Clinical trials and tribulations
Authors: P. Canter, E Ernst
Journal: Journal of the Royal Society of Medicine (2004)

Clinical trials, particularly those which are not commercially funded, are fast becoming an endangered species.1 The red tape involved in getting a clinical trial off the ground might stretch from London to Helsinki, and a EU Directive2 means that it could soon take in a tour of Brussels on the way back. The aim of the Directive, which has to be implemented in the UK by May 2004, is quite worthy—`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'.3 Unfortunately, those who made the rules were preoccupied with commercial research, at the expense of academically led clinical research of the sort to which we owe many of the big advances in medicine. Because the Directive was drafted with the commercial sector so much in mind, there is a threat that in future only the major pharmaceutical companies will have the money, time, person power and motivation to stay the distance and surmount the hurdles.

What are the implications of the Clinical Trials Directive for a small independent research unit such as our own? The flow diagram on the Medicines Control Agency website [www.mca.gov.uk/ourwork/licensingmeds/types/clintrialdir.htm], designed to help us understand the Directive, places funding at the beginning; and our research governance advisor tells us that the local research ethics committee will increasingly confine its work to applications with secured funding. However, before our protocol can be submitted to the ethics committee it must undergo an independent scientific review. This review and the ethics committee can both suggest amendments before approval can be given. These two different sets of `suggestions' will not necessarily concur and, even if they are reconcilable, the protocol which originally secured funding may well no longer apply. The funding application itself has probably gone through two rounds—an outline application and a full application, each of which had to wait for the next committee meeting of the funding body. So from the researchers' and the funders' point of view it would seem preferable to go to independent scientific review and ethics before seeking funding, and indeed some funders require that protocols already have ethics approval. No local research ethics committee applications without funding and no funding applications without ethics approval: does anyone detect a Catch 22?

The Directive requires that, in parallel with the ethics application, independent scientific review and funding application we must also apply to the Medicines and Healthcare Products Regulatory Agency (MRHA) for clinical trial approval. For our unit there is an added complication, in that the product concerned may well be a herbal extract, defined under the terms of the Directive as an `investigational medicinal product', and this must be manufactured at a licensed site under Good Manufacturing Practice conditions and authorized by a `qualified person'—further regulations with cost implications and requiring the cooperation of a manufacturer or other laboratory. Furthermore, according to the Directive, we have to persuade senior people in our medical school to act as `sponsor' for the trial and to take legal responsibility for monitoring it under the terms of Good Clinical Practice. Remember that this is all in the context of convincing funders and scientific reviewers that the trial is scientifically valid. Collectively, all this preparatory work can take well over a year; so who is going to fund the preparatory work? The answer, usually, is nobody. Researchers are tacitly expected to do all this in their `free' time or `steal' time from another funded project—the former not reasonable, the latter not honest. Considering all this, the outlook for clinical research is indeed gloomy.

If the Clinical Trials Directive is potentially so damaging to non-commercial, academically led, patient-focused research, can any action be taken at this late stage? The choice lies between reform and repeal. The Chief Executive of the MHRA3 points out that agreement has yet to be reached within the EU on either what constitutes `good clinical practice' or the guidance on pharmacovigilance, and the impact of the Clinical Trials Directive will depend on the scope for discretion under these headings. If the rules could be made proportionate to risk, some of the objections will melt away. Think, for example, of the widely sold herbal remedy whose efficacy we wish to test: such investigations are clearly different in kind from work on a novel chemical. Another argument for reform rather than repeal is that the Directive includes many elements that are clearly in the interests of researchers and the public. But arrayed against the reformers are those throughout the EU who judge the Directive too flawed for satisfactory amendment and thus a grave threat to clinical science. They make up an imposing body: a petition under the heading Save European Science, launched early last December, had within eight weeks attracted support from sixteen international research groups and more than 2300 individuals. An earlier press release [www.saveeuropeanresearch.org/8thJan2003.doc] outlined the threat to research even in mainstream areas where the `sponsor' will be required to take on all legal and financial responsibility, even to the extent of paying for routine treatments that are not being tested in the trial. The most telling argument, perhaps, is that `Little was wrong with the processes of academic or investigator led research... in the first place'.4 For those JRSM readers who wish to add their names to this petition, the website is [www.saveeuropeanresearch.org].