown between the dissolution rate in

vivo and in vitro, and the dissolution rate in vitro of the new product is equivalent to that of an already approved market leader under the same test conditions as were used to establish the correlation.

A product that differs from an already approved product only in the strength of the active substance does not require bioavailability data provided all of the following five conditions are met:

1. the pharmacokinetics of the medicine are linear within the therapeutic dose range, and2. the products are direct scales (or in the case of small strengths, the ratio between the

excipients is the same), and3. both products are produced by the same manufacturer using the same manufacturing process,

and4. a bioavailability or bioequivalence study has been performed with the original product, and5. under the same test conditions, the dissolution rate in vitro is the same.

Note: Products are said to be ‘direct scales’ only if the same granulate or mixture of powders is used to manufacture the various strengths, but the products are compressed or filled at varying weights corresponding to the various strengths.

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Products for which the application includes well-performed clinical trials (for the patient population and indication applied for) which establishes efficacy comparable to that of the innovator/market leader product. These products may be approved for distribution even though establishing therapeutic equivalence and interchangeability with the innovator/market leader product is considered a separate issue

14.3.4 Changes not requiring further bioequivalence testing

The following changes to already approved products do not usually require comparative bioavailability data or a justification for the lack of data.

Immediate release tablets, capsules and immediate release compressed implants, suppositories and pessaries:

(i) Minor adjustments to the quantities of currently used hydrophilic excipients, including hydrophilic lubricants/glidants, where dissolution profiles of the new and old formulations have been shown to be in the same range

(ii) Minor changes to the content of talc where dissolution profiles of the new and old formulations have been shown to be in the same range.

For detailed guidance on what constitutes a minor or major change to these products see the US FDA guidelines:

Guidance for Industry - Immediate Release Solid Oral Dosage Forms, Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation

Guidance for Industry - SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.

Moulded suppositories and pessaries:Minor quantitative changes in the currently used excipients where the dissolution profile is in the same range as previously, and Either(i) Microscopic imaging of particles has shown no visible change in size distribution and

morphology (particle sizing may also be conducted by other suitable means such as a Hegmann gauge).

Or (ii) It has been demonstrated that particle size and polymorphic form of the active raw material are

unaltered. If the method used to check polymorphic form has not been validated, at least two methods should be used including at least one of differential thermal analysis and differential scanning calorimetry. This does not apply where the active is in solution at any stage during manufacture of the finished product, or if it is in solution in the finished product or is present as liquid globules.

For detailed guidance on what constitutes a minor or major change to these products see the US FDA guidelines: Guidance for Industry - Nonsterile Semisolid Dosage Forms, Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Release Testing, and In Vivo Bioequivalence Documentation.

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Ointments, creams, lotions:Minor changes in the quantitative content of currently used excipients.

For detailed guidance on what constitutes a minor or major change to ointments and creams see the US FDA guidelines: Guidance for Industry - Nonsterile Semisolid Dosage Forms, Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Release Testing, and In Vivo Bioequivalence Documentation

Oral Liquids:(i) Minor changes to the nature or quantity of excipients in simple aqueous solutions,

particularly where evidence is provided to show that the osmolality has not been significantly affected

(ii) Minor quantitative changes to currently used excipients in aqueous suspensions where evidence regarding particle size and polymorphism is provided. See “moulded suppositories and pessaries” above.

Aqueous solutions for injection:Addition or deletion of up to 1% benzyl alcohol.

Other minor reformulations and minor changes to the manufacturing procedure, where it can be convincingly argued that the change will not affect bioavailability and where relevant, the dissolution profiles in vitro under the same test conditions are equivalent.

Other changes to manufacturing unlikely to affect bioavailability. For already approved products, notifications to change the site of manufacture, method of manufacture, manufacturing equipment or source of active ingredients do not usually require bioavailability data or a justification for the lack of bioavailability data. However, the following applies:

(i) Evidence should normally be provided that the dissolution profile is in the same range as previously for all solid dosage forms (e.g. tablets, capsules, suppositories, pessaries, implants) and all modified release dosage forms administered by whatever route (e.g. oral, transdermal, vaginal).

(ii) For semi-solid and liquid products (e.g. ointments, creams, lotions, moulded suppositories, pessaries), evidence regarding particle size and polymorphism is required (see “moulded suppositories and pessaries” above).

Medsafe may ask for additional information in certain cases, such as a major change in a method of manufacture for a modified release product. Changes to the synthetic route for an active substance do not require further bioequivalence testing unless the last stage of the synthesis and purification are changed.

Further information on the technical requirements for bioequivalence testing can be found in Sections 15 and 16.

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14.4 Interchangeability of Multi-source Medicines

Medsafe maintains and publishes a list of Interchangeable Multi-source Medicines (IMM). The list is available on Medsafe’s web site.

Two products are considered to be interchangeable if they meet the following criteria:

Either(a) they are pharmaceutically equivalent, and(b) their bioavailabilities (rates and extent of absorption) after administration in the same molar

dose are similar to such a degree that safety and efficacy are essentially the same. Or(a) they are pharmaceutically equivalent, and(b) they present no known or potential problems of bio-inequivalence, and (c) they meet a relevant in vitro standard.

In most cases products listed as interchangeable are identical dose forms. However, in general, tablets and capsules are clinically equivalent dose forms. Therefore, where the criteria of bioequivalence are met and interchange would not result in any clinical problems, tablets may be listed as interchangeable with capsules (or vice versa).

All new multi-source medicines are considered for interchangeability with the New Zealand Reference Product (see Section 14.4.2) during the evaluation process. If they meet the required criteria, they are added to the list of interchangeable medicines.

Where consent has already been granted for a multi-source medicine that is not already on the IMM list, the sponsor may submit a request for listing using the CMN form and provide the appropriate bioequivalence data and fee.

14.4.1 Style and content of the Interchangeable Multi-source Medicine List

The original IMM list published in 1994 as a booklet was based on work evaluating the interchangeability of the top 200 medicines sold in New Zealand at that time. Since 1994 the list has been gradually expanding to include all medicines for which there is a multi-source version approved for sale in New Zealand.

In the past Medsafe has only published interchangeable medicines in this booklet. With the current interest in substitution at pharmacy level, it seemed opportune to reinforce which medicines are not considered interchangeable in the 2000 edition and subsequent editions of the IMM List. Where a medicine is considered interchangeable with the reference product, it is included in Section 1 of the list. If it is not interchangeable, the medicine is published as such in the New Zealand Gazette and is now listed in Section 2 of the IMM list.

Each section is further divided into two parts as follows.

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SECTION 1: Interchangeable multi-source medicines

Medicines which either pose no risk (known or theoretical) of bio-inequivalence (Section 1.1) or have been proven to be bioequivalent to an appropriate reference product (Section 1.2).

Section 1.1 Medicines that pose no risk of bio-inequivalence

Many over-the-counter (OTC) products, including nasal sprays, are included in Section 1.1, along with medicines such as oral solutions and aqueous injections. Medicines in this section are assessed for safety quality and efficacy by Medsafe before they can be sold in New Zealand and any product included in this section can be considered interchangeable with any pharmaceutically equivalent medicine. A bioequivalence study is not required as part of the application to Medsafe.

The following groups of medicines are considered interchangeable:

All pharmaceutically equivalent restricted medicines, pharmacy-only medicines, and general sale medicines (all dose forms)

All pharmaceutically equivalent prescription medicines, or controlled drugs requiring a prescription, in the following dose forms:

oral solutions and powders for reconstitution for oral solutions aqueous injections and irrigations, and powder for reconstitution for aqueous injections pure substances (e.g. volatile liquids used as anaesthetics) nebuliser solutions

Why are some OTC medicines not included in Section 1.1?For a small number of OTC products, (e.g. isosorbide mononitrate) bio-inequivalence could produce serious medical consequences. In these instances, Medsafe requires a bioequivalence study to be submitted with the application. Depending on the result of the evaluation, the product will be listed as having been proven to be interchangeable (Section 1.2) or not interchangeable (Section 2).

Section 1.2 Medicines that have proven bioequivalent to a NZ Reference Product

All medicines listed in Section 1.2 are prescription medicines, or controlled drugs that require a prescription, which are likely to be associated with clinical consequences if bioequivalence is not demonstrated. Medsafe requires that the bioequivalence study submitted for evaluation prove that the multi-source product is in the same dosage and physico-chemical form as the reference product (i.e. pharmaceutically equivalent), and is bioequivalent with the reference product before the product can enter the NZ market. Medicines are listed alphabetically by active ingredient(s) name and are interchangeable at pharmacy level without compromising clinical outcome. Products are identified with the name of the distributor rather than the name of the manufacturer since this is the information that most clearly identifies the medicine for a prescriber or pharmacist using the list.

Why are some OTC active ingredients listed in Section 1.2?Medicines may contain an active ingredient which is classified in both prescription and OTC categories, however the indications for the different classifications are usually quite different. Medsafe requires products to demonstrate bioequivalence for the prescription formulations and indications. The OTC indications are usually for the treatment of minor, self-limiting conditions for which the clinical consequences of bio-inequivalence are minimal.

Why are some products which meet the criteria of Section 2.1 listed in Section 1.2?

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In some circumstances a prescription medicine, or a controlled drug that requires a prescription, is co-marketed by two companies. In such cases the products have identical formulations and dose forms and are therefore interchangeable even if they meet the criteria listed for non-interchangeability listed in Section 2.

SECTION 2: Medicines considered to be non-interchangeable

Medicines which are either generally considered to be non-interchangeable on pharmacological grounds (Section 2.1) or which fall outside of Medsafe’s bioequivalence guidelines, and have been gazetted as non-interchangeable (Section 2.2) are listed in these sections.

Section 2.1 Medicines generally considered to be non-interchangeable

While prescription medicines, and controlled drugs that require a prescription, listed in this section have met Medsafe’s requirements for entry to the market, they are not considered to be interchangeable owing to a number of pharmacological and pharmaceutical reasons including:

a) the product has a narrow therapeutic index (NTI). In cases where the margin between therapeutic and toxic effects is very small, i.e. an NTI, the differences in bioavailability between the reference and multi-source product permitted in bioequivalence testing may give rise to significant clinical consequences. Products with an NTI, such as anticonvulsants, antiarrhythmics, theophylline, warfarin, isotretinoin, cyclosporin, thyroxine, etc. are, therefore, not usually considered to be interchangeable.

b) the delivery systems or dose forms of the products are not pharmaceutically equivalent. Transdermal patches, systemically acting creams or ointments, or suppositories may have been supported by data demonstrating bioequivalence with oral, or other dose forms, as evidence of efficacy. The differences in pharmaceutical form, however, mean that the products are not considered to be interchangeable.

c) there is no acceptable method to establish bioequivalence e.g. some topical or locally acting medicines. In most circumstances products in this category must demonstrate efficacy on the basis of clinical trials data, and interchangeability with another product cannot be assessed. Multi-source nasal sprays marketed as prescription medicines, however, are an exception to this rule. Nasal sprays are approved for marketing when they meet appropriate pharmacopoeial standards and the majority of the dose is likely to be deposited at the required site. As the delivery device can have a large effect on the amount of dose delivered to the site of action, Medsafe cannot make any statement about the interchangeability of different nasal sprays with the same active ingredients unless they have been shown to meet an appropriate bioequivalence standard.

Note: Where there is an acceptable method of establishing bioequivalence, such as skin blanching tests for topical steroid preparations, or comparative clinical trial data have been submitted, the product will be listed in Section 1.2. All OTC nasal sprays are considered interchangeable as they pose no risk of bio-inequivalence).

Section 2.2 Medicines gazetted as non-interchangeable

In a small number of circumstances Medsafe may gazette a medicine as non-interchangeable. This may occur where the sponsor for a multi-source product has provided clinical trial data as evidence of efficacy, and so no assessment of interchangeability is possible. Alternatively, the bioequivalence study provided in the application may fail to meet the international bioequivalence criteria administered by Medsafe, by demonstrating that the multi-source medicine is more bioavailable than the comparator reference product.

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In such cases Medsafe liaises with its expert committee to assess whether the increased bioavailability is likely to cause any significant difference in the benefit:risk profile of the multi-source product compared to the innovator. If no difference in benefit:risk is expected, and the multi-source product meets all of Medsafe’s other safety and quality criteria, the product may be accepted as having been proven to be safe and effective. It may then be approved for distribution in New Zealand but gazetted as non-interchangeable.

This policy recognises the limitations of bioequivalence studies and the fact that “bioequivalence” means that on average two products can be expected to behave the same way, but in some patients there may be significant differences resulting in serious clinical consequences. Non-interchangeability in New Zealand does not mean that the generic medicine is inherently ineffective or defective. Instead, it means that, as a precaution, a patient should be prescribed one brand or the other and, if the medicine has satisfactory results at the prescribed dose, the patient should be maintained on the same brand and not switched back and forth between brands from prescription to prescription.

Where a product fails a bioequivalence test because it has decreased bioavailability compared to the innovator, the product may only be approved on the basis of further clinical trial data.

This approach to the evaluation of multi-source medicines has been in place since the 1991 review of Medsafe’s evaluation procedures.

14.4.2 New Zealand reference product

The New Zealand Reference Product (NZRP) is normally the innovator product, but where the innovator is not on the market in New Zealand, the NZRP is the market leader. A product is not included in the list as a NZRP until there is a multi-source product on the market in New Zealand for which bioequivalence with that reference product has been established.

It is possible to have more than one NZRP for a particular medicine e.g. where more than one product has entered the market through provision of clinical trial data as evidence of clinical efficacy. In this situation, a new multi-source medicine may use either of the NZRPs as the comparator product for a bioequivalence study, and would be listed as interchangeable only with the reference product with which it was compared in the study.

14.4.3 Maintenance of the Interchangeable Multi-source Medicine List

In the past, once a multi-source medicine has been gazetted, the sponsor company has been sent a letter informing it of the proposed entry on the IMM list and asking it to notify Medsafe when the product is marketed in New Zealand. Once confirmation has been received that the product is on the market, an entry for the product has been included in the web site and published in the subsequent monthly Med-safety e-mail.

When distribution of a product on the IMM list was discontinued, the entry for that product was amended to show the discontinuation. The entry remained in the list for two years to allow remaining stocks held in pharmacies to be dispensed. Two years after the date of discontinuation of the product, the entry as deleted from the list.

In future, Medsafe intends to adopt a different process. It will place products on the list as soon as they are approved for distribution in New Zealand rather than wait for companies to advise that marketing has commenced. Medsafe appreciates that the delay in marketing may sometimes be due to patent considerations, however, it is not in a position to know when patents are expiring and so must rely on the industry to deal with patent issues.

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Medsafe will also leave products on the list until their sponsors formally advise that marketing has permanently ceased, or until registration has lapsed for some reason.

While this will mean that some products listed may not actually be available on the market when they first appear on the list, the change in procedure will make the list much easier and quicker to compile, publish and maintain.

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Section 15: Bioequivalence Testing of Oral Medicines

Section summaryThis section describes the requirements for designing and conducting a bioequivalence study involving oral tablets, capsules and suspensions, and for analysing and interpreting the results

15.1 Introduction

Several major regulatory authorities overseas have produced guidelines for establishing bioequivalence. These guidelines describe, in varying degrees of detail, the principles involved in the design and conduct of bioequivalence trials, and the analysis of the data. They are continually being updated as experience and knowledge on bioequivalence grows.

Despite considerable international agreement on the general principles of bioequivalence and its establishment, there are differences of opinion regarding some aspects of how some bioequivalence studies should be conducted and how data should be evaluated.

This New Zealand guideline for bioequivalence testing is largely based on the guidelines listed below and what Medsafe regards as best current international practice. The evidence required for bioequivalence usually consists of comparative bioavailability data. In some exceptional cases other data (e.g. in vitro dissolution) may be sufficient, or the formulation may be such that no comparative testing is necessary.

Situations where comparative bioavailability studies are and are not necessary, and the choice of acceptable reference products for bioequivalence studies, are outlined in Section 14.

15.2 Important Overseas Bioequivalence Guidelines

The following overseas guidelines have been used as the basis for the New Zealand guideline.

European Commission Rules Governing Medicinal Products in the European Community Volume III and CPMP Notes for GuidancePharmacokinetic studies in man.

Investigation of bioavailability and bioequivalence.

Clinical testing of prolonged action forms with special reference to extended release forms.

Quality of prolonged release oral solid dosage forms.

Analytical validation.

United States Food and Drug Administration (FDA)The United States FDA guidelines have been published as two “General Information” chapters in the United States Pharmacopoeia XXIII, 1995:<1088> In vitro and In vivo Evaluation of Dosage Forms, USP XXIII, 1995, p 1924.

<1090> In vivo Bioequivalence Guidelines, USP XXIII, Seventh Supplement, 1997, page 4022.

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Australian Therapeutic Goods Administration (TGA)Australian Guidelines for the Registration of Drugs, Volume 1, July 1994, Appendix 22B).

Therapeutic Products Directorate, Health Product and Food Branch, Health CanadaConduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects (1992); and

Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations (1997).

World Health Organisation (WHO)Interchangeable multi-source pharmaceutical products: Multi-source (generic) pharmaceutical products: Guideline on registration requirements to establish interchangeability in WHO Technical Report Series 863, 1996, Annex 9.

15.3 Definitions

Bioavailability is a measure of the rate and extent of absorption of the pharmacologically active form or forms of the active ingredient from a medicine, as reflected by the time-concentration curve in the systemic circulation or by its excretion in urine.

In addition to the extent of absorption, the rate of absorption may be important for many medicines, e.g. if a rapid effect is needed or if therapeutic efficacy depends on attaining a certain peak concentration. Rapid absorption may, however, lead to transient side effects or serious toxicity for medicines with a narrow therapeutic index.

In some circumstances, determining the amount excreted or measuring an appropriate pharmacodynamic effect may be the only available method of gauging bioavailability or bioequivalence.

Factors affecting bioavailability include the physico-chemical characteristics of the active ingredient(s) (e.g. lipid/water solubility, stability in an acid medium, salt form, particle size), the nature and quantities of excipients, type of formulation (enteric coated, sustained release etc.) and the extent of first pass metabolism by the gut and liver. Patient factors include the timing of the dose in relation to eating, interactions with other medicines taken concurrently, gastrointestinal motility and concurrent disease states.

Bioequivalence is a comparative term. Pharmaceutically equivalent medicines are assumed to be bioequivalent if their bioavailabilities (rate and extent of absorption in the systemic circulation after administration) are so closely comparable that their therapeutic effect, with respect to efficacy and safety, will be essentially the same.

Whether differences in bioavailability between different dose forms, multi-source medicines and reformulations of a dosage form will result in significant differences in clinical effects depends on the nature of the medicine and the mode of its use. For example, quite small differences in bioavailability can lead to serious complications with medicines such as digoxin and quinidine which have low therapeutic indices. For other medicines (e.g. benzodiazepines used for their hypnotic or anti-anxiety properties) differences in bioavailability have to be greater in order to produce clear evidence of lack of efficacy or undesirable effects. Since it is impossible to formulate universally applicable rules for bioequivalence, each product needs to be considered individually.

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As a general principle, two products may be said to be bioequivalent if the 90% confidence intervals for their mean Cmax, Tmax, and AUC (from zero time to infinity for single doses or within a dosing

interval at steady state) are within ±20%.

The usually accepted criteria for concluding bioequivalence (based on a difference of not more than 20%) are that the 90% confidence intervals for the ratio between the test and reference geometric means for AUC and Cmax (determined using log-transformed data) lie wholly within the range of

0.80 to 1.25 and the non-parametric 90% confidence interval for the difference in Tmax between the

formulations lies within a clinically acceptable range.

Where close dosage control is critical, a 20% variation in the rate and extent of absorption may be considered too wide. Tighter limits for permissible differences in bioavailability may be required for medicines that have:

1. a narrow therapeutic index 2. serious, dose-related toxicity3. a steep dose/effect curve, or4. non-linear pharmacokinetics within the therapeutic dosage range.

Where an applicant considers a variation in the rate or extent of absorption greater than ±20% is acceptable, this must be explained and justified in the application dossier. The allowable limit will depend upon clinical considerations

Suprabioavailability is the term used when a multi-source product displays a bioavailability appreciably larger than the reference product. When this occurs, reformulation and a final comparative bioavailability study will be necessary. Otherwise, clinical trial data as required for a new chemical entity will be required to support the application for the proposed formulation.

15.4 Variables in a Comparative Bioavailability Study

The blood plasma or serum concentration-time curve of the pharmacologically active substance(s) compared to a reference formulation provides the best measure of bioavailability for medicines with a systemic effect. Where the parent drug substance is an active form and one or more of its metabolites are also active, contribution of the metabolite(s) to the total pharmacological response should be considered in determining whether the metabolite should be measured as well as the parent compound.

Where it is not possible or favourable to measure the active substance(s) in serum or plasma, other less direct measures will be necessary. These could include determining the quantity of the active substance or its metabolites excreted in urine, or measuring pharmacodynamic variables. If data based on measurements other than blood concentrations are presented (e.g. saliva or urine concentrations), their relevance must be demonstrated. Usually the quantification of pharmacodynamic parameters is less exact than the determination of concentrations of drug substances and metabolites in body fluids.

For medicines that are mixtures of geometric isomers (e.g. clomiphene), both isomers should normally be assayed.

15.4.1 Extent of absorption

The extent of absorption is the fraction of the dose which enters the systemic circulation, as estimated using the "area under the curve" (AUC) of plasma concentration versus time. Extent of absorption

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can also be estimated from the fraction of the dose excreted in urine as the active form and/or its metabolites.

15.4.2 Rate of absorption

The rate of absorption determines the time delay between administration of a medicine and the time of the maximum (peak) concentration in the fluid being assayed, usually plasma. The rate of absorption can influence the amount of medicine reaching the systemic circulation in the case of a medicine with non-linear kinetics, for example where there is saturable first-pass metabolism.

Other parameters that might provide a better estimate of the rate of absorption (e.g. the time to reach a particular concentration or fraction of Cmax) may be used where appropriate. The use of these

parameters must be justified in the dossier.

15.4.3 Pharmacodynamic responses

Where a suitable method for assaying the active form(s) in body fluids is not available, it may be possible to obtain an indirect indication of bioavailability or bioequivalence by repeated determinations of pharmacodynamic or biochemical responses following administration of a medicine.

