FFUL Lisbon Hilde Boone 29 May 2003 EMEA 1

Implementation of the CTD in Europe

&EMEA Experiences

Evaluation and Regulation of Medicines & Health Products

Why CTD

Industry initiative/request discussed at ICH level

To provide for a common format/template for the submission of information to the regulatory authorities in the 3 ICH regions

“Common Technical Document” signed-off by ICH in November 2000

2

Why CTD

Advantages / Objectives:

Resource saving for industry Facilitate simultaneous submission in 3 regions Facilitate exchange of regulatory information Harmonised format to be further supported by

e-CTD More efficient assessment; use of hyperlinks

etc… Faster availability of new medicines

3

Why CTD

However, CTD is only a FORMAT !

It’s not a “single” dossier, with a “single” content since

Legal requirements differ in the 3 regions ICH guidelines have not yet harmonised all

requirements Pharmacopoeias are not harmonised Applicant may have regional preferences

4

Modular structure of CTD

Part II Part III Part IV

Quality Non-clinical Clinical

Module 3 Module 4 Module 5

Module 2: written + tabular formats( replaces expert reports)

Module 1: administrative, regional info(not as such part of the ICH CTD) 5

Modular structure of CTD

Module 2: Quality Overall Summary Non-clinical Overview Clinical Overview Non-clinical Summaries (tables) Clinical Summaries (tables)

To provide a summary of the development plan and of the Q, S and E data

To integrate the most important information To facilitate the task of the assessor

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Modular structure of CTD

Module 2 should provide (a.o.):

Integrated & critical analysis of the key-parameters of the product

Summary and analysis of the main tox/clin data

Justifications for deviations from requirements and guidelines

Non-clinical and clinical strategy used by company

Comment on GLP, GCP status of data submitted

Benefit/risk conclusions Clear tabulated summaries of the tests/trials

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Modular structure of CTD

Module 3-4-5: Body of data / Study Reports+ references

Module 3 2 main parts: 3.2.S Drug Substance3.2.PDrug Product

Module 4-5: similar structure to current format

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QualityOverall

Summary2.3

NonclinicalOverview

2.4

ClinicalOverview

2.5

NonclinicalSummaries

2.6

ClinicalSummary

2.7

Module 3

Quality3.0

Module 4Nonclinical

Study Reports4.0

Module 5Clinical

Study Reports5.0

Module 2

CTD Table of Contents2.1

CTD Introduction2.2

Module 1Regional

Information1.0

Module 2-5 CTD

Module 1:Not Part of the CTD Content to be determined by EU, US, JP authorities

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Implementation of CTD

Each region (US, EU, Japan) to introduce CTD into

legislation or guidance

As of July 2003 :Mandatory use of CTD for EU, Japan (MHLW)

Highly recommended for US (FDA)

In EU: CTD reflected in Notice To Applicants (NTA) and in Legislation

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Why CTD implemented in NTA ?

‘old’ Annex I to Directive 2001/83/EC:

« …. Application …. shall be presented in 4 parts…taking account of guidance published by EC in Notice To Applicants ….. »

European Commission Publication (9 volumes):“Rules governing medicinal products in the EU”http://pharmacos.eudra.org/F2/eudralex/index.htm

Volume 1 = Community legislationVolume 2 = Notice To

Applicants……

11

What is NTA ?

Volume 2 = NTA* Volume 2A: Info on Procedures for

MA (guidance,

interpretation)

* Volume 2B: Presentation and content of a MA dossier (format template)

* Volume 2C: Regulatory guidelines

First published in 1986 - Regularly updated

http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm

2C2A

2B

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Current EU format for submission of applications

4 parts

Replace by new format based

on CTD - 5 Modules«4 parts may be presented as 5 modules»

Volume 2B

2C2A

“NTANTA”

5 Modules

“CTDCTD”

