Virgilio Vinas, MD, MPH, PhD.

Universitat Autonoma de Barcelona

Pierre-Marie Curie Paris-V

I. General principlesII. National marketing authorization in the EU – still ofuse for the applicant?III. The centralized marketing authorization procedure:procedures, timelines, responsibilitiesIV. The mutual recognition procedure (MRP) and thedecentralized procedure (DCP): timelines,responsibilitiesV. Summary

Different licensing procedures, but identical requirements on the documentation: Full application: demonstration of quality, safety and

efficacy Generic application: demonstration of quality for the

generic product plus bioequivalence to the reference product (only possible once data protection period has expired!)

Well-established use: demonstration of quality for the product plus literature reference establishing recognized efficacy and an acceptable level of safety

Structure of theCommon TechnicalDocument (CTD))

1.1 Table of contents (TOC)1.2 Application form1.3 Texts1.4 Information about the experts (CV, signature)1.5 Specific requirements for different types ofApplication

Annex: Environmental risk assessment

2.1 CTD TOC Modules 2-52.2 Introduction2.3 Quality Overall Summary2.4 Nonclinical Overview2.5 Clinical Overview2.6 Nonclinical Summary2.7 Clinical Summary

One page dealing withPharmacological classMode of actionProposed clinical use

1. General information2. Manufacture – Flow diagram3. Characterization -Tabulated summary of data, including graphical representation4. Control of drug substance – Tabulated summary of batch analysis data, with

graphical representation

5. Reference standards or materials6. Container closure system (CCS)7. Stability – Tabulated summary of study results, graphical

representation

1. Description and composition2. Pharmaceutical development – Tabulated summary of composition of formulations, dissolution profiles3. Manufacture - Flow diagram4. Control of excipients5. Control of drug product – Tabulated summary of batch analysis data, graphical representation

6. Reference standards or materials7. Container closure system (CCS)8. Stability – Tabulated summary of stability data, graphical

representation

1. Facilities and equipment – Biotech: with summary2. Adventitious agents safety evaluation – Measures to control adventitious agents in production – Summary of reduction factors• Novel excipients2.3.R Regional information

3.2 S Drug Substance 3.2 S1 General Information 3.2 S2 Manufacture 3.2 S3 Characterization 3.2 S4 Control of Drug Substance 3.2 S5 Reference Standards or Materials 3.2 S6 Container Closure System 3.2 S7 Stability

3.2 P Drug Product 3.2 P1 Description and Composition of the Drug Product 3.2 P2 Pharmaceutical Development 3.2 P3 Manufacture 3.2 P4 Control of Excipients 3.2 P5 Control of Drug Product 3.2 P6 Reference Standards or Materials 3.2 P7 Container Closure System 3.2 P8 Stability

A Appendices A1 Facilities and Equipment A2 Adventitious Agents Safety Evaluation A3 Novel Excipients

• R Regional Information

• C Key Literature References

Process validation scheme for the drug productMedical deviceDemonstrate compliance with TSE-NfG – CEP or – Scientific data – Provide table A (all applications) as well as tables B

or C (if applicable)

The National Procedure – one Member State only The Centralized Procedure – all Member Statessimultaneously The Mutual Recognition Procedure – a selected number of Member States > 1 (chosen by the applicant) The Decentralized Procedure – a selected number of

Member States > 1 (chosen by the applicant)

Scope: Marketing authorization in one MS ONLY! New active substances (if not mandatory for the centralized

procedure) Known substances alone or in a new combination Line extensions to national authorizations Abridged applications to national authorizations informed consent generic products to nationally authorized originators/innovators bibliographic applicationsTIMELINE: 210 days

Efficacy (Clinical Documentation)Deficiency letter to applicant / oral discussion if necessary

Applicant‘s Response Document

Phase 2 = Evaluation of the response document Quality, Toxicology-Pharmacology, Clinic Decision on the applicationN

ati

on

al

Pro

ced

ure

National committee/board

Marketing Authorization Pre-submission meeting for the MRP

‚Scientific Advice‘Pre-submission meeting

The Advantages: Economic aspect: fees are affordable even for small firms(procedure supports a wide variety of the regional ”pharmaceuticallandscape”) No need for translation of the dossier National Marketing authorization (MA) is the basis for the MRP procedure Application forms and requirements of the national competentauthority are well known The Disadvantages: Not all national competent authorities meet the timeline of 210

days Regionally limited validity of the MA

Medicinal products developed by means ofone of the following biotechnological processes:

Recombinant DNA technology Controlled expression of gene coding for biologically

active proteins Hybridoma and monoclonal antibody methods

As of Nov. 2005, in addition mandatory for• New active substances for the indications– Diabetes– Cancer– Acquired immune deficiency syndrome (HIV)– Neurodegenerative disorder (Alzheimer, …) not licensed before coming into force of regulationEC 726/2004• Orphan medicinal products

Cont.From 20th May 2008:• Auto-immune diseases and other immune dysfunctions• Viral diseases• Other extensions to be approved by the Council upon

proposal from the EC

Biosimilar Medicinal Products(‘Biogenerics’)

… if biotechnological medicinal products

Mandatory for the Centralized Procedure

• Products containing a new active substance not authorized before coming into force of the Regulation EC 726/2004

• Products constituting a significant therapeutic, scientific or technical innovation Will be evaluated on a

case by case basis (consultation of two sponsors out of CHMP and,when needed, the relevant working parties)

• Generic of a centrally –authorized product

• Products which are in the interest of patients at community level: - Generic of a National/MRP product - Pandemic medicinal products

Where to apply for a centralized MA?

EMEA(European Medicines Agency)

Who will grant a centralized MA?

