Deficiencies in proposed new EU regulation of clinical trials

BMJ 2012; 345 doi: (Published 20 December 2012)
Cite this as: BMJ 2012;345:e8522

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In addition to the deficiencies outlined, as it stands the proposed EU regulation of clinical trials will stop emergency care research once again.

In 2004 the European Clinical Trials Directive(1), incorporating the ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH GCP) on clinical research was translated in to law across its member states(2). This set valid informed consent as the cornerstone of experimental research involving human beings. However, the Directive made no provision for consent in emergency situations, thus creating a formidable barrier to research in this setting. Member states were forced either to operate at variance with the Directive or to accept restriction in emergency care research.

The Directive has been acknowledged to have hindered the conduct of clinical trials across Europe thereby prompting the need to address this important issue(3). The EU have proposed a Clinical Trial Regulation which will replace the existing provisions of Directive 2001/20/EC3. The proposed Regulation includes provision for emergency care consent procedures with the intention of harmonising practice across Europe. However, as currently written, the criteria would once again prevent emergency care research. The proposed regulations specify that information about the clinical trial may be given after its start, and informed consent obtained subsequently to continue the clinical trial, provided that all of the following conditions are fulfilled:
(a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, it is impossible to obtain prior informed consent from the subject and it is impossible to supply prior information to the subject;
(b) no legal representative is available;
(c) the subject has not previously expressed objections known to the investigator;
(d) the research relates directly to a medical condition which causes the impossibility to obtain prior informed consent and to supply prior information;
(e) the clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject.

Criteria (a) and (b) could be conflicting. The first criterion (a) clearly specifies that it is the urgency of the situation that prevents the informed consent process from occurring. However, the second criterion (b) states that if a legal representative is available then deferred consent could not be used, even in an urgent (i.e. emergency) situation meeting criteria (a), as a representative would have to provide consent prospectively.
This does not take account of the practicalities of emergency care research and the need to consider the impact of a delay in treatment to obtain informed consent from an available representative, or on the ability of that representative to understand trial information and make a decision under intense emotional strain and severe time pressure(4 5).

Analysis of data from the Medical Research Council (MRC) CRASH Trial, a multicentre randomised controlled trial of corticosteroid administration in acute severe head injury, provides an estimate of the delay associated with the requirement for written consent(6-8). The authors convincingly argue that the need for urgent trial treatment, even in patients who are conscious and whose relatives are available, itself excludes the possibility of fully informed consent. They conclude that seeking consent in emergency care is actually unethical if consent procedures delay the start of trial treatment resulting in obscured or reduced treatment effects.

Two studies undertaken in paediatric emergency departments, one a quasi-randomised(9) and the other a randomised controlled trial(10) of anticonvulsants in acute convulsive seizures used deferred consent. Both studies received ethical support, were accepted by over 98% of participating families and their results have led to a change in practice throughout the UK.

Deferred consent has been found to be acceptable in most patient and carer surveys(11,12). Deferred consent raises ethical dilemmas such as how to handle the situation where the patient dies before deferred consent can be sought; and the potential that the decision to decline consent is associated with a patient’s outcome, which could create bias in the trial results and conclusions(13-15).

The proposed regulations should focus on the urgent need to treat as the requirement for deferred consent with the removal of clause (b), which relates to the presence of a legal representative. Regulations should also consider the ethical dilemmas outlined above. They should also address how to use data collected prior to deferred consent and whether the consent encompasses continuation in the trial only, or only the use of the data collected to that point.

The impact of the proposed Regulation needs broader discussion amongst the medical community. A public consultation is taking place and failure to respond will result in Regulations that will prevent research in emergency care.

1. DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. []. 2001.
2. Medicines for Human Use (Clinical Trials) Regulations. S.I. 2004/1031., 2004.
3. European Commission. Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC., 2012.
4. Lecouturier J, Rodgers H, Ford G, Rapley T, Stobbart L, Louw S, et al. Clinical research without consent in adults in the emergency setting: a review of patient and public views. BMC Medical Ethics 2008;9(1):9.
5. Maitland K, Molyyneux, S., Boga, Mwamvua., Kiguli, S and Lang, T. Use of deferred consent for severely ill children in a multi-centre phase III trial. Trials 2011;12(90).
6. Roberts I, Prieto-Merino D, Shakur H, Chalmers I, Nicholl J. Effect of consent rituals on mortality in emergency care research. Lancet 2011;377:1071-72.
7. Roberts I, Chalmers I, Shakur H, Prieto-Merino D, Nicholl J. Consent in emergency care research - Authors' reply. Lancet 2011;377:27.
8. Collaborators C-. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377:1096-101.
9. Appleton RE, Sweeney A, Choonara I, et al. Lorazepam vs. diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol 1995; 37:682-6.
10. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse W, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomized controlled trial. Lancet 2005;366:205-10.
11. Gamble C, Nadel S, Snape D, McKay A, Hickey H, Williamson P, et al. What Parents of Children Who Have Received Emergency Care Think about Deferring Consent in Randomised Trials of Emergency Treatments: Postal Survey. PLoS One. 2012;5(5):e35982.
12. Maitland K, Molyneux S, Boga M, Kiguli S, Lang T. Use of deferred consent for severely ill children in a multi-centre phase III trial. Trials, 2011:90.
13. Jansen T, Kompanje E, Druml C, Menon D, Wiedermann C, Bakker J. Deferred consent in emergency intensive care research: what if the patient dies early? Use the data or not? Intensive Care Med, 2007:894-900.
14. Jansen TC, Bakker J, Kompanje EJ. Inability to obtain deferred consent due to early death in emergency research: effect on validity of clinical trial results. Intensive Care Med 2010;36(11):1962-65.
15. Nichol G, Powell J, van Ottingham L, Maier R, Rea T, Christenson J, et al. Consent in resuscitation trials: Benefit or harm for patients and society? Resuscitation, 2006:360-68.

Competing interests: None declared

Carrol Gamble, Statistician

Kerry Woolfall, Bridget Young, Paula Williamson, Richard Appleton

The University of Liverpool, Clinical trials Research Centre, University of Liverpool, Liverpool, United Kingdom

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I thank P C Goetzsche very much for his carefull analysis of the new EU regulation of clinical trials. He missed however that there are serious deficiencies from an ethical and trial participant's point of view too.

The proposal of the EU Commission is fundamentally different from the requirements of the present EU Directive 2001/20/EC: a comprehensive and independent consideration and vote by a multidisciplinary, independent Ethics Committee is no longer required. This violates international guidelines and ethical codes, such as the Declaration of Helsinki of the World Medical Association, the Bioethics Convention of the Council of Europe and the WHO International Guidelines. These internationally recognized principles require the approval of an independent Ethics Committee, including an examination of whether the protection of the rights, welfare and safety, as well as self-determination of potential study participants is guaranteed. By eliminating the mandatory requirement of an independent review by the national competent Ethics Committee, this protection can no longer be sustained.

Driven essentially by competitive motives, Brussels is aiming to establish a centralized approval process for clinical trials with extremely shortened time-lines, as a European location advantage. The already existing short lead times from 30 to 60 calendar days are to be drastically reduced even further. For certain processes laid down in the proposal, requiring national and often also international coordination, deadlines of 3,4, 6, 10 and 25 calendar days are set. Time limits like these do not allow for an appropriate assessment of complex clinical trials and their associated risks and must be considered as irresponsible in neglecting the welfare and protection of clinical trial participants.Against the background that planning, execution and evaluation of multinational studies often extends over several years, is also incomprehensible that by shortening the already existing tight timescales, any significant location advantages are to be achieved.
The planned changes restrict patient protection and undermine public confidence in drug trials. Thus there is an urgent need to modify the EU proposal in a way that it complies with the current version of the Declaration of Helsinki

Competing interests: I am the president of the Permanent Working Party of Research Ethics Committees in Germany and lead participant in the European LeukemiaNet

Joerg Hasford, Medical Statistician, Physician

Arbeitskreis Medizinischer Ethik-Kommissionen in Deutschland e.V., Scharnitzerstr.7 D-82166 Graefelfing, Germany

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