BMJ  2006;332:1405-1406 (17 June), doi:10.1136/bmj.332.7555.1405

Editorial

Consent for research in hyperacute stroke

Essential studies in the first six hours are hampered by rules on consent

Stroke accounts for 11% of deaths in England and Wales each year.¹ Without improvements in strategies for prevention or treatment in an increasingly ageing society the incidence of vascular events, particularly stroke, will increase by 33% by 2020.² Yet, according to the National Audit Office, "An emergency response to stroke with efficient and effective acute care is generally lacking."¹

Increased research capacity will be essential to developing such a response, and the recently established Stroke Research Network aims to develop this capacity to improve prevention, treatment, and rehabilitation in stroke. But recent European legislation may curtail participation by patients with stroke in such clinical trials.

The Medicines for Human Use (Clinical Trials) Regulations 2004³ implement the European Union Clinical Trials Directive (2001/20/EC),⁴ potentially restricting research with incapacitated adults. A considerable proportion of patients with stroke are unable to give informed consent owing to their neurological impairment. Most interventions in acute stroke have short therapeutic time windows, hence the maxim "Time is brain." Prolonged interruption of cerebral blood flow before intervention inevitably causes loss of neurones. To achieve maximum benefit, most experimental treatments must be given within three to six hours after acute stroke in the "hyperacute" period.

When a potential research participant lacks the necessary mental capacity to consent to participation in a trial, the regulations require informed consent to be given by a legal representative. Currently, English law does not cover the concept of such legal representation, nor does it recognise the notion of proxy consent. English law will change in this respect when the Mental Capacity Act 2005 comes into force, but this will not resolve the problem fully. The act does not define any family hierarchy, and thus there will still be uncertainty about who should take precedence when there is disagreement between family members.⁵ In a recent French study of 56 patients entering acute stroke trials, only 23 patients were able to provide consent.⁶ The responsibility for consent usually rested with relatives, of whom over half felt uncomfortable because of psychological stress induced by the need for urgent decision making.

Researchers argue that there is often insufficient time to identify a legal representative to provide consent before entering an incapacitated patient into a trial.⁷ Data from the Medical Research Council corticosteroid randomisation after significant head injury (CRASH) trial illustrate the delay incurred when proxy consent is mandatory.⁸ Time from injury to randomisation was just over one hour in hospitals allowing waived consent, compared with almost two hours in those where proxy consent was sought, and recruitment rates were lower in the group whose relatives were required to give such consent.

The requirement for proxy consent could jeopardise both the quantity and quality of future research on hyperacute stroke. A consultation document from the Medicines and Healthcare products Regulatory Agency (MHRA) last year suggested an amendment to the regulations which would provide an exception to this general requirement.⁹ But, even if the next of kin were able to act as legal representatives in this way, several ethical concerns will remain unresolved.

Is it wrong to recruit research participants with such acute medical problems?¹⁰ The International Conference on Harmonisation's tripartite guideline for good clinical practice requires that patients or relatives must be allowed time to consider all treatment options and the implications of taking part in a study, to ask questions, and to seek further advice if necessary.¹¹

In the hyperacute phase, next of kin are often shocked and distraught to learn of their relative's potentially life threatening or severely incapacitating illness. The impact of anxiety and distress on the consideration of complex information regarding participation in research may be further complicated by the potential burden of guilt in making such a decision for a family member. Psychosocial issues, conflict of interests, or divergence between personal preferences and the likely preferences of the patient and other relatives may all influence such a representative's ability to decide. Refusal may protect patients from the risks of research but may also deny them potentially beneficial treatments. Giving primacy to individual autonomy leads to a default position that assumes that incapacitated patients would not wish to participate in research without personally giving prospective consent. But the ethical principles of beneficence or social justice justify arguing the contrary position, namely that citizens have a moral obligation or at least a civic duty to participate in medical research provided that safeguards against malpractice are in place.¹²

The proposed amendments by the MRHA⁹—currently out for consultation—will have substantial implications for the conduct of all research in the UK in the hyperacute phase of conditions which reduce mental capacity. In turn, this could affect subsequent health outcomes. This consultation exercise provides a chance to reconsider the ethics of including incapacitated patients in research and should be conducted with this in mind.

School of Population and Health Sciences, Faculty of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH
(lynne.stobbart{at}ncl.ac.uk)

School of Population and Health Sciences, Faculty of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH

Department of General Internal Medicine, Freeman Hospital, Newcastle upon Tyne NE7 7DN

Stroke Research Group, Institute for Ageing and Health, Clinical Research Facility, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP

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Competing interests: SL, HR, and GF participate in trials involving patients with acute stroke. GF and HR are director and deputy director of the UK Stroke Research Network. The authors are currently conducting research regarding the processes and practices of consenting patients to hyperacute stroke treatment studies. This work is partly funded by a Stroke Association Project Grant led by MM. LS is funded by the Department of Health National Coordinating Centre for Research Capacity Development.

References

1. National Audit Office. Reducing brain damage: faster access to better stroke care. London: Department of Health, 2005. www.nao.org.uk/publications/nao_reports/05-06/0506452.pdf (accessed 20 April 2006).
2. Hankey G. Vascular disease of the heart, brain and limbs: new insights into a looming epidemic. Lancet 2005;366: 1753-4.[Medline]
3. Medicines for Human Use (Clinical Trials) Regulations 2004. www.opsi.gov.uk/si/si2004/20041031.htm
4. The European Union (2001) Directive 2001/20/EC of the European parliament and the council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementations of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official J Eur Communities 2001:L121/34. http://eudract.emea.eu.int/docs/Dir2001-20_en.pdf
5. Mental Capacity Act 2005. Elizabeth II. Chapter 9. London: Stationery Office, 2005.
6. Demarquay G, Laurent D, Nighoghossian N, Adeleine P, Philippeau F, Honnorat J, et al. Ethical issues of informed consent in acute stroke. Cerebrovasc Dis 2005;19: 65-8.[CrossRef][ISI][Medline]
7. Spohr F, Arntz HR, Bluhmki E, Bode C, Carli P, Chamberlain D, et al. International multicentre trial protocol to assess the efficacy and safety of tenecteplase during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest: the thrombolysis in cardiac arrest (TROICA) study. Eur J Clin Invest 2005;35: 315-23.[Medline]
8. CRASH Trial Management Group. Research in emergency situations: with or without relatives' consent. Emerg Med J 2004;21: 703.[Abstract/Free Full Text]
9. Medicines and Healthcare products Regulatory Agency. Consultation on amendment to the Medicines for Human Use (Clinical Trials) Regulations 2004. London: Medicines and Healthcare Products Regulatory Agency, 2005.
10. Maltby J, Eagle C. Informed consent for clinical anaesthesia research. Can J Anaesth 1993;40: 891-6.[Abstract/Free Full Text]
11. ICH [International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use] Steering Group. ICH harmonised tripartite guidelines for good clinical practice. Richmond: Brookwood Medical Publications, 1996.
12. Harris J. Scientific research is a moral duty. J Med Ethics 2005;31: 242-8.[Free Full Text]

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