A growing number of clinical trial sponsors, and particularly those from the commercial sector, are relying on the Voluntary Harmonisation Procedure (VHP) introduced in 2009 to streamline the assessment of multinational trial applications across the European Union, a regulatory affairs meeting in Italy heard recently.  

Addressing the 8th Annual Symposium of The Organisation for Professionals in Regulatory Affairs (TOPRA), held in Rome in conjunction with the Italian medicines agency, AIFA, Dr Chantal Bélorgey, chair of the EU’s Clinical Trials Facilitation Group (CTFG), said a total of 97 clinical trial applications (CTAs) involved the VHP procedure during its pilot phase between March 2009 and August 2011.

Of these procedures, more than 50 took place during the first six months of 2011, Bélorgey – who also heads up the clinical trials department at the French regulator, Afssaps – told the symposium. The total VHP count involved 54 different sponsors, 81% of which were commercial and 19% non-commercial. On average, each VHP took in six EU member states.

VHP guidance

A guidance document outlining the Voluntary Harmonisation Procedure was published in February 2009 by the Clinical Trials Facilitation Group, set up by the Heads of Medicines Agencies in the European Union to co-ordinate the implementation of the clinical trials Directive, 2001/20/EC.

One effect of the Directive’s translation into national law has been divergence in the national assessment of multinational clinical trials (MN-CTs), with protocol changes and the subsequent amendments required in other member states making some applications a “never-ending story”, as Professor Heiko von der Leyen of the Hannover Clinical Trial Centre in Germany described it at the TOPRA symposium.

Reasoning that harmonising procedures for CTA assessment after the applications had been filed would be difficult and perhaps even counterproductive, coming at the end of an already lengthy process, the CTFG’s guidance proposed a Voluntary Harmonisation Procedure that would occur before the initial phase of national assessment.

The VHP is an incremental process whereby  Phase 1 constitutes a ‘pre-procedural’ or ‘request for a VHP’ step; Phase 2 is an assessment step, involving the review of the draft CTA by the national competent authorities (NCAs) of participating member states; and  Phase 3 occurs at national level, with formal clinical trial applications to all of the concerned NCAs.

The procedure is also completely electronic, which helps to speed up the evaluations. In a best-case scenario, von der Leyen noted, the VHP should mean approval of the CTA in multiple member states within two months.

50-day average

In fact, von der Leyen pointed out, the first Voluntary Harmonisation Procedure, involving a multicentre trial sponsored by the Germany Liver Foundation (Hep-Net), took three months for approvals to come through in all of the concerned member states.

According to Bélorgey, in the VHP pilot phase running up to August 2011, the average time for the assessment process (i.e., Phases 1 and 2, prior to the national step) was 50 days.

Among the challenges highlighted by von der Leyen for clinical trial sponsors using the VHP are a short time window (10 days) for resubmission of draft CTAs if additional information is requested; the need to prepare national applications in advance to keep to the time schedule; and co-ordination with national ethics committee procedures.

Key options

A co-ordinated assessment procedure for clinical trials in the EU is one of the key options on the table in the European Commission’s ongoing revision of Directive 2001/20/EC, which is expected to produce a concrete legislative proposal next year.

Speaking at the TOPRA symposium, Dr Stefan Fuehring from the Commission’s pharmaceutical unit reminded delegates why improved harmonisation and co-operation are so important in this field.

Between 2007 and 2010, there was a 15% decline both in the number of MN-CTs with EU sites and the number of EU subjects participating in those studies, he noted. More specifically, there were 5,028 clinical trial applications across the EU in 2007 and only 4,193 in 2010.