Definition and Goals of Drug Regulatory Affairs and Good ... · PDF fileDefinition and Goals of Drug Regulatory Affairs and Good Regulatory Practice ZAFES – Curriculum Regulatory

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Dr. Christa SchröderPaul-Ehrlich-Institut, LangenUnit „European Procedures“

[email protected]

Definition and Goals of Drug Regulatory Affairsand Good Regulatory Practice

ZAFES – CurriculumRegulatory Affairs (Module 11)

Dr. Christa Schröder, Paul-Ehrlich-Institut2

Content

§ Information on DRA§ Legislation§ Marketing Authorisation§ Centralised procedure§ Mutual recognition procedure§ Decentralised procedure

§ Variations§ Good Regulatory Practices

mailto:[email protected]

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Information on DRA

§ Legislation§ Guidelines§ Decisions / statements of key regulators§ Comments / interpretations§ Discussions at trade association meetings

will be found in§ journals (Official Journal of the European Community (EU),

Bundesanzeiger (DE) , Regulatory Affairs Journal)§ databases and§ internet homepages, and is presented at§ meetings


Regulatory Information published by authorities (1)

§ Official Journal of the EuropeanUnion

The Official Journal is comprisedof two series:

The L series contains EUlegislation includingregulations, directives,decisions, recommendationsand opinions.

The C series contains reports andannouncements including thejudgments of the EuropeanCourt of Justice and the Courtof First Instance.

There is also a supplementary Sseries containing invitations totender.

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Regulatory Information published by authorities (2)§ Bundesanzeiger

§ Der Bundesanzeiger ist neben demBundesgesetzblatt ein weiteresVerkündungs- undBekanntmachungsorgan der deutschenBundesbehörden. Es wird vomBundesministerium der Justizherausgegeben. Zusätzlich ist derBundesanzeigerPflichtveröffentlichungsblatt fürgerichtliche und sonstigeBekanntmachungen, für alleHandelsregistereintragungen sowie fürgesetzlich vorgeschriebeneVeröffentlichungen vonJahresabschlüssen undHinterlegungsbekanntmachungen derUnternehmen. In den letzten Jahren wirddie herkömmliche Ausgabe auf Papiermehr und mehr durch den im Internetveröffentlichten elektronischenBundesanzeiger ersetzt. Dabei erfolgenVeröffentlichungen üblicherweise nichtparallel in beiden Formen.


Regulatory Information published by commercial editors

§ Websites of differentassociations e.g.§ EFPIA - Europ. Fed. Of Pharm.

Industries & associationshttp://www.efpia.org

§ VFA – Verband ForschenderArzneimittelhersteller

http://www.vfa.de

§ BPI - Bundesverband derPharmazeutischen Industrie

http://www.bpi.de

http://www.efpia.org

http://www.vfa.de

http://www.bpi.de

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Regulatory Information published by commercial editors

§ Commecial databases e.g.


Information on DRA

§ Links to Key European Institutions

§ European Commission, Enterprise DG

http://ec.europa.eu/enterprise/pharmaceuticals/index en.htm

§ European Medicines Evaluation Agency EMEA

http://emea.europa.eu/

§ (National) Medicines Authorities in the European Union

http://heads.medagencies.org/

http://ec.europa.eu/enterprise/pharmaceuticals/index

http://emea.europa.eu/

http://heads.medagencies.org/

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Information on DRA – Mutual Recognition Product Index ofmedicinal products approved through the MRP /DCP procedure


Website der HMA

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Information on DRA - European Public Assessment Report


Information on DRA – National lists of approved products

§ E.g. Rote Liste (Germany)

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Hierachy of the Community texts

Pharmaceutical Law1. Binding Legislation

Regulations (Verordnung) (e.g. 726/2004/EC)directly binding

Directives (Richtlinie)national law (e.g. 2001/83/EC 14. AMG Novelle)

2. Soft law – not legally bindingRecommendations (Council, Parl.)Guidelines (EU Commission, EMEA, CHMP, ICH, WHO)Notice to Apllicants


Rules Govering Medicinal Products in the EU (Eudralex)

§ Volume 1 – Community legislation§ Volume 2 – The Notice to Applicants (NtA)§ Volume 2A – Procedures for Marketing Authorisation§ Volume 2B – Presentation and content of the application dossier

