Definition and Goals of Drug Regulatory Affairs and Good Regulatory Practice

Definition and Goals of Drug Regulatory Affairs and Good Regulatory Practice ZAFES – Curriculum Regulatory Affairs (Module 11) Dr. Christa Schröder Pa...
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Definition and Goals of Drug Regulatory Affairs and Good Regulatory Practice ZAFES – Curriculum Regulatory Affairs (Module 11) Dr. Christa Schröder Paul-Ehrlich-Institut, Langen Unit „European Procedures“ [email protected]

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

§ Variations § Good Regulatory Practices

Dr. Christa Schröder, Paul-Ehrlich-Institut

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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

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Regulatory Information published by authorities (1) § Official Journal of the European Union The Official Journal is comprised of two series: The L series contains EU legislation including regulations, directives, decisions, recommendations and opinions. The C series contains reports and announcements including the judgments of the European Court of Justice and the Court of First Instance. There is also a supplementary S series containing invitations to tender.

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Regulatory Information published by authorities (2) §

Bundesanzeiger § Der Bundesanzeiger ist neben dem Bundesgesetzblatt ein weiteres Verkündungs- und Bekanntmachungsorgan der deutschen Bundesbehörden. Es wird vom Bundesministerium der Justiz herausgegeben. Zusätzlich ist der Bundesanzeiger Pflichtveröffentlichungsblatt für gerichtliche und sonstige Bekanntmachungen, für alle Handelsregistereintragungen sowie für gesetzlich vorgeschriebene Veröffentlichungen von Jahresabschlüssen und Hinterlegungsbekanntmachungen der Unternehmen. In den letzten Jahren wird die herkömmliche Ausgabe auf Papier mehr und mehr durch den im Internet veröffentlichten elektronischen Bundesanzeiger ersetzt. Dabei erfolgen Veröffentlichungen üblicherweise nicht parallel in beiden Formen.

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Regulatory Information published by commercial editors § Websites of different associations e.g. § EFPIA - Europ. Fed. Of Pharm. Industries & associations http://www.efpia.org § VFA – Verband Forschender Arzneimittelhersteller http://www.vfa.de § BPI - Bundesverband der Pharmazeutischen Industrie http://www.bpi.de

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Regulatory Information published by commercial editors § Commecial databases e.g.

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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/

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

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Website der HMA

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Information on DRA - European Public Assessment Report

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Information on DRA – National lists of approved products § E.g. Rote Liste (Germany)

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Hierachy of the Community texts

Pharmaceutical Law 1. 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 binding Recommendations (Council, Parl.) Guidelines (EU Commission, EMEA, CHMP, ICH, WHO) Notice to Apllicants

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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 or veterinary 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

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Basic Classification of Medicines § 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 medical diagnosis or to restoring, correcting or modifying physiological functions in human beings § Article 2(2) In cases of doubt, where, taking into account all ist characteristics, a product may fall within the definition of a „medicinal product“ and within the definition of a product covered by other Community legislation the provisions of this Directive shall apply

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Basic Classification of Medicines Acc. To Directive 2001/83/EC Biological 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 the production 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

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

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Marketing Authorisation Options § Centralised Procedure

§ Mutual Recognition Procedure

Mutual Recogntion Centralised Decentralised

National

§ Decentralised Procedure

§ National Procedure

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CENTRALISED PROCEDURE FOR MARKETING AUTHORISATION APPLICATIONS EVALUATION

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Optional Scope - Regulation (EC) No 726/2004

§ 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.

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Compulsory scope of Centralised procedure/ Therapeutic areas Regulation 2004/726/EC: Medicinal products to be authorised by the Community include medicinal products for human use containing a new active substance which, on the date of entry into force of this Regulation, was not authorised in the Community, for which the therapeutic indication 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 Procedure Day 0 - 120 Presubmission

Primary evaluation

CLOCK STOP

Day 121 - 210 Secondary Decision evaluation

Opinion/

LAUNCH

Post authorisation Activities Dr. Christa Schröder, Paul-Ehrlich-Institut

Quelle: EMEA

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Landscape

CHMP Committee for Medicinal Products for Human Use

Other groups

COMP Committee for Orphan Medicinal Products

13 WPs 7 Scientific Advisory Groups

Working Parties Quelle: EMEA

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CHMP Working Parties Scientific Advisory Groups (SAGs (SAGs))

Scientific Advice WP

Paediatric WP

- HIV/Viral Diseases - AntiAnti- Infectives (not HIV) - Cardiovascular - Central Nervous System - Diabetes & Endocrinology - Diagnostics - Oncology

