Federal Institute for Drugs

and Medical Devices

MRP & DCP

step by steb instructions how to apply
and how the procedures are conducted
06 May 2013
Dubrovnik, Croatia
Dr. Peter Bachmann
Head of Unit ‘Coordination Group‘
European and International Affairs
Federal Institute for Drugs and Medical Devices (BfArM)
and
Chair CMDh
c/o EMA, London
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… European Pharmaceutical Legislation

2
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

„United in
EU / EEA Diversity“
(+ Iceland, Norway,
Liechtenstein)
Political union of 27
Member States

501 Mio
inhabitants

23 official
languages

3
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Types of MA in the EU/EEA

central national

MA valid for the MA valid for a single

EU EEA-MS

4
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

National Marketing Authorisation

MRP and DCP

Scope

5
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Scope of MRP/DCP:
National Marketing Authorisation - (1)
• new active substances (if not mandatory for the
centralised procedure)
• known active substances under Article 8(3)
• biological medicinal products (incl. biosimilar) (if not
mandatory for the centralised procedure)
• generic medicinal products to national (and
centralised) authorised reference medicinal products
• well established use (WEU) (“bibliographic
applications”)
6
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Scope of MRP/DCP:
National Marketing Authorisation - (2)
cont.
• known active substances in new combination
• informed consent to national MA
• (line) extension applications to national authorisations
• homeopathics
• traditional herbal medicinal products

7
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Where to apply for a national MA?

Competent Authority (CA)

of a Member State (MS) of the EU/EEA

Who will grant a national MA?

CA of the MS
8
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Procedures for a MA-Application

central national

MRP/DCP single

one MA valid
for the EC
more than MA for only one
one EEA-MS
EEA-MS

9
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP

10
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

What is the
Mutual Recognition Procedure (MRP)
and the Decentralised Procedure (DCP)?

• describes the procedure to get national MAs in MSs

of the EEA for the same medicinal product

mandatory procedures

• work sharing between MS

11
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Article 17 of Directive 2001/83/EC

“1. ...
Applications for marketing authorisations in two or more
Member States in respect of the same medicinal product
shall be submitted in accordance with Articles 27 to 39.
2. Where a Member State notes that another marketing
authorisation application for the same medicinal product
is being examined in another Member State, the Member
State concerned shall decline to assess the application
and shall advise the applicant that Articles 27 to 39 apply.”

12
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Article 18 of Directive 2001/83/EC

“Where a Member State is informed in accordance with

Article 8(3)(1) that another Member State has authorised a
medicinal product which is the subject of a marketing
authorisation application in the Member State concerned, it
shall reject the application unless it was submitted in
compliance with Articles 27 to 39.”

13
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Same medicinal product ?

If  Same qualitative and quantitative

active ingredient
 There may be the differences in excipients provided that there
is no impact on safety and efficacy

and  Same pharmaceutical form, but …

and  Link between companies

 all legal entities

 all license holders

 companies who have agreed to act in a concerted action

= MRP/DCP
(Commission Communication July 1998)
14
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP - (1)

Two routes to receive a MA for the same

medicinal product
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

MRP & DCP 11.05.2011 15

The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP – (2)

MRP – Interpretation (RMS):
(with regard to ‘the medicinal product’ and
‘duplicate application’)
1. You have to use the first national MA for the
MRP
or
2. You need a national MA to start the MRP,
but you don’t have to use an existing MA
(submission of an “updated copy”-application
for DCP)
16
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP - (3)

• ‘CMDh Recommendations on Multiple/Duplicate
Applications in Mutual Recognition and Decentralised
Procedures’ (Rev 3, June 2007)

• CMDh Q&A No 1:
The CMDh has agreed that a duplicate application of a medicinal
product authorised via the Mutual Recognition Procedure can be
accepted via the Decentralised Procedure, provided that the same
Reference Member State is used.
17
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP

DCP
(= Decentralised Procedure)

18
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - Overview

1. Pre-procedural Step
• scientific/regulatory advice
• validation
2. Assessment step I – 120 days
incl. clock-stop
3. Assessment step II – 90 days
4. National step to grant MA – 30 day
incl. Public AR

19
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (1)

Revision 4, March 2013

1. Pre-procedural Step
Before Day - 14 Pre-submission discussions between
Applicant and RMS

Day - 14 Submission of the dossier to RMS and CMSs

Validation of the application

20
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Pre-submission discussions ….

S L O T S !!!!!!

