The Voluntary Harmonisation Procedure (VHP) for the Assessment of Multinational Clinical Trial Applications in the EU

Transcription

1 The Voluntary Harmonisation Procedure (VHP) for the Assessment of Multinational Clinical Trial Applications in the EU CMC Perspectives on Biological Investigational Medicinal Products in Clinical Trials, Lisbon, April 2009 Hartmut Krafft, PhD Chair CTFG Head, Clinical Trial Unit Paul-Ehrlich Institute Paul-Ehrlich-Str Langen Germany Fax: +49 +(0) Telefon: +49 +(0)

2 Topics Present system of CTA approval in Europe (Divergent) Decisions of Competent Authorities and/or Ethics Committees Work-sharing of Competent Authorities Way forward (Voluntary Harmonisation Procedure ) Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 2

3 Approval of Clinical Trials in Europe: Present Clinical Trial Application system in Europe (after / ) inplementation of Dir. 2001/20/EC: - common minimal basis Defined in EU-Directives and Guidelines But implemented in national laws, ordinances, decree of costs etc at different times The approval remains a national issue, even if the application has been submitted in all europ. countries in parallel. Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 3

4 Scheme of the CT applications and assessment by the National Competent Authorities Application by Sponsor Additional information by Sponsor Additional information by Sponsor Formal Deficiencies Assessment Re-assessment Info. to Sponsor on formal deficiencies Grounds for nonacceptance or approval Decision Different time lines according to national regulations possible Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 4

5 One Clinical trial on its way through the approval procedure Time 0 Competent Authorities Ethics Committees Results Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 5

6 Factors influencing multinational CT approvals between different Member states Different Application times in one Member State: Competent Authorities and Ethics Committees Different application times between Member States: Competent Authorities and Ethics Committees Partly different documentation between Member States Different, divergent decisions on the same clinical trial i.e. rejections Changes of the decisions in some Member States i.e. temporary hold, premature end of the clinical trial substantial amendments and SUSARs Annual safety reports Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 6

7 Clinical Trials in Europe May June 2008 Number of Clinical Trials recorded in the EudraCT Database: Total number of Clinical Trials recorded by Member State Competent Authorities in the EudraCT Database Clinical Trials recorded per Sponsor Type: Commercial: 79.5% Non-Commercial: 20% Not indicated: 0.5% Total number of Clinical Trial Site Inspections 905 EudraCT Number will be used for a Clinical Trial conducted in a third country (outside of the EU / EEA) and contained in an agreed Pediatric Investigation Plan 203 Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 7

8 Clinical Trial Applications in Europe in % (Status: June 2008) 100,0 90,0 80,0 % of CT in Europe 70,0 60,0 50,0 40,0 30,0 20,0 28,2 64,9 60,1 50,7 10,0 0,0 single site multiple sites multi-national CT involving 3rd countries Number of Clinical Trials recorded in the EudraCT Database: Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 8

9 Decisions on clinical trial applications (June 2008) 150,0 100,0 50,0 96,8 97,5 % of CT in Europe 1,7 1,5 0,3 2,2 0,0 NCA- authorised CT NCA-withdrawn NCA-refused EC- favorable EC- withdrawn EC- non-favorable Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 9

10 Divergent decisions of Competent Authorities/Ethics Committees in Europe (May June 2008) CA Refusal / EC Favourable 89 CA Approval / EC non-favourable 155 CA Refusal / EC non-favourable 81 Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 10

11 Divergent decisions of Competent Authorities in Europe (multi-national CTA only*) Year Clinical Trial Applications (until ) * Except refusals by EC which had to be adopted by the CA Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 11

12 EudraCT Alerts until Sep including mono-national/multinational CT Alerts arising because the trial has been interrupted early or terminated for reasons of safety or lack of efficacy, IMP quality related issues, or the trial has been suspended or prohibited = 282 Alerts arising because the competent authority has refused to provide authorisation for the trial or the ethics committee has given a negative opinion on the trial, or the applicant has withdrawn the application = 509 Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 12

13 How does the Clinical Trials Facilitation Group (CTFG) communicate to deal with these numbers Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 13

14 Communication between Member States Alerts on critical events (refusals, interrup-tions, pre-mature endings, withdrawals of ap-plications) Personal communication during parallel assess-ment (assessor to assessor) via the (CFTG) contacts CTFG plenary meetings / meetings dedicated to specific topics e.g. FIH, advanced therapy prod. Sharing of assessment report of CTAs Teleconferences on findings/ e.g. Clinical Trial results in one MS with importance on other CTs Assessment sharing of Annual Safety Reports (planed) Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 14

15 Steps forward to increase assessments sharing and harmonisation of decisions Further harmonisation of CTA documentation - reduce/simplify additional national requirements Agreed common structure of electronic submission of CTAs Improve the functionality of EudraCT Shared Assessment of Annual Safety Reports / DSURs from ICH Process Improve alert and teleconf. systems Parallel assessment of critical CTA via the Voluntary Harmonisation Procedure Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 15

16 The CTFG voluntary harmonisation procedure (VHP) W. Kannegiesser / VHP-Co-ordinator at the Paul-Ehrlich Institute

17 Criteria for application/selection During the pilot phase, only MN-CTs with the following criteria would undergo the VHP: - MN-CTs involving an IMP without MA in the EU and any of the following : - FIH MN-CTs and particularly with investigational medicinal products with known or anticipated risk factors as described in EMEA/CHMP/SWP/294648/ MN-CTs with Critical investigational medicinal products (limited community expertise e.g. IMP with novel modes of action, novel manufacturing process, novel administration and storage requirements, links to a class of medicinal product with recognised safety concerns, unresolved pre-clinical abnormal findings, for instance monoclonal interfering with immune regulation, advanced therapies) or Critical MN- CTs (e.g. for limited trial populations e.g. orphan diseases, less common types of cancer, paediatrics diseases with small numbers, adult diseases with small numbers or unmet medical needs), based on NCA s judgement, endorsed by the CTFG - MN-CTs with very large population and where the sponsor indicates a need for harmonisation (e.g. large phase III CTs and many MS concerned) CTA decisions in VHP- Phase III remain on a national level. Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 17