Some pharmacodynamic variables respond rapidly to a medicine and are easily and accurately measured (e.g. heart rate). However, since there is a complex relationship between the onset, intensity and duration of the response and the concentration-time curve of the medicine and/or its metabolites in biological fluids, these variables may not be ideal. In addition, pharmacodynamic measurements may not be sufficiently precise to detect significant differences in bioavailability. For these reasons, bioavailability/bioequivalence studies based on chemical assays of the active form(s) are preferred.

If pharmacodynamic data only are provided, the applicant should outline which other methods were tried and the reasons why they were unsuitable.

The following requirements should be recognised when planning, conducting and assessing the results of a study intended to demonstrate equivalence by measuring pharmacodynamic responses to a medicine: The response which is measured should be a pharmacological or therapeutic effect which is

relevant to the claims of efficacy and/or safety. The methodology should be validated for precision, accuracy, reproducibility and specificity. Neither the test formulation nor the reference product should produce a maximal response in

the course of the study, since it may be impossible to distinguish differences between formulations given in doses which give maximum or near-maximum effects. Investigating dose-response relationships may be necessary.

The response should be measured quantitatively under double-blind conditions and be recorded in a machine-produced or machine-recorded fashion on a repetitive basis to provide a record of the pharmacodynamic events which are substitutes for plasma concentrations. If such measurements are not possible, recordings on visual analog scales may be used. Where data are limited to qualitative (categorised) measurements, appropriate special statistical analyses will be required.

Non-responders should be excluded from the study by prior screening. The criteria by which responders versus non-responders are identified should be stated in the protocol.

Where an important placebo effect can occur, comparison between products can only be made by a priori consideration of the placebo effect in the study design. This may be achieved by adding a third phase, with placebo treatment, in the design of the study.

A cross-over design should normally be used where appropriate, but where a cross-over design is inappropriate, a parallel group study design should be chosen.

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The underlying pathology and natural history of the condition should be considered in the study design. There should be knowledge of the reproducibility of the base-line conditions.

In studies where continuous variables could be recorded, the time course of the intensity of the drug action can be described in the same way as in a study in which plasma concentrations are measured. From this, parameters can be derived which describe the area under the effect-time curve, the maximum response and the time when maximum response occurred.

Statistical considerations for the assessment of the outcome of the study are, in principle, the same as for bioequivalence studies using plasma concentrations. However, a correction for the potential non-linearity of the relationship between the dose and the area under the effect-time curve should be made, on the basis of the outcome of the dose ranging study.

The conventional acceptance range, as applied for bioequivalence, is not appropriate in most cases. It should be defined on a case-by-case basis and described in the protocol.

15.4.4 Comparative in vitro dissolution rate

If it can be demonstrated that there is no suitable ethically acceptable in vivo method of establishing bioequivalence, and that such a method cannot be developed, appropriate comparative in vitro dissolution data may be an acceptable substitute.

Dissolution studies should possess suitable discriminatory power and be carried out at 37°C and physiologically meaningful pHs. More than one batch of each formulation should be tested. Comparative dissolution profiles, rather than single point dissolution test data, should be generated. The design should include:

Individually testing at least six dosage units (e.g. tablets, capsules) of each batch. Mean and individual results should be reported along with their standard deviations or standard errors.

Measuring the percentage of nominal content released at a number of suitably spaced time points to provide a profile for each batch, e.g. at 10, 20 and 30 minutes or as appropriate to achieve virtually complete dissolution.

Conducting the tests on each batch using the same apparatus and, if possible, on the same or consecutive days.

Final specifications for routine dissolution testing of the test product should be based on the data generated in this comparative study used to support equivalence of the test and reference products.

15.5 Designing a Comparative Bioavailability Study

Good trial design is essential. Investigators should consider what is already known about the nature and pharmacokinetics of the test medicine. When published data are not available, a pilot study may be necessary to ascertain: the likely Tmax and Cmax so that the final design will provide a sufficient number of

samples around Tmax to characterise this parameter and Cmax adequately

the sampling times, in single dose studies, needed to characterise the terminal elimination rate constant and the AUC from the last data point to infinity

the adequacy of the assay sensitivity and precision at the intended dose, and the variance in Cmax and AUC to allow estimation of the number of subjects required to

achieve appropriate statistical power

The study should be a balanced cross-over design with appropriate randomisation of the subjects to the different treatment sequences, unless the nature of the medicine means that a return to baseline values is not expected within a reasonable washout period between trial phases. Parallel group design may be suitable, but is often avoided because of the need to increase the number of subjects. The use

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of a cross-over design does run the risk of sequence effects, but if the study is appropriately designed sequence effects are not usually a problem.

15.5.1 Single dose versus steady-state studies

Single dose studies are appropriate in the majority of cases. A steady-state study may be appropriate in the following circumstances: Where the medicine has a long terminal elimination half-life and blood concentrations after a

single dose cannot be followed for sufficient time. Where assay sensitivity is insufficient to follow the terminal elimination phase for an

adequate period of time. For medicines which are so toxic that, ethically, they can only be administered to patients for

whom they are a necessary part of therapy, but where multiple dose therapy is required, e.g. many cytotoxics.

For modified-release products where it is necessary to assess the fluctuation in plasma concentration over a dosage interval at steady state.

For those medicines which induce their own metabolism or show large intra-individual variability.

For enteric-coated preparations where the coating is innovative. For enteric coated preparations, for which the release characteristics have been previously established, a steady-state study is not always required.

For combination products where the ratio of plasma concentration of the individual substances is important.

For medicines that exhibit non-linear (i.e. dose- or time-dependent) pharmaco-kinetics. Where the medicine is likely to accumulate in the body.

In steady state studies, the administration scheme should follow the usual dosage recommendation.

15.5.2 Parameters

The parameters that should be determined in a bioavailability study include:

maximum medicine concentration (Cmax);

time taken to reach the maximum concentration (Tmax)

area under the medicine concentration time curve (AUC) terminal elimination rate constant (kel), and

others as appropriate

These parameters should be calculated using the original concentration vs. time data rather than by curve fitting methods based on compartmental models.

For modified-release products given as a single dose, absorption rate plots should be prepared.

15.5.3 Choice of subjects

To reduce variability caused by disease, bioavailability studies are usually carried out in adult human volunteers of both genders (where appropriate) who are in good health, of average weight (e.g. within 15% of their ideal weight as given in the current Metropolitan Life Insurance Company Height and Mass Tables) and in the age range prior to the onset of age-related physiological changes (usually 18-60 years of age).

The supervisory physician should initially obtain a comprehensive recent medicine history (including alcohol intake, smoking and use of oral contraceptive tablets) to exclude possible interference with assays, effects on pharmacokinetics, pharmacological interactions and adverse reactions such as

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hypersensitivity. As well, the physician should conduct a medical examination and test liver, kidney and haematological function. Psychological characteristics should also be assessed to exclude subjects unlikely to comply with study restrictions and/or unlikely to complete the study.

During the study, the health of the subjects should be regularly monitored so that the onset of side effects, toxicity, or any intercurrent disease may be recorded and appropriate measures taken.

Preferably both genders should be included in the study. However, the choice of gender must be consistent with usage and safety criteria. Women should be required to give assurance that they are not pregnant, nor likely to become pregnant until after the study. This should be confirmed by a pregnancy test immediately prior to the first and last dose of the study.

For a medicine representing a potential hazard in one group of users, the choice of subjects may need to be narrowed, e.g. studies on teratogenic medicines should be conducted in males.

Where the risk of side effects or toxicity is significant, studies may have to be carried out in patients who are being treated with the test medicine but whose disease state is stable.

15.5.4 Standardisation of experimental conditions

For medicines taken orally, gastrointestinal conditions should be standardised. Subjects should be fasted for at least 10 hours before and 2-4 hours after dosing, or (if more appropriate for the medicine concerned) the dose should be given with or before/after a standardised meal. Meals consumed after dosing and during the blood-sampling period should be standardised and taken at standardised times after the dose. Any fluids taken with the dose should be the same for all subjects.

Standardisation of posture and physical activity is important to minimise variation in liver blood flow, especially for high clearance medicines, and should approach the conditions likely to be encountered in clinical use. Posture may also affect gastric emptying rates. Therefore, subjects should not be allowed to recline until at least two hours after oral administration of the medicine.

The times at which samples are taken should be similar in all subjects.

15.5.5 Number of subjects

The minimum acceptable number of subjects may be as low as 12, however, the number should be sufficient, in the case of confidence intervals, to give precise estimates of the target parameters and, in the case of hypothesis testing, sufficient to provide the necessary discriminatory power (normally 80%) to detect the maximum allowable difference (usually ±20%) in Cmax, AUC etc. This

number, "n", may in many cases be estimated in advance using means, standard deviations and sample sizes from published or pilot data. The calculation formula depends on the statistical method to be used in the analysis of the results at the completion of the study. Computation methods are outlined in Section 15.10.

The number of subjects recruited should be sufficient to allow for possible withdrawals or removals from the study. Reasons for any withdrawals (e.g. adverse reactions) should be reported and the subject’s plasma/serum/blood level data provided.

It is acceptable to replace a subject withdrawn from the study, once it has begun, provided the substitute follows the same protocol originally intended for the withdrawn subject.

If the calculated number of subjects appears to be higher than is ethically justifiable, it may be necessary to accept a statistical power which is less than desirable. Normally it is not practical to use more than about 40 subjects in a bioavailability study. Where calculations suggest that an excessive

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number of subjects is required, clinical efficacy and/or safety studies are an alternative. The use of a co-administered active ingredient labelled with non-radioactive isotope as a reference, or studies in which treatments are replicated within each subject, may improve discriminatory power for highly variable medicines.

Sequential testing may also be acceptable for studies expected to require a large number of subjects, i.e. a study is conducted on a predetermined subset of the required sample and the intended statistical analysis is performed. If the acceptance criteria are met, no further subjects need to be tested. If the acceptance criteria are not met, the results from the first part of the study can be used to determine how many more subjects should be tested. Appropriate statistical tests (e.g. sequential t-test) which make allowance for this design should be used. The ethically justifiable maximum number of subjects should also be considered. The final statistical analysis then uses all of the data.

15.5.6 Formulation and quality control data requirements

The detailed formulation of the test medicine used should be provided, or otherwise declared to be identical to that intended for marketing.

For tablets and capsules the test formulation used should originate from either a production-run batch or a pilot-scale batch of at least 10% of the full production scale or 100,000 units, whichever is the greater, and manufactured using full production-scale equipment, unless otherwise justified. In the case of a production batch being less than 100,000 units, the sample should originate from a full production batch.

For suspensions the test formulation used should originate from either a production-run batch or a pilot-scale batch of at least 10% of the full production scale and manufactured using full production-scale equipment, unless otherwise justified.

All medicines used in bioequivalence studies should be manufactured in accordance with good manufacturing practice (GMP).

Quality control data should be provided for both the test and reference products used in the trial. The minimum data required is the batch number, date and scale of manufacture, mean potency, uniformity of potency as determined by assaying 10 individual dosage units and, for tablets and capsules, disintegration time and dissolution profiles determined in aqueous media using standard BP, Ph Eur or USP equipment and procedures. Alternatively, other fully validated dissolution procedures may be used.

Note that any final specifications for in vitro dissolution of the multi-source product should be derived from the dissolution profiles for the batch that was found to be bioequivalent to the reference product.

The mean potencies of the test and reference product should not differ by more than 5%.

15.5.7 Number and timing of samples

The number (typically 12-18 blood samples per dose) and timing of samples should be sufficient to enable reasonably accurate estimates of Cmax and Tmax, and accurate estimates of AUC and the

elimination rate. This information may be obtained in advance from literature data or a pilot study.

The blood sampling period in trials using a single dose of a prompt-release product should extend to at least three elimination half-lives in the terminal elimination phase. Sampling should be continued for a sufficient period to ensure that the area extrapolated from the time of the last measured concentration to infinite time is only a small percentage (normally less than 20%) of the total AUC.

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The use of truncated AUCs, i.e. AUCt, is undesirable but it may be unavoidable in certain

circumstances such as in the presence of enterohepatic recycling where the terminal elimination rate constant cannot be calculated accurately.

There should be sufficient points on the terminal linear part of the log-concentration vs. time curve to calculate the terminal elimination rate constant. The calculation should be based on at least four experimental points at appropriate intervals on the graph. The number of points used to calculate the terminal elimination rate constant should preferably be determined by eye from a semi-logarithmic plot, rather than by allowing a computer program to make the decision.

Intervals between successive data points used to calculate the terminal elimination rate constant should, in general, not be longer than the half life of the medicine.

In steady state studies, sampling should be carried out over a full 24 hour cycle so that any effects of circadian rhythms may be detected, unless these rhythms can be argued not to have practical significance.

In experiments requiring urine collection, it is important that subjects be carefully trained and supervised to ensure that all urine samples are collected according to the protocol. Any urine not collected will invalidate this part of the trial and should be taken into account during analysis of the data. For a 24 hour study, sampling times of 0-2, 2-4, 4-8, 8-12, 12-24 hours are usually appropriate. Where urinary excretion is measured in a single-dose study it is necessary to collect urine for seven or more half-lives.

15.5.8 Fasting and non-fasting studies

Generally a single dose study should be conducted after an overnight fast of at least 10 hours, with a subsequent fast of 2-4 hours following dose administration. However, where the dosage form is a modified release product or when it is recommended that the medicine be given with food, then the influence of food on the bioavailability should be examined. The meal should contain approximately 30-40g of fat as this is likely to cause maximum perturbation to the release and absorption of the medicine. If a recommendation is made about when the medicine should be taken in relation to eating (e.g. immediately before food), this should also be taken into account in the design.

Fed studies are also required when fasted studies make assessment of Cmax and Tmax difficult.

15.5.9 Medicine administration

The quantity, type and timing of food and fluid taken concurrently with the medicine should be stated, and should be controlled. The time of day the medicine was taken should also be stated, and whether or not the subjects were ambulatory and for how long.

Concurrent use of other medicines, including oral contraceptives, intake of alcohol and caffeine, and smoking cigarettes, should be stated and should be controlled.

Whenever possible and safe, and when given by the same route, the molar equivalent doses of medicine in the test formulation(s) and the reference product should be the same. In studies comparing a modified-release product with a prompt-release product, it may be appropriate for reasons of safety and comparability of plasma concentrations to give the prompt release product in divided doses or as a single, lower dose.

In single dose trials, a sufficient interval should be allowed between the administration of each formulation to ensure that the previous dose of medicine and any metabolites being measured have been completely eliminated. Approximately ten elimination half-lives of the medicine after the peak

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is usually a sufficient interval. Consideration will need to be given to extending this period if active metabolites with longer half-lives are produced.

In steady-state trials, the dosage regimen should be identical to the established dosage regimen of the reference product. Sampling of blood or urine should be carried out after the plateau (steady state) has been attained. It should be demonstrated that the plateau has been attained. Washout of the previous treatment can overlap with build-up of the second treatment, provided the build-up period is sufficiently long (at least three times the dominating half-life).

The pattern of blood or urine collections, or other sampling procedures, should be standardised for each subject.

Wherever possible the trial design should ensure that the order (sequence) of administering medicine treatments to subjects is randomised and balanced.

15.6 Modified-release Products

This section refers to orally administered modified-release (MR) dosage forms of medicines which do not have complicated characteristics.

15.6.1 Characteristics

A modified-release dosage form is defined as one for which the medicine-release characteristics of time course and/or medicine-release location are chosen to accomplish therapeutic or convenience objectives not offered by prompt-release dosage forms. For the purpose of these guidelines, these include: delayed release sustained release mixed immediate and sustained release mixed delayed and sustained release mixed immediate and delayed release

Generally, these products should: act as modified-release formulations and meet the claims made by the applicant; preclude the possibility of any dose dumping effect; provide a therapeutic performance comparable to the reference prompt-release formulation

administered by the same route in multiple doses (of an equivalent daily amount) or to the reference modified-release formulation;

produce consistent pharmacokinetic performance between individual dosage units; and produce plasma levels which lie within the therapeutic range (where appropriate) for the

proposed dosing intervals at steady state.

If all of the above conditions are not met but the applicant considers the formulation to be acceptable, a case to this effect should be provided.

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15.6.2 Parameters

Clinical studies may be required to support claims for the efficacy and safety of MR formulations. Bioavailability data should be obtained for all MR dose forms although the type of studies required and the pharmacokinetic parameters which should be evaluated may differ depending on the active ingredient involved. Factors to be considered include whether or not the formulation represents the first market entry of the drug substance, and the extent of accumulation of the medicine after repeated dosing.

If the formulation is the first market entry of the drug substance, the product’s pharmacokinetic parameters should be determined. If the formulation is a second or subsequent market entry then comparative bioavailability studies using an appropriate reference product should be performed.

For medicines where close control is critical the bioequivalence of each strength of the formulation should be established. For other medicines, if the formulations of different strengths are such that the proportion of excipients to the medicine are the same, and adequate documentation of development pharmaceutics is provided, it is sufficient to establish the bioequivalence of one strength.

For formulations for which the drug substance (or active form) is unlikely to accumulate in the body after multiple dosing (AUCTS/AUC 0.8), studies can be performed with single dose

administration in the fasting state as well as following an appropriate meal at a specified time. The following pharmacokinetic parameters should be calculated from plasma (or blood or serum) concentrations of the medicine and/or major metabolite(s): AUCTS (AUC over the same interval

following a single dose) AUCt, AUC, Cmax, and kel.

For formulations for which the drug substance (or active form) is likely to accumulate (AUCTS/AUC <0.8), studies should be performed with single dose administration in the fasting

state as well as following an appropriate meal. In addition, studies are required at steady state. The following pharmacokinetic parameters should be calculated from single dose studies: AUCTS, AUCt,

AUC, Cmax, and kel. The following parameters should be calculated from steady state studies:

AUCTCSS (AUC measured over one dose interval at steady state), Cmax, Cpd (the concentration

immediately pre-dose), Cmin, and DF (the degree of fluctuation in concentration as a proportion of

the average concentration over the dose interval).

Where the ratio AUCTS/AUC, cannot be reliably determined, it is to be assumed that accumulation

occurs.

15.6.3 Study design

It is necessary to confirm the bioequivalence of modified release products that are likely to accumulate and those that are unlikely to accumulate, both in the fasted and non-fasting state. If the effect of food on the reference product is not known (or it is known that food affects its absorption), two separate 2-way cross-over studies, one in the fasted state and the other in the fed state, may be carried out. If it is known with certainty (e.g. from published data) that the reference product is not affected by food, then a 3-way cross-over study may be appropriate with

1. the reference product in the fasting state 2. the test product in the fasted state, and 3. the test product in the fed state.

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15.6.4 Requirements for modified release formulations unlikely to accumulate

This section outlines the requirements for MR formulations which are used at a dose interval that is not likely to lead to accumulation in the body (AUCTS/AUC 0.8).

When the MR product is the first market entry of that type of dosage form, the reference product should normally be the innovator’s prompt-release formulation. The comparison should be between a single dose of the MR formulation and doses of the prompt-release formulation which it is intended to replace. The latter must be administered according to the established dosing regimen.

When the MR product is the second or subsequent entry on the market, comparison should be with the reference MR product for which bioequivalence is claimed, administered as single doses.

The 90% confidence interval calculated using log transformed data for the ratios (Test:Reference) of the geometric mean AUC (for both AUCTS and AUCt) and Cmax (where the comparison is with an

existing MR product) should generally be within the range 80 to 125% both in the fasting state and following the administration of an appropriate meal at a specified time before taking the medicine.

The pharmacokinetic parameters should support the claimed dose delivery attributes of the modified-release dosage form.

15.6.5 Requirements for modified release formulations likely to accumulate

This section outlines the requirements for MR formulations that are used at dose intervals that are likely to lead to accumulation (AUCTS/AUC < 0.8).

When a modified release product is the first market entry of the MR type, the reference formulation is normally the innovator’s prompt-release formulation. Both a single dose and steady state doses of the MR formulation should be compared with doses of the prompt-release formulation which it is intended to replace. The prompt-release product should be administered according to the conventional dosing regimen.

When the MR product is the second or subsequent MR entry, single dose and steady state comparisons should normally be made with the reference MR product for which bioequivalence is claimed.

The 90% confidence interval for the ratio of geometric means (Test:Reference medicine) of AUC (for both AUCTS and AUCt) and Cmax (where the comparison is with an existing MR product)

determined using log-transformed data should generally be within the range 80 to 125% when the products are compared after single dose administration in both the fasting state and the fed state.

The 90% confidence interval for the ratio of geometric means (Test:Reference medicine) for AUCTCSS, Cmax, and Cmin determined using log-transformed data should generally be within the

range 80 to 125% when the formulations are compared at steady state.

The pharmacokinetic parameters should support the claimed attributes of the modified-release dosage form.

Pharmacodynamic data may reinforce or clarify interpretation of differences in the plasma concentration data.

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Where these studies do not show bioequivalence, comparative efficacy and safety data may be required for the new product.

15.7 Analytical Methods

Analytical methods and conditions of sampling should be fully described, preferably in the form of a standard operating procedure. The chosen analytical methods should be "state of the art" for a given analyte and should be specific and adequately sensitive. Preference should be given to chromatographic techniques such as high pressure liquid chromatography (HPLC) or gas chromatography (GC). Assay validation (see Section 15.7.1) should be conducted in the laboratory which generated the study data, using the same analytical procedures. Quality control of assays, while conducting the study, is vital. The investigators’ criteria for accepting or rejecting assay data should be stated clearly in the protocol or study report.

If an assay procedure is to be used at different sites, it should be validated at each site and cross-site comparability of results and variability should be established.

Copies of all of the original chromatographic printouts (except for a few examples to demonstrate sensitivity and selectivity) need not be included in the study report. However, the original printouts should be retained by the investigators and be available on request, at least until Medsafe’s assessment and approval processes have been completed.

15.7.1 Chromatographic assay validation

Detailed validation data on the specificity, accuracy, reproducibility and sensitivity of the analytical procedure and stability of the analytes in plasma/serum or other applicable body fluids should be included in the study report.

SpecificityEvidence should be provided that the assay does not suffer from interference by endogenous compounds, degradation products, other medicines likely to be present in study samples, and metabolites of the medicine(s) under study. Reference standards of metabolites will frequently not be available, but investigators should address this problem as far as is practicable.

Stability of measured medicine/metabolitesData should be accumulated which establish the stability of the measured entities (normally parent medicine and/or active metabolites) in the relevant biological environment from time of sampling to assay, under the conditions and duration of storage that apply. The absence of any sorption by the sampling containers and stoppers should also be established.