• tool for workplanning

• two models currently in use/discussion
–‘continium’
–‘quantum’

21
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

22
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

23
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… current problems

• high number of cancellations or delays

– 54 % - with 34 % total cancellation
– ongoing discussion with trade associations

24
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Validation – (1)
• Administrative validation (!) – therefore no
validation of the content of the application
• Reduction of national requirements

a lot of effort – but not totally sucessful

Still additional national requirements for some
of the MSs

25
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 National requirements
Federal Institute for Drugs
and Medical Devices

NO
YES

26
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Validation – (2)

• Validation issues

27
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

• Application not received/modules are missing

• Missing/incorrect fee
• Application form/cover letter not signed/not signed with original signature
• The application form is incorrect (eg. information missing, incorrect type of procedure,
legal basis incorrect, incorrect reference medicinal product, reference to an European
reference medicinal product although there is a nationally authorised medicinal product)
• Documents in accordance with NtA, vol. 2B are missing or absence not justified (eq.
Braille, Consultation with Target Patient Groups, Pharmacovigilance System,
Environmental Risk Assessment, Specific Requirements for Different Application Types,
Paediatric Regulation(where applicable))
• Annexes to the application form are missing or absence not justified (eg Declaration
from the QP, TSE certificates for excipients of animal origin)
• Manufacturing licenses, GMP certificates and/or import licenses have not been updated
or are missing. Proposed batch releaser is situated outside the EEA
• ASMF and/or letter of access to ASMF missing or incorrect version of the ASMF has
been submitted
• Confirmation that identical dossiers are submitted in both RMS and the CMS is missing.
• ... 28
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… progress

Two categories
• validation issues which prevent the start (closed list !) e.g.
only national requirements which are published on the
CMDh website
• procedure can be started, but non-validation issues has to
be solved with day 60 response (MRP) or day 106 response
(DCP) at latest
29
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (2)

2. Assessment step I – 120 days

Day 0 RMS starts the procedure and the

assessment of the dossier
Day 70 RMS forwards PrAR, SmPC, PL and labelling
to CMSs and Applicant
Day 100 CMSs send comments to RMS and Applicant
RMS may consult CMS to close procedure
Day 105 RMS close the procedure or stops the clock

30
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (3a)

Clock-off period

• recommended period of 3 months, which could be

extended for further 3 months and if justified

31
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Reasons for long clock-stop …

• on request from the applicant !!!

• new or additional BE-study/studies

• missing studies
• GMP / GCP inspection
• wait for the outcome of ongoing discussions
• …
Don´t Submit Premature Dossiers !
Improve Quality of the Dossier !
32
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (3b)

Clock-off period

• recommended period of 3 months, which could be

extended for further 3 months and if justified
• Applicant send draft response to RMS – if not letter to
RMS about the submission date of the final response
• Applicant agree with the RMS the date of submission of
the final response
• Applicant submit final response document to MS

33
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (4)

Day 106 valid submission of the response of the

applicant received
= Restart of the procedure
RMS updates PrAR to prepare draft AR (DAR),
draft SmPC, draft PL and draft labelling

Day 120 if consensus – RMS close procedure

if consensus not reached

34
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (5)

3. Assessment step II – 90 days

Day 120 RMS sends draft AR, draft SmPC, draft PL and
draft labelling to CMSs and Applicant
Day 145 CMSs send (final) comments on draft AR, ...
Day 150 if consensus – RMS close procedure
no consensus – RMS to dicuss items with applicant
(and CMS) and prepare of a report on outstanding
issues to the CMD (until Day 180)
Day 195 Break-out Session
CMSs send final comments

35
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (6)

Day 210 closure of the procedure

mutual approval
or
disagreement and referral to the
Coordination Group (CMDh)
(based on ‘potential serious risk to public health’)

36
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (7)

4a. National step to grant MA – 30 days

Day 215 (95) Applicant sends national translations of
SmPC, PL and labelling
Day 240 (120) granting of the national MA

This timeframe of 30 days is equally valid for the

CMS in the MRP !!!
37
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP and DCP

MRP
RU-MRP (Repeat Use MRP)

38
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP - flow chart - (1)

1. Validation
Before Day - 14 Submission of Dossier by Applicant to
CMS
Submission of Assessment Report to
CMS (and Applicant)

Day - 14 Start of the Automatic Validation

Def. “automatic”: ‘not against’ is ‘in agreement’

39
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Why Validation Issues ? - (1)