NTA - Volume 2B Presentation &

Content

2C 2A

2B

Revised NTA incorporating CTD: published 29 June 2001

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QualityOverall

Summary2.3

NonclinicalOverview

2.4

ClinicalOverview

2.5

NonclinicalSummaries

2.6

ClinicalSummary

2.7

Module 3

Quality3.0

Module 4Nonclinical

Study Reports4.0

Module 5Clinical

Study Reports5.0

Module 2

CTD Table of Contents2.1

CTD Introduction2.2

Module 1Regional

Information1.0

Module 2-5 CTD

Module 1:Not Part of the CTD Content to be determined by EU, US, JP authorities

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NTA CTD implementation

Topics to be addressed in EU

Give EU specific guidance in the Introduction

Defining scope & application types

Agree onTime frame for implementation

Defining Region-Specific items

Content of Module 1

Prepare FAQs document

Prepare amendment of Directive 2001/83/EC

to legally reflect CTD structure by July 2003 15

NTA CTD implementation Time-

Frames NTA (CTD) Volume 2 published June 2001 July 2001 – July 2003 :

TRANSITIONAL PERIOD

Dossier can be presented using the * 1998 NTA Vol. 2 B edition, or* 2001 NTA Vol. 2 B edition

Mixtures of both formats between modules could be accepted, but not within parts/modulese.g. Q module 3 + S & E Parts III + IV

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17

Mixed format applications

See EC WebSite

Part / Module Content

All "Old" NTA

Q only CTD

NC only CTD

C Only CTD

Q + NC CTD

Q + C CTD

NC + C CTD

All "New" (CTD) NTA

Part I Part IA XPart IB XPart IC:- Quality E.R. X X" X" X"- Pre-Clin E.R. X X" X" X"- Clinical E.R. X X" X" X"

Part II X X^ X~ X~Part III X X X XPart IV X X# X# X#

Module 1 ToC X X X X X X XApplic. Form X X X X X X XProduct Inform. X X X X X X XSignatures- Signature Q X X X X- Signature NC X X X X- Signature C X X X XSpecific Inform. X X X X X X X

Annex: ERA:- Non-GMO * X * X * X X- GMO X * * X X * X

Module 2 ToC X X X X X X XIntroduction X X X X X X X Q Summary X X X XNC Overview X X X X C Overview X X X XNC Summary X X X X C Summary X X X X

Module 3 X X X XModule 4 X X X XModule 5 X X X X

As of July 2003 :Mandatory for EU, Japan (MHLW) Hihgly recommended for US (FDA)

Commission to amend Relevant EU legislation

to fully reflect CTD (Annex I to Dir. 2001/83/EC)

New Annex I to be published SOON !

NTA CTD implementation Time-

Frames

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NTA CTD implementation Scope

Applicable to all types of EU procedures:- Centralised procedure- Decentralised (MR) procedure- National procedures

Applicable to all types of products:- NCEs- Biologicals, biotech- Herbal medicinal products specific guidance will be provided- OTC products

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Applicable to all types of applications:

- Full, new applications- Bibliographical applications- Abridged, Generic applications- Line-extensions & Variations

NTA CTD implementation Scope

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Regional (EU) specific Information – Module

1 Requirements for content of EU application:

* Directive 2001/83/EC – Art. 8-12

* Directive 2001/83/EC – Annex I

Administrative and Scientific information

* required by EU legislation provide

in

* but not reflected in CTD Module

121

Module 1 of Volume 2B (NTA)

1.11.1 Overall Table of ContentsOverall Table of Contents

(complete application; modules 1-5)

1.21.2 Application Form = current IA-Application Form = current IA-

formform

1.31.3 SPCSPC, , LabellingLabelling & & Package Package

LeafletLeaflet

1.41.4 ExpertsExperts

1.51.5 Specific RequirementsSpecific Requirements

AnnexAnnex Environmental Risk AssessmentEnvironmental Risk Assessment

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Module 1.2 Application Form

Complete revision by NTA group, to reflect

Principles agreed in Chapter 1 (Vol. 2A)