Minimum quantifiable concentration (MQC)This is a contentious issue and many approaches are encountered. Terms such as 'limit of detection' and 'minimum detectable concentration' may be misleading in this context since it is typically possible to detect quantities of an analyte substantially below those which can be assigned a meaningful quantitative value. The parameter "three times baseline noise" is often encountered in this context, but reflects what concentration can be detected rather than what can be quantified.

A better approach is to define the MQC as the lowest concentration which has an inter-day coefficient of variation for multiple injections of 20% (as well as this can be measured). It is not necessary to define a MQC if the lowest concentration encountered during sampling has a coefficient of variation of less than 20% during assay validation.

Shape of calibration curve

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Linearity is preferred. The shape of the calibration curve should be defined in mathematical terms on more than one occasion (optimally three), preferably over a concentration range from the MQC to a value greater than the Cmax expected in the study. Calibration standards in the 1,2,5,10,20,50 -------

pattern of concentration are preferable. The coefficient of determination (r2) should normally exceed 0.99 (r > 0.995). Alternative approaches may be used provided justification is supplied.

Assay precision and accuracyPrecision (the degree of reproducibility of individual assays) is established by replicate assays on standards, preferably at several concentrations. Accuracy is the degree to which the ‘true’ parameter of the medicine is estimated by the assay. Precision and accuracy should normally be documented at three concentrations (low, medium, high) where ‘low’ is in the vicinity of the lowest concentration to be measured, ‘high’ is a value in the vicinity of Cmax and ‘medium’ is a suitable intermediate value.

Intra-assay precision (within days) in terms of coefficient of variation should be no more than 10%, although no more than 20% may be more realistic at values near the MQC. Inter-assay precision (between days) may be higher than 10% but not more than 20%.

Accuracy can be assessed in conjunction with precision and is a measure of the extent to which measured concentrations deviate from true or nominal concentrations of analytical standards. In general, an accuracy of ±10% should be attained.

RecoveryDocumentation of extraction recovery at high, medium and low concentrations is essential since methods with low recovery are, in general, more prone to inconsistency. If recovery is low, alternative methods should be investigated. Recovery of any internal standard used should also be assessed.

15.7.2 Radioimmunoassays

Similar principles apply to chromatographic and bioassays such as radioimmunoassays and pharmacological procedures, but the details may vary. In addition to the principles outlined for chromatographic methods in Section 15.7.1, the following points relate to radioimmunoassays.

AntibodyThe characteristics of the radioimmunoassay depend on the antibody, which varies from animal to animal. Therefore, the following validation details should be repeated for each new batch of antibody: specificity, calibration curve, MQC, precision, and accuracy. It is preferable to use the same batch of antibody for the whole study.

Specificity (cross-reactivity)Data should be provided that demonstrate which part of the antigen is binding to the antibody, as well as the degree of binding of closely related substances such as metabolites and breakdown products at the antibody titre employed. Specific antibodies should be employed.

Calibration curveFor radioimmunoassays, calibration curves should be fitted to a computer model or transformed by a logit analysis to give a linear relationship between percent bound and concentration of analyte.

Controls Controls for radioimmunoassay should include blanks comprising pre-dose samples (e.g. plasma) from each subject in the study. These should demonstrate that the assay does not indicate the presence of antigen when it is absent. A set of standards from 0 to 90% displacement of label is necessary.

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15.7.3 Assay of study samples

The following guidelines describe an acceptable approach to assaying samples.

Daily calibration standardsCalibration standards and a sample blank (e.g. plasma) are analysed with each batch of study samples on a daily basis. Two possible approaches are: use three concentrations of standards in triplicate. These can conveniently be the same three

concentrations (low, medium and high) used to estimate precision and accuracy in the pre-study validation; or

use at least five concentrations of standards from the MQC to the highest concentration encountered in the study.

Calibration standards should be blank samples (e.g. plasma) spiked with known concentrations of medicine, and prepared freshly each day from pure reference substance.

Seeded controls should be spaced throughout the batch. Failure to obtain reproducibility and linearity for the daily standards necessitates re-assay of the batch.

Seeded controlsSeeded controls (sometimes called “spikes”) are a valuable component of in-study quality assurance. Control samples at three or more concentrations are prepared in plasma in bulk at the time of pre-study assay validation, or at the time of study sample collection, and are aliquoted into storage vessels.

A control for each concentration is assayed on each occasion that study samples are assayed, and the concentration determined by reference to that day's calibration standards. If the concentration values determined for the controls are not within ±15% of the expected concentrations, the batch should be considered for re-analysis. If not within ±20% of the expected concentrations, the batch should be re-analysed unless there is very good reason not to do so.

Seeded controls, therefore, provide a constant reference point between batches of assays as well as determining whether the medicine is stable under the storage conditions used.

Re-analysis of samplesIn most studies some samples will require re-analysis because of aberrant results due to processing errors, equipment failure or poor chromatography. The reasons for re-analysis of such samples should be stated.

When the results of repeat assay differ from the original by more than 15%, a third analysis should be done. When the three analyses indicate that one is spurious, then the average of the other two should be used.

Range of reported valuesConcentration values less than the lowest calibration standard should be reported as such and should not normally be used in data analysis. Concentration values greater than the highest concentration used in the linearity studies should be highlighted and accompanied by validation data. Concentration values marginally (up to 20%) above daily calibration standards may be reported if pre-study linearity data extended beyond such values Concentration values less than the MQC should not be used in data analysis.

15.8 Reporting Data

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The concentration of the entities measured in the plasma/serum/blood for each subject, sampling time and formulation should be tabulated. Any deviations (e.g. missed samples or late collection of samples) should be clearly identified in these tables. The order in which the formulations were administered to each subject should also be indicated.

Two graphs should be drawn for each subject, and two for the mean values of all subjects. One should be linear and the other a semi-logarithmic plot of the concentrations from the reference and test formulations against sampling times. It is preferable that the semi-logarithmic plots should also display the regression lines which were employed to estimate the terminal elimination rate constants. Alternatively, the number of points used may be indicated or tabulated elsewhere in the study report.

Where plasma concentration data have been generated, the minimum acceptable pharmacokinetic data set for each subject and each treatment is:

(i) CmaxGenerally this should be reported as the highest measured concentration, rather than a value obtained from curve-fitting. The adequacy of such data is a function of the sampling intervals in the vicinity of Cmax.

(ii) TmaxGenerally this should be reported as the time at which Cmax was observed, using actual sampling

times rather than nominal times or values obtained from curve-fitting.

(iii) AUCtThe area under the curve to the last sampling time (AUCt) should be calculated by the trapezoidal

rule (the area contribution for each sampling interval is the mean of the concentrations at the beginning and end of the interval multiplied by the length of the interval). The actual sampling times, rather than the nominal times, should be used in the calculations.

(iv) AUCFor single dose studies, the area under the curve to infinity (AUC) should be calculated using the

equation:

AUC = AUCt + Ct/kel

where Ct is the plasma concentration at the last sampling time t and kel is the terminal elimination

rate constant (where plasma concentrations fluctuate in the terminal region of the curve, it is preferable to estimate Ct from the log/linear plot of plasma concentrations against time).

Tabulations of the proportion of AUC which is extrapolated, should be provided.

(v) kel (or t½)

Tabulations of kel (or t½) should be provided.

(vi) Other ParametersOther parameters, such as total urinary excretion, may need to be calculated in some cases.

15.9 Presentation of Summarised Data

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All bioavailability parameters should be tabulated, preferably as mean ± standard deviation with the

observed range given in parenthesis [e.g. AUC = 25 ± 8 (7-40) ng.h.ml-1]. The units of

measurement for the parameter should always be given.

It is important to specify whether measured medicine concentrations refer to plasma, serum or whole blood concentrations.

Where appropriate, AUC and Cmax and statistical analyses should be normalised for medicine

content (mean assay) of both dosage forms. Ratios and confidence intervals should be normalised if the potencies of the batches of medicines compared differ by more than 3% and/or the calculated confidence intervals lie close to the 80% or 125% limits and normalisation could affect the conclusion. It should be clearly stated in the study report whether data have or have not been normalised.

15.10 Statistical Analysis

The following statistical methods should be used in the analysis of bioavailability trial data. Other methods of analysis may be acceptable, but their use should be justified.

Statistical comparisons between formulations should be based on data derived from individuals and not only on averaged data.

15.10.1 Number of subjects

The minimum acceptable number of subjects is usually 12. However, the number of subjects should provide the study with a sufficient statistical power (usually 80%) to detect the allowed difference (usually 20%) between the test and reference medicines for AUC and Cmax. This number (n) may, in

many cases, be estimated in advance from published or pilot study data using the following formula:

n > 2s2/2 (t + tß)2

the required significance level of the study and is equal to 0.05.(1-ß) - the required minimum power of the study and is normally not less than 0.80s2 - the (residual) error mean square from a cross-over ANOVA - the allowed difference required to detect as a proportion of the mean for the reference

treatment. is generally taken to be (0.2 x mean for reference) and should be in the same units as s.

t, tß - the one-tailed Student t distribution values for and respectively. The degrees of

freedom for t are those of the ANOVA (residual) error mean square.

Where the data are log-transformed, s2 is the (residual) error mean square from the cross-over ANOVA of the logarithms of the AUC or Cmax values, and is the logarithm of 1.20.

Because n is unknown a priori, it will be necessary initially to use values of the Normal distribution parameters z and zß in place of the Student ‘t’ distribution parameters t and tß to derive an

estimated value for n and subsequently to perform a simple iteration using this initial estimate to determine n more precisely.

It will be necessary to obtain estimates of s2 and the reference mean using mean and standard deviation data from the literature and/or from the pilot study. However, as the study variance may

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differ from the literature or pilot study values, it would be prudent to err on the side of generosity in numbers.

If the calculated number of subjects appears to be higher than is ethically justifiable, it may be necessary to accept a statistical power which is less than desirable. It is usually not ethically justifiable to use more than about 40 subjects.

15.10.2 Analysis of variance (ANOVA)

Analysis of variance (ANOVA) is a technique for investigating how much of the total variability in a set of observations can be ascribed to different causes. The components of the variances are analysed further to tests the null hypothesis H0 that all of the samples have been drawn from the same population. The alternative hypothesis H1 is that one or more systematic differences exist.

An ANOVA taking account of subjects, sequence, period (phase) and treatment (formulation) effects should be performed for Cmax, AUC, Tmax and other parameters as appropriate to determine if there

are any statistically significant differences. A more complex ANOVA may be appropriate in some circumstances, for example if treatments are replicated or if a study has been conducted as two independent phases.

The assumptions underlying such an ANOVA are: Randomisation of samples. (The subjects chosen for the study should be randomly assigned

to the sequences of the study.) Homogeneity of variances. (The variances associated with the two treatments, as well as

between the sequence groups, should be equal or at least comparable.) Additivity (linearity) of the statistical model. (There should be no interactions between the

subject, sequence, period and treatment effects for a standard 2 x 2 cross-over study.) Independency and normality of residuals. (The residuals of the model should be

independently and normally distributed.)

The assumptions of normality of residuals and homogeneity of variance in the model are known to be relatively robust. That is, small or moderate departure from each or both of these assumptions will not have a significant effect on the final result. If there is significant evidence of departures from the assumptions then a parametric ANOVA should not be performed on the raw data.

If the assumptions above are not met, the data should be transformed prior to the ANOVA. A non-parametric analysis should be used e.g. Tmax (see below).

Many biological data correspond more closely to a log-normal distribution than to a normal distribution. In particular, the parameters AUC and Cmax tend to be skewed and their variances to

increase with their means. Log transformation is likely to remedy these defects and make the positively skewed distributions more symmetrical. Consequently, AUC and Cmax data should be log

transformed prior to statistical analysis.

The primary comparison of interest in a bioequivalence study is the ratio, rather than the difference, between average parameter data from the test and the reference formulations. Using log-transformation in the analysis allows inferences about the difference between the two means on the log scale. Re-transformation then allows inferences about the ratio of the averages on the original scale. Log transformation thus achieves a comparison based on a ratio rather than on a difference.

Non-parametric analyses (e.g. tests based on ranks and computation of 90% confidence intervals for differences between test and reference medicine) should be used for Tmax data as the observed values

are discrete even though the underlying distribution is continuous.

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15.10.3 Confidence intervals

It is recommended that confidence interval methods be used instead of hypothesis tests in the estimation of relative bioavailability. The 90% confidence interval for the ratio between the test and reference geometric means for AUC and Cmax should be determined using log-transformed data.

Confidence intervals wholly within the range of 0.80 to 1.25 will generally be accepted as an equivalence criterion for AUC and Cmax.

The non-parametric 90% confidence interval for the difference in Tmax between the formulations

should lie within a clinically acceptable range.

15.10.4 Power of ANOVA

Calculation of power is necessary whenever two formulations have been directly compared in terms of a null hypothesis of zero difference in conjunction with an ANOVA.

The power of a 2-way ANOVA (accounting for treatments and subjects) to detect a difference between two means amounting to a given fraction of the mean of the reference formulation can be calculated for each bioavailability parameter according to the following equation:

tß, = (n/2s2) - t,

Where:

1-ß - power - the degrees of freedom of the ANOVA (residual) error mean square - fraction of mean of the reference formulationn - number of subjectss2 - (residual) error mean square from the ANOVA - the required significance level of the test and ‘t’ values are one-tailed

Where the data are log-transformed, s2 is the (residual) error mean square from the cross-over ANOVA of the logarithms of the AUC or Cmax values, and is the logarithm of 1.20.

Adequate sensitivity of the statistical test is usually defined as a power of at least 0.8 (80%) with = 0.05. Strictly, the above equation should not be applied to a 3-way ANOVA. In practice, however, since any sequence effect is usually small, it gives a reasonable approximation of the power.

15.11 Data Requirements

The bioequivalence study report should include (as a minimum) the following information: Table of contents Title of study and any relevant reference Names and affiliations of the responsible investigators Signatures of the principal and other responsible investigators authenticating their respective

sections of the report Site of the study The period of dates over which the study was conducted Names and batch numbers of the products compared The formulation of the test product(s) or a signed declaration that this was identical to that

intended for marketing

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Results of assays and other pharmaceutical tests (e.g. physical description, dimensions, mean weight, weight uniformity, comparative dissolution) carried out on the batches of products compared

The full protocol for the study including a copy of the informed consent form and the criteria for inclusion, exclusion or removal of subjects

Documentary evidence that the study protocol was approved by an appropriate independent ethics committee or institutional review board and was carried out in accordance with good clinical and laboratory practice

Age, height, weight, ethnicity and smoking habit data for the subjects Results of clinical and laboratory screening tests Details of and a justification for any deviations from the protocol Details of any adverse reactions observed Details of any withdrawals from the study Details of analytical methods used, full validation data, quality control data and criteria for

accepting or rejecting assay results Representative chromatograms Actual sampling times All individual and averaged assay results presented in a clear way (both tabular and graphical

as appropriate) Details of how pharmacokinetic parameters were determined Individual and summarised average pharmacokinetic parameters Details and results of statistical analyses Justification for any departures from conventional statistical methodology. Summary and Conclusions Copies of any literature referred to in the report and not readily available

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Section 16: Equivalence Testing of Inhaled Medicines

Section summaryThis section describes how to design and conduct a study to compare the clinical efficacy of different formulations or brands of inhaler products.

16.1 Introduction

All applications to market multi-source metered dose inhalers and other inhaler devices must be supported by data establishing physical and clinical equivalence with the reference product. Similarly, applications to market inhalers where a chlorofluorocarbon (CFC) propellant has been replaced with a non-CFC propellant must be supported by data establishing equivalence with the previously approved CFC-containing product.

The following guideline for establishing equivalence of inhalers draws upon the major pharmacopoeia and the following overseas guidelines:

Guidelines on the preparation of Applications to Register Metered Dose Aerosols (Pressurised and Non-pressurised), Appendix 24 in "Australian Guidelines for the Registration of Drugs" Therapeutic Goods Administration: Canberra, July 1994.

Replacement of chlorofluorocarbons (CFCs) in metered dose inhalation products, CPMP Note for Guidance III/5378/93, December 1993.

Draft guidelines on in vivo criteria to establish equivalence of safety and efficacy of a multi-source or second entry drug delivered by metered dose inhaler for drugs intended for delivery to the lower respiratory tract. Health Protection Branch, Health and Welfare Canada: Ottawa, 1992.

The British, European and United States Pharmacopoeia (BP, Ph Eur and USP) include details of the general requirements for quality control and the various physical tests and test equipment appropriate for metered dose inhalers and other inhaler devices.

The specifications for the ingredients, containers and metering devices, the in process controls during manufacture, and the release and shelf-life specifications for the finished product should adequately control the following: defective containers and metering devices, pressure testing, leakage rates, moisture content, active substance delivered per dose (mean and dose uniformity), number of doses delivered, and deposition of dose.

Details of the development of the product and justification for each formulation should be provided in the application dossier. Information should be supplied on the following: excipients chosen, component/propellant ratios, extractables from the elastomeric components of the device, microbial testing, metering valve performance and control, consistency of delivery of dose over time, over the life of the canister, and with or without priming of the valve, quality of active ingredient (including crystal form, if relevant), and particle size distribution by mass of the active ingredient (except in

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cases where the active ingredient is in solution at any stage of the finished product manufacturing process).

16.2 Physical equivalence

16.2.1 Measuring particle size distribution

Particle size distribution of the inhaled aerosol or powder can significantly affect deposition within the respiratory tract. It is important that the mass distribution rather than the number distribution of the aerosol particles be determined, and that the particles measured actually contain the medicine. Because of the non-uniformity of material distribution in poly-disperse droplets and particles which are physically and chemically heterogeneous, it is critical that the sizing method be able to distinguish the active substance from other components of the aerosol. The probability that any given aerosol droplet contains the active substance is dependent on the drug concentration and both droplet and drug particle size.

Light scattering or optical methods are unsuitable for pressurised aerosols as they are unable to distinguish between droplets containing drug and those containing only excipients, and do not give any information about the aerodynamic diameter of the particles. With the exception of microscopy they are, however, suitable for routine quality assurance of aerosols generated from solutions, or dry powder inhalers which contain no excipients, particularly where the diameter of particles is 2 micrometres.

The most direct method for determining particle size distribution is to fractionate the material by impaction using a multistage liquid impinger or a multistage cascade impactor, each with sufficient stages to enable the distribution to be defined adequately. The amount of drug substance in each fraction is then determined.

Instruments are commercially available which have been factory calibrated using mono-disperse aerosols at various flow rates.

Careful design of the input port of the inhaler device is required to take into account initial deposition of the aerosol in the mouth resulting from incomplete evaporation of the propellant, and to reduce the chances of overloading the first stage of a cascade impactor. The use of a large expansion chamber for the input port is not recommended as it would effectively act as a spacer. Input ports similar to those in Apparatus A or B of the BP are suitable.

In determining the particle size distribution of a product by cascade impaction, the number of actuations employed per replicate should be kept to a minimum to avoid the masking of variations, and should be consistent with the limit of sensitivity of the best available assay method.

If a manufacturer does not carry out the sizing under appropriate conditions or cannot provide a rational quantitative estimate of hygroscopic growth by an indirect method, then a justification should be provided as to why such data are not necessary.

If the mass of the particles is log-normally distributed, the mass median aerodynamic diameter and the geometric standard deviation of the particles give a good characterisation of the aerosol. The distribution pattern of two aerosols can then be compared statistically. The 90% confidence intervals for the ratio of the mass median aerodynamic diameters may also be a useful parameter for comparison of two products.

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In cases where the particle size distribution of aerosols deviates significantly from log-normal, comparison of the respirable and non-respirable fractions may be more useful.

While the twin-impinger method for determining the particle size of pressurised aerosols (such as that adopted by the BP) is based on measurement of the drug mass aerodynamic diameter, it is limited in that only 2 fractions can be collected (particles above and below approximately 6.5 micrometres in the case of the BP). Therefore, a complete aerodynamic mass distribution cannot be defined.

It follows that the twin-impinger method is generally not useful for product development nor for comparison of multi-source and innovator metered dose aerosols, although it may be suitable for routine quality control of products. The twin impinger may also be acceptable for product development where a manufacturer has established an in vitro / in vivo correlation for the product in question.

Comparison of the particle size distributions of different products should be carried out under conditions which are clinically relevant. For example: slow flow rates of 25-35 L.min-1 are likely to reflect the ‘worst possible’ case of the effect of

inspiration on de-aggregation of dry powders by patients unable to breathe at a faster rate dry powder inhalers generally produce smaller particle sizes at higher flow rates, and with propellant-driven generators, slow flow rates may produce unrealistically small particle

sizes by allowing excessive time for evaporation of the propellants.

A rationale should be provided for whatever the flow rate and other test conditions are chosen, preferably reflecting in vivo data and/or clinical use.

16.2.2 Particle size

For corticosteroids and other medicines where side effects may follow oropharyngeal deposition, it is recommended that specifications be established for the: maximum amount of drug leaving the aerosol generator and likely to deposit in the

oropharynx (aerodynamic diameter greater than approximately 4.7 micrometres); and amount likely to deposit predominantly at the desired sites (i.e. the amount of drug contained

in aerodynamic size fractions below approximately 4.7 micrometres).

The actual cut-off diameters may vary from one therapeutic class of medicine to another. This variability should be based on clinical evidence of optimum site of deposition. For example, for new beta-2 agonists the optimum mass particle size distribution is in the order of >40% below 3-4 micrometres aerodynamic diameter so as to ensure acceptable airways penetration.

16.3 Clinical Equivalence

The minimum requirement for establishing clinical equivalence is a comparison of clinical efficacy with the reference product, in a properly designed and conducted study of acceptable statistical power. The study should incorporate appropriate monitoring of adverse effects. Pharmacodynamic measurements should be incorporated in the protocol.

Applicants must provide certification that the study was carried out with Ethics Committee or Institutional Review Board approval, using appropriate codes of Good Clinical Research Practice.

Bronchoconstriction may occur in sensitive individuals during clinical studies comparing products which do not contain a bronchodilator. Therefore, all clinical studies involving products containing non-bronchodilator medicines should include measures to detect bronchoconstrictive responses.

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Supporting clinical and physical (particle size distribution) data are required for spacer devices recommended for use with inhaled products. These data should be generated for each product recommended for use with each spacer device.

