EMEA SUBMISSION PROCEDUREEMEA SUBMISSION PROCEDURE The application for a centralized marketing...

Alessio Ferrari

EMEA SUBMISSION PROCEDURE


SUMMARY

Authorities / organisation

Marketing Authorisation Procedures

Centralised Procedure

Decentralized Procedure (DCP)

The Role of the Reference Member State

Mutual Recognition Procedure

Centralised Procedure vs Mutual Recognition Procedure

National procedure

Post Marketing Authorisation Procedures

Future outlook


EMEAEuropean Agency for the Evaluation of Medicinal Products

Management BoardCommittee for Proprietary Medicinal Products (CPMP)Committee for Veterinary Medicinal Products (CVMP)Permanent Secretariat



2 scientific Committees (CPMP & CVMP) :objective high level scientific adviceproper co-ordination of work between the Agency and National Competent AuthoritiesCommittee for proprietary Medicinal Products (CPMP) - 2 representatives from each MSCommittee for Orphan Medicinal Products (COMP)


COMP (Committee forOrphan Medicinal Products ®

(1 member from each MS3 members of patient

organisations3 EMEA Representatives)

ScientificCommittees

CPMP for human products(2 member from each MS)

Management Board(2 representatives from

each MS, 2 from theCommission and 2appointed by the

European Parliament)CVMP for veterinary

products(2 members from each MS)

Executive Direction

EXPERTS

RAPPORTEURS

WORKING PARTIES

PERMANENT SECRETARIAT

Administrationvalidation of dossiers

EXPERTS

RAPPORTEURS

WORKING PARTIES

COMMISSION Standing committee COUNCIL

Community decision

AGENCY

FLOW CHART



How to market a medicinal product in the EU?European Centralised ProcedureDecentralized Procedure (DCP)European Mutual Recognition ProcedureEuropean Community Appeal, Referral / ArbitrationPost-Approval ProceduresSpecific Procedures



European Centralised ProcedureGranted by the European CommissionValid in the 15 Members States of the EUMandatory for biotechnological products,

developed using the recombinant DNA technologydeveloped using hybridoma and monoclonal antibody methods

Optional for innovative medicinal products



European Mutual Recognition ProcedurePre-requisite = Medicinal Product not falling under the scope of the Centralised ProcedureNational Procedure => product will only be placed on the market of one Member StateAs soon as more than one Member State, the Mutual Recognition Procedure must be used



European Mutual Recognition Procedure application submitted in one MS (Reference Member State = RMS)once Marketing Authorisation has been granted:identical applications submitted in the other Member States (Concerned Member States = CMS)request to the CMS to mutually recognise the Marketing Authorisation already granted



European Mutual Recognition Procedure The RMS has an important role!

At the choice of the applicantFirst marketing Authorisation in EUPreparation of an assessment reportCo-ordination of the MRP between applicant and CMSsChair the Mutual Recognition Facilitation Group (MRFG)



European Mutual Recognition Procedure The CMS is highly involved in the MRP!

Initiation of the MRP as soon as the 1st MA is grantedRecognition of the 1st MA within 90 daysConsultation of the Assessment Report prepared by the RMSMember in the MRFGNational MA to be granted



European Centralised ProcedureDecentralized Procedure (DCP)European Mutual Recognition Procedure



The application for a centralized marketing authorisation has to be submitted directly to the EMEA (European Medicines Agency), London. According to the submitted documentation a committee belonging to the EMEA, the CHMP (Committee for Medicinal Products for Human Use) – consisting of one delegate from each Member State - is to assess the clinical applicability by considering the risk/benefit rate of the medicinal product. The European Commission will make the decision on the fact of authorisation which is to be considered obligatory in all Member States. However the manufacturer decides whether putting the product on the market.

European Centralised Procedure


The application for marketing authorisation is always assessed by two CHMP-members - the rapporteur and the co-rapporteur -asigned by the CHMP-chair. The first assessment is to be done until the 70th day of the procedure. Then a list of questions is compiled according to the assessors' and the CHMP-members' opinions – this is to be forwarded to the applicant. The applicant has 30 days to respond these questions (however if there is a need for more time to collect data for answering the questions the clock may be stopped at the request of the applicant). To decide whether the applicant's responses are satisfactory 20 more days are available. Finally the rapporteur and the co-rapporteur prepare the Assessment Report (AR) and after approval by the CHMP send it to the applicant.



