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, PhDChair CTFG
Head, Clinical Trial UnitPaul-Ehrlich Institute
Paul-Ehrlich-Str. 55-5963225 Langen
Germany
Fax: +49 +(0)6103 771277Telefon: +49 +(0)6103 771811E-Mail: [email protected]
http://www.pei.de
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 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 Pro-cedure )
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 3
Approval of Clinical Trials in Europe:
Present Clinical Trial Application system in Europe (after 1.5.2004/1.1.2007) 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 4
Scheme of the CT applications and assessment by the National Competent Authorities
Additional information by Sponsor
Grounds for non-acceptance or approval
AssessmentFormal
Deficiencies
Decision
Re-assessment
Application by Sponsor
Info. to Sponsoron formal deficiencies
Additional information by Sponsor
Different time lines according to national regulations possible
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 5
One Clinical trial on its way through the approval procedure
+
++
+
-
++
+
+
+ -
TimeCompetent Authorities Ethics Committees
Results
0
30
60
90
120
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 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 7
Clinical Trials in EuropeMay 2004 - June 2008
Number of Clinical Trials recorded in the EudraCT Database:
15729
Total number of Clinical Trials recorded by Member State Competent Authorities in the EudraCT Database
30376
Clinical Trials recorded per Sponsor Type:
Commercial: Non-Commercial: Not indicated:
79.5%20%0.5%
Total number of Clinical Trial Site Inspections 905
EudraCT Number will be used for a Clinical Trialconducted 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 8
Clinical Trial Applications in Europe in %(Status: June 2008)
28,2
64,9
50,760,1
0,010,0
20,030,0
40,050,060,0
70,080,0
90,0100,0
single
site
multiple
sites
multi-n
ation
al CT
involv
ing 3rd
countr
ies
% o
f CT
in E
urop
e
Number of Clinical Trials recorded in the EudraCT Database: 15729
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 9
Decisions on clinical trial applications(June 2008)
96,8
1,7 1,5
97,5
0,3 2,20,0
50,0
100,0
150,0
NCA- auth
orise
d CT
NCA-with
drawn
NCA-refus
ed
EC- favo
rable
EC- with
drawn
EC- non-f
avorab
le
% o
f CT
in E
urop
e
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 10
Divergent decisions of Competent Authorities/Ethics Committees in Europe (May 2004 - June 2008)
CA Refusal / EC Favourable 89
CA Approval / EC non-Favourable 155
CA Refusal / EC non-Favourable 81
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Divergent decisions of Competent Authorities in Europe (multi-national CTA only*)
Year Clinical Trial Applications 2004 72005 302006 282007 382008
(until 1.6.2008)32
* Except refusals by EC which had to be adopted by the CA
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 12
EudraCT Alerts until Sep. 2008including mono-national/multinational CT
Alerts arising because the trial has been interruptedearly 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 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 14
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) contactsCTFG plenary meetings / meetings dedicated to specific topics e.g. FIH, advanced therapy prod.Sharing of assessment report of CTAsTeleconferences on findings/ e.g. Clinical Trial results in one MS with importance on other CTsAssessment sharing of Annual Safety Reports (planed)
Communication between Member States
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Steps forward to increase assessments sharing and harmonisation of decisions
Further harmonisation of CTA documentation- reduce/simplify additional national requirementsAgreed common structure of electronic submission of CTAsImprove the functionality of EudraCTShared Assessment of Annual Safety Reports / DSURs from ICH ProcessImprove alert and teleconf. systemsParallel assessment of “critical” CTA via the Voluntary Harmonisation Procedure
The CTFG voluntary harmonisation procedure(VHP)
http://www.hma.eu/77.html
W. Kannegiesser / VHP-Co-ordinatorat the Paul-Ehrlich Institute
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 17
Criteria for application/selectionDuring 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/294648/2007.
- 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.
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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
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Phase 2. AssessmentRequests
Phase 1.
SelectionandSub-
Mission
Noquestions
Endof
VHP
questions
questions
response by sponsor
&re-assessment
Questionsresolved
Endof
VHP
Questionsnot resolved
re-discussion by NCAs&
information of Sponsor
-+
+++--
Endof
VHP
Phase 3. National
submission and approval
VHP work flow and options
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VHP Phase 1Phase 1 Request for VHP
Electronic submission of request to VHP-C Before 5th of each Month The VHP-C circulates the TC agenda, along with electronic
copies of the LI-VHP and synopsis to all NCAs,
Discussion of new request(s) during monthly teleconference (TC)
Around the 3rd Thursday 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
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VHP Phase 2 (1/2)Phase 2 VHP Draft CTA assessment step
Day 1 15 days after the electronic submission of the VHP dossier to the VHP-C by the applicant via E-Mail
Validation of the content by the VHP-C
Electronic acknowledgment of receipt by the VHP-C to the applicant
Day1- Day 3
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 e-mail or TC; identification of GNAs or RFIs
If no GNA or RFI: information (VHP-C) of the applicant
End of VHP and start of 3 / National step
Day 29-30
In case of GNA and/or RFI: compilation of the GNA/RFI by VHP-C and transfer to the applicant and the P-NCAs .
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VHP Phase 2 (2/2)Day 40 – Day 50 VHP assessment step II
Deadline for electronic submission of additional documentation and revised draft CTA to VHP-C by the applicant
Day 40
Distribution to the P-NCAs by the VHP-C
Day 40-47 Review of the applicant’s response by the P-NCAs
Day 50 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 proposedsolutions.Revised CTA approvable with changes :- Information of the applicant by the VHP-C
End of VHP and start of Phase 3 / National step
Day 50-57
Revised CTA not approvable :
Day 60 - End of the VHP: Letter to the applicant with details of GNAs byNCAs
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VHP Phase 3 / National stepPhase 3 National step
Within 20 days of receipt of approvability statement
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)
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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 25
Documents to be submitted during the VHP II
VHP Application dossier :
1. General Information1.1 Covering Letter including Eudract number1.2 Notification of acceptance in VHP1.3 Application form if available1.4 List of NCAs concerned
2. Protocol related folder2.1 Current Protocol (including the summary/synopsis)
3. IMP related folder3.1 IB3.2 IMPD (including viral safety data if applicable)
3.3 Scientific advises and PIP summary report (if applicable)
The CTFG voluntary harmonisation procedure(VHP)
http://www.hma.eu/77.html
Contact:[email protected] Tel.:+ 49 6103 771811
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 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 28
Backup Slides
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 29
Reasons for refusals in the context of divergent decisions
Total procedures 170Refusals related to:
Protocol 41Pharm.-Tox. 10Clinical 22Quality of the IMP 15Other 19No information given 63
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 30
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 decisionsEvaluate divergent decisions and contribute to finding solutions to the underlying scientific issuesContribute 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
Mandate of Clinical Trials Facilitation Group / Examples
Clinical trials in Europe / Voluntary Harmonisation Procedure (VHP) H. Krafft Page 31
Development of CT in different countries
Thiers et al. Nature Reviews | Drug Discovery © 2008 Nature Publishing Group - 14 | January 2008 | Volume 7 - www.nature.com/reviews/drugdisc