16.3.1 Statistical analysis

When conducting clinical trials to compare two similar metered dose inhalers (such as two bronchodilators) the confidence interval approach would be an appropriate form of statistical analysis. The procedure is outlined above in Section 15.10.

In general, two products may be considered clinically equivalent if their relative effect does not differ by more than 20%, i.e. if the confidence interval for the effect ratio of multi-source to reference product (calculated using log-transformed data) falls within the range 80-125%.

However, a confidence interval width of 80-125% may not always be appropriate for clinical studies for non-steroidal prophylactic products and glucocorticoids, due to the inherently greater variability in such studies. The applicant should justify any confidence interval falling beyond 80-125%.

16.3.2 -Sympathomimetic medicines

The minimum requirement to establish the bioequivalence of a multi-source -sympathomimetic product against the reference product is a comparison of:

(i) the bronchodilator effect, using the forced expiry volume in one second (FEV1) and/or measurements of the area under the curve (AUC) for FEV1 over time in mild to moderate asthmatics; and

(ii) the broncho-protective effect, using controlled challenge tests such as a histamine provocation test.

Subjects participating in bronchodilation and broncho-protective effect studies should have reversible airflow obstruction. They should be stable asthmatics who have shown a bronchodilator response of at least 20%, and have been shown to be stable for at least 4 weeks prior to the study, that is, their levels of symptoms and medication should be constant and they should be free from viral infections. The stability of FEV1 between study days should be assured (i.e. 15% or below is preferable) and there should be guidelines on the continuation or cessation of other medication. Slow release theophylline should be withheld for at least 24 hours prior to the study, and other inhaled bronchodilators for an adequate washout period. On the study day, subjects should be stable for half an hour before the study commences and medicine administration should be standardised.

BronchodilationA double blind placebo-controlled cross-over study should be conducted to compare 1, 2, and 4 puffs of reference product versus 2 puffs of the multi-source medicine versus 2 puffs of placebo in stable asthmatics to measure the maximum increase in FEV1 time course and duration of bronchodilation. Two puffs of the multi-source product should have significantly greater effect than 1 puff of reference product, and less effect than 4 puffs of reference product (p < 0.05). Two puffs of the reference and 2 puffs of the multi-source product should not be significantly different (p> 0.05).

Broncho-protective effectsA double blind placebo-controlled methacholine challenge cross-over study (n=16) should be conducted to compare 1, 2, and 4 puffs of reference product versus 2 puffs of multi-source product versus 2 puffs of placebo in stable asthmatics. The dose of methacholine required to induce a 20% fall in FEV1 of a patient pre-treated with ß-agonist at the time of expected maximum effect should be measured and the time course and duration of the effect should be examined. The higher the challenge dose of methacholine required, the higher the protective effect of the beta-agonist.

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The multi-source product must not produce a significantly worse cardiovascular response or a significantly greater incidence of adverse events than the reference product.

A spacer device could be used for the study if it is recommended that the device routinely be used with the product.

For multi-source -sympathomimetics, it is accepted that two products are considered clinically equivalent if their relative effect does not differ by greater than 20%, i.e. if the 90% confidence interval (calculated using log-transformed data) lies within the range 80-125% of the value for reference product. This range would also take into account the expected consistency of overall delivery of medicine from the product.

Study numbers should be based on power calculations to detect a difference if one really exists (e.g. 90% power to detect a 20% difference at the 0.05 level).

AUC for FEV1 over time should usually be measured for a sufficient duration to define fully each response curve. Extrapolation to infinite time is not necessary. Provided the baseline is tightly controlled, it would be sufficient to base the comparisons on absolute values.

If no difference in efficacy is shown by the study, and the propellants and dispersing agents in the multi-source product are not new to aerosol formulations, then no further clinical studies should be required.

16.3.3 Anticholinergic medicines

The principles applying to establishing clinical equivalence of -sympathomimetic medicines outlined above in Section 16.3.2 also apply to applications for consent to distribute multi-source inhalers containing anticholinergic agents.

16.3.4 Non-steroidal prophylactic medicines

Applications for consent to distribute multi-source medicines used for the prophylactic treatment of asthma, by inhibition of the release from effector cells of mediators of the allergic reaction, should be supported by acute clinical studies (and sometimes, long term clinical studies) comparing efficacy against the reference product.

A comparison of their ability to protect against a challenge (such as cold air, exercise, or sulphur dioxide) may suffice. Providing this study shows equivalent performance, and the aerodynamic behaviour of the products is comparable, no further studies are required. However, if a difference in effect is shown by the acute study, long term comparison of clinical efficacy (such as improvement of spirometry or a reduction in the need for medication) or a study defining the in-vivo deposition profile of the multi-source inhaler in relation to the reference will be required.

As determination of pharmacodynamic effects for non-steroidal prophylactic medicines are inherently more variable than those for bronchodilators, appropriate allowance should be made in terms of discriminatory power and acceptable difference.

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16.3.5 Glucocorticoids

For inhaled glucocorticoids, two methods can be used to establish clinical equivalence. These are described in guidance notes published by the European Commission’s Committee for Proprietary Medicinal Products (CPMP) and Health Canada.

The CPMP Note for Guidance: Replacement of chlorofluorocarbons (CFCs) in metered dose inhalation products gives the following advice and procedure for establishing equivalence of glucocorticosteroid inhalers:

“The demonstration of clinical bioequivalence of inhaled glucocorticosteroids is difficult and at this stage in our knowledge the only definitive efficacy studies are the parallel group “head-to-head” direct clinical comparisons, preferably in steroid-naive patients, with demonstration of clinical efficacy based on assessments made by the patient at home, recorded on diary cards, and made at regular, say 2 weekly, intervals in the clinic. Assessments would include pulmonary function measurements, symptoms scores, inhaled bronchodilator requirements and rate of exacerbations, defining beforehand an adequate primary outcome-variable. Studies should address a particular disease severity/dose regimen. The duration of treatment would need to be a minimum period of 4 weeks; longer treatment periods may be advantageous.

Since improvement in patients who are stabilised on corticosteroids is unlikely, the use of such patients is discouraged. However, if patients on corticosteroids must be entered into a trial, the pre-entry criteria, the expected improvements and the size and duration of the trial should be justified.

Single dose allergen challenge studies are artificial compared with natural exposure. There is a body of evidence which would support the use of the late response as a clinical model for the evaluation of potential new therapeutic agents, for early dose ranging in Phase II studies and the investigation of basic mechanisms of allergic asthma.

However, there is very little information on the reproducibility or dose-dependency of the late response and therefore its use in the demonstration of clinical bioequivalence is extremely limited and would not be appropriate.

Appropriate safety monitoring should be carried out, including some measure of systemic effect, e.g. assessment of hypothalamic adrenocortical function and assessment of paradoxical bronchospasm.”

The Canadian Draft guidelines on in vivo criteria to establish equivalence of safety and efficacy of a multi-source or second entry drug delivered by metered dose inhaler for drugs intended for delivery to the lower respiratory tract, published by the Health Product and Food Branch of Health Canada describe a different approach where dose back-titration is used to determine if the minimum effective dose is the same for the reference and test product. The products are compared in a double blind parallel-group comparison in asthmatic patients already controlled on inhaled steroid (e.g. a minimum of 800µg beclomethasone per day). The daily dose of steroid is reduced in a stepwise manner (e.g. by 200µg/dose each week) until patients have an exacerbation of their asthma. The exacerbation is treated by resuming twice the previous minimum dose of steroid. There must be no statistically significant difference in the dose of inhaled steroids between the reference and test product at the time of exacerbation in the two groups.

Study numbers should be based on power calculations to detect a difference if one already exists (e.g. 90% power to detect a 20% difference at the = 0.05 significance level). Adverse effects such as dysphonia, thrush, adrenal suppression should be monitored in these clinical studies.

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16.4 Powders for Inhalers

Where a new medicine is essentially the same as a product already on the market, an abridged application should be submitted. Where the two products are not essentially the same, a New Medicine Application including clinical safety and efficacy studies is required. The principles applying to determination of equivalence for pressurised inhalers, in terms of clinical requirements, are applicable to powders for inhalation.

As the delivery device can significantly alter the deposition profile of an inhaled powder, changes in the device can result in the modified system being regarded as a new product. Comparative efficacy data are then required. Major changes in the formulation of the inhaled powder itself must also be accompanied by comparative efficacy data, as the deposition profile may again be affected (see Section 16.3 for details).

For a minor change in the powder component of an already approved product, the medicine mass aerodynamic properties of the two formulations should be defined. If the two formulations display similar performances in vitro, no further studies will normally be required.

However, if a difference is observed, clinical data to confirm equivalence or a justification as to why such data are not required, should be provided.

16.5 Nasal Inhalation Products

Nasal inhalations, administered for a local effect, should have a particle size distribution appropriate for nasal application, i.e. particles are greater than 20 micron aerodynamic diameter or the deposition data show that >90% of particles are deposited in the nose.

Nasal inhalation intended to be absorbed and produce a systemic effect should be supported by in vivo bioavailability data as outlined in Section 15 (Bioequivalence Testing of Oral Medicines).

16.6 Changes to Currently Marketed Products

Sponsors may propose changes to inhaled products with consent to distribute in New Zealand. The change may be major (such as valve size or design of the inhaler) or minor (such as a change in the content of propellant which has minimal effect on the partial pressure of the mixture). Providing the change is relatively minor, physicochemical methods such as measurement of drug mass aerodynamic particle size distribution of the changed and current products will normally be sufficient to establish equivalence of performance. However, if a difference in physical performance is found, or if the proposed change is likely to cause a difference in particle size distribution or clinical effect, either a clinical study or a justification as to why this is unnecessary should be provided.

16.6.1 Rubber or plastic components

Any notification to a product which involves, or is likely to affect, rubber or plastic components should include data establishing whether or not leaching occurs. If leaching occurs, the identity and quantities of the leached substances should be established and comment provided on their toxicological and clinical implications.

16.6.2 Replacement of chlorofluorocarbons

As the production and use of chlorofluorocarbons (CFCs) is being phased out internationally, many companies are replacing these propellants with non-CFCs. The European Commission has produced the guideline Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products

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(CPMP Guideline III/5378/93). Applicants who wish to replace existing chlorofluorocarbons with alternative propellants should follow this guideline.

16.6.3 Changes to powders for inhalation

As the delivery device can have a significant influence on the deposition profile of an inhaled powder, any modification to its design or method of operation usually means the modified product is a new product and thus requires full clinical as well as physicochemical data. Similarly, a substantial change in the formulation of the inhaled powder, such as addition of an agent to modify its flow or hygroscopic properties or the removal or substitution of carrier, will necessitate the same data because the deposition profile could change markedly.

Physical measurements, such as drug mass aerodynamic particle size distribution of the delivered aerosol, are usually sufficient to support minor changes in the content of an excipient in an already approved powder for inhalation or minor changes to the delivery device. These data should be generated at several flow rates. However, if significant physical differences are observed, either clinical data or a justification as to why such data are unnecessary should be submitted.

Any comparative efficacy study performed to support a change to a powder for inhalation should encompass the principles for establishing clinical equivalence of inhaled products as outlined above.

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Section 17: Classification and Reclassification of Medicines

Section summaryThis section explains the process for classification of medicines

Legislation to read in conjunction with this sectionMedicines Act 198, Section 9: Medicines Classification CommitteeFirst Schedule to the Medicines Regulations 1984 & Amendments (Medicines Classification)

17.1 Medicines Classification Committee

The Medicines Classification Committee (MCC) is a Ministerial advisory committee whose terms of reference are to make recommendations to the Minister of Health regarding the classification of medicines as prescription medicines, restricted medicines or pharmacy-only medicines. As well, the Committee will consider and report to the Minister on any matter concerning the classification of medicines and access to medicines by health professionals and the public.

The MCC meets twice a year (usually in April and October) to discuss classification issues and to consider changes in the classification of medicines. Secretarial support is provided by Medsafe.

The Committee comprises two nominees from each of the New Zealand Medical Association and the Pharmaceutical Society of New Zealand and two members of the Ministry of Health, one of whom is to be appointed as chairperson. Nominees are appointed for a three-year term and may be re-appointed for one further term of office. Ministry members retain their appointments "during the pleasure of the Minister".

17.2 Classification categories

The Medicines Act defines three classification categories for medicines:

Prescription MedicinePrescription medicines may be supplied only on the prescription of a medical or dental practitioner, midwife or veterinary surgeon. They may also be used by a registered member of another specified health profession when permitted in the First Schedule to the Medicines Regulations or amendments.

Restricted Medicine (also referred to as Pharmacist Only Medicine)Restricted medicines may be sold without a prescription, but the sale must be made by a registered pharmacist, in a pharmacy, and details of the sale must be recorded.

Pharmacy-Only Medicine (also referred to as Pharmacy Medicine) Pharmacy-only medicines may only be sold in a community or hospital pharmacy, or a shop in an isolated area that is licensed to sell that particular medicine. The sale may be made by any salesperson.

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Medicines in each of these classification categories are listed in the First Schedule to the Medicines Regulations 1984 and amendments. Medicines not listed in the classification schedules are deemed to be unclassified, and are referred to as General Sale Medicines. These medicines may be sold from any outlet.

17.3 First Schedule to the Medicines Regulations 1984

Medicines are generally classified according to their active ingredients. The international non-proprietary name (INN) is the name of choice. If the medicine has more than one active ingredient, the active with the most restrictive classification determines the classification of the product.

The First Schedule to the Medicines Regulations is a list of active ingredients grouped under their respective classifications. There are several ‘catch-all’ classification statements in the Schedules. For example, injectables are pharmacy-only medicines unless the active ingredient of the injection has a more restrictive classification in its own right. This means that an injection can never be a general sales medicine, even when it only contains sodium chloride and water.

Classification changes occur approximately every six months. Updates may occur either through an amendment to the Medicines Regulations or through publication of a notice in the New Zealand Gazette. Amendments are usually published in June each year. When checking a classification, refer to the latest amendment to the Regulations and any subsequent update published in the Gazette. Alternatively, Medsafe’s web site includes an alphabetical list of medicine classifications.

17.4 Classification of Controlled Drugs

Narcotics and certain psychotropic agents are regulated under the Misuse of Drugs Act 1975 as controlled drugs. The Act defines three classes of controlled drugs. These are Class A, Class B (further subdivided into Parts I, II & III) and Class C (further subdivided into Parts I to VII). The controlled drugs in each class are listed in the Schedules to the Misuse of Drugs Act.

The Misuse of Drugs Act and Regulations contain the requirements for the manufacture, sale, supply, prescribing and labelling of controlled drugs. Controlled drugs that are also medicines are required to meet the requirements of both the Misuse of Drugs legislation and the Medicines legislation. Where there is any inconsistency between the two sets of legislation the Misuse of Drugs legislation takes precedence over the Medicines legislation.

Any controlled drug named in Part VI of the Third Schedule to the Misuse of Drugs Act and fulfilling the specified requirements is by definition a pharmacy-only medicine and can be labelled as such in accordance with the Medicines legislation. All other controlled drugs must be labelled in accordance with the Misuse of Drugs Regulations.

17.5 Classification of Medicines

The MCC recommends the classification of active ingredients where these have not previously been scheduled. Most new active substances are initially classified as prescription medicines. The MCC also considers applications for the reclassification of medicines.

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17.6 Classification Criteria

To qualify for a shift from prescription to over-the-counter (OTC) status, a prescription medicine should:

have been marketed for three years or more have had wide use during those three years have a low adverse reaction profile with serious reactions occurring only rarely, and be suitable for OTC sale.

Note: The three-year period of use need not have been in New Zealand. However, it must have been in a country with a well-developed pharmacovigilance system.

The MCC uses the following definition adopted in 1990 by the Commission of the European Communities for suitability for OTC sale:

Medical products which may be available without prescription shall show a substantial safety in use in the treatment of minor ailments or symptoms, usually capable of rapid and spontaneous relief, which are easily identifiable by users and do not justify a medical consultation.

The Committee considers the following factors when reviewing a medicine for reclassification for OTC sale. The list is not ranked in any order of importance. The criteria may vary in importance according to the medicine being considered for reclassification. In some cases one factor alone may be sufficient to outweigh all others in determining whether or not a medicine should be reclassified.

Consumer convenience Accessibility of the medicine and suitability for self-treatment. Accessibility includes time and location factors. Conditions suitable for self-treatment are usually minor and self-limiting.

PotencyThe ability of a medicine to produce a wanted pharmacological effect.

Current availabilityThe availability of products with a similar therapeutic purpose.

Therapeutic indexThe margin between therapeutic and toxic effects.

ToxicityThe potential of a substance to produce adverse preclinical and clinical effects. Adverse clinical effects will be assessed by frequency and severity.

Abuse potentialThe use of a medicine for gratification-producing effects not required for therapy.

Inappropriate useFactors relevant to the minor ailment or symptom for which the medicine is indicated, including the suitability of the condition for self-monitoring and the likelihood of misdiagnosis.

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PrecautionsFactors relevant to the medicine under consideration such as contraindications, side-effects and interactions with other medicines.

Communal harmThe possibility of community harm resulting from wider use of the medicine in question, e.g. the development of antibiotic resistance in bacteria.

17.7 Classification Process

It takes approximately six months from the date a submission is lodged until the classification change is notified in the NZ Gazette. A maximum of 6 further months is allowed in the legislation for companies to amend labelling to reflect classification changes.

There are nine phases in the classification process, as outlined below.

Phase 1: SubmissionWhile applications usually come from sponsor companies, anybody may make a submission to MCC for the reclassification of a medicine.

Closing dates for submissions to MCC are the end of January and the end of July each year. Submissions are placed on the agenda for the next meeting. Because of the need for consultation, late items cannot usually be accepted.

Submissions are reviewed by Medsafe evaluators, and a report is forwarded to Committee members along with the original submission.

Phase 2: ConsultationImmediately following the closing date for submissions, forthcoming agenda items are posted on Medsafe’s web site. This provides an opportunity to send written comment on reclassification proposals to the MCC Secretary. Comments are forwarded to Committee members with other agenda material before each meeting. Approximately six weeks is available for the preparation of comments. Closing dates are provided on the web site.

Although Medsafe will usually consult with companies likely to be affected by a proposed reclassification, companies should refer to the web site to determine whether any of their products are likely to be affected.

Medsafe may seek advice on classification matters, where appropriate, from experts or specialist organisations.

Phase 3: RecommendationFollowing each MCC meeting, the confirmed minutes are forwarded to the Minister’s delegate.

Phase 4: DecisionThe Minister’s delegate accepts or declines the recommendations made by the Committee.

Phase 5: CommunicationClassification recommendations and proposed reclassifications are notified on the web site. Those who have made submissions to the Committee receive individual letters explaining the outcome. A period of four weeks' advance notice is provided before changes are effected by a notice in the Gazette.

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Phase 6: ObjectionNotice of intention to object to a recommendation for reclassification should be lodged with the Secretary by the date given on the web site. Approximately 10 working days are allowed. The objection itself need not be lodged at this time but 8 copies, including supporting data, should be submitted to the Secretary by the closing date for the next meeting. If a notice of intention to object is received, the medicine is removed from the draft Gazette list until the objection is resolved.

This is an opportunity to object to the recommendation, rather than to the initial proposal. Objections must be made on the basis of new safety data not available to the Committee at the time the recommendation was made. Supporting safety data should accompany an objection. Financial or commercial reasons are not acceptable grounds for objection.

Medsafe considers the evidence submitted in support of the objection and will decide whether or not the matter should be referred back to the MCC. Normally objections will be referred back to the Committee only when there is substantial new safety evidence to support the objection. Medsafe advises the objector of the outcome and gives the original applicant a chance to comment to the Committee about the objection.

Phase 7: ConfirmationThe Minister’s delegate signs a notice for publication in the Gazette to confirm those recommendations which have not been the subject of an objection.

Phase 8: NotificationClassification changes are effected by notification in the Gazette. They are subsequently incorporated into the First Schedule of the Medicines Regulations by means of an amendment.

Phase 9: ImplementationFollowing a reclassification, a change of labelling is usually necessary. This requires the sponsor to submit a Self-assessable Change Notification.

The legislation allows three months from the date of notification of a classification change for stock labelled with the old classification to be replaced at wholesale level and six months for replacement of stock at retail level. Companies should contact Medsafe if they are unable to meet these time-frames.

17.8 Submissions for Reclassification

Submissions to the MCC are usually made by pharmaceutical companies, health professional organisations or Medsafe. Individuals or groups making submissions are advised to liaise with the pharmaceutical companies who market the medicines for which a change of classification is sought.

A submission for the reclassification of a medicine should include:

Part A1. International Non-proprietary Name (or British Approved Name or US Adopted Name) of the

medicine2. Proprietary name(s)3. Name of company/organisation/individual requesting reclassification4. Dose form(s) and strength(s) for which a change is sought5. Pack size and other qualifications6. Indications for which change is sought7. Present classification of medicine

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8. Classification sought9. Classification status in other countries (especially Australia, UK, USA, Canada)10. Extent of usage in NZ and elsewhere (e.g. sales volumes) and dates of original consent to

distribute11. Labelling or draft labelling for the proposed new presentation(s)12. Proposed warning statements if applicable13. Other products containing the same active ingredient(s) and which would be affected by the

proposed change.

Part BReasons for requesting classification change.This section should be supported where relevant by the following:

1. A statement of the benefits to both the consumer and to the public expected from the proposed change

2. Ease of self-diagnosis or diagnosis by a pharmacist for the condition indicated3. Relevant comparative data for like compounds4. Local data or special considerations relating to NZ5. Interactions with other medicines6. Contraindications7. Possible resistance8. Adverse events - nature, frequency etc.9. Potential for abuse or misuse.

All claims made in a submission should be supported by researched data. Only key papers need be supplied. References are adequate for other material.

The Committee does not make recommendations to the Minister on moral or ethical matters or on financial matters other than in terms of access for consumer convenience.

Eight copies of each submission are required. As copies of submissions need to be distributed to Committee members and filed at Medsafe, it is preferable that they are bound with a simple codafile pin. Do not use bulky ring binders. Spiral binding is acceptable.

In addition to the 8 paper copies of each submission required by Medsafe and the MCC, please submit an electronic copy (in MS Word format) on a floppy disk. The electronic copy should contain Parts A and B as specified above. An executive summary may also be included. Please do not send the supporting data in electronic copy.