The following step of the procedure is the phase of decision making: the opinions and annexes (e.g. Product Information Leaflet, Summary of Product Characteristics) of all Member States on their own languages are sent by the EMEA to the European Commission where these documents are examined from the legal point of view and then framed to a legally binding decision valid in all Member States. The Commission has 30 days to prepare the draft decision which is sent for report to the Committe for Medicinal Products for Human Use (one delegate from each Member State).



The Member States have 15 and 30 days for resending their opinions on linguistic, scientific or technical issues. Views of the different Member States are exchanged in written form, however if any Member State had a well-established objection the Commission in full force assemble for discussion. In so far as the marketing authorisation is given a favourable verdict a final decision is to be issued. Both the Marketing Authorisation Holder and the Member States are informed about this fact and the final decision is published in the offical paper of the European Commission, in the Official Journal of the European Communities.

The centralized marketing authorisation is valid for five years, the application for extension has to submitted to the EMEA 3 months before the expiry.



Decentralized Procedure (DCP)The procedure in details:

Day -14- Day 0: validation period – it starts when the procedure appears in the CTS (Communication Tracking System) and the documentation has been submitted to the National Institute of Pharmacy Day 0: Assessment Step I starts (the validation issues has to be solved by this time) Day 70: the Preliminary Assessment Report (PrAR) is sent by the Reference Membe State (RMS) to all Concerned Member States (CMS) Day 100: CMSs send their comments to the RMS Day 105: clock-stop – the procedure is stopped temporarily; the applicant receives the RSI – Request for Supplementary Information document Clock-off period: during this period the applicant has to prepare the response document.


Decentralized Procedure (DCP)The procedure in details:

Day106: it is fixed by the RMS, when the applicant's response document is considered to be satisfying Day120: the procedure may be closed if there are no more comments from the CMSs' side - consensus if there is no consensus reached… Day120: Assessment Step II starts, Draft Assessment Report (DAR) is sent by the RMS to all CMSs Day145: CMSs send their comments to the RMS Day150: the procedure may be closed if there are no more comments from the CMSs' side - consensus, Final Assessment Report (FAR) is sent by the RMS to all CMSs if there is no consensus reached… the remaining questions are sent to the applicant by the RMS, the applicant submits supplementary responses to the RMS


Decentralized Procedure (DCP)

The procedure in details:

Day180: the RMS prepares a short report and forwards it to all CMSs Day205: CMSs send their final comments Day210: the procedure may be closed if there are no more comments from the CMSs' side - consensus, otherwise the procedure will be referred to the CMDh (Coordination Group for Mutual Recognition and Decentralized Procedure) 30-day-long national phase starts when the applicant submits the Hungarian translations of the final Summary of Product Characteristics, Patient Information Leaflet and Labelling.


The reference member state plays a pivotal role in both the European Union mutual recognition procedure and the decentralised procedure. Recently, however, concerns have been voiced that the burden of acting as the reference member state is falling unfairly on the shoulders of a limited number of countries. During the first three quarters of 2007, the Netherlands was the most common reference member state in applications for approval under the mutual recognition procedure, accounting for 23% of all applications, according to data published on the website of the Danish Medicines Agency, the DKMA. Other countries that were commonly used as reference member states included Sweden (16%), Denmark (14%) and Germany (13%).

The Role of the Reference Member State in the European Union


During the same period, Germany was the member state most likely to take on the role of reference member state for applications under the decentralised procedure (30% of applications), followed by Denmark (25%) and the UK (19%), with the Netherlands (12%) fourth. Under the mutual recognition procedure, where the applicant seeks approval in additional member states (concerned member states) for a product already approved in an initial member state (the reference member state), the reference member state prepares an assessment report, which the concerned member states must approve or reject within 90 days.



Under the decentralised procedure, which is used for products not previously approved in the EU, the applicant requests one or more concerned member states to approve a draft assessment report, summary of product characteristics (SmPC), labelling and package insert as proposed by the reference member state chosen by the applicant. (That is what should happen, in theory at least – in practice, the choice of reference member state may be restricted). In either case there is provision for arbitration by the Coordination Group for Mutual Recognition and Decentralised Procedures (human) (CMD(h)) if the various member states are unable to agree whether to approve an application...