§ Volume2C – Regulatory Guidelines§ Volume 3 - Guidelines – Quality, safety, efficacy§ Volume 4 - guide to Good Manufacturing Practice for

Medicinal products§ Volume 5-8 – Veterinary issues§ Volume 9 – Pharmacovigilance§ Volume 10 – Good Clinical Practice

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Basic Classification of Medicines

§ Medicinal products / Medicinal devices for human orveterinary use

§ New active substances / Generic medicinal Products§ Biological Products / Biotechnology Products§ Immunological Medicinal Products§ Prescription / non-prescription§ Herbal Medicinal Products / Traditional Herbal Medicinal

Products§ Radiopharmaceuticals



§ Directive 2001/83/EC, Article 1 (2) Medicinal Product§ Any substance or combination of substances presented for treating

or preventing disease in human beings§ Any substance or combination of substances which may be

administered to human beings with a view to making medicaldiagnosis or to restoring, correcting or modifying physiologicalfunctions in human beings

§ Article 2(2) In cases of doubt, where, taking into account all istcharacteristics, a product may fall within the definition of a„medicinal product“ and within the definition of a product coveredby other Community legislation the provisions of this Directive shallapply

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Acc. To Directive 2001/83/ECBiological Product§ A biological medicinal product is a product, the active substance of

which is a biological substance§ Produced by or extracted from a biological source§ That needs for its characterization and the determination of ist quality a

combination of physiochemical-biological testing, together with theproduction process and ist control

§ The following shall be considered as biological medicinal products:§ Medicinal products derived from human blood and human plasma as

defined, respectively in paragraphs (4) and (10) of Article 1§ Medicinal products falling within the scope of Part A of the Annex to

Regulation (EEC) No 2309/93§ Advanced therapy medicinal products as defined in Part IV of this Annex


Basic Classification of MedcinesBiotechnology Product (Annex to Regulation 726/2004/EC)

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Marketing Authorisation

Options§ Centralised Procedure

§ Mutual Recognition Procedure

§ Decentralised Procedure

§ National Procedure

NationalDecentralised

CentralisedMutual Recogntion

CENTRALISED PROCEDURE FOR MARKETINGAUTHORISATION APPLICATIONS EVALUATION

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§ Article 3(1): “mandatory” scope

§ Article 3(2): “optional” scope

§ (a) new active substance not authorised; or

§ (b) significant therapeutic, scientific or technical innovation or

interests of patients at Community level.

Optional Scope - Regulation (EC) No 726/2004


Compulsory scope of Centralised procedure/Therapeutic areas

Regulation 2004/726/EC: Medicinal products to be authorised by theCommunity include medicinal products for human use containing a newactive substance which, on the date of entry into force of this Regulation,was not authorised in the Community, for which the therapeuticindication is the treatment of any of the following diseases:

-acquired immune deficiency syndrome-cancer-neurodegenerative disorder-diabetes

and with effect from 20 May 2008:-auto-immune diseases and other immune dysfunctions-viral diseases

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Overview of the Centralised ProcedureOverview of the Centralised Procedure

Day 121Day 121 -- 210210

CLOCKSTOP

Pre-submission

Primaryevaluation

Day 0Day 0 -- 120120

Secondary Opinion/Decisionevaluation

Post authorisationActivities

LAUNCH

Quelle: EMEA


CHMPCHMP

Landscape

COMP

Othergroups

13 WPs

Committee for Medicinal Products for Human Use

Committee forOrphan Medicinal Products

Working Parties

7 ScientificAdvisory Groups

Quelle: EMEA

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Quality Review of DocumentsQuality Review of Documents

ScientificScientific AdvisoryAdvisoryGroups (Groups (SAGsSAGs))- HIV/ViralHIV/Viral DiseasesDiseases-- AntiAnti--InfectivesInfectives ((notnot HIV)HIV)-- CardiovascularCardiovascular-- CentralCentral NervousNervous SystemSystem-- DiabetesDiabetes && EndocrinologyEndocrinology-- DiagnosticsDiagnostics-- OncologyOncology

+ specific ad+ specific ad--hoc working groups orhoc working groups orsubgroup meetings when neededsubgroup meetings when needed

