The enlargement of the EU to 27 member states brought with it many procedural complications, not least gaining approval for clinical trials in Europe. Prior to 1 May 2004, there were 15 national approaches, involving a combination of Ethics Committees and Competent Authorities, but after 1 January 2007 there were 27 national approaches with a common minimal basis.
Although the clinical trials approval process is defined in a series of Directives and Guidelines, their implementation in national laws has been carried out at different times and taking into account a number of individual factors, such as costs. And even if the application has been submitted in all European countries in parallel, approval remains a national issue, leading to inconsistent decisions and undue delays.
For this reason a Voluntary Harmonisation Procedure (VHP) has been put in place. It is a pilot programme that allows a sponsor to obtain a consolidated EU health authority assessment for a multinational clinical trial application, and its aim is to harmonise divergent decisions among member states and enable the sponsor to get a clinical trial approved in multiple member states within an acceptable time frame.
Dr Hartmut Krafft, chair of the Clinical Trials Facilitation Group (CTFG) and head of the Clinical Trial Unit at the Paul-Ehrlich Institute, told delegates at the recent TOPRA/EMA conference that between May 2004 and June 2008 there were 89 clinical trial applications where the Competent Authorities were opposed but the Ethics Committees were in favour; 155 cases where the Competent Authorities were in favour but the Ethics Committees were not; and just 81 where both parties were non-favourable.
During the pilot phase, only multinational clinical trials involving an Investigational Medicinal Product (IMP) without a Marketing Authorisation in the EU would be eligible for selection for the VHP, as long as they also satisfied one of the following:
- First in human multinational clinical trials and particularly with IMPs with known or anticipated risk factors as described in EMEA/CHMP/SWP/294648/2007.
- Multinational clinical trials with "critical" IMPs (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" multinational clinical trials (e.g. for limited trial populations i.e. orphan diseases, rare types of cancer, paediatric diseases with small numbers, adult diseases with small numbers or unmet medical needs) based on the national Competent Authorities" judgement, endorsed by the CTFG.
- Multinational clinical trials with a very large population and where the sponsor indicates a need for harmonisation (e.g. large phase III trials and involving many member states).
The VHP consists of three phases. Phase 1 is a "pre-procedural" or "Request for a VHP" phase and should take around seven days. It involves a request by sponsors, including the identification of participating national competent authorities (NCAs) and a full dossier, and a decision by member states to participate in the VHP.
Phase 2 is the assessment phase and should take a maximum of 60 days. It consists of a review of the clinical trial application by all the participating NCAs, with a first common position emerging around day 30.
In Phase 3 formal clinical trial applications are made to the NCAs and, assuming a positive response, approval is given within short timelines. CTA decisions in Phase 3 remain on a national level, stressed Krafft.
Key features of the VHP are:
- 1. Only electronic documents sent to one address
2. Only general documents are required that are part of any clinical trial application (Protocol, Investigators brochure, Investigational Medicinal Product Dossier)
3. Reliable timelines for sponsor and member states
4. Harmonised scientific discussion results in harmonised applications in the member states - no tracking of member states" specific modifications is necessary and there is only one consolidated list of questions submitted through the VHP co-ordinator; any questions submitted at this stage will not be repeated in Phase 3
5. It is flexible, when changes are required:
- Co-ordinating member state for list of questions
- Reducing time for VHP-Phase 1: a pre-procedural. or Request for a VHP. phase
- widening the inclusion criteria for the VHP (case by case)
- Addition of substantial amendment for successful Voluntary Harmonisation Procedures.
In the seven months of the pilot phase of the VHP, which ran from April last year, there were 20 applications, of which nine were for standard VHP and 11 were for accelerated VHP for pandemic influenza vaccines. Fourteen have been concluded: two received a negative response, but this was changed to a positive after new batch data was submitted; two were withdrawn before the dossier was submitted; and three are still ongoing. Each standard VHP involved between two and 18 member states, making an average of six per application.
Reactions to the VHP have been mixed. Those sponsors who used the VHP were generally positive about it, but some are still hesitant, fearing that timelines will be longer than for applications filed in multiple national applications or reaction times for sponsors to questions or grounds for non-acceptance are too short. On the other hand, some organisations consider the entire process to be too long without even having experienced it, Krafft said.
Recent modifications to the VHP have included some internal changes, for example streamlining the list of grounds for non-approval; widening the inclusion criteria for the VHP case by case, skipping the VHP-Phase I fixed application time lines and documentation, and inclusion of substantial amendments for successful VHPs. An updated version of the Guideline was expected in January 2010, Krafft told delegates.
According to Dr Elmar Schmitt, of Global Regulatory Oncology, Merck KGaA, one thing is certain: a change in the status quo is definitely needed to harmonise the range of content, format and language requirements and to reduce the high workload involved in each clinical trial application. There are two current views on how this should be done: either an optional, centralised approval process enforced through a new EU Regulation in parallel to Directive 2001/20/EC; or modifications to the existing Directive to bring about greater harmonisation.
Merck Serono believes that the VHP pilot could be a first step to improving the current situation, as it will focus on facts rather than on opinions. "The main question was whether a parallel CTA assessment by multiple EU health authorities would result in a different scientific evaluation compared with the individual national submissions," he said.
Getting the go-ahead to apply for a VHP required a degree of lobbying, both internally and externally, Schmitt added. "We had several discussions with the CTFG chairman and the VHP co-ordinator to gain more specific guidance, because not every situation was covered in the guidelines. We had to get buy-in from our internal line management and discuss it with our CROs, service providers and also with the team that would be responsible for the work in responding to the list of questions and preparing the documentation," he explained.
In the end it was left up to the individual project team to decide whether or not to go for a VHP, and in two cases it was agreed to go ahead based on the pros and cons and if assessment of risk/benefit was positive.
However, Merck's experience of the procedure was that not all health authorities displayed the same level of commitment, nor did they all follow the approved time-lines. Also, in countries where the Ethical Committees take the lead it was difficult for the respective health authorities to contribute to the VHP. On the positive side, Schmitt said, the VHP provided Merck Serono with the opportunity to act as a partner and not as an applicant, and the CTFG accepted sponsor requests to introduce new ideas and suggestions.
On the whole, he concluded, the VHP is a valuable strategic tool to streamline implementation of multinational clinical trials in the EU. It achieved timely consolidated health authority approval based on good VHP-C/CTFG collaboration, and its fixed timelines enabled internal decisions and planning to be speeded up. The elimination of certain external activities, such as translation of questions and response documents reduced costs, and there was less strain on internal resources compared with the standard national submission process.
However, not every clinical trial is suitable for the VHP, and should be evaluated on a case-by-case basis.
The role of the CTFG
In 2004 the EU Heads of Medicines Agency (HMA) set up a clinical trials facilitation group (CTFG) to co-ordinate implementation of the EU clinical trials directive 2001/20 EC across the member states. The CTFG is attended by representatives from the NCAs, European Commission and the European Medicines Agency and acts as a forum for discussion to agree on common principles and processes to be applied throughout the European medicines regulatory network. It also promotes harmonisation of clinical trial assessment decisions and administrative processes across the national competent authorities (NCA).
The CTFG received a new mandate and terms of reference from the HMA, which was adopted in 2008. The group set out a two-year work plan encompassing the tasks:
- Sharing of scientific assessment of multinational clinical trials
- Harmonising processes and practices relating to clinical trials mainly in the fields of clinical trial applications (CTA), clinical trial amendments and safety procedures
- Developing data sharing and participating in the improvement of information systems
- Communicating with stakeholders and co-operating with other EU working groups