Safety WP Efficacy WP

CHMP

Quality WP

Pharmacogenetics WP

Pharmacovigilance WP

Gene Therapy WPWP- Cell based therapy WP Vaccine WP

Biological WP Blood Products WP

(Pre(Pre-)clinical WP on comparability + specific adad-hoc working groups or subgroup meetings when needed

Quality Review of Documents

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Quelle: EMEA

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Dossier Assessment Dossier Assessment Based on Assessment by Rapp/Co-Rapp Peer Review Precise and operational format Reports to CHMP Scientific Advice

SAWP Possible oral explanations + BWP VWP SWP QWP

Quelle: EMEA

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

PMF VAMF

BWP

Pandemic flu MAA (future)

VWP

BWP VEG SAG •Anti-infectives (not HIV) •Diagnostics •central Nervous System •Cardiovascular •Diabetes / Endocrinology SWP QWP

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MA Post Authorisation Pharmacovigalance

PhVWP BWP VWP SWP

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Where to find Information about EMEA

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Where to find WP and SAGs information

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PrePre-Submission phase

PrePre-submission

-1 m Request for accelerated procedure -7/-6 m Appointment Rapporteurs + Pre- submission meetings - 18m/-12m Filing strategy/ Confirmation Eligibility Invented name review Quelle: EMEA

Orphan Drug designation

- 12 to -36m Scientific Advice Dr. Christa Schröder, Paul-Ehrlich-Institut

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Submission / Validation Phase 10 working days

Submission Application Modules 1-5

Acceptability of application

D1 Start of procedure

PTL (with relevant PTMs): check Administrative part Technical part (compliance with legal/regulatory requirements) Possible interaction with (Co-) rapporteurs to discuss questions on admissibility

No scientific evaluation at this stage Quelle: EMEA

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M od ul e1

Common Technical Document (CTD) Not part of CTD e.g Environmental risk assessment Orphan Exclusivity, Risk Management System

1

Nonclinical Overview

Mo d

u

le Ov Q er ua 2 all lit Su y mm ar y

Regional Administrative Information

3

Quality Data Study Reports

Clinica l Overview

2 Nonclinical Summaries

4

Nonclinical Data Study Reports

Clinical Summary

5

Clinical Data Study Reports

Raw Data

Quelle: EMEA

CT D

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Primary Evaluation Phase

Stop Clock

D 1 D 80

D 100

Rapp./Corapp AR

CHMP EMEA

Quelle: EMEA

CHMP comments + peer reviewer

Applicant

D 112

D 120

Peer review CHMP consolidated List of Questions TeleApprovability/nonconference approvability

Applicant

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Secondary Evaluation Phase

Opinion

D 121

D 150

D 180

Day 181

Joint Rapp./ Co-rapp. AR

Hearing?

Hearing

Benefi t

Risk

D 210

Opinion

D 170

Comments CHMP CHMP EMEA

Consensus? Vote?

Applicant Dr. Christa Schröder, Paul-Ehrlich-Institut

Quelle: EMEA

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Different type of MA Conditional MA

MA under Exceptional Circumstances § Comprehensive data cannot be provided (specific situations foreseen in the legislation)

§ § § §

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 a renewable basis

§

Once the pending studies are provided, it can become a “normal” marketing authorisation

§ Reviewed annually to reassess the risk-benefit balance § Will not (normally) lead to completion of the dossier and become a “normal” market authorisation

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Accelerated procedure Ø Scientific opinion in 150 days (instead of 210) § 1st phase similar § Day 120 Opinion or List of outstanding issues § Day 121-150 Oral explanation if applicable + Opinion

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Dr. Christa Schröder, Paul-Ehrlich-Institut

Overview Orphan Medicinal Products

Orphan Designation mandatory access to CP

Orphan Designation By COMP/EC Orphan Designation Procedure

Protocol assistance by SAWP

CP

Protocol assistance procedure

EC Decision

Medicinal Products for the Community CHMP Opinion

Scientific Advice by SAWP

Scientific Advice Procedure

CHMP Opinion

CP: Standard Evaluation or Accelerated Procedure

MA

Conditional Approval Exceptional Circumstances “Normal” Circumstances EC Decision

MA Compassionate Use Procedure

Compassionate Use Procedure

Compassionate Use Procedure

Compassionate Use Procedure

Medicinal Products for outside the community in collaboration with WHO WHO eligibilit y

Scientific Advice Procedure WHO eligibility

Scientific Advice by SAWP CP Dr. Christa Schröder, Paul-Ehrlich-Institut

CHMP Opinion

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Compassionate Use (Reg 726/2004/EC Art. 14 and Dir 2001/83/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

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Getting a MA for a new medicinal product CHMP Opinion(s) English

Translation to all other 19 official European languages + Bulgarian & Romanian

(as signed off by the CHMP Chairman)

day 0 Quelle: EMEA

Version

Transmission

Commission

M.S.

