The European Unions’ Clinical Trials Directive
Authors: Alan Earl Slater
Journal: Journal of the Royal Society of Medicine (2001)

A European Union Directive1 published in May 2001 is generating mixed reactions in medical circles2,3,4,5. It aims to harmonize the ‘market’ for clinical trials on medicinal products—that is, the circumstances in which trials are conducted1. Unlike an EU Regulation, a Directive does not specify exactly how the results are to be achieved. For the Clinical Trials Directive, the necessary legislation in Member States must come into effect by 1 May 2004.

Enthusiasts see the Clinical Trials Directive as a step towards more uniform standards and greater transparency, whereby important new medicines will get to patients more quickly without compromise to safety, efficacy and quality. Europe, they say, will become a more attractive place to do clinical trials, with all the benefits that flow from this sort of research. Sceptics declare that the Directive came about without full and open consultation, that it adds an unnecessary layer of bureaucracy, that it vests too much power in centralized systems and that it distances patients and healthcare professionals from decision making. They argue that safety, efficacy and quality could even worsen, the desired harmonization will not be achieved and European countries will become less rather than more attractive settings for trials. So who is right?

Will the Directive result in a single EU market in clinical trials? No. It applies only to interventions with investigational medicines, so it does not cover the hundreds of non-drug clinical trials involving surgery, transplants, healthcare technologies, counselling, physiotherapy, psychotherapy, patient education and so on. Possibly, however, trials of this sort will get caught up in the new systems that Member States develop to come into line with the Directive. Will the Directive achieve a single market for clinical trials involving investigational medicines? Maybe. Even if the clinical trial systems in Member States were in complete harmony—in letter and spirit—the decisions in different Member States might not concur. Organizations and individuals wishing to conduct a trial are not obliged to apply in every Member State; nor does the Directive provide for an arbitration system when national differences emerge.

Will the Directive distance and disempower individual healthcare practitioners and patients from decision making? Yes and no. Under the Directive, trial applicants will require the approval of only a single ethics committee to start the trial in that Member State. For some, this is not quite new: in England a multicentre trial need be approved by only a single ethics committee to be conducted anywhere in the country. However, nobody is obliged to take part, and individual doctors, consultants and potential host institutions (e.g. hospitals, primary care groups) have to be convinced that, on balance, the trial is worth the effort of involvement. I predict a future where we shall see more emphasis on marketing of clinical trials to promote and sustain local enthusiasm and generate greater feelings of ownership.

To complicate matters, for trials planned to be conducted across various Member States, the applicants need to get approval from only one ethics committee in each State. Little thought seems to have been given in the Directive to circumstances where the trial application is successful in some Member States but not others. The numbers might then come out too low for adequate statistical power, in which case the trial could not ethically proceed. If, however, a trial is designed to take into account the possibility of a Member State not approving it, then the starting numbers are too high; it is over-powered. Would it then be ethical for anybody to approve it? What we may see in a few years' time is the evolution of a central EU body with the power to authorize the go-ahead of a clinical trial in all Member States—akin to the European Medicines Evaluation Agency system to which one can apply for a licence to market a drug anywhere in the European Union.

There is also a series of practical questions about what happens when an international trial is stopped, suspended, or completed at a certain time in one Member State but not in the others. Trials cannot be expected to progress uniformly between sites even in the same country, let alone in different countries. The Directive offers little guidance on how to handle this difficulty. But in another area, ethics committees, the Directive is remarkably prescriptive: these committees will be required to work to specific time-scales. For many countries this will be the first time that ethics committees have been constrained by deadlines. In general for a ‘legitimate application’ the committee will have 60 days in which to respond. Moreover, the Directive states that the committee can make only a single request to the applicant for more information. A likely reaction by some committees, I foresee, is to postpone declaring an application legitimate, so that during the ‘illegitimate time’ they can ask as many questions as they like and interact constructively with the applicant to improve and clarify issues of concern6.

Will the Directive create uniform standards? Yes, but only in certain aspects of clinical trials. For example the European Commission will, after consultation with Member States and as yet unidentified ‘interested parties’, draw up and publish detailed guidance on the application format and documentation to be submitted for ethics committee approval. There will also be guidance on the documentation to be submitted in support of quality and manufacture of the investigational product, the toxicological and pharmacological tests, the protocol and the clinical information in the investigators' brochure. Yet, in terms of informed consent, of the involvement of children, of liability and of data protection, it will be the individual Member States' laws and regulations that reign supreme. Unless these are harmonized there will be no uniformity of standards here.

Will the Directive get important new medicines to patients more quickly than before, without compromise to safety, efficacy and quality? Across the EU, and even within the same country, the reality is that access to medicines is not based solely on clinical criteria. The EU is a patchwork of systems where individual Member States retain and exercise their rights to put other hurdles in the path of a new drug. For example, in some countries detailed and prolonged negotiations are conducted on drug pricing and reimbursement. In the UK there is the National Institute for Clinical Excellence, which looks more widely at the clinical and cost-effectiveness of medicines and then provides recommendations to the whole National Health Service. Examination of the diffusion of new medicines in the EU indicates that they seldom reach Member States at the same time, and in certain markets a new drug never gains entry at all.

Finally, will the Directive make the EU a more attractive place to do clinical trials? In my view the answer fundamentally depends on how the individual Member States align their current systems to the new Directive6. If it is anything like how they align themselves to the EU's Transparency Directive, which deals with pharmaceutical pricing and reimbursement, then we can expect a mix of complex and sometimes contradictory systems, making the EU less attractive to trial sponsors than it is now. But if the spirit could be closer to that of the pan-EU licensing system, then the EU could in fact become a more attractive venue for clinical trials. The Clinical Trials Directive deserves much wider debate2,3,4,5, because the manner in which Member States comply with it has enormous implications for those who sponsor, conduct and host the trials and also for those who hope to benefit from their results6,7,8,9.