An electronic copy of the submission is required, as Parts A and B (but not the supporting data) of all submissions since March 2000 are published on Medsafe’s web site under “Agenda Items”. Any reports written for the MCC by Medsafe are also published.

Submissions, and all other communications on classification matters, should be addressed to:

The SecretaryMedicines Classification CommitteeMedsafePO Box 5013Wellington

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Section 18: Clinical Trials of Medicines

Section summaryThis section explains how to apply for an exemption from the Medicines Act in order to conduct a clinical trial of a medicine.Note: For the requirements for clinical trials of medical devices see Section 2.5 of these Guidelines.

Legislation and guidelines to read in conjunction with this section:Medicines Act 1981, section 30: Exemption for clinical trialNew Zealand Regulatory Guidelines for Medicines. Volume 3: Interim Good Clinical Research Practice Guideline (August 1998)

18.1 Introduction

The Medicines Act 1981 defines the parameters and requirements for the sale, manufacture and supply of medicines in New Zealand. Section 30 of this Act describes the process that a study sponsor or manufacturer must follow to obtain an exemption from sections 20 and 24 of the Act for medicines required for use in clinical studies. Section 30 also describes the obligations of the sponsor for reporting adverse effects and progress to the Ministry of Health during the course of the study.

An exemption is required for investigational and comparator medicines which:

are new chemical entities (NCEs) and/or are new or different dose forms, delivery systems, or formulations of established medicines,

which have not been approved for marketing in New Zealand,

except where the study is solely designed to compare the bioavailability of a new medicine with one which is currently marketed.

A study designed solely to compare bioavailability of a new medicine with one with consent to distribute, using healthy volunteers, is not considered a clinical trial and does not require an application for approval under section 30 of the Medicines Act. However, ethics committee approval is still required.

Medicines for which consent to market has already been granted do not require a Section 30 exemption when the study protocol proposes that the medicine is used for an indication which has not been approved for the product in New Zealand.

The principal investigator must obtain approval of the study protocol and related documents from an ethics committee. The committee must be constituted and operated according to the National Standard of Ethics Committees, and be accredited by the Health Research Council’s Ethics Committee, or the Director-General of Health, as being qualified to review clinical trials involving human participants.

The Director-General of Health may grant approval for use of a medicine in a clinical trial after receiving:

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a favourable recommendation from the Health Research Council’s Standing Committee on Therapeutic Trials (SCOTT) about the safety of the medication and the validity of the study protocol, and

approval from an accredited ethics committee for the study protocol.

All medicines distributed under the provisions of section 30 of the Medicine Act must be labelled ‘To be used by qualified investigators only’ or words of similar meaning. It is the responsibility of the importer or manufacturer to ensure that the medicine is supplied only to an authorised investigator.

Detailed requirements for clinical trials conducted in New Zealand are outlined in the Medsafe publication entitled New Zealand Regulatory Guidelines for Medicines. Volume 3: Interim Good Clinical Research Practice Guideline. An electronic copy can be accessed at Medsafe’s web site (http://www.medsafe.govt.nz).

18.2 Application for Approval of a Clinical Trial

Section 30 of the Medicines Act 1981 requires that any application for a clinical trial of a medicine (whether approved for distribution in New Zealand or not) must be lodged by or in the name of a person or company resident in New Zealand. An overseas company wishing to carry out a clinical trial of a medicine in New Zealand needs to have a New Zealand-based subsidiary or appoint a local individual or company as its New Zealand agent to act for it in New Zealand as the sponsor for the clinical trial concerned. The New Zealand subsidiary or agent is the sponsor legally responsible for the trial, and is the “applicant” when the Director General’s consent for the trial is being sought.

Where an overseas company or a local or overseas consultant acts on behalf of a New Zealand sponsor in submitting an application, a letter from the sponsor confirming the overseas company’s or consultant’s authority to act on the sponsor’s behalf, for the specific clinical trial for which the application is made should be forwarded to Medsafe either with the application or separately.

Joint applications in which all or part of the data are shared, may be made by two or more sponsors. It should be clearly indicated in the application that each sponsor supports the shared use of the data. This may be indicated by the covering letter(s) being signed by all sponsors. The letter(s) must identify the person to whom questions and other correspondence relating to the application should be addressed.

An application for approval of a clinical trial should be made using the application form in New Zealand Regulatory Guidelines for Medicines. Volume 3: Interim Good Clinical Research Practice Guideline. An electronic copy can be accessed at Medsafe’s web site (http://www.medsafe.govt.nz)

ONE copy of the completed application form, with supporting data and application fee ($2,800 incl. GST), should be sent to the Manager, Medsafe at the address given in Section 1.2:

FOUR copies of the completed application form and supporting data should also be sent to the Chairperson of SCOTT, at the address given in Section 1.2.

All subsequent communication with the SCOTT should be addressed through Medsafe.

The Director-General of Health will advise the applicant (or the applicant’s representative) of the final outcome of the application within 45 days of its receipt. If the decision is to decline the application, the reasons for declining will be provided.

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Section 19: Pharmacovigilance

Section summary New Zealand has an established and effective pharmacovigilance system for post-marketing

surveillance of medicine use. This includes the spontaneous adverse reactions reporting scheme and an Intensive Medicines Monitoring Programme.

Sponsors have a responsibility to advise Medsafe of investigations of safety issues by overseas regulatory authorities, and data warranting a change to a data sheet.

Legislation to read in conjunction with this sectionMedicines Act 1981, Section 41: Duty of importer or manufacturer to report untoward effects of medicines

19.1 Spontaneous Adverse Medicine Reaction Reporting Scheme

A voluntary adverse reaction reporting scheme for the monitoring of adverse reactions to medicines, vaccines and fractionated blood products occurring in New Zealand is operated by the Centre for Adverse Reactions Monitoring (CARM) under the guidance of the Medicines Adverse Reactions Committee (MARC). New Zealand now has the highest reporting rate of adverse medicine reactions of all member countries in the WHO International Drug Monitoring programme.

Prescribers and pharmacists are encouraged to report to CARM any suspected reaction that is of clinical concern. In particular, CARM is interested in receiving reports of:

All suspected to reactions to new medicines All suspected interactions Reactions to any medicines suspected of causing:

- Death- Danger to life- Admission to hospital or prolongation of hospitalisation- Persisting disability- Significant intervention to manage the reaction and prevent disability- Absence from productive activity- Birth defects

All serious allergic reactions, even if well known All suspected adverse reactions listed in Prescriber Update as Adverse Reactions of Current

Concern.

Postage paid reporting cards are distributed with each issue of the New Ethicals Catalogue. Reporting guidelines are printed on the inside back cover of the Catalogue and are available on the web site. As well, the reporting form can be downloaded from Medsafe’s web site (http://www.medsafe.govt.nz). A copy of this reporting card is included in Appendix 15.

A separate reporting form is used to report adverse reactions to fractionated blood products. Local blood centres supply these forms on request. The reporting form can also be downloaded from Medsafe’s web site (http://www.medsafe.govt.nz). A copy is included in Appendix 16.

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19.2 Intensive Medicines Monitoring Programme

A small number of medicines are monitored in the Intensive Medicines Monitoring Programme (IMMP). They are usually novel agents which are recommended for consideration for inclusion on the programme by the Medicines Assessment Advisory Committee. A medicine may also be monitored, following a recommendation from the Medicines Adverse Reactions Committee, if a safety concern is identified after marketing.

Practitioners are requested to report to CARM all adverse clinical events occurring in patients receiving IMMP medicines (whether or not they are thought to be causally related to the medicine concerned). Pharmacists are requested to send in records of all dispensings of these medicines.

The current list of medicines in the IMMP is published in each issue of New Ethicals Catalogue and Prescriber Update. Sponsors should include a statement that the medicine is in the IMMP in all advertising and promotional material and in the data sheet. Six-monthly sales figures should be supplied to the Medical Director of the IMMP.

Following a recent review of pharmacovigilance in New Zealand a new policy and process for placing medicines on the IMMP has been adopted. These are as follows:

PolicyAt least the first two members of a new class of medicine are considered for monitoring at the time of recommendation for approval for distribution in New Zealand. This applies to all products recommended from 1 September 1999. In addition, the MARC may recommend that a medicine is monitored in the IMMP because it has identified questions or concerns which it believes could (and should) be addressed by monitoring.

ProcessThe process is as follows:

Step 1The recommendation for monitoring is received by Medsafe which then advises the sponsor company of the recommendations and the subsequent process for deciding whether monitoring should proceed, and encourages the sponsor company to participate in the process.

Step 2The Director of the IMMP prepares a feasibility study for monitoring and submits it to Medsafe within 8 weeks of the initial recommendation. Each study will include a monitoring methodology and a discussion of the merits of monitoring the medicine compared with other candidates for monitoring. The Director will develop this study in consultation with the sponsor company and provide a copy of the feasibility study to the sponsor. Sponsor companies may provide a separate opinion/report on the merits of monitoring as an appendix to the Director’s report.

Step 3The feasibility study is considered by an IMMP advisory panel which advises Medsafe whether it recommends proceeding with monitoring of the product. The panel members are the Senior Medical Advisor to Medsafe, the Director of the IMMP, and the Chairpersons of the MAAC and MARC. The panel will make its recommendation within 4 weeks of receiving the Director’s report.

Step 4Medsafe decides whether monitoring should proceed and advises the sponsor company and the CARM of its decision. Sponsor companies will be supplied with a copy of any material relevant to the decision.

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Appeal mechanismThe only grounds for appeal are that matters relevant to the decision have not been considered. Appeals, with supporting information, may be lodged with Medsafe within 14 days of the letter from Medsafe advising of the decision to monitor the medicine. Appeals will be considered by the MARC.

Duration and funding of monitoringA review of the need for continued monitoring will occur 2 years after the commencement of monitoring and annually thereafter. Monitoring will be funded by Medsafe.

19.3 Responsibility of Companies to Report Adverse Medicine Reactions

19.3.1 Reporting adverse reactions to CARM

Prescribers or pharmacists informing sponsors of serious or unexpected adverse medicine reactions occurring in New Zealand should be encouraged to report cases directly to CARM. However, the sponsor should report cases directly if they consider the prescriber or pharmacist is unlikely do so. In these instances, the reporting card should be completed and forwarded to CARM at the following address:

The Medical AssessorCentre for Adverse Reactions MonitoringPO Box 913DunedinTelephone +64 03 479 7185

Fax +64 03 477 0509

19.3.2 Reporting substantial untoward effects of medicines

Section 41 of the Medicines Act requires medicine manufacturers or importers to report to the Director-General any substantial untoward effects of their medicines that have arisen at any time, whether in New Zealand or overseas. In practical terms, this means that Medsafe should be informed promptly of an investigation of a safety issue by an overseas regulatory authority and/or any safety information necessitating a change in the data sheet.

Information on investigations of safety issues and data warranting a change in a data sheet should be forwarded to:

The SecretaryMedicines Adverse Reactions CommitteeMedsafePO Box 5013Wellington

Copies of individual adverse reaction case reports received from overseas countries should not be forwarded to CARM or Medsafe, but should be retained by the company. Likewise, Medsafe should not routinely be sent Periodic Safety Update Reports (PSURs). However, these should be held by the sponsor, and may be requested if a safety issue warrants review by Medsafe. In addition, a sponsor may include a recent PSUR in a submission to Medsafe on a safety issue.

19.3.3 Media interest in medicine safety issues

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Medsafe should be informed promptly of any interest by the local or overseas media in a medicine safety issue. This enables Medsafe to investigate the issue using New Zealand data and prepare a response to the New Zealand media that averts any unnecessary speculation and concern amongst the public and prescribers.

19.4 Centre for Adverse Reactions Monitoring (CARM)

CARM processes all reports of adverse reactions and enters the information into its database. A response, with comment on the case, is sent to the reporter.

After the reports have been assessed using the WHO causality and severity criteria and the reaction designated using the WHO terminology, CARM transmits adverse reaction reports to the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. This information adds to the international database of adverse reactions to medicines.

Pharmaceutical companies can purchase adverse reaction reports for any medicine from CARM. Companies can arrange for customised reports on named medicines to be sent to them on a regular basis (multiples of quarters). There is an initial set-up fee for the customisation which includes an historical printout of adverse reactions to date. Each printout thereafter incurs a fee.

19.5 Medicines Adverse Reactions Committee

The Medicines Adverse Reactions Committee (MARC) is a ministerial advisory committee of general practitioners and medical specialists. MARC oversees the spontaneous adverse reaction reporting scheme and the IMMP, reviews adverse reaction data published in the medical literature and advises the Minister and Medsafe on issues relating to the safety of medicines, including information to be disseminated to prescribers and pharmacists.

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Appendix 1: Schedule of Fees

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Schedule of Fees

The fees applying to the various types of applications and notifications are listed below

Application for consent to distribute a new medicine (incl. a new combination product) containing a new active pharmaceutical ingredient

$15,300 for 1 strength of 1 dose form(plus additional fees for any additional names/dose forms/strengths/flavours

(See NMA form for details) Application for consent to distribute a new multi-source prescription or OTC medicine containing one or more active ingredients

$7,800 for 1 strength of 1 dose form(plus additional fees for any additional names/dose forms/strengths/flavours.

(See NMA form for details)Application for consent to distribute a new name, dose form, strength, classification or flavour of a currently distributed medicine or related product or a new combination pack containing two or more currently distributed medicines

(See relevant NMA or NRPA form for details)Application for consent to distribute a new related product

$ 5,500(plus additional fees for any additional names/dose forms/strengths/classifications/flavours.

See NRPA form for details)Application for provisional consent to distribute a new medicine

$ 5,000

Application for renewal of provisional consent$ 500

(Plus an additional fee of $200 for each additional name/dose form/strength/flavour)

Material change(s)(See CMN or CRPN form for details)

Self-assessable change(s)

Note: No fee is payable if a self-assessable change(s) is notified at the same time as another assessable change(s) for which a CMN or CRPN fee is payable.

$ 200(For any number of self-assessable changes to a single product or data sheet)

Application for consent to conduct a clinical trial $ 2,800

Appeal to the Medicines Review Committee $ 9,000

Issue of a Certificate of Pharmaceutical Product $ 250

(For each name, dose form, strength and flavour of each productand each country for which a certificate is required.)

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Appendix 2: NMA Form

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NEW MEDICINE APPLICATION (including additional name, dose form, strength or flavour)

This form is to be used when applying for consent to distribute a new medicine including a product that is substantially the same as an approved parent product, but differs from the parent product in name, dose form, strength or flavour. One copy of the form must be completed for each separate product (name + dose form + active ingredient(s) + strength + classification + flavour, as applicable, of a medicine).Do not use this form for a new related product application. Instead, use the separate NRPA Form

Section 1: Administrative data

1.1 Proposed product details

Trade name:

Dose form:[See Guidelines for acceptable terms]

Active ingredient(s):[Use INN and also give CAS Number for new chemical entities]

Strength:

Route of administration:

Pharmacotherapeutic group:[e.g. Antibacterial, Diuretic, Vaccine]

1.2 Type of product (tick one)

Type I Lower-risk medicines

Type II Intermediate- or Higher-risk medicine other than biological or biotechnological products (but including antibiotics and like substances derived from micro-organisms)

Type III Biological or biotechnological products (i.e. vaccines, serums and allergens, medicinal products derived from human blood or plasma, immunological medicinal products, and products derived from biotechnology)

1.3 Legal classification (tick one)

Controlled Drug: Class _______

Prescription medicine

Restricted (Pharmacist Only) medicine

Pharmacy-Only medicine

General sales medicine

Not yet classified

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1.4 Product packaging, patient information and shelf-life

Container, closure type and administration device:

Pack size(s) to be registered in New Zealand:

A patient information leaflet is to be supplied with the product in New Zealand: (Yes/No)

The patient information leaflet is to be published as Consumer Medicine Information (CMI): (Yes/No)

Proposed shelf-life and storage conditions:

Unopened:

Opened:

Reconstituted:

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1.5 Manufacturing, packing and testing details

A. Manufacturer(s) of active ingredient(s)

Name of ingredient:

Name of manufacturer:

Address of site of manufacture:

GMP Certification (if available) issued by:

Date of Issue:

Drug Master File and “letter of access” submitted: Yes / No [If DMF previously submitted, give Medsafe File No(s). Note that a new letter of access may be required.]

TT60- ………….………

TT60- ………….………

Certificate of Suitability (with “letter of access”) submitted in lieu of DMF: (Yes/No)

B. Manufacturer(s) of finished product



GMP Certification issued by:

Date of Issue:

Manufacturing steps carried out at this site:

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C. Packer(s) of finished product

Name of packer:

Address of site of packing:

GMP Certification issued by:

Date of Issue:

Packaging steps carried out at this site:(e.g. primary packaging, secondary/outer packaging, labelling, overlabelling)

D. Site(s) responsible for testing of finished product and batch release

Name of site:

Address:

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1.6 Product composition

Name of ingredient Quantity Quality standard[Ph Eur / BP / US / House]

Active(s):

Excipients:

1.7 Transmissible Spongiform Encephalopathy Status

List any ingredients of animal origin included in the formulation:

List any ingredients of animal origin with which the product comes in contact during its manufacture:

TSE Declaration: (tick one)

The product contains no ingredients derived from animals. If applicable, any stearate or stearic acid in the product is derived from a vegetable source.

The product contains (or comes into contact during its manufacture) with animal-derived materials that are potential sources of TSE agents but appropriate precautions are taken in accordance with the European Commission and US Food and Drug Administration requirements to minimise the risk of contamination with TSE agents.

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1.8 Regulatory status

A. Overseas applications and approvals

Name of regulatory authority Date of application

Application status(incl. dates of any approvals)

European Medicines Evaluation Agency (EU Centralised Procedure)

(Individual European country agency) (National

approval procedure or EU Mutual Recognition Procedure):

Australian TGACanadian Health Product and Food BranchUS FDA

B. New Zealand Environmental Risk Management Authority (ERMA)

Indicate if the product requires ERMA consent for import and use in New Zealand and, if so, when an application was lodged with ERMA and the status of the application. (See Section 2.11.2 of New Zealand Regulatory Guidelines for Medicines Volume 1 for details of requirements.)

This product is a hazardous substance or a new organism in terms of the Hazardous Substances and New Organisms legislation and requires approval from ERMA before being released in New Zealand

Yes / No

(If Yes) An application for consent was lodged with ERMA on (date): ……………………

If an application has been lodged with ERMA, has approval been given?

Yes / No

(If Yes) The ERMA Approval Code is: ………………………………………………..…….

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1.9 List of attached documents

DocumentationTick if

included or mark “N/A”

Administrative Data:

Detailed table of contents for the dossier of technical data [must be included]

Draft label(s) and Labelling Declaration(s) [A full size copy or a full size draft indicating colours for each primary and secondary label, and a completed check list for each label, and a signed Labelling Declaration covering all of the labels must be supplied.]

Patient Information Leaflet/Package Insert [if applicable]

Draft data sheet, checklist and declaration [if applicable]

Good Manufacturing Practice documentation [if applicable]

Tabular summary of subjects in clinical trials [if applicable]

Ph Eur Certificate(s) of Suitability for active ingredient(s) with letter(s) of access [if applicable]

Copies of evaluation reports from overseas regulatory authorities [if available]

Copies of company responses to issues raised by overseas regulatory authorities where relevant to New Zealand requirements [if available]

Completed check list for completeness of chemical, pharmaceutical, biological and bioavailability data package [must be included for a new multi-source (generic) prescription medicine. Not required for a new innovative medicine or a new lower risk medicine]

Technical Data: [ICH Common Technical Document (CTD) format Modules 2-5 or EU format Parts IC – IV]

CTD Module 2 Overviews and Summaries or EU format Expert Reports [if available]

No of Vols: ______

Chemical, pharmaceutical and biological documentation [CTD Module 3 or EU format Part II]

No of Vols: ______

Toxicological and pharmacological (pre-clinical) documentation [if applicable][CTD Module 4 or EU format Part III]

No of Vols: ______

Clinical Documentation [if applicable][CTD Module 4 or EU format Part III]

No of Vols: ______

Drug Master File(s) with letter(s) of access [if applicable]

No of Vols: ______

Plasma Master File(s) with letter(s) of access [if applicable]

No of Vols: ______

Bioequivalence study report(s) [if applicable]

No of Vols: ______

Total number of volumes of data submitted:

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1.10 Fee calculation

Tick one box in the left hand column beside the appropriate type of application. Copy the amount from the corresponding “Fee” box to Part 1.11 “Application fee enclosed” below)

(Tick one box only) Type of application Fee

($)

New medicine containing one or more new active substances 15,300

New medicine that does not contain a new active substance 7,800

New medicine - Provisional consent 5,000

New medicine - Renewal of Provisional consent 500

Additional name - Grade 1 400


Additional classification (with/without new name) 400

Additional strength - Grade 1 800

Additional strength - Grade 2 1,600




Additional flavour or type of sweetening 800

Additional dose form - Grade 1 4,800

Additional dose form - Grade 2 6,400

New combination pack containing 2 or more currently approved products

1,600

1.11 Application fee paid: $ _________ .00

1.12 Method of payment:

Cheque enclosed Direct credit (details enclosed)

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1.13 Applicant/Sponsor details and declaration

In accordance with the Medicines Act 1981 and the Medicines Regulations 1984,I hereby apply for consent to distribute in New Zealand the product described above. I certify that the information supplied is complete and correct to the best of my knowledge and that no relevant information has been omitted.

Name, designation and address of person submitting the application:[All correspondence relating to the application will be sent to this person unless otherwise requested.]

Email address:

Signature: ____________________________________ Date: ___________________

Sponsor name and address:

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Section 2: Identification of parent product and differences

Complete this section only if this application is for consent to distribute an additional name, dose form,strength, flavour or classification of an existing parent product. Otherwise, submit only Section 1.If the category of difference(s) is/are not clearly covered by one of the categories in the table in Section 2.2, please contact Medsafe for guidance before submitting the application and fee.

2.1 Identification of parent product

This application is for consent to distribute a new product that is substantially similar to the following parent product:

Parent product(s) name(s):

Dose Form:

Strength:

Medsafe File Ref. TT50-

Comments:

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2.2 Differences between parent product and new product

Tick the box below that best describes the difference(s) between the new and parent products. If appropriate, describe the similarities and differences between the new and parent products in greater detail under “Comments” in section 2.1 of the form.

