The Unintended Consequences of Clinical Trials Regulations

McInnes GT (2009) The Unintended Consequences of Clinical Trials Regulations. PLoS Med 6(11): e1000131. doi:10.1371/journal.pmed.1000131 The Unintended Consequences of Clinical Trials Regulations Alex D. McMahon 0 1 David I. Conway 0 1 Tom M. MacDonald 0 1 Gordon T. McInnes 0 1 0 Abbreviations: GCP, good clinical practice; ICH, International Conference on Harmonisation; MHRA, Medicines and Healthcare Products Regulatory Agency 1 1 Dental School, Faculty of Medicine, University of Glasgow , Glasgow, Scotland , 2 Ninewells Hospital & Medical School, University of Dundee , Dundee, Scotland , 3 Gardiner Institute, Faculty of Medicine, University of Glasgow , Glasgow, Scotland Summary Points N Trial regulations are damaging noncommercial research and patients. N The International Conference on Harmonisation (ICH) version of Good Clinical Practice (GCP) is inapplicable to most noncommercial research. N ICH GCP is not usually legally binding (as conceded by the regulatory authorities in the UK). N Other parts of the world should learn a lesson from the misguided trial regulations that have been created in Europe. - The experience of clinical researchers worldwide indicates that a major obstacle to undertaking academic research is the ever-increasing bureaucracy attached to the process. Recent changes in research governance were intended to ensure that clinical trials are safe and informative. However, the regulatory burden is now obstructing high quality science and has become the biggest single threat to research carried out in academia [1]. We illustrate here this international problem by reference to the regulations imposed by the European Union and the incorporation of these restrictions into UK national law concerning Good Clinical Practice (GCP). GCP sounds like a sensible idea that all researchers would aspire to. However, it used to have a technical meaning in the pharmaceutical industry when attempting to license new pharmacological entities with government agencies such as the Food and Drug Administration in the US. This technical meaning was to follow (specifically) the International Conference on Harmonisation (ICH) document on GCP [2], to facilitate the conduct of multinational drug trials sponsored by the pharmaceutical industry. The harmonisation process was developed over many years by the industry. ICH GCP and the attendant regulations apply to medicinal products for human use only. Nonmedicinal treatments such as psychological interventions and surgery are exempt. There are serious concerns that the onerous procedural requirements for data management and documentation stipulated by ICH are deterring academic research where registration of a new pharmaceutical entity is not an objective. The rigid bureaucracy of GCP as defined by ICH has already been recognised as an impediment to clinical research, resulting in The Policy Forum allows health policy makers around the world to discuss challenges and opportunities for improving health care in their societies. an effect opposite to that originally envisaged [3]. The ICH guideline on GCP provides extremely detailed instructions on data management and reporting of trials, as would be appropriate for drug companies seeking to license a new pharmaceutical entity with the relevant drug agencies. The true purpose of GCP, based upon foundations in the original Declaration of Helsinki, is to protect patients from unethical research, ensure that patients provide informed consent, and to conduct all trials to the highest possible standard. Few would dispute the need to incorporate the highest standards of GCP in all clinical trials, but does full application of ICH facilitate this goal? Unfortunately the standards of ICH GCP have been rolled out across Europe for all trials of medicinal products in humans in a series of regulations. Regulation in Europe By May 2004, The European Directive 2001/ 20/ EC on clinical trials (The Directive) had been adopted across the European Union [4]. Implicit in the title of The Directive is the implementation of GCP and articles of The Directive include informed consent, ethics committees, reporting of adverse events, and national inspection of trials. The Directive was incorporated into the law of the United Kingdom in the Medicines Act [5] and is described on the Medicines and Healthcare Products Regulatory Agency (MHRA) website [6]. The conditions and principles of GCP which apply to all clinical trials are based on the ICH guideline. The European Directive 2005/28/EC attempts to provide more detailed guidelines on GCP [7]. This GCP Directive instructs that the ICH guideline on GCP should be taken into account. The content of this directive appears advisory rather than prescriptive. Whether it was intended for academic clinical trials to be included is uncertain. The Medicines Act stipulates only the general principles section of ICH rather than the more detailed sections [5,6]. The GCP Directive states that noncommercial research as carried out by public bodies can make the application of certain of the details of good clinical practice unnecessary or guaranteed by other means, with member states providing for specific modalities. However, the eventual draft guidance mainly discusses treatment labelling and trial documentation [8]. Following the 2005 GCP Directive, the UK Medicines Act had to be amended. The first amendment (August 2006) mainly addressed technical matters such as document handling and payment of fees to MHRA but with no mention of taking into account the ICH GCP document [9]. The second amendment (December 2006) was specifically designed to enable trials in emergency medicine where informed consent could not be obtained from an incapacitated patient [10]. Explanatory memoranda for both amendments are on the MHRA website [11,12]. When queried, the MHRA clinical trials helpline () made the following statements: ICH is the standard expected by the CHMP for trials used for centralised licensing submissions; ICH is only mentioned in the recital of European Directive 2005/28/EC. The recital is not legally binding; Some member states chose to make ICH GCP their legal standard the UK did not. Despite this, trial centres in the UK are being aggressively audited to ICP GCP standards. The academic and public research communities were alarmed at the prospect of the directive of May 2004 [1317]. These regulations were clearly created for the benefit and/or regulation of the pharmaceutical industry [18,19], and it was inevitable that the number of noncommercial trials would decrease [20]. It was also anticipated that the pharmaceutical industry itself would avoid the extra costs by moving trials out of Europe and into less developed countries [21]. The potential problem for noncommercial research was clearly recognised by the MHRA, which appeared powerless to intervene [22]. A second GCP Directive followed and three UK laws were passed to implement these Directives. Th (...truncated)