18 The VHP consists of three phases Phase 1 : a pre-procedural or Request for a VHP phase - Request by sponsors (letter of intention for VHP) - Decision by CTFG to include the request into the VHP system - Identification of the participating NCAs Phase 2 : the assessment phase - Review of the CTA by all the participating NCAs - 1st common position around D30, total period maximum 60 days - Administrative coordination by the VHP coordinator Phase 3 : the national Member States step - Formal CTA applications to NCAs. - CTA approval by NCAs within short timelines Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 18

19 VHP work flow and options Requests Phase 2. Assessment Phase 1. Selection and Sub- Mission No questions questions questions End of VHP Questions resolved Questions not resolved End of VHP Phase 3. National submission and approval End of VHP response by sponsor & re-assessment re-discussion by NCAs Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 19 & information of Sponsor

20 VHP Phase 1 Phase 1 Before 5th of each Month Request for VHP Electronic submission of request to VHP-C The VHP-C circulates the TC agenda, along with electronic copies of the LI-VHP and synopsis to all NCAs, Around the 3rd Thursday Discussion of new request(s) during monthly teleconference (TC) If MN-CT eligible for VHP, Information of the applicant Letter of intention : - Covering Letter - Letter of intention describing the key features of the CT and the reason(s) why a VHP is warranted - List of the CA the applicant intends to submit a CTA in the national phase - Summary/synopsis of the current protocol Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 20

21 Phase 2 Day 1 Day1- Day 3 VHP Phase 2 (1/2) VHP Draft CTA assessment step 15 days after the electronic submission of the VHP dossier to the VHP-C by the applicant via Validation of the content by the VHP-C Electronic acknowledgment of receipt by the VHP-C to the applicant Distribution of electronic copies to the P-NCAs by the VHP-C Day 3 Day 30 VHP assessment step I Day3 Day 26 Review by the P-NCAs and exchange of opinions by or TC; identification of GNAs or RFIs Day If no GNA or RFI: information (VHP-C) of the applicant End of VHP and start of 3 / National step In case of GNA and/or RFI: compilation of the GNA/RFI by VHP- C and transfer to the applicant and the P-NCAs. Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 21

22 VHP Phase 2 (2/2) Day 40 Day 50 VHP assessment step II Day 40 Deadline for electronic submission of additional documentation and revised draft CTA to VHP-C by the applicant Distribution to the P-NCAs by the VHP-C Day Day 50 Day Day 60 Review of the applicant s response by the P-NCAs If the revised draft CTA is considered approvable: information (by the VHP-C) of the applicant End of VHP and start of Phase 3 / National step If the revised draft CTA is considered not approvable, the VHP-C sets up a TC for discussion of all remaining issues and proposed solutions. Revised CTA approvable with changes : - Information of the applicant by the VHP-C Revised CTA not approvable : End of VHP and start of Phase 3 / National step - End of the VHP: Letter to the applicant with details of GNAs by NCAs Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 22

23 VHP Phase 3 / National step Phase 3 Within 20 days of receipt of approvability statement National step Submission of formal CTA to each P-NCA with the letter of decision on VHP Within 10 days of valid CTA Procedure and decision according to national laws After P-NCA s decision Information of the VHP-C on the outcome of the national CTAs (with respect to the VHP decisions) Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 23

24 Documents to be submitted during the VHP I Letter of intention: - Covering Letter - Letter of intention describing the key features of the CT and the reason(s) why a VHP is warranted - List of the CA the applicant intends to submit a CTA in the national phase - Summary/synopsis of the current protocol Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 24

25 Documents to be submitted during the VHP II VHP Application dossier : 1. General Information 1.1 Covering Letter including Eudract number 1.2 Notification of acceptance in VHP 1.3 Application form if available 1.4 List of NCAs concerned 2. Protocol related folder 2.1 Current Protocol (including the summary/synopsis) 3. IMP related folder 3.1 IB 3.2 IMPD (including viral safety data if applicable) 3.3 Scientific advises and PIP summary report (if applicable) Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 25

26 The CTFG voluntary harmonisation procedure (VHP) Contact: or Tel.:

27 Thank you for your attention Example of the need for assessment sharing? Paul Ehrlich in his study Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 27

28 Backup Slides Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 28

29 Reasons for refusals in the context of divergent decisions Total procedures 170 Refusals related to: Protocol 41 Pharm.-Tox. 10 Clinical 22 Quality of the IMP 15 Other 19 No information given 63 Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 29

30 Mandate of Clinical Trials Facilitation Group / Examples Sharing Scientific Assessment: Develop and support a network of assessors to provide a forum for expert discussion of scientific issues related to clinical trials; Promote co-operation between NCAs in the evaluation of multi-national clinical trials (e.g. work sharing) and harmonised decisions Evaluate divergent decisions and contribute to finding solutions to the underlying scientific issues Contribute to the identification and evaluation of factors of risk in clinical trials based on the experience of individual applications particularly for first-in-human trials Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 30

31 Development of CT in different countries Thiers et al. Nature Reviews Drug Discovery 2008 Nature Publishing Group - 14 January 2008 Volume Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 31