(Tick one)Difference between parent product and new productAdditional name - Grade 1

new name to be used in addition to existing name all other details identical to parent product except for labelling new label displays new name, but all other information on the label

is essentially the same as on the parent product label (even if layout is different)

Additional name - Grade 2

new name to be used in addition to existing name all other details identical to parent product except for labelling new label displays new name layout of label may be different from that of parent product some other information on the label is different from that on the

parent product label

Additional classification

new classification to be used in addition to existing classification (with or without a new name)

all other details identical to parent product except for labelling new label displays new classification (and new name, pack size,

indications, dosage instructions, if applicable)

Additional strength - Grade 1

new and parent products have the same dose form new product is a direct scale of parent product, or uses same

excipient matrix all other details identical to parent product except for labelling

and specifications


new and parent products have the same dose form new product is not a direct scale of parent product bioequivalence study not required all other details identical to parent product except for labelling

and specifications


new and parent products have the same dose form new product is not a direct scale of parent product bioequivalence study not required other details different from parent product


new and parent products have the same dose form new product is not a direct scale of parent product bioequivalence study included all other details identical to parent product except for labelling

and specifications


new and parent products have the same dose form new product is not a direct scale of parent product bioequivalence study included other details different from parent product

Additional flavour or type of sweetening

new and parent products have the same dose form new product has a flavour or type of sweetening different from

the parent product all other details identical to parent product except for labelling (if

applicable)and specifications

Additional dose form - Grade 1

new and parent products have different dose forms and the same or different strengths

bioequivalence not relevant to new dose formAdditional dose form - Grade 2

new and parent products have different dose forms and the same or different strengths

bioequivalence study or clinical data includedNew combination pack

new combination pack containing two or more currently approved finished products

primary packaging for each component unchanged, or any change does not affect stability/shelf-life

(End of form)

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Appendix 3: NRPA Form

191


NEW RELATED PRODUCT APPLICATION (including additional name, dose form, strength or flavour)

This form is to be used when applying for consent to distribute a new related product, including a product that is substantially the same as an approved parent product, but differs from the parent product in name, dose form, active ingredient, strength or flavour. One copy of the form must be completed for each separate product (name + dose form + active ingredient(s) + strength + flavour, as applicable, of a related product).

Section 1: Administrative data

1.1 Proposed product details

Trade name:

Type of Product:[e.g. Anti-dandruff shampoo, fluoride toothpaste, antiseptic, throat lozenge]

Active ingredient(s):

Strength:

Container and closure type:

Pack size(s) to be registered in New Zealand:

Proposed shelf-life and storage conditions:[if applicable]

1.2 Manufacturing and packing details



Name of packer:

Address of site of packing:

192


1.3 Product composition

Name of ingredient Quantity Quality standard[Ph Eur / BP / US / House]

Active(s):

Excipients:

1.4 List of attached documents

DocumentationTick if

included or mark “N/A”

Administrative Data:

Table of contents [must be included]

Draft label(s) and Labelling Declaration(s) [A full size copy or a full size draft indicating colours for each primary and secondary label, and a completed check list for each label, and a signed Labelling Declaration covering all of the labels must be supplied.]

Chemical and Pharmaceutical Data:

Composition and Presentation of Product

Method of Preparation

Specifications for Active Ingredient(s)

Specifications for Finished Product

Stability

Other Information

193


1.5 Fee calculation

Tick one box in the left hand column beside the appropriate type of application. Copy the amount from the corresponding “Fee” box to Part 1.11 “Application fee enclosed” below)

(Tick one box only) Type of application Fee

($)

New related product 5,500



Additional strength 800

Additional flavour or type of sweetening 800

1.6 Application fee paid: $ _________ .00

1.7 Method of payment:

Cheque enclosed Direct credit (details enclosed)

1.8 Applicant/Sponsor details and declaration

In accordance with the Medicines Act 1981 and the Medicines Regulations 1984,I hereby apply for consent to distribute in New Zealand the product described above. I certify that the information supplied is complete and correct to the best of my knowledge and that no relevant information has been omitted.

Name, designation and address of person submitting the application:[All correspondence relating to the application will be sent to this person unless otherwise requested.]

Email address:

Signature: ____________________________________ Date: ___________________


194


Section 2: Identification of parent product and differences

Complete this section only if this application is for consent to distribute an additional name, dose form,strength, flavour or classification of an existing parent product. Otherwise, submit only Section 1.

If the category of difference(s) is/are not clearly covered by one of the categories in the table in Section 2.2, please contact Medsafe for guidance before submitting the application and fee.

2.1 Identification of parent product

This application is for consent to distribute a new product that is substantially similar to the following parent product:

Parent product(s) name(s):

Dose Form:

Strength:

Medsafe File Ref. TT50-

Comments:

2.2 Differences between parent product and new product

Tick the box below that best describes the difference(s) between the new and parent products. If appropriate, describe the similarities and differences between the new and parent products in greater detail under “Comments” in section 2.1 of the form.

(Tick one)Difference between parent product and new productAdditional name - Grade 1

new name to be used in addition to existing name all other details identical to parent product except for labelling new label displays new name, but all other information on the

label is essentially the same as on the parent product label (even if layout is different)

Additional name - Grade 2

new name to be used in addition to existing name all other details identical to parent product except for labelling new label displays new name layout of label may be different from that of parent product some other information on the label is different from that on the

parent product label

Additional strength new and parent products have the same dose form new product is a direct scale of parent product, or uses same

excipient matrix all other details identical to parent product except for labelling

and specificationsAdditional flavour or type of sweetening

new and parent products have the same dose form new product has a flavour or type of sweetening different from

the parent product all other details identical to parent product except for labelling

(if applicable)and specifications(End of form)

195


196


Appendix 4: Checklist for New Multi-source Medicine Data

197


CHECKLIST FOR NEW MULTI-SOURCE MEDICINE APPLICATION DOSSIER

Product: …………………………………………………………………………

Where any required information is not supplied, the omission must be explained and justified in a covering letter

(Tick as applicable)

Provided N/A

COMPOSITION1. Composition of the medicinal product

The composition of each product and strength is clearly defined.

The function of each excipient is defined and justified or obvious. (Note: The functions of the excipients may sometimes be found in Section IIA.4: “Development Pharmaceutics”.)

If starch is used, the source (e.g. wheat, maize, rye, barley, oat) is indicated.

If more than one strength of a product is to be marketed, it is clear how the different strengths are distinguished (e.g. by differences in size, colour, shape, markings, etc.)

2. Container (brief description)

The primary (immediate) and secondary (outer) packaging and packaging materials (e.g. type of glass or plastic), pack sizes, any dosing device, and any desiccant or cotton wool contained in the package are defined.

If a desiccant is included in the package, this is labelled with a warning such as “Not to be taken”.

If NZ Medicines Regulations require the product to be in a safety container, it is so packaged.

Any induction seal or tamper proof seal is adequately defined.

3. Clinical trial formula(e)

There is a clear indication of any differences between the formulation(s) intended for marketing and that (or those) used in bioequivalence and/or clinical studies.

4. Development pharmaceutics

The justification for the choices of salt, isomer, and stereoisomer/ racemate of the active substance, the dose form(s), formulation(s) and manufacturing processes, sterilising processes, any overages, and the packaging are self-evident or have been justified.

198


Provided N/A

METHOD OF MANUFACTURE

1. Manufacturing formula

The batch formula has been supplied for each strength of each dose form.

In each case, the batch size(s) has been defined in terms of total mass/volume and number of units produced.

The quantities of the individual ingredients correspond to those claimed for the unit composition, and there are no unexplained or hidden overages.

Any overage(s) of active ingredient(s) has been justified.

If ranges are given for quantities of excipients, these have been justified and validated.

Any overfill of the container(s) has been justified.

Details (incl. quantities and quality standards) have been provided for any solvents used but removed in the process.

Details (including quality standards) have been provided for any gases used in the process or used to fill the headspace in the product container.

2. Manufacturing process

Each manufacturing, sterilisation (if applicable) and packaging process and the equipment used has been described.

If alternative processes are intended at some steps in the manufacture, or at different manufacturing sites, these have been justified and shown to yield product of equivalent quality.

The in-process controls (incl. Temperatures, mixing times and speeds, completeness of sterilisation of equipment and product, test methods and acceptance limits at each step) are defined.

If relevant, any processing (e.g. washing, sterilisation) of the containers before filling is described.

3. Validation of the manufacturing process

Detailed validation data have been provided for all critical steps in the manufacturing process (including any cleaning and/or sterilisation steps).

Validation data have been generated at each manufacturing site involved in the production of the product.

Validation data have been generated at either production scale or at pilot scale (10% of full scale or 100,000 solid dose units, whichever is the greater unless otherwise justified) using production scale equipment or, in the case of the production scale being less than 100,000 units, at production scale.

If only pilot scale validation has been completed, full scale validation is scheduled for when commercial scale production commences.

199


Provided N/A

CONTROL OF STARTING MATERIALS

1. Active substance(s)

A complete DMF(s) and accompanying “letter of access” (or a Ph Eur Commission “Certificate of Suitability” in lieu of a DMF) has been submitted in support of this NMA (or a previous NMA) for each manufacturer of bulk active.

The full specifications applied to the bulk active ingredient by the finished product manufacturer are provided.

If the specifications are non-pharmacopoeial, all of the testing procedures and requirements are described in detail.

If certain tests are not carried out routinely, justification has been provided.

Validation data have been provided for all assay tests (whether pharmacopoeial or not) and the data cover (as applicable):1. specificity or selectivity2. accuracy (agreement with true value)3. intra-assay precision, intra-laboratory 4. inter-assay repeatability5. linearity 6. stability of solutions7. robustness/ruggedness.

Validation data have been provided for all related product/ degradation product tests (whether pharmacopoeial or not) and the data cover (as applicable):1. specificity or selectivity2. limit of detection (LOD)3. limit of quantification (LOQ)4. accuracy (agreement with true value)5. intra-assay precision6. inter-assay repeatability7. linearity 8. stability of solutions9. robustness/ruggedness.

Validation data have been provided for all residual solvent tests (whether pharmacopoeial or not) and the data cover (as applicable):1. specificity or selectivity2. limit of detection (LOD)3. limit of quantification (LOQ)4. accuracy (agreement with true value) 5. intra-assay precision6. inter-assay repeatability 7. linearity 8. stability of solutions9. robustness/ruggedness.

Validation data (or at least evidence of system suitability) have been provided for all microbiological tests (whether pharmacopoeial or not)

Where two or more testing laboratories are involved, evidence has been provided that the test procedures have been adequately validated at each site.

Batch analytical data generated by the finished product manufacturer(s) have been supplied for typical batches of bulk active substance from each supplier.

200


Provided N/A

2. Excipient(s)

Details of the quality standards applied to each of the excipients (including capsule shells, commercial pre-mixed coating materials, and any gases used in filling vials and ampoules) have been provided.

Evidence that adequate measures are taken to ensure that any ingredients of animal origin (e.g. gelatin, magnesium or calcium stearate, stearic acid) used in the product are free from TSE contamination has been provided.

Representative batch analytical data are provided for any excipients controlled by non-pharmacopoeial specifications. [Note: Batch data are not normally required for commonly used excipients controlled by pharmacopoeial specifications.]

3. Packaging material (immediate packaging)

The materials used (polymers, types of glass, etc.) construction, dimensions and physical properties for containers, any induction seals, closures and any delivery device are defined.

The full specifications and routine tests on the proposed marketing containers and closures are provided.

Evidence has been provided to confirm that plastic and rubber packaging components are free from leachable toxic impurities and comply with the Ph Eur and USP requirements for polymeric materials used in packaging of medicines.

Representative batch analytical data have been supplied for each container, closure, packaging material and delivery device (if any).

CONTROL TESTS ON INTERMEDIATE PRODUCTS

Specifications and representative batch analytical data are provided for any intermediate product.

CONTROL TESTS ON THE FINISHED PRODUCT

1. Specifications and Routine Tests

The full specifications for the finished product are provided.

Any non-pharmacopoeial test procedures used as replacements for, or in addition to, the procedures in the pharmacopoeial monograph have been explained and justified.

In any in house specifications supplied it is clear which requirements apply at release and which apply throughout the shelf-life.

If all specified tests are not carried out routinely, acceptable justification is given.

If the product is tested in more than one test laboratory, there is an indication of whether the test procedures are the same in each laboratory, or if there are any differences, these have been defined and justified.

201


Provided N/A

CONTROL TESTS ON THE FINISHED PRODUCT (cont’d)

2. Scientific Data

The test procedures have been validated at each testing site intended for routine quality control of the product.

Where two or more testing laboratories are involved, evidence has been provided that the test procedures have been adequately validated at each site.

Validation data have been provided for all assay tests (whether pharmacopoeial or not) and the data cover (as applicable):1. specificity or selectivity2. accuracy (agreement with true value)3. intra-assay precision 4. inter-assay repeatability5. linearity 6. stability of solutions7. robustness/ruggedness.

Validation data have been provided for all related product/ degradation product tests (whether pharmacopoeial or not) and the data cover (as applicable):1. specificity or selectivity2. limit of detection (LOD)3. limit of quantification (LOQ)4. accuracy (agreement with true value)5. intra-assay precision6. inter-assay repeatability7. linearity 8. stability of solutions9. robustness/ruggedness.

Validation data have been provided for the assay method used to monitor dissolution and the data cover (as applicable):1. specificity or selectivity2. accuracy (agreement with true value), 3. intra-assay precision 4. inter-assay repeatability5. linearity 6. stability of solutions7. robustness/ruggedness.

Validation data (or at least evidence of system suitability) have been provided for all microbiological tests (whether pharmacopoeial or not) (e.g. sterility, microbial counts, abnormal toxicity, endotoxins) have been provided. [Note: Validation of LAL tests is formulation-specific and must be repeated if any change is made to the formulation.]

Validation data have been provided for any other test procedures, (whether pharmacopoeial or not) that are not self-validating.

Recent complete analytical reports (in tabular form or as signed certificates of analysis) have been included for each strength of each dose form of the final market formulation(s) of the product manufactured at least at pilot scale on production scale equipment at each of the proposed manufacturing sites.

For each batch reported, the batch number, the date of manufacture, the batch size, and the batch number/code for the bulk active ingredient(s) used in manufacture have been provided.

202


Provided N/A

STABILITY

1. Stability Tests on Active Substance(s) [Normally included in the DMF, if applicable]

2. Stability Tests on the Finished Product

The shelf-life specifications are provided (or referenced)

All of the test procedures have been defined.

Any non-pharmacopoeial test procedures used as replacements for, or in addition to, the procedures in a pharmacopoeial monograph have been justified.

Any differences between test procedures for the shelf-life and release specifications have been justified and validated.

The stability data cover at least 12 months storage at (or above) the recommended maximum storage temperature.

The stability trials were carried out in accordance with ICH guidelines, unless otherwise justified.

The dates on which the stability batches were manufactured and the dates on which they were placed on stability trial have been reported.

The trials were carried out using the proposed marketing formulation of the product (or formulations that may reasonably be expected to have the same stability).

Where there is only one strength/potency, at least 3 batches of the product were included in the trial. Two of these should be at least pilot scale (the other may be smaller, if justified).

Where different strengths/potencies are direct scales, at least 2 pilot scale batches of the highest and lowest strengths/potencies were included or, where different strengths/potencies of the medicine are not direct scale-ups, at least 2 pilot scale batches of each strength/potency were included in the trial.

If the trials used pilot-scale batches, trials using production-scale batches have commenced or are scheduled.

If the product is manufactured at more than one manufacturing site, batches from each manufacturing site were included in the stability trials, or data are to be generated for batches manufactured at the omitted site(s).

Batch numbers or codes are reported for the batches of active substance used in the manufacture of the finished product used in the stability trials.

The packaging for the stability batches is clearly defined.

Each of the proposed local marketing containers (or acceptable equivalents or less protective packagings) was among those used in the trials.

203


Provided N/A

Stability Tests on the Finished Product (cont’d)

It is clear whether or not the real time stability samples were stored protected from light (e.g. in the outer cartons).

In the case of liquid products in a stoppered container, the orientation of the primary containers (e.g. upright and/or inverted) is clearly indicated.

If relevant, photostability has been investigated in accordance with ICH Guidelines.

The storage temperatures and relative humidities used in the trials are defined.

All of the test procedures have been validated in the laboratory used to analyse the stability samples.

If there were any changes in test procedures during the course of the trials, there has been comparison and correlation of results generated by the alternative methods.

The assay methods used for active substance and degradation products have been validated as stability indicating.

If relevant, transmission of moisture in/out of the container has been investigated.

If relevant, leaching of substances from plastic/rubber containers or closures has been investigated.

If relevant, preservative levels (or effectiveness) were monitored.

If the data do not cover the whole of the proposed shelf-life, statistical and regression analysis of the data have been provided to support the proposed shelf-life.

If relevant, the stability of the product after first opening, reconstitution or dilution (as applicable) has been investigated.

Adequate storage instructions and time-limits for use of the product after first opening or reconstitution or dilution have been provided on the draft product label, in any package insert and in the Data Sheet.

204


Provided N/A

BIOEQUIVALENCE

1. Compliance with Good Clinical Research Practice (GCRP)

The biostudy report includes (a) the dates for the trial and (b) the dates and times of dosage and (c) dates of analysis of the plasma/serum/urine samples and, (d) details of the sites where the clinical and analytical aspects of the study were carried out.

The study report includes (a) names, (b) affiliations and (c) signatures for each of the responsible investigators and analysts.

The study was carried out in accordance with the requirements of GCRP and with ethics committee approval.

A copy of the study protocol has been provided.

Subject ages, sexes, weights and heights (and smoking habits, if relevant) have been provided.

Clinical and laboratory screening data for the subjects are included in the study report.

The details of any adverse reactions (if any) experienced by the subjects during or after the study are included in the study report.

2. Formulations compared and their QC data

The reference product is clearly defined

The source from which the batch of reference product was obtained is clearly identified.

If the batch of reference product was obtained from outside New Zealand, appropriate evidence that its formulation was definitely the same as that distributed in New Zealand has been provided.

The batch number/code and source of bulk active ingredient used to manufacture the batch trial medicine(s) are identified.

The batch size of the trial medicine(s) was full production scale in the case of production scale being less than 100,000 solid dose units or at least 10% of full production scale or 100,000 units, whichever is the greater, unless justified, in the case of production batch being more than 100,000 units.

Complete quality control data (incl. Mean assay, content uniformity, disintegration, and dissolution) have been provided for the batches of reference product and trial medicine used in the biostudy.

The batches of reference and trial medicines used in the biostudy had not expired at the time of the study.

The in vitro dissolution profiles of the medicines compared in vivo in the biostudy have been compared and shown to be comparable, or any significant differences have been discussed and justified.

205


Provided N/A

3. Study design

The study design is reported in detail.

The dose of medicine given is reported.

Any meals consumed during the study periods are defined (e.g. menus provided)..

Any restrictions on subjects’ diet, physical activity, and use of other medication before and during the study are defined.

Sampling times are clearly defined.

Any significant departures from the protocol are detailed and explained.

The time between the different phases of the study is defined.

If the study was ‘single dose, the washout period was adequate and plasma/serum levels of drug and metabolites were back to zero for each subject before the next dose was administered.

If the study was ‘steady state’, evidence that a steady state was actually achieved in each phase of the study before blood sampling was commenced has been provided.

If relevant, any subject dropouts and withdrawals have been explained.

4. Assay method and procedures

The body fluids monitored are clearly defined.

The entities measured (unchanged drug substance and/or active/significant metabolites) are clearly defined.

The assay method, sample preparation and assay procedures are described in detail.

The sources of the reference standards (drug substance, any metabolites and internal standards) used in the analytical validation and assay procedures are reported.

206


Provided N/A

5. Pre-study validation of assay procedure

Validation data were generated at the site used for assaying the actual study samples.

Specificity has been validated for each entity measured.

Representative chromatograms or other data have been submitted to confirm the specificity of the assays.

The minimum quantifiable concentration (MQC) has been validated [MQC is the concentration with RSD = ca 20%.]

Intra-assay precision has been validated (e.g. RSD typically <10% and 20% near MQC).

Inter-assay accuracy has been validated (e.g. RSD typically <10% and 20% near MQC).

Accuracy (e.g. standards within <10% of actual) has been validated.

Linearity (r>0.99) (or the calibration curve) has been established using 5 or more standards with appropriate concentrations across the range of concentrations encountered in the study.

The recovery has been measured at low, medium and high concentrations and is reasonably uniform.

The stability of the samples during storage and freeze-thaw cycling has been established.

6. Quality control of study sample assays

At least 5 daily calibration standards with concentrations covering the required range were used in the assays of the study samples.

The investigators’ criteria for accepting or rejecting results have been provided.

The QC sample assay data have been reported.

7. Pharmacokinetic parameters

The individual subject concentration vs. time data have been reported in both tabular and graphical form.

The mean concentration vs. time data have been reported in both tabular and graphical form.

Only concentrations at or above the MQC have been used in calculation of elimination rates and AUCs.

If actual and nominal sampling times were significantly different, the actual times were used in calculation of pharmacokinetic parameters.

8. Statistical analyses of results

The statistical analyses of the Tmax, Cmax (and Cmin for a steady state study) and AUC data are reported.

207


The results have been normalised (if necessary) for mean potencies of the administered formulations.

Comments:

………………………………………………………………………………………………

………………………………………………………………………………………………

………………………………………………………………………………………………

………………………………………………………………………………………………

………………………………………………………………………………………………

………………………………………………………………………………………………

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………………………………………………………………………………………………

………………………………………………………………………………………………

208


Appendix 5: CMN Form A

209


CHANGED MEDICINE NOTIFICATION FORM A

This form is to be used when notifying a material change (including self-assessable changes) to an approved Type I product (lower risk medicine) or a Type II product (intermediate- or higher-risk medicine other than a biological or biotechnological product - but including antibiotics and like substances derived from micro-organisms). Use CMN Form B for a biological or biotechnological product (i.e., vaccine, serum, allergen, medicinal product derived from human blood or plasma, or immunological medicinal product, and any product derived from biotechnology)Do not use this form for notifying a changed related product. Use the CRPN form instead.

Section 1: Product details

Copy details from the database report for the currently approved product. A separate form must be used for each different product (name + dose form + active ingredient(s) + strength + classification + flavour, as applicable).

