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EDITORIALS: Gorm Boje Jensen and John Hampton Early termination of drug trials BMJ 2007; 334: 326 [Full text]

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Patients' perspective highlights ethical dimension of drug trial termination

Jennifer M Coleman, David Legge, La Trobe University; David R. Cairns, Macquarie University   (13 March 2007)

Patients' perspective highlights ethical dimension of drug trial termination 13 March 2007
Jennifer M Coleman, Clinical Nurse Consultant - MS Trials Co-ordinator Dept of Neurology, Austin Health, Studley Road, Heidelberg. Vic. 3084. Australia, David Legge, La Trobe University; David R. Cairns, Macquarie University Send response to journal: Re: Patients' perspective highlights ethical dimension of drug trial termination	Jensen and Hampton(1) draw attention to the difficult choices data and safety monitoring boards face in deciding whether to terminate a drug trial. One important dimension of prematurely terminated drug trials not considered by Jensen and Hampton is that of the impact early termination has on participants. We explored this dimension in an interview study(2) of 21 participants in a phase III trial of a multiple sclerosis treatment, prematurely terminated because of unexpected mortality. In spite of a rigorous informed consent process which had included warning patients prior to enrolment that the study may be discontinued for any reason, only a minority (24%) of participants was unperturbed by the reality of the trial’s sudden termination. The responses of the remainder: marked disappointment (43%), considerable distress (29%) and suspicion (5%); demonstrated a compromised ability to take an objective, philosophical view of the trial’s unexpected outcome. When asked to cease the study drug some participants overtly or covertly refused. Some subjects investigated independently obtaining an ongoing supply of the drug, some avoided research staff to delay relinquishing the drug. Anger and resentment about having no say in whether the trial continued were observed. Some patients were perturbed by the fear (or reality) of increased disease activity when the drug was ceased. That a clinical drug trial could be terminated without warning, in spite of early results showing promise, was a tough lesson for research participants to learn first hand. That an experimental drug could be peremptorily withdrawn regardless of the preparedness of individual research subjects to risk serious side effects was, similarly, a difficult realisation, in some instances compounding pre-existing frustrations about a lack of personal control over their circumstances. Data and safety monitoring boards are charged with responsibility for decisions that protect research patients from harmful treatment effects but which, in effect, potentially extinguish hope of access to innovative drugs. Members of such boards can take little comfort from our observation that apparent understanding by research subjects at the outset that a clinical drug trial may be terminated, does not ensure acceptance of this as an outcome. Our observation, however, reinforces the crucial need for these boards to function independently and employ the highest standard of clinical and statistical expertise. The ethical principle of respect for persons is embodied in recognition of a person’s autonomous right to take the risks associated with participating in a clinical trial. It is upheld in the course of a trial, but only insofar as these risks of harm are not considered to be too great by others who have responsibility for the safety of research subjects. When the prerogative to discontinue a clinical trial is exercised and it is terminated early due to the discovery of an unacceptable risk of adverse effects, nonmaleficence (the moral duty to do no harm) has been the over-riding ethical principle. The recommendation that membership of a data and safety monitoring board be recognised as equivalent to co- authoring (1) can, therefore, be supported for the ethical as well as the scientific merit of the decision-making that is a requirement of such membership. References 1. Jensen GB, Hampton J. Early termination of drug trials: What are the ramifications for drug companies and drug safety monitoring boards? BMJ 2007;334:326 (17 February) 2. Coleman JM, In Spite of Informed Consent: limitations of human research ethics processes when a clinical drug trial is abruptly terminated. Unpublished thesis; School of Public Health, La Trobe University. 2005 Competing interests: None declared