The Voluntary Harmonisation Procedure (VHP) for the ... · solutions. Revised CTA approvable with changes : - Information of the applicant by the VHP-C End of VHP and start of Phase

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 )


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.


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


One Clinical trial on its way through the approval procedure

+

++

+

-

++

+

+

+ -

TimeCompetent Authorities Ethics Committees

Results

0

30

60

90

120


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 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 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


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


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


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


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


How does the Clinical Trials Facilitation Group (CTFG) communicate to deal with these numbers


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


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


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.


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


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


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


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 .


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


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)


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


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


Thank you for your attention

Example of the need for assessment sharing?

Paul Ehrlich in his study


Backup Slides


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


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


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