Product name:

Medsafe File No: TT50-

Dose form:

Strength:

Classification :

Type of product:(Tick one)

Type I Lower-risk medicines

Type II Intermediate-risk or Higher-risk medicines other than biological or biotechnological products (but including antibiotics and like substances derived from micro-organisms)

210


CMN Form A

Section 2: Applicant and Sponsor details and declaration

In accordance with section 24 of the Medicines Act 1981, I hereby notify the Director-General of Health of material changes proposed for this product. I certify that the information supplied is correct to the best of my knowledge and that no relevant information has been omitted.

Name, designation and address of person submitting the notification:[All correspondence relating to the notification will be sent to this person unless otherwise requested.]

Email address:

Signature: _______________________________ Date: ___________________


211


CMN Form A

Section 3: Proposed changes

Instructions

1. Tick the box(es) in the left hand column beside the description(s) that most accurately reflects the changes for which approval is sought. The main change and the consequential changes listed under the “Description of change” are all covered by the fee shown in the “Product type & fee” column. Where no product type is specified in the “Product type and fee” column, the same fee applies to all product types.

2. It is not necessary to submit pages listing change descriptions that are not relevant to the notification.

3. For each box ticked, write the appropriate fee in the “Fee to pay” column. Add together all amounts in the “Fee to pay” column and transfer this total to the fee calculation box in Section 5.

4. When a self-assessable change is notified at the same time as other changes for which a fee is paid, the $200 administrative fee for the self-assessable change does not apply (except in the case of a data sheet update, where the update is independent and not consequential of any of the proposed changes). “N/A” (not applicable) should be written in the “Fee to pay” column for the self-assessable change.

5. If applicable, the Consumer Medicine Information (CMI) for the product should also be updated in line with the changes and a revised version forwarded to Medsafe once the consent letter for the CMN or SACN has been received. There is no additional fee for the CMI.

Product name

Note: If a product is to be marketed under a new name in addition to the existing name, it is a new product and a New Medicine Application must be completed.

Tick box

Description of change Product type & fee

Fee to pay($)

Product name

new product name to replace existing name no change in formulation

Consequential changes included (if applicable) are: revised data sheet and labelling

$400

for each new name

212


CMN Form A

Formulation

Note: If a formulation change results in a change in the actual manufacturing process, this must be separately notified as a “Finished product manufacturing process” change in the “Finished product” section of this form.

Tick box


Fee to pay($)

Formulation - Grade 1

change in overage of an active ingredient or excipient, or other excipient change where either:

the product is one for which comparative bioavailability data are not required; or

the change is not considered likely to affect bioavailability or stability

Consequential changes included (if applicable) are: new or revised specifications for excipient revised specifications for finished product revised labelling and data sheet amended batch manufacturing documentation,

provided there is no significant change in manufacturing process

$800

for any number of excipient changes


changed active ingredient salt, or change in status of ingredient from active to excipient, or removal of active ingredient with no other changes

change not considered likely to affect stability

Consequential changes included (if applicable) are: new specifications/test methods for active

ingredient and finished product revised labelling and data sheet amended batch manufacturing documentation,


I: $800

II: Not permitted (NMA required)


changed active ingredient salt or removal of active ingredient with no other changes

stability study included


ingredient and finished product revised labelling and data sheet amended batch manufacturing documentation,


I: $1200

II: Not permitted (NMA required)

213


CMN Form A

Formulation (cont'd)

Tick box


Fee to pay($)


excipient change that may affect, or is considered likely to affect, bioavailability, stability or safety(see Sections 4.6.1 and 8.3 of the Guidelines for details)

Consequential changes included (if applicable) are: new or revised specifications/test methods for

excipient revised labelling and data sheet

I: $1200 II: $2400


Active ingredient

Tick box


Fee to pay($)

Active ingredient manufacturing site

new site of manufacture manufacturing process unchanged

$400

for any number of new sites

Active ingredient manufacturing process - Grade 1

new manufacturing process Certificate of Suitability provided in lieu of DMFConsequential changes included (if applicable) are: new site of manufacture

I: Not applicable

II: $400

for any number of new sites

Active ingredient manufacturing process - Grade 2

new manufacturing process DMF or equivalent documentation supplied

Consequential changes included (if applicable) are: process validation for active ingredient revised specifications/test methods for active

ingredient new site of manufacture

I: Not applicableII: $1600

for each new process

214


CMN Form A

Active ingredient (cont’d)

Tick box


Fee to pay($)

Active ingredient specifications/test methods - Grade 1

tightening of limits for active substance

$200(self-assessable)


new specifications/test methods for a substance controlled according to a pharmacopoeial monograph (resulting from change to a different pharmacopoeia, not simply updating to the latest edition)

$400


adoption of additional or different specifications/test methods not specified in the pharmacopoeial monograph for an active ingredient otherwise controlled according to a pharmacopoeial monograph

$400

for each active


revised specifications/test methods/testing protocol for a substance not controlled according to a pharmacopoeial monograph

I: $400II: $800

for each activeingredient

Excipient

Tick box


Fee to pay($)

Excipient specifications/test methods - Grade 1

revised specifications/test methods for a substance controlled according to a pharmacopoeial monograph (resulting from change to a different pharmacopoeia, not simply updating to the latest edition)

$200(self-assessable) for any number of excipients


revised specifications/test methods for a substance not controlled according to a pharmacopoeial monograph

$400

for each excipient

215


CMN Form A

Excipient (cont’d)

Tick box


Fee to pay($)


adoption of additional or different specifications/test methods not specified in the pharmacopoeial monograph for an excipient otherwise controlled according to a pharmacopoeial monograph

$400

for each excipient

Finished product

Tick box


Fee to pay($)

Finished product packing site

new packing site that is not a site of manufacture

includes overlabelling

$400

for any number of sites

Finished product manufacturing site - Grade 1

no change in manufacturing process or type of equipment used

specifications/test methods unchanged

Consequential changes included (if applicable) are: packing at same site

$400

for each new site


change in manufacturing process or type of equipment used

Consequential changes included (if applicable) are: packing at same site

I: $1600II: $2000

Finished product manufacturing process - Grade 1

type of manufacturing process unchanged, but changes to mixing times, batch scaling, type of equipment etc.

Consequential changes included (if applicable) are: revised specifications/test methods new site of manufacture and packing

I: $800 II: $1200


216


CMN Form A

Finished product (cont’d)

Tick box


Fee to pay($)


new type of manufacturing process

Consequential changes included (if applicable) are: revision or reconfirmation of shelf life revised specifications/test methods new site of manufacture and packing

I: $1600II: $2000


Finished product specifications/test methods - Grade 1

revised specifications/test methods no change in manufacturing process product controlled according to a

pharmacopoeial monograph (resulting from change to a different pharmacopoeia, not simply updating to the latest edition)



tightening of limits for active substance no other changes to specifications no changes to test methods



adoption of additional or different specifications/test methods not specified in the pharmacopoeial monograph for a product otherwise controlled according to a pharmacopoeial monograph

$400


revised specifications/test methods no change in manufacturing process product not controlled according to a

pharmacopoeial monograph

I: $800II: $1200


change in shape, engraving or coding of tablets no change in dissolution or bioavailability

$200(self assessable)

217


CMN Form A

Product stability and packaging

Tick box


Fee to pay($)

Shelf life/storage conditions - Grade 1

decrease in storage temperature from 30C to 25C with no change in shelf life and no other changes

addition of a statement such as “Protect from light”

Consequential changes included (if applicable) are: revised labelling and data sheet

$200 (self-assessable)


revised shelf life and/or storage conditions with no other changes


$800

Container/closure/packaging - Grade 1

new pack size evidence provided that stability study not

required no effect on dose measurement or dose

delivery

Consequential changes included (if applicable) are: revised labelling and data sheet revised packaging specifications



new container or closure type and/or new pack size and/or new packaging material type

evidence provided that stability study not required

no effect on dose measurement or dose delivery


$400

for any number of new container/closure/packaging combinations




affects dose measurement or dose delivery


$800

for each new container/closure/packaging combination

218


CMN Form A

Product stability and packaging (cont’d)

Tick box


Fee to pay($)



revised shelf life and/or storage conditions (stability study included)

does not affect dose measurement or dose delivery


$1200





affects dose measurement or dose delivery


$1600

for each container/ closure/ packaging combination

Indications and dosage

Tick box


Fee to pay($)

Indications/dosage - Grade 1

new indication (see section 3.1.1 of the Guidelines for details)

supporting clinical data required

Consequential changes included (if applicable) are: new dosage instructions revised data sheet and labelling

Note: CMN will generally be referred under section 24(5).

$1600

for each new indication


modified indication (see section 3.1.1 of the Guidelines for details)




$800

for each modified indication

219


CMN Form A

Indications and dosage (cont’d)

Tick box


Fee to pay($)


new dosage regimen no change to indications supporting clinical data required


$800

for each new dosage regimen


revised wording of indications/dosage with no actual change to indications or dosage


$400


new or revised indications/dosage for a multi-source medicine to match indications approved for innovator product


$400

Contraindications, Warnings and Precautions

relaxation of contraindications, and/or relaxation of warnings and precautions

regarding use in pregnancy, lactation or particular population/patient subgroups



$800

Data sheet

Tick box


Fee to pay($)

Data sheet - miscellaneous changes

update or addition to safety information with no change to approved product details, and/or

expansion of pharmacokinetic and/or pharmacodynamic data, and/or

change in name or address of distributor with no change to approved product details

$200 per data sheet(self-assessable)

220


CMN Form A

Labelling

Tick box


Fee to pay($)

Labelling - Grade 1

re-design of label, and/or change in name and address of distributor no change to product name, strength, dose

form, dosage instructions or indications


Not applicable if a change of the classification makes the product a Controlled Drug

Labelling - Grade 2

design or re-design of a New Zealand compliant label and/or

change in the classification to Controlled Drug no change in actual strength, but a change in

the way the strength is expressed (if applicable)

$400

Labelling - Grade 3

request for a labelling exemption, or request for renewal of a labelling exemption

NOT APPLICABLE for a CONTROLLED DRUG

$400 (plus $200 for each additional name/ dose form/ strength/ flavour)

Other

Tick box


Fee to pay($)

Sponsor

change of product sponsor from one company to another (not simply a change in the name or address of an existing sponsor)

Consequential changes included (if applicable) are: change of name and address of distributor on

label and in data sheet.


Note: A CMN/CRPN for change in packing site(s) may also be required.

Interchangeable Multi-source Medicines (IMM) List

application for inclusion of a product on the IMM list

supporting bioequivalence data required

I: Not applicableII: $2400

221


CMN Form A

Section 4: Summary of proposed changes

Use a separate summary sheet for each change.

Description of change (copy heading from “Description of change” box in Section 3):

Summary of current and proposed details:

Current product details Proposed details

Reason for change:

Consequential changes:

Acceptance overseas:

222


CMN Form A

Section 5: Fee details

Complete this section once for each notification package submitted. If you are simultaneously notifying an identical change or set of changes to a number of products, list all the products covered by the notification in the following table. Each dose form and each strength and flavour of each dose form of a product must be separately listed. Note: A separate copy of Sections 1 and 2 of this notification form must be completed for each of the products listed. Only one copy of Sections 3 and 4 is required. All the forms must be submitted in the same notification package.

File No. Product name Dose form Strength

Fee calculation

Note 1: If you are notifying identical changes to a number of products, the evaluation fee shown in the box below must be the largest fee that would apply to any single product. For example, if the notification covers Type I and Type II products, the evaluation fee applicable for a Type II product must be entered below.Note 2: In no case will the CMN/CRPN evaluation fee for a single product exceed $7,800 for a medicine or $5,500 for a related product. Note 3: Additional names, dose forms, strengths and flavours are each regarded as “additional products” and each one attracts an additional $200 (administrative) fee.Note 4: The fee for a changed data sheet is $200 per data sheet

Evaluation fee calculated for a single product:[Total all amounts in “Fee to pay” boxes in Section 3]

Administrative fee for _____ additional products @ $200 each

Total fee:

$ .00

$ .00_____________

$ .00

Method of payment: Cheque enclosed Direct credit (details enclosed)

Check and indicate that the notification package sent to Medsafe contains the following (as applicable):

(Y or N/A)

A completed copy of Sections 1 and 2 of the CMN/CRPN form for each product covered by the notification

One completed copy of Sections 3, 4 and 5 of the CMN/CRPN form

One copy of the supporting data

A copy of the current product database report(s)

A copy of the label and a completed checklist and declaration if the notification includes a self-assessed labelling or data sheet change

A copy of an assessment report from an appropriate overseas regulatory authority

(End of form)

223


Appendix 6: CMN Form B

224


CHANGED MEDICINE NOTIFICATIONFORM B

This form is to be used when notifying a material change (including self-assessable changes) to an approved Type III (biological or biotechnological) product (i.e., a vaccine, recombinant product, monoclonal antibody or variant thereof, or a medicinal product derived from blood or plasma).Use CMN Form A for any other (Type I/II) medicine, including antibiotics and like substances derived from micro-organisms. Do not use this form for notifying a changed related product.


Copy details from the database report for the currently approved product. A separate form must be used for each different product (name + dose form + active ingredient + strength + classification, as applicable).

Product name:

File No: TT50-

Dose form:

Strength/Potency:

Classification:




Email address:

Signature: _________________________ Date: ________________


225


CMN Form B


Instructions1. Tick the box(es) in the left hand column beside the description(s) that most accurately reflects the changes for which approval

is sought. The main change and the consequential changes listed under the “Description of change” are all covered by the fee shown in the “Product type & fee” column. Where no product type is specified in the “Product type and fee” column, the same fee applies to all product types.

2. It is not necessary to submit pages listing change descriptions that are not relevant to the notification.


4. When a self-assessable change is notified at the same time as other changes for which a fee is paid, the $200 administrative fee for the self-assessable change does not apply (except in the case of a data sheet update, where the update is independent and not consequential of any of the proposed changes). “N/A” (not applicable) should be written in the “Fee to pay” column for the self-assessable change.

Product name


Tick box

Description of change Product type & fee Fee to pay($)

Product name

new product name to replace existing name no change in formulation


$400

for each new name

Formulation/Excipients

Note: If a formulation change is associated with a change in the actual bulk active manufacturing process, this must be separately notified as a “Bulk Active manufacturing process” change in the “Bulk Active” section of this form

Tick box


Fee to pay($)


change of excipients including the addition or removal of excipients

Consequential changes included (if applicable) are: new or revised specifications for excipient revised data sheet and labelling amended batch manufacturing documentation,


$1600


Formulation – Grade 2

strain update of active ingredient for influenza vaccines

$400for any number of strains

226


CMN Form B

Bulk Active

Tick box


Fee to pay($)

Bulk Active manufacturing site

Change in site of manufacture of any stage in the process up to, and including, the manufacture of the final bulk.

This would be considered as a New Medicine Application

Consequential change (if applicable) Method of manufacture

$7800

Bulk Active methods of manufacture

Change in any step of the method of manufacture.

This would include, but is not restricted to: changes in mixing time, batch scaling type of equipment new master cell bank new working cell bank new source(s) of plasma for blood products

$1600 per step change to a maximum of $7800

This category of change could be expected to be referred as an NMA under section 24(5)

Change in site of lyophilisation $1600

Revalidation of lyophilisation process $1600

Active ingredient method of manufacture

No change to the actual manufacturing process or type of equipment used

Specifications/test methods unchanged Editorial changes for the manufacturing

process records only

$400

227


CMN Form B

Finished product manufacture and packing

Tick box


Fee to pay($)

Finished product manufacturing site

new site for dispensing final bulk finished product into primary containers

$1600

for each new site

Finished product secondary packing site

new secondary packing site that is not a site of manufacture

packing finished product into cartons includes overlabelling

$400



type of manufacturing process unchanged, but changes to mixing time, batch scaling, type of equipment etc.

Consequential changes included (if applicable) are: new site of manufacture and packing

$1600

Finished product manufacturing process – Grade 2


Consequential changes included (if applicable) are: revision or reconfirmation of shelf life new site of manufacture and packing

$1600

Finished product manufacturing process

No change to the actual manufacturing process or type of equipment used

Specifications/test methods unchanged Editorial changes for the manufacturing

process records only

$400

228


CMN Form B

Test methods and specifications

Tick box


Fee to pay($)

Test methods and specifications - Grade 1

change to any method used to assay potency of each active moiety

$1600


change to specifications used to describe potency

$1600

for each active moiety potency specification


change to standard used in assessment of potency

$1600


change to any method used to assess other physical or chemical properties of the product

$800


addition / removal / change to any specification used to describe other physical or chemical properties

$800


tightening of specification limits for active ingredient


for any number of active ingredients

229


CMN Form B


Tick box


Fee to pay($)

Shelf life/storage conditions - Bulk Actives and Intermediate Bulks

revised shelf-life and/or storage conditions with no other changes

$800

for each bulk active or each process intermediate

Shelf life/storage conditions - Finished Product



$800


new container or closure and/or new pack size and/or new packaging material type

revised shelf-life and/or storage conditions

supporting stability data provided no effect on dose measurement or dose

delivery

Consequential changes included (if applicable) are: revised packaging specifications revised labelling and data sheet

$800


new container or closure and/or new pack size and/or new packaging material type

revised shelf-life and/or storage conditions

supporting stability data provided changes affect dose measurement or

dose delivery

Consequential changes included (if applicable) are: revised packaging specifications revised labelling and data sheet

$1600

for each container/closure packaging combination


new pack size evidence provided that no stability data

required no effect on dose measurement or dose

delivery



230


CMN Form B

Changes affecting the Diluent component of Type III (biological or biotechnological) products.

If the diluent contains biological/blood product ingredient, use CMN Form B and select appropriate category of change.

If the diluent DOES NOT contain biological/blood product ingredient, use CMN Form A and select appropriate category of change.


Tick box


Fee to pay($)


new indication (see Section 3.1.1 of the Guidelines for details)



Note: CMN will generally be referred under section 24(5)

$1600



modified indication (see Section 3.1.1 of the Guidelines for details)



Note: CMN will generally be referred under section 24(5)

$800



new dosage regimen no change to indications supporting clinical data required


$800


231


CMN Form B

Indications and dosage (cont’d)

Tick box


Fee to pay($)




$400


new or revised indications/dosage for a multi-source medicine to match indications approved for innovator product


$400

Contraindications, Warnings and Precautions

relaxation of contraindications, and/or relaxation of warnings and precautions

regarding use in pregnancy, lactation or particular population/patient subgroups



$800

Labelling

Tick box


Fee to pay($)

Labelling - Grade 1

Labelling for this category must be based on, and submitted with, currently approved labelling.

re-design of label, and/or change in name and address of

distributor no change to product name, strength,

dose form, dosage instructions or indications, or

change in dosage to “as directed by a physician”


232


CMN Form B

Labelling (cont’d)

Tick box


Fee to pay($)

Labelling - Grade 2

design or re-design of a New Zealand compliant label

no change in actual strength, but a change in the way the strength is expressed (if applicable)

any labelling change not covered by Labelling – Grade 1 or Labelling – Grade 3

$400

Labelling - Grade 3

request for a labelling exemption, or request for renewal of a labelling

exemption

$400(plus $200 for each additional name/ dose form/strength/ flavour)

Data Sheet

Tick box


Fee to pay($)

Data sheet - miscellaneous changes

update or addition to safety information with no change to approved product details, and/or

expansion of pharmacokinetic and/or pharmacodynamic data, and/or

change in name or address of distributor with no change to approved product details

$200 per data sheet.(self-assessable)

Other

Tick box


Fee to pay($)

Sponsor



label and in data sheet.

Note: A CMN for change in packing site(s) may also be required.


233


CMN Form B






Reason for change:


Acceptance overseas:

234


CMN Form B



File No. Product name Dose form Strength

Fee calculation

Note 1: If you are notifying identical changes to a number of products, the evaluation fee shown in the box below must be the largest fee that would apply to any single product. For example, if the notification covers Type I and Type II products, the evaluation fee applicable for a Type II product must be entered below.Note 2: In no case will the CMN/CRPN evaluation fee for a single product exceed $7,800 for a medicine or $5,500 for a related product. Note 3: Additional names, dose forms, strengths and flavours are each regarded as “additional products” and each one attracts an additional $200 (administrative) fee.Note 4: The fee for a changed data sheet is $200 per data sheet



Total fee:

$ .00

$ .00_____________

$ .00



(Y or N/A)






A copy of an assessment report from an appropriate overseas regulatory authority

(End of form)

235


Appendix 7: CRPN Form

236


CHANGED RELATED PRODUCT NOTIFICATION

This form is to be used when notifying a material change (including self-assessable changes) to an approved related product. Do not use this form for notifying a changed medicine. Use the appropriate CMN Form instead.


Copy details from the database report for the currently approved product. A separate form must be used for each different product (name + dose form + strength + classification + flavour, as applicable).

Product name:

Type of product:

Strength:

Medsafe File No: TT50-




Email address:

Signature: _______________________________ Date: ___________________


237


CRPN Form


Instructions1. Tick the box(es) in the left hand column beside the description(s) that most accurately reflects the changes for which approval is

sought. The main change and the consequential changes listed under the “Description of change” are all covered by the fee shown in the “fee” column. It is not necessary to submit pages listing change descriptions that are not relevant to the notification.


3. When a self-assessable change is notified at the same time as other changes for which a fee is paid, the $200 administrative fee for the self-assessable change does not apply. “N/A” (not applicable) should be written in the “Fee to pay” column for the self-assessable change.

Product name


Tick box

Description of change Fee Fee to pay($)

Product name

new product name to replace existing name

no change in formulation

Consequential changes included (if applicable) are: revised labelling

$400

for each new name

Formulation


Tick box



change in overage of an active ingredient or excipient, or other excipient change

the change is not considered likely to affect stability

Consequential changes included (if applicable) are: new or revised specifications for excipient revised specifications for finished product revised labelling

$800


238


CRPN Form

Formulation (cont’d)


Tick box



changed active ingredient salt, or change in status of ingredient from active to excipient, or removal of active ingredient with no other changes

change not considered likely to affect stability


ingredient and finished product revised labelling

$800


changed active ingredient salt, or removal of active ingredient with no other changes

stability study included


ingredient and finished product revised labelling

$1200

Active ingredient

Tick box



tightening of limits for active substance



new or revised specifications/test methods

$400

for each active

239


CRPN Form

Finished product

Tick box


Finished product packing site

new packing site that is not a site of manufacture

includes overlabelling, if required

$400



no change in manufacturing process or type of equipment used

specifications/test methods unchanged packing at same site

$400

for each new site


change in manufacturing process or type of equipment used

packing at same site

$1600


type of manufacturing process unchanged, but changes to mixing times, batch scaling, type of equipment etc.