Decision by the European Commission

CHMP appoints rapporteur and co-rapporteur (among its own members) according to objective

criteria which will allow the use of the best available Expertise in the EU on the relevant scientific area.

Rapporteur and co-rapporteur (from different MS) select their team of experts according to the criteria mentioned above.

Rapporteur and co-rapporteur perform assessment of dossier and draft assessment report.

All other member states to comment on the assessment report, taking into consideration the information in the

dossier, if necessary “peer-review” of work performed by rapporteur and co-rapporteur.

-12 bis -6 m -------- Scientific Advice (national/EMEA) -12m -------------------- Submission strategy -------------------- Pre-sub Meeting EMEA-4 bis -6 m---------- Rapporteur/co-Rapporteur-10 d ----------------- Submission and validation

Pre-submission Phase 1 ClockStop

Phase 2 Opinion Decision

PostAuthorization

Pre-submission Phase 1ClockStop

Phase 2

OpinionDecision

PostAuthorization

Day 0• -----------------Start of procedureDay 80--------------- -Rapporteur/Co-Rapporteur’s Assessment ReportsDay 100--------------- Comments of CHMP member States / expertsDay 120----------------Adoption of the consolidated List of Questions) (Q, S, E, SPC, Labelling, PIL)

Clock Stop Day 120(GCP/GMP Inspection in parallel)

Restart of the Clock Day 121applicant’s responses during 3 month

Prolongation for 3 month is possible

report from GCP/GMP inspection available?

Pre-submission Phase 1 ClockStop

Phase 2

OpinionDecision

PostAuthorization

Day 150 Joint Response Rapp/Co-Rapporteur Assessment Report (JointRespAR)Day 180 • List of Outstanding Issues (LoOI) ?

• Oral Explanation (OE) necessary? • Written explanation before OE? ? New Clock stop ? • Preparation of the Adoption (including SPC) • Preparation of EPAR • withdrawal?

Day 210 • Adoption of CHMP’s opinion

• SPC translation and package leafleat by National Authority • Marketing Authorization by Commission

Pre-submission Phase 1ClockStop Phase 2

OpinionDecision

PostAuthorization

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 applicationor

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

Describes the procedure to get national MAs inMSs of the EEA for the same medicinal product.

Method of work sharing and harmonization between MS

Mandatory procedures

New active substances (if not mandatory for the centralized procedure)

Generic medicinal products to national (and centralized) authorized reference medicinal

Products (if not a biotechnological medicinal product)Informed consentWell established use (WEU) (bibliographic applications)

Cont.Line extensions to national authorizationsKnown substances in new combinationHomeopathicsTraditional herbal medicinal products

Applicant selects reference member state (RMS) and files first (national) applicationRMS assesses the dossier and clarifies open issuesRMS grants marketing authorization and writes assessment reportSelected concerned member states (CMS) evaluate the assessment report, clarify open questions with information provided in the dossier, and are supposed to recognize theRMS marketing authorization – unless there is a serious risk

to public health.

National evaluation and50 days licensing process (normally 2 phase procedure)

Application to firstmember state

First Authorizatio

n

210 days

Assessment reportincluding SPC

Mutual Recognition Process

Further National Authorization(s)

Objections

clarification and dialogue / point ofview of applicant (orally or writing)

resolution of issues

50 days

35 days5 days

Applicant requestmutual recognitionof the referenceauthorization

90 days

Applicant submits dossier

Validation Concerned Member States

Day 0 - 50 - Evaluation of assessment report and experts reports (and dossier) - Quality (Chemical, Pharmaceutical and Biological Documentation) - Safety ( Toxicological-Pharmacological Documentation) - Efficacy (Clinical Documentation) -Comments/Objections to Reference Member State and Applicant

Applicants Response Document

Evaluation of the response documentDay 75 Break out session /discussion

Day 90 Decision on the application

EU-MSs National authorities/agencies

Marketing authorizationApplicant submits national texts

Applicant can choose procedureConsultation between MS´s before the first MA is issued‘Clock stop’ period to clarify open issuesFinal AR, SPC, PL and labelingDecision about the MA at the ‘same time’ in MS´s of the EU/EEATimeline: 210 days, i.e. up to 180 days less thanMRP (90 days for AR + 90 days for MR-phase)

Applicant selects RMS and CMS. All authorities receive the application and documentation simultaneouslyRMS assesses the dossier and clarifies open issues, CMS may already commentRMS writes assessment reportApplicant clarifies questions asked by RMS and CMSRMS and CMS grant marketing authorization at the same time, if application is o.k. for themCMS with open issues (risk to public health) can file for arbitration without delaying the marketing authorization in

other member states

Validation 14 days

Assessment I RMS assessment, Preliminary AR, comments from CMS, clock-stop Applicant submit valid response document, restart, RMS prepares Draft AR, SPC, PL and Labeling (= Day 120)

Assessment II CMS comments, Break out Session, FAR, approval or CMD-Referral (= Day 210)

National step granting of a national MA (= Day 240)

If no agreement between RMS/CMS can be reached at end of procedure

Referred to Coordination Group (CG) - 60 days for negotiation between the MS concerned (RMS and CMSs) - Consultation of the applicant in written or oral form

Still disagreement after this consultation – theelements of disagreement are forwarded to theAgency Arbitration, referral to CHMP MS´s that are in agreement with the AR and SPC may authorize the medicinal product, without waiting for the outcome of the procedure

Four different licensing procedures available

No difference in requirements regarding quality, safety and efficacy

For certain products, reduced quantity of data regarding safety and efficacy (generics, line extensions)

Target time for approval: 210 days (MRP: plus 90 days)

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