CHMP Working PartiesCHMP Working Parties

CHMP

Biological WPBiological WP

Safety WPSafety WP

BloodBlood ProductsProducts WPWP

Quality WPQuality WP

EfficacyEfficacy WPWP

PharmacovigilancePharmacovigilanceWPWP

Scientific Advice WPScientific Advice WP

Gene Therapy WPGene Therapy WP-- CellCellbased therapy WPbased therapy WP

Vaccine WPVaccine WP

(Pre(Pre--)clinical WP on comparability)clinical WP on comparability

Paediatric WPPaediatric WP

PharmacogeneticsPharmacogenetics WPWP

Quelle: EMEA


Dossier AssessmentBased on Assessment by Rapp/Co-Rapp

Peer ReviewPrecise and operational format

Reports to CHMPScientificAdvice MAA

•Initial MAA•List of Questions•Prior to Opinion•Possible Oral explanation•Variations•Line Extensions•Referrals

PMFVAMF

Pandemic fluMAA

(future)

MAPost AuthorisationPharmacovigalance

SAWPPossible oralexplanations

+BWPVWPSWPQWP

BWPVEGSAG

•Anti-infectives (not HIV)•Diagnostics•central Nervous System•Cardiovascular•Diabetes / Endocrinology

SWPQWP

BWP VWP PhVWPBWPVWPSWP

Dossier Assessment

Quelle: EMEA

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Where to find Information about EMEA


Where to find WP and SAGs information

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Dr. Christa Schröder, Paul-Ehrlich-Institut29Scientific Advice

- 12 to -36m

Filing strategy/ Confirmation EligibilityInvented name review

- 18m/-12m

-7/-6 mAppointment Rapporteurs +Pre- submission meetings

Orphan Drugdesignation

PrePre--submissionsubmission

PrePre--Submission phaseSubmission phase

-1 mRequest foraccelerated procedure

Quelle: EMEA


SubmissionApplication

Modules 1-5

Acceptabilityof application

D 1D 1Start ofStart of

procedureprocedure

PTL (with relevant PTMs): checkAdministrative partTechnical part (compliance with legal/regulatoryrequirements)Possible interaction with (Co-) rapporteurs todiscuss questions on admissibility

10 workingdays

Submission / Validation PhaseSubmission / Validation Phase

No scientific evaluation at this stageNo scientific evaluation at this stageQuelle: EMEA

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Common Technical Document (CTD)Common Technical Document (CTD)

1Regional

AdministrativeInformation

Clinical DataStudy Reports

Quality DataStudy Reports

Nonclinical DataStudy Reports

Raw Data

Modul

e 2Mod

ule 1

NonclinicalOverview

Clinical

Over-view

Qualit

y

Overa

ll Sum

mar

y

NonclinicalSummaries

ClinicalSummary

Not part of CTDe.g Environmentalrisk assessmentOrphanExclusivity, RiskManagementSystem

CTD

2

3 54

Quelle: EMEA


Primary Evaluation PhasePrimary Evaluation Phase

D 112D 112Peer review

Tele-conference

D 1D 1 D 120D 120CHMP consolidated

List of QuestionsApprovability/non-

approvability

StopClock

Applicant

D 80D 80Rapp./Co-rapp AR

CHMPEMEA Applicant

D 100D 100CHMP

comments+ peer

reviewer

Quelle: EMEA

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Secondary Evaluation PhaseSecondary Evaluation Phase

OpinionOpinion

D 180D 180Hearing?

D 121D 121 DD 150150Joint Rapp./Co-rapp. AR

D 210D 210Opinion

CHMPEMEA Applicant

D 170D 170Comments

CHMP

Day 181Day 181Hearing

Consensus?Vote?