Consequential changes included (if applicable) are: revised specifications/test methods new site of manufacture and packing

$800




Consequential changes included (if applicable) are: revision or reconfirmation of shelf life revised specifications/test methods new site of manufacture and packing

$1600


Finished product specifications/test methods

revised specifications/test methods no change in manufacturing process

$400

240


CRPN Form


Tick box



decrease in storage temperature from 30C to 25C with no change in shelf life and no other changes

addition of a statement such as “Protect from light”






$800


new pack size evidence provided that stability study not

required







$400

for any number of new container/closure/packaging combinations





$1200


241


CRPN Form


Tick box


Fee to pay($)


new indication (see section 3.1.1 of the Guidelines for details)

Consequential changes included (if applicable) are: new dosage instructions revised labelling


$1600



modified indication (see section 3.1.1 of the Guidelines for details)



$800



new dosage regimen no change to indications


$800





$400

242


CRPN Form

Labelling

Tick box


Fee to pay($)

Labelling - Grade 1

re-design of label, and/or change in name and address of

distributor no change to product name, strength,

dose form, dosage instructions or indications


Labelling - Grade 2

design or re-design of a New Zealand compliant label and/or

change in the classification to Controlled Drug

no change in actual strength, but a change in the way the strength is expressed (if applicable)

$400

Other

Tick box


Sponsor



label.


Note: A CRPN for change in packing site(s) may also be required.

243


CRPN Form






Reason for change:


244


CRPN Form



File No. Product name Strength

TT50-

TT50-

TT50-

TT50-

Fee calculation

Note 1: If you are notifying identical changes to a number of products, the evaluation fee shown in the box below must be the largest fee that would apply to any single product. For example, if the notification covers Type I and Type II products, the evaluation fee applicable for a Type II product must be entered below.Note 2: In no case will the CRPN evaluation fee for a single related product exceed $5,500. Note 3: Additional names, types, strengths and flavours are each regarded as “additional products” and each one attracts an additional $200 (administrative) fee.



Total fee:

$ .00

$ .00_____________

$ .00



(Y or N/A)






(End of form)

245


Appendix 8: Labelling Declaration

246


LABELLING DECLARATION

Complete one declaration to cover all primary, secondary and tertiary labels relating to eachseparate product (name + dose form + strength + classification + flavour, as applicable)

I declare that the label(s) for

..........................................................…………………..............................................................(Product name, dose form, strength, classification, and flavour as applicable)

[Medsafe file No. TT50- .......….......... ]

has/have been assessed and is/are in compliance with the requirements of the legislation.

All information on the label(s) is consistent with the details of the medicine currently approved in New Zealand or described in the current New Medicine or Related Product Application.

The following documents are attached:

(tick)

Labelling Checklist(s)

Copy of previously approved label(s)

Copy or colour draft of proposed label(s)

Signature: ................................................... Date............................

Name, designation and address of person submitting label:[Note: All correspondence relating to the label will be sent to this person unless requested otherwise.]

Name and address of sponsor:

247


Appendix 9: Labelling Checklist for Medicines

248


LABELLING CHECKLIST FOR MEDICINES(Use this checklist for all medicines, including Controlled Drugs,

but not including contact lens solutions, for which there is a separate checklist)

Product: ....................................................................................................................(Name, dose form and strength, and flavour if applicable)

Classification: ............................................................................................................(Prescription, Restricted/Pharmacist Only, Pharmacy Only, General Sales)

Label assessed: .........................................................................................................(Primary label on container, Secondary label on outer package)

(tick box)

1. Physical Label (Medicines Regs 17) Yes

Is the label:

a) printed on or firmly and securely attached to the container?

b) unlikely to become detached or defaced or illegible during use?

c) positioned so that it will not be damaged or removed when the container is opened?

d) not obscured by any other label or leaflet, or any part of the product or packaging?

2. Language and Text (Medicines Regs 17 and 18)

Is all the information required to be on the label

a) in English?

b) in lettering that is clear, distinct and legible, and the height of letters with ascenders is not less than 0.75mm in the case of a small label, or not less than 1.5mm in any other case?

3. Principal Display Panel (Medicines Regs 13 & 15 & Amendments)

Does the label have a Principal Display Panel (PDP) that is visible when the container is stored in the normal manner?

Does the PDP contain the following information:

a) the trade name of the product?

b) the pharmacopoeial name/appropriate designation of the product, or the name of each active ingredient, and strength?

c) the contents of the container (weight, volume or number)?

d) the dose form or presentation?

249


Labelling Checklist for Medicines (cont’d)

(tick box)

4. Other Requirements (Medicines Regs 13, 16, 19, 20 & Amendments)

Yes No N/A

A. If the product contains a scheduled medicine, does the label state in a prominent way the appropriate classification using one of the expressions below?

“Prescription Medicine* or Prescription Only Medicine* or the acronym POM or the symbol RxRestricted Medicine or Pharmacist Only Medicine orPharmacy-Only Medicine* or Pharmacy Medicine*[* or words of a similar meaning]

B. Does the label also contain the following information:

a) the name and strength (or potency in the case of a biochemical preparation) of each active ingredient?

b) the dose or directions for use, if the product is a physician’s sample pack or an OTC medicine?

c) ‘Caution - not to be taken’ or ‘For external use only’ or similar wording if the product is for external use?

d) the name and address of the manufacturer, sponsor, or distributor (as applicable)?

e) the batch/lot number? [The draft label should indicate its placement.]

f) the expiry date? [The draft label should indicate its placement.]

g) the recommended storage conditions, if applicable?

h) all warning statements required by Regulation 22, as applicable?

i) the names and strengths of any antiseptics and/or preservatives if the medicine is for injection or is a biochemical preparation?

C. Is the product intended for sale without a prescription?

If so, is all of the following information grouped together on the Consumer Information Panel (CIP), or, if the label is too small, on a separate information sheet?

the purpose for which the medicine is recommended any warning statements required to appear on the label the recommended storage conditions

250



(tick box)

5. Special Requirements (Medicines Regs 16 & Amendments & Misuse of Drugs Regs 25)

Yes No

A. Is the product a controlled drug?

If so, does the label include all of the following information as required by Regulation 25 of the Misuse of Drugs Regulations (in addition to the information required by the Medicines Regulations)?

a) the words “CONTROLLED DRUG” in conspicuous block letters, followed by the appropriate designation (i.e. class code A, B1, C1, etc.) indicating in which part of which schedule to the Misuse of Drugs Act the controlled drug is listed

b) the name of the controlled drugc) recommended dose and frequency, if for internal use, OR, directions

for use, if for external used) the name of the preparation, mixture or article (i.e. dose form), if anye) the amount of the controlled drug in each dose unit or in the

preparation, including a statement of whether any percentage strength is calculated on the basis of weight in weight, weight in volume, or volume in volume

B. Is the product required by Regulation 37 to be in a safety container (blister pack)?

If so, is each of the following requirements of Regulation 37 met?a) each dose unit container (i.e. blister) is labelled with:

the trade name of the product the pharmacopoeial name/appropriate designation of the

medicine, or the name of each active ingredient the strength of the medicine

b) each strip of containers (or each container, if not in a strip of containers) is labelled with the manufacturer’s batch number/code

c) the container(s) or strips of containers is/are enclosed in a package that is fully labelled.

C. Is the product packaged in a safety container (blister pack) or a sachet less than 35 mm at its greatest dimension, even though not required by Regulation 37 to be in a safety container?

If so, is each of the following requirements met?a) each strip of containers is labelled with:

the trade name of the product the pharmacopoeial name/appropriate designation of the

medicine, or the name of each active ingredient the manufacturer’s batch number/code

b) the container(s) or strip(s) of containers is/are enclosed in a secondary package (e.g. carton) that is fully labelled.

251



(tick box)

Special Requirements, cont’d Yes No

D. Is the product a transdermal patch and packaged in a pouch or sachet?

If so, is each of the following requirements met?a) each pouch or sachet is labelled with:

the trade name of the product the name and strength of each active ingredient the manufacturer’s batch number/code the expiry date

b) the pouch(es) or blisters) is/are enclosed in a secondary package (e.g. carton) that is fully labelled.

c) the pouch(es) or blister(s) is/are not for individual sale apart form the secondary package

d) The product is not a Controlled Drug

E. Is the product sterile and packed in a primary container (ampoule, vial, dental cartridge, etc.) that is too small to bear all of the information normally required on a label? (See Section 12 of New Zealand Regulatory Guidelines for Medicines Volume 1 for details.)

If so, is each of the following requirements of Regulation 16 and Amendments met?

a) each primary container is labelled with: the trade name of the product (if any) the pharmacopoeial name/appropriate designation of the

medicine, or the name of each active ingredient the strength of each active ingredient

b) the primary container(s) is/are enclosed in a package that is fully labelled.

6. Package Inserts, etc.

Is any product information leaflet or any other additional written, pictorial or descriptive matter on or attached to or supplied or displayed with the product?

If so, is it consistent with the approved data sheet or NZ-approved details of the product?

(end of form)

252


Appendix 10: Labelling Checklist for Contact Lens Solutions

253


LABELLING CHECKLIST FOR CONTACT LENS SOLUTIONS

Product: ...........................................................................................…........…...........(Name and dose form)

Label assessed: ......................................................................………........................ (e.g. Primary label on container, Secondary label on outer package, Tertiary label on outermost package)

(tick box)


Is the label:







a) in English?


3. Principal Display Panel (Medicines Regs 13 & 15 & Amendments)




b) a description of the preparation?

c) the net contents of the container (weight, volume or number)?

d) the dose form or presentation?

254


Labelling Checklist for Contact Lens Solutions (cont’d)

(tick box)

4. Other Requirements (Medicines Regs 13) Yes No

Does the label also contain the following information:

a) a description of the composition, including the names and strengths of preservatives and any other ingredients critical to the performance of the solution?

b) full instructions for use?

c) the name and address of the manufacturer, sponsor, or distributor (as applicable)?

d) the batch number? [The draft label should indicate its placement.]

e) the expiry date? [The draft label should indicate its placement.]

f) the types of lens with which the product can be used, and, if appropriate, a statement that the solution should not be used with any particular type of lens?

g) the precautions to take when using the product (e.g. the words “Caution: Not to be Taken, or “For External Use Only”, or “Not for use directly in the eye”, or words of similar meaning, as applicable)?

h) a statement about the shelf-life of the opened container?

i) the properties of the solution, such as pH, tonicity and buffering?

5. Package Inserts, etc. (Medicines Regs 25)


If so:a) is it consistent with the NZ-approved details of the product?

b) can you confirm that it does not contradict or modify any statement or label required by the Regulations?

255


Appendix 11: Labelling Checklist for Related Products

256


LABELLING CHECKLIST FOR RELATED PRODUCTS

Product: ......................................................................................................................(Name, dose form and strength, and flavour if applicable)

Label assessed: ........................................................................………..........(e.g. Primary label on container, Secondary label on outer package)

(tick box)


Is the label:







a) in English?


3. Principal Display Panel (Medicines Regs 15)




b) the pharmacopoeial name/appropriate designation of the related product, or the name of each active ingredient, and strength?

c) the contents of the container (weight, volume or number)?

d) ‘Caution - not to be taken’ or ‘For external use only’ or similar wording if the product is for external use (other than a toothpaste)?

257


Labelling Checklist for Related Products (cont’d)

(tick box)

4. Other Requirements (Medicines Regs 14) Yes No N/A

A. Does the label also contain the following information:

a) a description that indicates the nature of the product (e.g. shampoo, toothpaste)?

b) directions for use and frequency of use?

c) the name and address of the manufacturer, sponsor, or distributor (as applicable)?

d) the batch number? [The draft label should indicate its placement.]

e) the expiry date (if appropriate)? [The draft label should indicate its placement.]

f) all required warning statements?

B. Is the product packaged in a blister pack?

If so, is each of the following requirements met?a) each strip of blisters is labelled with:

the trade name of the product the name and strength of each active ingredient the manufacturer’s batch number/code

b) the strip(s) of blister is/are enclosed in a package that is fully labelled.

5. Package Inserts, etc. (Medicines Regs 25)


If so is it consistent with the NZ-approved details of the product?

258


Appendix 12: Data Sheet Declaration

259


NEW ZEALAND DATA SHEET DECLARATION(All parts are to be completed)

Product Name: …………………………………………………………………..…..

Dose forms and strengths included in this Data Sheet:

………………………………………………………………..……..

………………………………………………………………..……..

This declaration relates to:

(tick one)

a new data sheet consequential to an NMA for which consent was gazetted on:

(Date)………………………

a revised data sheet consequential to a CMN for which consent was granted on:

(Date)………………………..

a self-assessable data sheet update

Other: (please specify)

……………………………………………………………………………………..………………

I declare that the product descriptive information accurately reflects the product approved/proposed for distribution in New Zealand and the indications and dosages contained in this data sheet are:

(tick one)

identical to those contained in the currently approved NZ data sheet for:

................................................................…………..................... of ....................…........ (Product name) (Date of preparation)

not identical to those contained in the currently approved NZ data sheet for:

..................................................................…………..................... of .............................. (Product name) (Date of preparation)

as approved with the NMA for which consent was gazetted on: .................…….... (Date)

as approved with the CMN for which consent was granted on: ..................…….... (Date)

260


261


Data Sheet Declaration Form (cont’d)

and the safety information in this data sheet is:

(tick one)

the same as the safety information in the published NZ data sheet for:

................................................................………….................... of ....................…........ (Product name) (Date of preparation)

the same as the safety information in the currently approved:

Australian Prescribing Information

USPDR document

Canadian Product Monograph

UK Data Sheet

European Summary of Product Characteristics

Company international prescribing information

[Attach a copy of the source document showing date of approval]

and all required NZ safety information (listed in the NZ Regulatory Guidelines for Medicines Volume 1) is included in this data sheet.

Name, designation and address of person submitting the data sheet:[All correspondence relating to the data sheet will be sent to this person unless requested otherwise.]

Email address:

Signature: …………………….……………

Date: …………………………………….…

Name and address of sponsor:

262


Appendix 13: Checklist for NZ Format Data Sheet

263


CHECKLIST FOR NEW ZEALAND FORMAT DATA SHEET

Product name..........................................................................……………..................

Date of preparation of data sheet....................................……………………...

Note: 1. This check list is to be used only for data sheets prepared using the New Zealand format as

detailed in the Medicines Regulations. It is not for use with data sheets based on an overseas approved data sheet.

2. Where only a “Yes” box is given, the heading or information indicated must be included in the data sheet.

3. Any non-compliant aspect of the data sheet should be explained in an accompanying letter.

Indicate whether the data sheet includes each of the following:

Yes N/A

1 Trade name of the medicine

2 Pharmacopoeial name or INN of the medicine or each active pharmaceutical ingredient

3 Strength of each active pharmaceutical ingredient

4 Pharmacopoeial grade

5 “Presentation” heading

6 Description of each available dose form, including strength, colour, flavour, dimensions and markings

7 “Uses” heading

8 “Actions” subheading

9 Pharmacotherapeutic group

10 Mechanism of action

11 Pharmacodynamic effects

12 Onset and duration of action

13 Antibiotic class

14 Antibiotic nature and mode of action

15 Information on the concentration dependent bactericidal activity

16 Susceptibility data with species listed alphabetically under relevant categories

17 Table of resistance categories

18 Clinically relevant MIC ranges

19 Detail of the in vitro methods, e.g. inoculum size, source of strains

264


Yes N/A

20 “Pharmacokinetics” subheading

21 Absorption and bioavailability data

22 Distribution data - plasma protein binding, volume of distribution, tissue and plasma concentration

23 Biotransformation data for active metabolites, inactive metabolites and active substance in the case of a prodrug

24 Elimination data - elimination half life, total clearance, excretion routes with reference to actives and metabolites

25 Relationships between plasma/blood concentrations and therapeutic activity or adverse reactions

26 Variations in the pharmacokinetic profile with respect to age, concomitant pathological status, or polymorphic metabolism

27 “Indications” subheading

28 Purpose of the medicine

29 List of NZ-approved indications

30 “Dosage and Administration” heading

31 Dose, dosage interval and timing in relation to food

32 Duration of treatment

33 Dosages with respect to age category, including paediatric

34 Dosage adjustments for renal and hepatic insufficiency

35 Dosage adjustments for other concomitant disease

36 Advice for monitoring

37 Procedural steps that are critical to the safe administration of the medicine

38 “Contraindications” heading

39 List of all situations where the medicine should not be used

40 “Warnings and Precautions” heading

41 Significant preclinical results, including mutagenicity and carcinogenicity studies

42 Significant warnings for patients with renal, hepatic or cardiac failure, and any other warnings (e.g. habituation)

43 Description of conditions under which may be recommended to sub-groups of at-risk patients

44 Precautions to prevent or decrease the harm from adverse reactions

45 Conclusions from animal reproduction/fertility studies

265


Yes N/A

46 Risk of use in pregnancy and class statement used in the 4th edition of Prescribing medicines in pregnancy

47 Data on the use of the medicine by fertile or pregnant women

48 Information on the excretion of actives or metabolites in breast milk and consequences for the well-being of the child

49 One of the following statements (or words of similar meaning) plus any relevant warnings or precautions: Presumed to be safe or unlikely to produce an effect on

the ability to drive or use machinery Likely to produce minor or moderate adverse effects on

the ability to drive or use machinery Likely to produce severe adverse effects or presumed

to be potentially dangerous on the ability to drive or use machinery

50 “Adverse Effects” heading

51 A list of all adverse reactions occurring at a frequency of 1% or more (i.e. significant) and all serious or potentially serious adverse reactions

52 Frequency of each significant adverse effect, and an indication of severe or serious adverse reactions.

53 MARC/MAAC-recommended statements

54 “Interactions” heading

55 Interactions with other medicines, other substances etc., including mechanism of action, effect on plasma levels, clinical consequences and recommendations on dosage adjustment

56 Abnormal laboratory test results associated with the medicine

57 Interactions with food or alcohol

58 “Overdosage” heading

59 Symptoms of overdosage

60 Treatment of overdosage

61 “Pharmaceutical Precautions” heading

62 Shelf life of the medicine as packaged.

63 Shelf life following reconstitution and after first opening (if appropriate)

64 Instructions for dilution or reconstitution

65 Maximum and/or minimum storage temperatures

66 Special storage precautions with regard to humidity or light

266


Yes N/A

67 Incompatibilities with other medicines

68 Significant problems of sorption of the medicine to the container

69 “Medicine Classification” heading

70 Classification statement

71 “Package Quantities” heading

72 Pack sizes of each dose form and strength

73 “Further Information” heading

74 Relevant information that does not fit into any other section, such as: chemical structure, list of excipients, provisional consent under section 23 of Medicines Act, and any specific conditions applying to distribution of the product in New Zealand

75 “Name and Address” heading

76 Name, business address, and telephone number of the sponsor company

77 “Date of Preparation” heading

78 Date

267


Appendix 14: Form for Reporting Supply of Unapproved Medicine

268


Medsafe Declaration/Notification Form for medicines supplied pursuant to Section 29 of the Medicines Act 1981

INN / generic name of medicine:

Trade name of medicine:

Dose form:

Month and year of supply:

I declare that:

the above named medicine was supplied under the provisions of section 29 of the Medicines Act 1981 during the month stated above

the name of the medicine as stated above is correct

the following records have been kept:

the name(s) of the medical practitioner(s) who requested the supply of the medicine

the name(s) of the patient(s) the medicine was required for the dose form(s) and strength(s) of the medicine the date(s) of the month the medicine was supplied the name(s) of the place(s) the medicine was supplied to

the complete and accurate records are available for audit by Medsafe

the Supplier has a licence, issued under the Medicines Act 1981, which allows the supply of the medicine or is exempt from this requirement under section 26.

Signature:.............................................................. Date:.........................................

Name, Designation, Address and Contact Details:

Name and address of Supplier, being the New Zealand importer or manufacturer:

269


Appendix 15: Form for Reporting Adverse Reaction to Medicines, Vaccines, Medical Devices and IMMP

270


Form for Reporting Adverse Reactions to Medicines, Vaccines and Devices and all Clinical Events for IMMP

H1574PATIENT

Surname: First Name(s): Nat Health Index No

A Address: DoB Sex

ALL MEDICINES IN USE - ASTERISK SUSPECT MEDICINE(S)Medicine(s); Vaccine(s) + batch no Daily Dose Route Date Begun Date Stopped Reason for Use

DESCRIPTION OF ADVERSE REACTION OR INCIDENT

Date of Onset .................................................................

Recovered Not yet recovered Unknown Fatal Date of Death: ...............................................

Severe ? Yes No Rechallenge ? No Yes Result: .........................................................................................................

OTHER FACTORS - Please circleRenal Disease Hepatic Disease Allergy Other Medical Condition OTCs Industrial, Agricultural

Chemicals etc.

REPORTING DOCTOR/PHARMACIST

Name:

Address: Telephone:

Signature: ................................................................... Date: ........... /........... /..........

DANGER/WARNING: .................................................................................... Input by: ......................................................... Date: .........................................

271


Appendix 16: Form for Reporting Adverse Reaction to Fractionated Blood Products

272


Form for Reporting Adverse Reactions to Fractionated Blood Products

PATIENTSurname First Name(s) Nat. Health Ind. No.

Address Date of birth Sex/ / M / F

Diagnosis/main problem(s) Surgical Procedures (with dates)

BLOOD PRODUCTSBlood Product Manufacturer Batch

NumberExp. Date Dose/volume Duration of

TransfusionDate/Time

Previous Administration

MEDICINES IN USEMedicine Route Dose Date/Time

startedDate/Timestopped

Duration

Regular/current medicines

Pre-medication

Anaesthetics/medicinesduring procedure

Medicines after procedure

DESCRIPTION OF ADVERSE REACTION OR INCIDENT

Date of onset:............................. Time transfusion started:............... Time of onset:..............................

Recovered Not yet recovered Unknown Fatal Date of Death: ...............................................

Severe ? Yes No Rechallenge ? No Yes Result: .........................................................................................................

OTHER FACTORS - Please circleRenal Disease Hepatic Disease Allergy Other Medical Condition OTCs Industrial, Agricultural Chemicals etc.

REPORTING DOCTOR/OFFICER

Name Address Telephone:..........................

Signature:.................................................. Date:........./............./........... Fax:......................................

273


274