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Applicant(s) day 27 38

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EPAR - European Public Assessment Report = CHMP Assessment Report after deletion of information of

commercially confidential nature Summary authorised presentations

available in all EU languages available in English

Package Leaflet

All readers Patients

Summary of Product Characteristics

Health professionals

Labelling

Pharmacists/patients

Authorisation Scientific Basis

Scientific community Health professionals

Steps taken for the assessment of the product

Quelle: EMEA

All readers

Anyone interested

Steps taken after granting Anyone interested the Marketing Authorisation 39 Dr. Christa Schröder, Paul-Ehrlich-Institut

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 centralised procedure) § generic medicinal products to national (and centralised) authorised reference medicinal products (if not a biotechnological 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

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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 at the time of application or

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

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MRP and DCP

Procedures

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Co-Ordination Group for Mutual Recognition and Decentralised Procedures (CMD)

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MRP

DCP

MA RMS

Dossier

Dossier

RMS CMSs 120 days

AR, SPC, PL, label

90 days

Update of AR

MA RMS

Applicant

Dossier

RMS

CMSs

Draft AR, SPC, PL

Proposal for changes (CMSs)

90 days

Final SPC, PL, label

MA CMS

MA CMS

Discussion between all MSs

Final AR, SPC, PL

MA CMS

MA CMS

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MA CMS

MA CMS

MA RMS 47

Marketing Authorisation EU DCP

MRP §

§ § §

§ §

First application to the Reference Member State and granting of a national Marketing Authorisation (MA) – Assessment Report (AR) For products with an existing national MA the RMS has to update the AR Identical applications to selected Concerned Memeber States (CMS) If agreement is reached after 90 days – subsequent national Authorisations in the cMS (Authorisation dates different) If no agreement is reached – further 60 days negotiation phase in the Coordination Group (CMD) 1 SPC, Package leaflet, labelling; different brand names possible

§ § § § §

§ §

Only possible, if a national MA has not yet been granted Identical applications to be submitted simultanously to RMS and CMS RMS prepares preliminary draft AR – comments by the cMS RMS distributes Draft AR If agreement is reached after 90 days – subsequent national Authorisations in the RMS and CMS (Authorisation dates different) If no agreement is reached – further 60 days negotiation phase in the Coordination 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 legal basis for the Marketing Authorisátion of the medicinal product – archived at the competent authority

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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 the scientific advice, opinions, the establishment of Maximum Residue Levels, inspection and assessment reports and related documents, taking into consideration legal requirements and guidance in order to protect and promote human and animal health.

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Good Regulatory Practices in a growing network of authorities § 1988 ICH Conference in Japan: harmonisation of technical requirements for registration of pharmaceuticals in human use § Authorities worked more and more together (CTD, exchange of information, etc) – EU enlargement § Implies a common understanding of technical /regulatory requirements and consistency in interpretation and application whether in the area of assessments, inspections or 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

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The Peer Review Group as a tool to drive Good Regulatory Practice § PEI Peer Review Group: Definition The PRG is a PEI-internal scientific panel, which by discussion of assessment reports… …widens the scientific basis of decisions made by internal and external assessors, …provides assistance in critical / controversial issues. ...provides access to „regulatory memory“

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

Quelle: C. Schneider

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The Peer Review Group as a tool to drive Good Regulatory Practice PRG meeting mandatory if: PEI is Scientific Advice/Protocol AssistanceCo-ordinator PEI is (Co-) Rapporteur in centralised procedure 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 blood components for transfusion, parallel imports, )

Quelle: C. Schneider

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EU Medicines Network What is BENCHMARKING Of EUROPEAN MEDICINES AGENCIES BEMA? Compare To enrich, to learn, to find best practices, which are (cost)-effective, efficient, feasible

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BEMA - Aim § Identify and share best practices across the network of EU and EEA medicines agencies § Comparing individual management systems or processes with the aim of learning from one another § Carried out by colleagues from another competent authority who are fulfilling the same responsibilities under legislation in different and complementary ways learning from one another § The purpose of BEMA is to enable mutual exchange of information, with a view to introducing improvement measures within agencies

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Thank you very much!

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