* Legal basis

* Annex II / Line-extension

Latest MS/EMEA requirements

NEW developments: Orphan Drugs, TSE,

Scientific Advice, GMOs

To be used in current & new dossier

format 23

Module 1.3 SPC/Labelling/PL

* Based on EMEA/QRD Templates

* National templates may apply

(for MR or national procedures)

In line with SPC and Readability

guideline

Standard headings and sentences

Available in 13 languages (EMEA

Web)

* Mock-ups or Specimen of sales presentation

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Module 1.4 Experts

Art. 12 of Directive 2001/83/EC * experts must provide detailed reports

on the Q, S & E data * duties of experts

Annex I to Directive 2001/83/EC

SIGNED expert reports

« critical » evaluation25

Module 1.4 Experts

Expert Reports Module 2

Overviews &

Summaries

Signatures Module 1.4

Info on experts Module 1.4

(education, experience)26

Module 1.5 Specific Requirements

1.51.5 Specific requirements for different Specific requirements for different types types

of applicationsof applications

1. Information for bibliographical applications

summary document on justification for “well-established use” claim

22. Information for generics applicationssummary document on evidence for “essential similarity” claim 27

Intended for “Old” products; no Essential Similarity

Explain grounds for using publications

Literature to be included in Module 4 and/or 5 Discussion in Module 2 (overviews and

summaries; incl. WEU claims)

Summary of WEU demonstration in Module 1.5 addressing each indent of of Part 3I/4I of Annex I to Dir. 2001/83/EC

Well-established use(bibliographical applications)

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Module 1.5: to contain summary document on: Active substance (« same ») Overall S/E profile Bio-availability , Bio-equivalence

Demonstrate « Essential Similarity » as defined by the NTA (chapter 1)Case-by-case validation decision by authorities

Essential Similarity(generic applications)

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Module 1Annex

ANNEX:ANNEX: Environmental Risk AssessmentEnvironmental Risk Assessment

(Separate binder)(Separate binder)

Incl. Risk Assessment OverviewIncl. Risk Assessment Overview

* Non GMO containing medicinal products

* Medicinal product containing/consisting of

GMOs

There is no There is no ANNEXANNEX II ! II ! (orphan drugs)30

Questions & Answers

General CTD questions & Module 3-5General CTD questions & Module 3-5 ::

IFPMAIFPMAhttp://http://wwwwww..ichich..orgorg

ctd-related.question@ifpma.org

EU-specific Regulatory / Administrative questionsEU-specific Regulatory / Administrative questions

Questions on Module 1Questions on Module 1 :: EC EChttp://pharmacos.eudra.org/F2/eudralex/vol-2/B/

ctdqa_032003.pdf

Aim to maintain harmonised approachAim to maintain harmonised approach Shared, common interpretationShared, common interpretation Refinement of guidanceRefinement of guidance

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EU Questions & Answers

• Q1Q1: : Guidance on on Mixed format applications• Q2Q2: Need to reformat ‘old’ dossiers?• Q3Q3: Reformatting = variation? Fee?• Q4Q4: Format of Variation applications?• Q5Q5: Mixed formats allowed after July 2003?• Q6Q6: Format of Line Extensions?• Q7Q7: Format of Generic applications?• Q8Q8: Module 2 for Generic applications?• Q9Q9: Format of Herbal Medicinal Product applicat.?

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EU Questions & Answers

• Q10Q10: : Format of Mutual Recognition Applications?• Q11Q11: Reformatting of MRP dossiers ?• Q12Q12: Location of Certificate of Suitability?• Q13Q13: Format of bibliographical applications?• Q14Q14: Format of EDMFs in CTD applications?• Q15Q15: Use of ‘old format’ EDMFs in CTD

applications?• Q16Q16: Format of variations to EDMFs?

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EU Questions & Answers

Q2Q2: Need to reformat ‘old’ dossiers?

