European Regulatory Procedures: Centralised vs DCP

1. European Regulatory Procedures: Centralised vs DCP . Dr Ian Hudson Director, Licensing Division, MHRA Vice Chair CHMP June 2013

2. Regulatory Routes • National Procedure • European Procedures • Centralised Procedure • Mutual Recognition • Decentralised Procedure

3. Centralised Procedure • Legal basis – Council Regulation EC 726/2004 committee, CHMP • A single application • A single evaluation • A single authorisation • Operated by EMEA and its scientific

4. Composition of CHMP • 1 Delegate and 1 alternate per Member State Up to 5 co-opted members • Members act as Rapporteurs for assessment work

5. Work of CHMP • Centralised licensing work • Referrals • Scientific advice • Guidance • Scientific opinions on wide range of topics • Pharmacovigilance • Preparing for new technologies

6. Centralised Procedure • Mandatory for all new applications • Biotechnology procedure • Orphans • AIDS, cancer, neurodegenerative disorder, diabetes • Autoimmune disease and other immune dysfunction and viral diseases (from May 08) • Eligible/Optional at present • A new active substance • Innovative products with novel characteristics • In the interests of patients at community level • Generics of centrally authorised products

7. Centralised ProcedureEvaluation time table: new applications • Pre-submission meeting • Selection of Rapporteurs – those best able to perform task • The evaluation process completed within 210 days (excluding clock stops) • Landmarks • Day 1 – Start of the procedure (Monthly starting date following validation) • Day 80 – Assessment Report circulated by Rapporteur/ Co-Rapporteur to CHMP members and the EMEA

9. Centralised Procedure • Day 100 – Rapporteurs/EMA receive comments from CHMP members • Day 115 – A draft list of questions incorporating comments received from the Member States (including overall conclusions and overview of scientific data) is circulated to CHMP members and the EMA prior to the main CHMP meeting • Peer review teleconference

10. Centralised Procedure • Day 120 • CHMP finalises the list of questions after scientific discussion at the meeting • The overall conclusions and the review of the scientific data is revised following the discussion • Rapporteurs’ position may be updated • Final list of questions sent to the applicant by the EMEA CLOCK STOP Opportunity for clarification with Rapporteurs Company has up to 3 or 6 months to respond

11. Centralised Procedure • Day 121 • Submission of the response by the applicant to the list of questions • CLOCK RESTART (On 11 official dates per year) • Day 150 • Joint response assessment report is circulated to CHMP and the EMEA

12. Centralised Procedure • Day 170 • Deadline for comments from CHMP members to Rapporteurs • Day 180 • Discussion by CHMP and decision whether oral explanation and/or list of outstanding issues is needed Clock Stop if oral explanation needed • Day 181 – Oral explanation Clock Restart Opportunity for clarification with Rapporteur

13. Centralised Procedure • Day 185 – Applicant to provide rapporteurs, CHMP members and EMEA, final draft of the English SPC, PIL and labelling • Day 210 – CHMP opinion ****************************************************** • Post Day 210 – Finalisation of translation of SPC, PIL and Labelling in all of official languages of the EU • Finalisation of AR and EPAR • Transmission to Commission, Standing committee phase, licence grant

14. Interactions With CHMP • Alert Rapporteurs/NCAs to issues • Be open with Rapporteurs/NCAs i.e. deficiencies and difficulties • Recognise our wish to see innovative products available to patients • Recognise our role in public health protection Work with regulators

15. Decentralised Procedure (1) • Intended to address some of the problems encountered in the current Mutual Recognition Procedure • Relatively new procedure: introduced in 2005 • Allows involvement of other Member States during initial evaluation and before European phase starts • Withdrawal allowed throughout procedure, however still results in CMDh referral if withdrawal once European phase has started • Mandatory arbitration

16. Decentralised Procedure • Accounts for a large part of LD work • UK is one of the leading MS in this procedure

18. Decentralised Procedure (2) • Article 28 (3-5) of Directive 2001/83/EC • For MA in more than one MS, application based on identical dossier. • Applicant to request a Member State to act as RMS • In case where the medicinal product has not received a marketing authorisation at the time of application, the applicant shall request the Reference Member State to prepare a draft assessment report, draft SPC, draft labelling and leaflet

19. Decentralised Procedure (3) Time table – Assessment step I • D 0 – Start of procedure • D 70 – RMS to forward Preliminary Assessment Report, SPC, PIL and labelling to CMSs • D 100 – CMSs send their comments • D 100-105 – Consultation between RMS, CMSs and applicant CLOCK STOP – If consensus not reached

20. Decentralised Procedure (4) • D 106 – On receipt of response the RMS restarts the clock • D 106 – 120 – RMS updates AR, SPC, PIL & circulates to CMSs • D 120 – Procedure closed if consensus reached – Proceed to national 30 days step