The mutual recognition procedure is to be used in order to obtain marketing authorisations in several Member States where the medicinal product in question has received a marketing authorisation in at least one Member State at the time of application.

Mutual recognition procedure (MRP)


The Mutual Recognition Procedure:

DAY -14 – DAY 0: validation period – starts when the procedure is entered into the CTS (Communication and Tracking System), the documentation and the Assessment Report prepared by the RMS has been received by the CMSs DAY 0: starts when every CMS has validated the documentation (every deficiency has been supplied) DAY 50: the CMSs send their comments DAY 60: the applicant sends the response to the comments DAY 75: the CMSs send their comments



The Mutual Recognition Procedure:

DAY 80: the applicant sends the response to the comments DAY 85: the CMSs send their comments DAY 90: if there is a consensus the RMS closes the procedure –otherwise the case is referred to the CMDh (Coordination for Mutual Recognition and Decentralized Procedure) The applicant submits the Hungarian SmPC, PIL and Labelling and therefore starts the national phase of the procedure.



1 Health Authority1 Application / 1 dossier

1 Assessment

1 Marketing Authorisation in 15 European countries

+ Norway+ Iceland


1 harmonised dossier

1 harmonised Approval decision

simultaneously up to17 applications17 national Authorities17 marketing authorisations in

single countries



Proposal for rapporteur1 Tradename1 presentationNegative opinion of one MS influences EU wide decision

1 MA for the EU wide marketprocedure rather fasttransparent processonly one authority (EMEA)maintenance = 1 variation


free choice of the RMSdifferent tradenames possiblenational presentation possiblepossibility to withdraw a submission in specific countries if negative opinion

up to 17 single MAssometimes delay / national leveldecision process +/- transparentup to 17 authoritiesmaintenance = up to 17 variations


NATIONAL PROCEDURE

Flowchart of the national procedure in case of new application.Day 0: the procedure starts with the submission of the application Validation letter (deficiencies of the documetnation) is sent to the applicant – the clock is stopped – the National Institute of Pharmacy provides 15 days for the applicant to submit the requested supplementary documentation – if the applicant do not replies in time the application will be refused by the National Insitute of Pharmacy in a decision As soon as the supplementary documentation is submitted the clock will be restarted.


NATIONAL PROCEDURE

Day 90: the comments concerning the documentation from the assessors are sent to the applicant – the applicant has to submit the response documents in 15 days - if the applicant do not replies in time the application will be refused by the National Insitute of Pharmacy in a decision If necessary the applicant may ask for more time – this means that the procedure will be suspended, the clock will be stopped The assessment of the documentation will be prosumed as soon as the response documentation is submitted (the clock will be restarted after the possible suspension) If the documentation is not appropriate the National Institute of Pharmacy will refuse the application in a decision Day 210: issuing the Marketing Authorisation.


Post-Approval Procedures:Renewal in Europe, the MA is valid for 5 years

Specific situation of all new approved Products for the first 5 years:Periodic Safety Update Report (PSUR)

6 monthly - 2 years after authorisationAnnually for the subsequent 2 yearsAt the first renewal5 yearly renewals

renewal mainly based on the pharmacovigilance data and the benefit to risk ratioto be applied at least 3 months before expiry date


Future outlook : Innovation for the benefit of the patients Timeframes

Centralised procedure: EMEA: from 210 days (normal authorization) to 150 days (fast-track); Decision-making: Member States consultation: reduced from 30 to 15 days; streamlined Commission procedure (new comitology); Expected total: +/- 270 days (currently +/- 1year)National procedures: from 210 days (now) to 150 days;Decentralised procedure: from 300 days (now) to 210 days.Target: all procedures below 1 year (International best average standard)


Future outlook :Promoting Industry competitiveness and competition

Administrative Data protection periods to be harmonised between Member States (10 years)Possible one year extension in case of additional innovative indications bringing important clinical benefit for the patientsPossibility for generic companies to perform trials before patent(s) expiry (“Bolar” type provision)


Future outlook : Cutting the red-tape reduction paper flow

Removal of the five year renewal rule for marketing authorisationsStrengthening pharmacovigilance in particular through systematic electronic exchange of dataAccelerated and simplified decision-making process


DISPONIBILIDAD DEL MATERIAL DE LAS CONFERENCIAS

http://www.latconsultores.com.ar/novedades

[email protected]

Alessio Ferrari

THANKS FOR YOUR ATTENTION

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