NO

Clinical, non-clinical = not useful

Quality = recommended, encouraged

-> complete Quality part (incl.DMF if

applicable)

- > signed declaration from the MAH

- > no need for Quality Summary

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EU Questions & Answers

Q4Q4: Format of Variation Application?

NO requirement to reformat ‘old’ dossier

- New Variation data = mandatory in CTD

- Cross-reference to ‘old’ data allowed

- Copies of approved docs to be provided:

take first variation opportunity to

reformat

the doc / section concerned.35

EU Questions & Answers

Q6Q6: Format of Line Extensions?

NO requirement to reformat ‘old’ dossier

- New data = mandatory in CTD

- Always Module 1 + 2

- Cross-reference to ‘old’ data allowed

- Follow guidance on ‘mixed’ applications

- MAHs are encouraged to reformat ‘old’

quality

data (may not always be feasible)36

EU Questions & Answers

37

Q10Q10: : Format of Mutual Recognition Applications?

If MRP starts after 1 July 2003

CMS will accept the submission of dossiers in the ‘old EU’ -format until 31 December 2004

MAH to submit reformatted dossier to RMS first. -> no update of the RMS AR necessary-> simple acknowledgement

Other EU initiatives

Training for EU EU and CADREAC Assessors

(~200): June – July 2001

Quality, Safety, Efficacy workshops

Update of CPMP Assessment Report

Templates

(available on EMEA Website since March

2002)

Included list of CPMP/ICH guidelines as an

Annex to Modules 3-5

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Other EU initiatives

EC: Revision of EC: Revision of

LegislationLegislation

Update of Annex I to Dir 2001/83/EC to reflect

CTD format & terminology implement by July

03

Will be published soon check EC’s

Website !

Update of Directive 2001/83/EC as part of the

Review proposals:

‘expert reports’  ’detailed summaries’

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CTD Applications received

July 01 – May 03EMEA (Centralised Procedure):

16 new applications in full CTD format

6 new applications in mixed CTD+’old’

format

Of those, 5 concerned ‘Part A’ products

21 concerned ‘Part B’ products

9 line extensions (Q only; Q + C) 40

Experience so far is positive

Most questions & issues handled during Pre-Submission contacts with Applicants or during validation of the application.

So far, no feedback from assessors on any difficulties encountered during assessment.

Issues encountered now clarified via Q&A on Web

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EMEA ExperienceGeneral issues

No deviations from headings & numbering

leave CTD headings & numbering unchanged

OK to introduce further sub-headings under existing CTD headings

x other deviations refusedNO additionsNO deletionsNO re-numbering

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EMEA ExperienceGeneral issues

Sections “not applicable” or cross-referring to “old” data to be maintained in dossier structure + commented in Overviews

No new Appendices or Annexes:All information to be included in the relevant sections of Modules 3-5 and not at the end of the Module as new appendices not foreseen in CTD (e.g. stability protocols, validation data).

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EMEA ExperienceGeneral issues

Advice to Applicants

Follow CTD guidance; do not invent or adapt

Consult Q&A on ICH and Commission’s

Website

In case of doubt: consult relevant Authority

or send questions to ICH / EC mailbox

EMEA provides assistance to applicants in

the pre-submission stage44

Conclusion - Overall Benefit

Common format for applications, to be used in

the 3 Regions

Requires commitment & (re-)organisation Resource saving for industry Single dossier

andPossible simultaneous submissions in the 3

regions Implementation of electronic CTD (e-CTD)More consistent assessmentAccelerate availability of new medicines ?

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Useful Websites

ICH – CTD Guidelines + Q&A + e-CTD:ICH – CTD Guidelines + Q&A + e-CTD:

http://www.ich.org/ich5c.html

EU – NTA incorporating the CTD + Q&A:EU – NTA incorporating the CTD + Q&A:

http://pharmacos.eudra.org/F2/eudralex

/vol-2/home.htm#2b

FDA - Guidance on CTDFDA - Guidance on CTD

http://www.fda.gov/cder/guidance/4539O.htm

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