CMDh –Procedural Advice on Repeat-Use (Rev. 7, July 2011)

Granted MA are with proofen safety and

efficacy, but new application in the CMS !!!!
 is the dossier still up-todate
− changed Guidelines (e.g. bioequivalence)
− new legislation (e.g. pharmacovigilance)
− science still state of the art ?
 status of the SmPC/PL?
– are the indications state of the art ?
– patient consultation ?
40
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Why Validation Issues ? - (2)

cont.

 all (national) variation are finished ?

 ongoing (national) renewal ?
 still conditions to fulfil from the time of approval?
 (updated) assessment report available ?
 change of assessor
 change of clinical philosopy
 prescription status …

41
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Why Validation Issues ? - (3)

• legal basis of the application (10a, 10b)
• outdated GMP- and CEP-certificates
• problems related with ASMF
• unknown GCP-problems
and therefore…
– an update is necessary before submission
– takes time and resources
… but no security against surprises
during the MR-Procedure !!!
42
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP - flow chart - (2)

2. The 90 Days-Procedure
Day 0 RMS starts the procedure
Day 50 CMS send comments to RMS and Applicant
Day 58 Draft “Applicant’s Response Document = ARD”
to RMS
Day 60/68 Final ARD and “Assessor’s Response
Document” (if applicable) to CMS
Day 75 CMS comments on ARD to RMS
Response of Applicant to CMS
Possibility of a Break-out Session
n-’comments and answers circles’
43
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP - flow chart - (3)

Day 85 “finally proposed SmPC” to CMS

Final comments of CMS
Day 90 closure of the procedure

mutual approval
or
disagreement and referral to the
Coordination Group (CMDh)
(based on ‘potential serious risk to public health’)

44
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

MRP - flow chart - (4)

if CMS
3. National step – 30 days
Day 95 Applicant sends national translations of
SmPC, PL and labelling
Day 120 granting of the national MA

if RMS:
3. update of the national MA + Public AR

45
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Why update of the existing MA?

MRP
• changes to the dossier, SmPC, PL, labelling
during the procedure
• need to update the existing national MA

Repeat-Use MRP
• Procedure only between RMS and new CMS
• no changes are possible during the procedure
– ‘yes or no-decision‘ for the new MS
– ‘old‘ MS have to agree with changes
• MAH ‘agree‘ to introduce the changes ask for via
a variation
46
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

Public AR
Transparency of Marketing Authorisations

 MA and SmPC public available

 Public Assessment Report (PAR) is public
accessible
 without any information of a commercially confidential
nature
 a justification for each indication applied for shall be
given
 in MRP/DCP written and updated (Variations,
Renewal) by the RMS for the CMS
 Consultation between RMS and Applicant on the
content of the PAR (CMDh-BPG)
 Summary in lay language
47
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

DCP - flow chart - (8)

4b. Public AR
(CMDh BPG FOR THE PUBLIC ASSESSMENT REPORT IN THE
DECENTRALISED AND MUTUAL RECOGNITION PROCEDURE January
2006 )

End of MRP (Day 90) or DCP (Day 210) = Day 0

Day 10 RMS send draft of PAR to Applicant

Day 20 comments on PAR to RMS
Day 25 - RMS to check answers of Applicant
- prepare final PAR
Day 60 - publication of the PAR on the website of the
Heads of Medicinal Agencies (HMA)

48
The BfArM isDCP/MRP BAH-WiDi
a Federal Institute 22.portfolio
within the 03. 2011of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… http://www.hma.eu

49
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… the new product index – (1)

50
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… the new product index – (2)

51
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

52
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs
and Medical Devices

… (new) development

• for historic reasons only positively concluded

DCP are published 30 days after the end of the
procedure (exemption: CMDh-Referral)
• new policy:
– rejected DCP are published 30 days after closing of the
procedure, starting 01. 09. 2012
– list of involved MS will be published
– negativ PAR will be published
• DCP-applications withdrawn after Day 120 will be
published (in preparation)
53
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
 Federal Institute for Drugs Federal Institute for Drugs
and Medical Devices

and Medical Devices (BfArM)

... special thanks to all CMDh-

Members/Alternates/Experts …
for the hard work and time
spend
... many thanks
for your kind attention
54
The BfArM
The BfArM is a Federal
is a Federal Institute
Institute within
within thethe portfolio
portfolio of of
thethe Federal
Federal MinistryofofHealth
Ministry Health