Benefit

Risk

Quelle: EMEA


Different type of MADifferent type of MAMA under Exceptional CircumstancesMA under Exceptional Circumstances

§ Comprehensive data cannot beprovided (specific situationsforeseen in the legislation)

§ Reviewed annually to reassessthe risk-benefit balance

§ Will not (normally) lead tocompletion of the dossier andbecome a “normal” marketauthorisation

Conditional MAConditional MA

§ positive benefit-risk balance§ comprehensive data likely to be provided§ unmet medical fulfilled§ benefit to public health of immediate

availability outweighs risk inherent –additional data is required

§ Authorisation valid for one year, on arenewable basis

§ Once the pending studies are provided, itcan become a “normal” marketingauthorisation

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Accelerated procedureAccelerated procedure

ØØ Scientific opinion in 150 daysScientific opinion in 150 days (instead of 210)(instead of 210)

§ 1st phase similar§ Day 120 Opinion or List of outstanding issues

§ Day 121-150 Oral explanation if applicable + Opinion


Overview

Medicinal Products for the Community

Scientific AdviceProcedure

Scientific Advice by SAWP

CP: Standard Evaluation orAccelerated Procedure

CHMPOpinion

EC DecisionMA

Conditional ApprovalExceptional Circumstances“Normal” Circumstances

CompassionateUse Procedure




Orphan Medicinal ProductsOrphan Designation

By COMP/ECOrphan Designation

Procedure

Orphan Designationmandatory access to CP

Protocol assistanceby SAWP

Protocol assistanceprocedure

CP

CHMPOpinion

EC DecisionMA

Medicinal Products for outside the community in collaboration with WHOWHO

eligibility Scientific Advice Procedure

ScientificAdvice

by SAWP

WHOeligibility

CP CHMPOpinion

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Compassionate Use (Reg 726/2004/EC Art. 14 and Dir2001/83/EC)

§ Supply of an unlicensed medicinal product to patients for

whom no standard alternative therapies are available

§ Usually reserved for the treatment of serious diseases

§ Takes place before or during the assessment procedure for

the granting of a MA and ends with the result of the

procedure

§ Enables innovative drugs to be made available to patients

during the development programme


Getting a MA for a new medicinal productGetting a MA for a new medicinal product

CHMPOpinion(s) Translation to all other

19 official EuropeanEnglish languages + Bulgarian & Version

Romanian(as signed offby the TransmissionTransmissionCHMPChairman)

day 0day 0 day 27day 27Commission M.S. Applicant(s)

Quelle: EMEA

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Summary

authorisedpresentations

Labelling

AuthorisationScientific Basis

Steps taken for the assessmentof the product

Steps taken after grantingthe Marketing Authorisation

Summary of ProductCharacteristics

All readers

All readers

Health professionals

Scientific communityHealth professionals

Pharmacists/patients

Anyone interested

Anyone interested

available in English

available in allEU languages

Package LeafletPatients

== CHMP Assessment Report after deletion of information ofCHMP Assessment Report after deletion of information ofcommercially confidential naturecommercially confidential nature

EPAREPAR -- European Public Assessment ReportEuropean Public Assessment Report

Quelle: EMEA


European Public Assessment Report

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Mutual Recognition Procedure

Decentralised procedure


Scope of MRP/DCP:National Marketing Authorisation - (1)

§ new active substances (if not mandatory for the centralisedprocedure)§ generic medicinal products to national (and centralised)

authorised reference medicinal products (if not abiotechnological medicinal product)§ informed consent§ bibliographic applications (well established use (WEU))

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Scope of MRP/DCP:National Marketing Authorisation - (2)

cont.§ line extensions to national authorisations§ known substances in new combination§ homeopathics§ traditional herbal medicinal products


MRP and DCP

Two routes to receive a MA

1. Mutual recognition procedure (MRP)where the medicinal product has already received in a MS a MA atthe time of application

or

2. Decentralised procedure (DCP)where the medicinal product has not received in a MS a MA at thetime of application

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MRP and DCP

Procedures


Co-Ordination Group for Mutual Recognition and DecentralisedProcedures (CMD)

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Discussionbetween all MSs90 days

MARMS

MARMS

MACMS

MACMS

MACMS

MACMS

MARMS

MACMS

MACMS

MRP DCPRMS

CMSsRMSApplicantDossier Dossier

CMSsAR, SPC,PL, label

90 days

Final SPC,PL, label

Draft AR,SPC, PL

Final AR,SPC, PL

Updateof AR

Proposal forchanges (CMSs)

Dossier120 days


Marketing Authorisation EUMRP§ First application to the Reference

Member State and granting of anational Marketing Authorisation(MA) – Assessment Report (AR)