21. Decentralised Procedure (5) • Time table – Assessment step II • D 120 (Day 0) – No consensus – draft AR, SPC, PIL circulated to CMSs • D 145 (Day 25) – CMSs send their comments to RMS • D 150 (Day 30) - Procedure closed if consensus reached • D 180 (Day 60) – If no consensus, outstanding issues to be communicated to the applicant, receive any additional clarification • D 205 (Day 85) – Breakout group to reach consensus

22. Decentralised Procedure (6) • D 210 (Day 90) • Closure of the procedure including CMSs approval of AR, SPC, PIL or Referral to CMD • Proceed to national 30 days step for resolution • D 270 (at the latest) – Final position adopted by the CMDh (60 days procedure) with referral to the CHMP if issues cannot be resolved. Member States use their best endeavour to reach agreement on the action to be taken. Applicant allowed the opportunity to make his point of view known orally or in writing. ►CMD decision by consensus of MS involved in the procedure

23. National Procedure • New National Procedures decreasing in number • Rarely restricted to national authorisation only • Usually in context with subsequent MRP • Important role to play in decentralised procedures • Option for the companies only if they wish to restrict marketing to a single market • Still a lot of maintenance activity on older licences

24. Mutual Recognition Procedure (1) Legal basis • Directive 2001/83/EC • The mutual recognition can be achieved by asking the other Member States to mutually recognise, within 90 days, the marketing authorisation granted by the Reference Member State

25. Mutual Recognition Procedure (2) • Application to first Member State – Assessment report including SPC leading to first authorisation • Applicant requests MR of the RMS’s authorisation • Update and issue of AR (90 days)

26. Mutual Recognition Procedure (3) Timetable • Validation – 14 days, Provision of automatic validation if no grounds are given within 14 days • Day 0 – 7 days after validation confirmed by all CMSs • Day 50 – Objections raised by Concerned Member States (CMSs). If no objections raised, acceptance of MA in principle The RMS and the applicant receive responses from all CMSs

27. Mutual Recognition Procedure (4) • Day 60 – The applicant, in consultation with the RMS prepares the responses to D 50 questions in set format (text for major questions and tabulated format for the SPC points) and circulate it to CMSs • Day 60 to 75 – Responses from CMSs to RMS and the applicant whether their major objections/issues are resolved. Ongoing clarification and dialogue by phone or email if not resolved. ? Need for breakout session • Day 75 – Breakout session

28. Mutual Recognition Procedure (5) Breakout session • Arranged by the RMS in consultation with the applicant to resolve the outstanding issues. EMEA needs to be informed. • Experts involved with the application ideally need to attend • Applicant expected to be present with their experts • Following discussion the applicant may be invited in to address the group and answer the questions to resolve the issues

29. Mutual Recognition Procedure (6) • D75 to D85 – Further negotiation takes place. Final position should be clear by now • Post D85 – The applicant submits final SPC for CMS taking into account all the changes suggested and agreed • D85 – D89 – CMSs should indicate whether they are prepared to recognise the RMS’s authorisation

30. Mutual Recognition Procedure (7) • D90 – By this day it will be clear to the RMS and the applicant as to which MSs are not prepared to accept the marketing authorisation of the RMS and the grounds for it • Arbitration is triggered automatically. Option to withdraw without discussion at CMD no longer available • Referral to CMD – If not resolved there to CHMP

31. Mutual Recognition Procedure (8) Aids to operating procedures • Mutual recognition Procedure timetable is almost written in stone and cannot be changed. Procedure must close on Day 90 • Responses are not optional but mandatory • Resource intensive, advance planning required • RMS – Central point. All dialogues must be channelled through RMS • Additional studies are not acceptable during the procedure

32. Mutual Recognition Procedure (9) Advantages • Suitable for products where there is common ground and data is robust • Definite time lines hence can be planned according to need • Option to choose whether to include all or some Member States in the procedure • Most of the times possible to get marketing authorisation in some Member States • Advantages/Disadvantages of binding arbitration

33. Mutual Recognition Procedure (10) Disadvantages • Resource intensive and requires meticulous planning for best result • Difficult to negotiate when there are significant differences in the SPC in Member States. Time limit does not allow extended discussion. • Once arbitration is triggered the whole process is delayed • Not suitable for data which is not robust - No procedure is suitable if data is not robust.

34. Conclusions Choice of Regulatory Route • Nature of application • Preference of the applicant • Resources available • Strategic marketing targets of the company • Robustness of data • Any controversial issue/novel development • Consultation with Regulatory Authorities (EMEA/National Agencies) • Reflection of medical practice

35. Conclusions • Regulatory environment is complex and evolving • Regulatory agencies have many customers, but want to see products of appropriate standards on the market and Public Health gains as a consequence. • Regulatory agencies also wish to support innovation; innovation office, scientific advice • Work with agencies in relation to your applications and new technologies • Present applications in user friendly way, follow guidance • Be open and frank about the issues – we may have seen it before! • The public will be best served by regulators and industry working together.