Implementing the European clinical trials directive

The European Union's clinical trials directive must be implemented in United Kingdom law by May 2004.¹ It is intended to simplify and harmonise the regulation of clinical trials across the European Union, thereby facilitating the internal market in medicinal products while protecting participants and public health. Yet some have expressed concern that it will actually impede and inhibit publicly funded clinical trials, a sector of research in which the United Kingdom has always been strong.^2-4 What are the contentious issues, and where do matters now stand?

The Medicines and Healthcare products Regulatory Agency (MHRA) is the regulatory body responsible for drafting the UK legislation to be laid before parliament early in 2004. In preparation for this the agency consulted widely in February 2003 and provided advice and a helpline via its website (http://medicines.mhra.gov.uk/ourwork/licensingmeds/types/clintrialdir.htm).⁵ The main concerns elicited were around the role and responsibilities of the sponsor of the trial, the delay and cost imposed by additional bureaucracy, and new requirements for good clinical practice, pharmacovigilance, and good manufacturing practice standards for investigational medicinal products.⁶,⁷ A joint project has been set up by the Department of Health and the Medical Research Council to help trialists and the Medicines and Healthcare products Regulatory Agency by documenting current best practice in these areas and to provide advice on systems and approaches that will comply with the law while minimising unnecessary burdens.⁸

The directive defines a sponsor as “an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial” and sets out the legal obligations of the sponsor. The model is clearly based on the industry context, where the company taking an innovative compound through its development programme is self evidently the sponsor. Non-commercial trials have usually operated on a different basis. The principal investigator, his or her employer (often a university), a funding body (which might be a charity, the Medical Research Council, or part of the NHS research and development programme) and a clinical host organisation (typically one or more NHS trusts) collectively take responsibility for various aspects of research governance. However the UK regulations are framed, there will need to be more explicit allocation of responsibilities between partner organisations. This is right in principle both for the protection of patients and the assurance of scientific rigour, though the details of how this is best achieved continue to be debated. Some concern has been expressed at the penalties to which the sponsor would be liable. These should be seen in the context of liabilities which already exist. To use an analogy, the introduction of compulsory testing of motor vehicles created a new penalty for driving a vehicle without a valid test certificate—but it reduced the larger risks, financial and physical, of driving on bald tyres.

For good clinical practice and pharmacovigilance, the appropriate level of supervision would be expected to differ for a drug undergoing first use in humans and a long marketed drug now being tested in a new indication. Such proportionality would answer many of the concerns raised about needless bureaucracy. Neither the directive on good clinical practice nor the guidance on pharmacovigilance has yet been agreed within the European Union. This has delayed the drafting of UK regulations, which will be influenced by the level of detail specified in the directive. The United Kingdom has a treaty obligation to transcribe the directive into national legislation, and thereafter it will be the task of the Medicines and Healthcare products Regulatory Agency to act as the regulatory body. Much will therefore depend on the degree of discretion permitted by the directive with regard to good clinical practice and pharmacovigilance.

If monitoring is made proportionate to risk, no logical basis exists for a different standard of supervision in commercial and non-commercial clinical trials. The directive makes no distinction between the two. More research staff with better professional training and support may be needed in some publicly funded research in order to safeguard quality and safety. The case for extra funds is best supported by an objective examination of the infrastructure needed to attain the required standard.

Research is an essential component of a high quality healthcare system, not an optional extra. Publicly funded clinical trials in the United Kingdom have made a large contribution to improved care. A wider debate is beginning on how clinical trials can be fostered in the NHS, and how therapeutic innovation can be encouraged and the research potential of the NHS better used.⁹,¹⁰ All research partners (investigators, universities, funders, and NHS organisations) have a shared interest in achieving high standards of research governance, but their procedures for doing so need to be better coordinated. Compliance with the directive will challenge us to review many details of current practice. Can we find ways of streamlining the initiation of trials without compromising patient safety?