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Tuesday, September 27, 2011

Calls for revision to the European Clinical Trials Directive continue to make news

In the Telegraph: EU regulations hindering drug development, say charities name a few - this is a theme we've been talking about with various organisations in the last year - indeed we've collaborated in the preparation of an introduction to European legislation's impact on clinical research which present for the first time here:

Overview: As with domestic legislation, there is a perception, and evidence to support it, that European legislation has had a negative effect on UK-based clinical research. A number of initiatives have reform in their sights.

The European Clinical Trials Directive and its interpretation in UK law have also contributed to the issues mentioned above in relation to the home market – namely time to initiation of and resource levels required for research: L J Frewer’s editorial in the BMJ (April 2010) Has the European Clinical Trials Directive been a Success? concludes that “Today, five years after implementation, evidence shows that the directive has had a negative effect on translational research.”[1]

This conclusion has been reached by several others in the last few years[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13]; although there are some dissenting voices[14], they are in the minority. The Academy of Medical Sciences’ report summarises the situation thus: “The broad scope and ‘one size fits all’ approach of the EU Clinical Trials Directive places an unnecessary regulatory burden on clinical trials of both new products and established drugs. The Medicines and Healthcare products Regulatory Agency (MHRA) provides timely authorisation of clinical trials but there are concerns about its interpretation of the EU Directive, the lack of consistent advice to investigators and sponsors, and the approach taken during some clinical trial site inspections. In combination, this situation is hampering clinical trials and discouraging academic and commercial health research sponsors from conducting their studies in the UK.”[15]

The EU-wide Impact on Clinical Research of European Legislation (ICREL) study sought to measure the impact of the Directive on key stakeholders between 2003 and 2007 and reported that non-commercial organisations had been obliged to nearly double their staff performing administrative tasks and pharmacovigilance as a result of the legislation.[16] Furthermore a Cancer Research UK study indicated that the Directive resulted in a doubling of the cost of running non-commercial cancer clinical trials in the UK, in addition to delaying the start of trials.[17]

The transposition of the Directive into UK law and its interpretation (perceived to be more stringent and less pragmatic than that of other EU states) have disadvantaged the UK as the Directive appears to have been implemented inconsistently across the EU: “The UK’s share of global patient recruitment into clinical trials fell from 6% to 2-3% between 2000 and 2006, while the share of the core EU Member States fell less dramatically from 21% to 14% during this period. The UK’s declining position is further exemplified by data that show the time taken to set up for phase III trials in the UK has been above the European average since 2006, and that in 2009, Germany recruited over 2.5 times more patients than the UK into Phase III trials. These data also show that the UK failed to recruit as many patients as France or Spain.”[18]

As with the impact of domestic regulation, the Academy’s respondents felt that there were no discernable improvements to patient safety or to the ethical basis of clinical trials as a result of the Directive.

Again, this appears to have been understood by funders. The MRC express their intent to “ensure that European Union (EU) and UK regulations, such as those set out by the EU Directive on Clinical Trials and NHS Research Governance, and interpretation of these regulations do not present unnecessary barriers to producing evidence about the safety and efficacy of treatments.” [19] The Academy of Medical Sciences’ report also recommends that the Department of Health and Department for Business, Innovation and Skills – supported by the MHRA and other stakeholders should seek to ensure that the Directive is revised to reduce its scope, ensure that its monitoring requirements are appropriate to risk and simplify its reporting requirements.[20]

Additionally, one of the stated aims of the European Clinical Research Infrastructures Network (ECRIN), an EU-funded programme, is to develop a European regulatory framework offering minimal obstacles to medical institutions through requirements adapted to the risk of the individual trial.

[1] L J Frewer, British Medical Journal April 2010: BMJ 2010; 340:c1862 editorial

[2] Meunier F, Dubois N, Negrouk A, Rea LA, Saghatchian M, Tursz T, et al. Throwing a wrench in the works? Lancet Oncol2003;4:717-9

[3] Moulton B. Save European research campaign. BMJ2004;328:286

[4] Hartmann M, Hartmann-Vareilles F. The clinical trials directive: how is it affecting Europe’s noncommercial research? PLoS Clin Trials2006;1:e13

[5] Bosch X. Europe’s restrictive rules are strangling clinical research. Nat Med 2009;11:1260

[6] Singer EA, Druml C. Collateral damage or apocalypse now for European academic research. Intensive Care Med 2005;31:271

[7] Elwyn G, Seagrove A, Thorne K, Cheung WY. Ethics and research governance in a multicentre study: add 150 days to your study protocol. BMJ2005;330:847

[8] Hemminki A, Kellokumpu-Lehtinen PL. Harmful impact of EU clinical trials directive. BMJ2006;332:501-2

[9] Keim B. Tied up in red tape, European trials shut down. Nat Med2007;13:110

[10] Hearn J, Sullivan R. The impact of the “clinical trials” directive on the cost and conduct of non-commercial cancer trials in the UK. Eur J Cancer2007;43:8-13

[11] Pritchard-Jones K. Clinical trials for children with cancer in Europe—still a long way from harmonisation: a report from SIOP Europe. Eur J Cancer2008;44:2106-11

[12] European Science Foundation. Investigator-driven clinical trials. 2008.

[13] Walker, E., Hankins, M. C. and White, S. M. (2009), The effect of the European Clinical Trials Directive on published drug research in anaesthesia. Anaesthesia, 64: 984–989. doi: 10.1111/j.1365-2044.2009.06011

[14] 4. Berendt L, Hakansson C, Bach KF, Dalhoff K, Andreasen PB, Petersen LG, et al. Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006. BMJ2008;336:33-5

[15] The Academy of Medical Sciences: A new pathway for the regulation and governance of health research

[16] Impact on clinical research of European legislation.]

[17] Hearn J and Sullivan R (2007) The impact of the “Clinical Trials Directive on the cost and conduct of the non-commercial cancer trials in the UK. European Journal of Cancer 43, 8-13.

[18] The Academy of Medical Sciences: A new pathway for the regulation and governance of health research

[19] From the MRC Strategic Plan 2009-2014, Strategic Aim Two – Regulation, ethics, governance and working with decision-makers:

[20] The Academy of Medical Sciences: A new pathway for the regulation and governance of health research

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