§ For products with an existingnational MA the RMS has to updatethe AR

§ Identical applications to selectedConcerned Memeber States (CMS)

§ If agreement is reached after 90days – subsequent nationalAuthorisations in the cMS(Authorisation dates different)

§ If no agreement is reached – further60 days negotiation phase in theCoordination Group (CMD)

§ 1 SPC, Package leaflet, labelling;different brand names possible

DCP§ Only possible, if a national MA has

not yet been granted§ Identical applications to be

submitted simultanously to RMSand CMS

§ RMS prepares preliminary draft AR –comments by the cMS

§ RMS distributes Draft AR§ If agreement is reached after 90

days – subsequent nationalAuthorisations in the RMS and CMS(Authorisation dates different)

§ If no agreement is reached – further60 days negotiation phase in theCoordination Group (CMD)

§ 1 SPC, Package leaflet, labelling;different brand names possible

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Variations

§ Definition of a Variation

Any amendment to the documentation – which is the legalbasis for the Marketing Authorisátion of the medicinalproduct – archived at the competent authority


Classification of Variations

Acc to Reg‘s 1085/2003/EC and 1084/2003/EC Annexes

§ Urgent safety restrictions: immediate information of the

EMEA / competent authorities

§ Type IA and IB (minor variations): Notification – Decision by

RMS

§ Type II is an approval procedure e.g. additional therapeutic

indication

§ Extension Application – leads to a Marketing Authorisation

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Good Regulatory Practices

Good Regulatory Practices (GRP) can be defined as:

M. Korteweg, EMEA:A quality system to ensure that the users of medicinal

products, the applicants, the regulators are satisfied with thescientific advice, opinions, the establishment of MaximumResidue Levels, inspection and assessment reports andrelated documents, taking into consideration legalrequirements and guidance in order to protect and promotehuman and animal health.


Good Regulatory Practices in a growing network of authorities

§ 1988 ICH Conference in Japan: harmonisation of technicalrequirements for registration of pharmaceuticals in humanuse

§ Authorities worked more and more together (CTD, exchangeof information, etc) – EU enlargement

§ Implies a common understanding of technical /regulatoryrequirements and consistency in interpretation andapplication whether in the area of assessments, inspectionsor pharmacovigilance

§ Need to ensure quality, consistency in a growing EU –establishment of management systems

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Tools

§ Paul-Ehrlich-Institut: Peer Review

§ Medicines Agencies‘ Network: Benchmarking


§ PEI Peer Review Group: Definition

The PRG is a PEI-internal scientific panel, which bydiscussion of assessment reports…

…widens the scientific basis of decisions made by internal and externalassessors,

…provides assistance in critical / controversial issues....provides access to „regulatory memory“

The Peer Review Group as a tool to drive Good RegulatoryPractice

Quelle: C. Schneider

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Regulatory Peer Review – why?

§ Regulatory decisions should include the following principles:

§ Based on science

§ At least for biological and biotechnological medicinal products: Bridging quality –non-clinical – clinical part

§ Consistency with previous regulatory decisions§ …for similar active substances from the same class§ …for active substances based on a similar

mechanism of action§ …for similar clinical indications

§ Requirements for Applicants should be similar



PRG meeting mandatory if:

PEI is Scientific Advice/Protocol AssistanceCo-ordinator

PEI is (Co-) Rapporteur in centralised procedure

The Peer Review Group as a tool to drive Good RegulatoryPractice

Scope recently extended:

PEI is Reference Member state in a MRP/DC

Referrals if induced by PEI

National Procedures(except certain cases, e.g. not virus-inactivated bloodcomponents for transfusion, parallel imports, )


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EU Medicines Network

What isBENCHMARKING

OfEUROPEAN MEDICINES AGENCIES

BEMA?

CompareTo enrich, to learn, to find best practices, which are

(cost)-effective, efficient, feasible


BEMA - Aim

§ Identify and share best practices across the network of EUand EEA medicines agencies

§ Comparing individual management systems or processeswith the aim of learning from one another

§ Carried out by colleagues from another competent authoritywho are fulfilling the same responsibilities under legislationin different and complementary ways learning fromone another

§ The purpose of BEMA is to enable mutual exchange ofinformation, with a view to introducing improvementmeasures within agencies

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Thank you very much!