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The paper by Roth and colleagues1 on a randomised controlled trial of BCG revaccination in Guinea-Bissau highlights the importance of conducting vaccine trials in developing countries as well as the ethical difficulties faced by investigators in these settings. Guinea-Bissau has an infant mortality rate of 117 per 1000 live births, the fifth highest rate in the world.2 The best hope for substantial improvements in child health comes from public health interventions, including effective vaccine programmes. Vaccine efficacy might be lower in developing countries because of poverty and malnutrition. Once the efficacy of a vaccine is established, however, it is commonly assumed that it will confer a proportional survival benefit. The results of the BCG revaccination trial show that non-vaccine factors might undermine this assumption, and the authors conclude correctly that trials should examine the impact of vaccines on survival.
There are many ethical challenges facing investigators conducting vaccine trials in developing countries.3 These challenges include the need for appropriate ethical review, choosing a suitable control, the provision of ancillary care to participants, and obtaining valid informed consent. By and large, the authors have met these challenges. The trial was approved by the Danish central ethics committee and the Guinean Ministry of Health’s research coordination committee. The choice of a placebo control in the trial is consistent with the ethical requirement of clinical equipoise because the effect of BCG revaccination on survival in this setting was unproved and children in the study received all standard vaccinations.3 Additionally, for the duration of the study children were given access to medical consultations and essential drugs free of charge. Finally, procedures for obtaining informed consent were well conceived. In particular, use of field workers, verbal and written descriptions of the study, and inviting mothers to bring their child to the local health centre seem likely to enhance both comprehension and the voluntary nature of participation.
The trial’s lack of a data monitoring committee and formal stopping rules, however, is scientifically and ethically problematic. The authors “did not have sufficient funding for a data monitoring and safety board” and instead the senior author performed an informal analysis of mortality data on a quarterly basis. The need for a data monitoring committee and formal stopping rules is well accepted for trials in which mortality or serious morbidity is likely. The role of the committee is to “safeguard the interests of study patients. . . [and] to preserve the integrity and credibility of the trial.”4 The informal mechanism used by the authors serves neither of these ends adequately. In the absence of formal stopping rules, repeated checks of mortality data increase the probability of a false positive result, thereby undermining the credibility of the trial. Furthermore, the interests of participants can be adequately protected only by the review of accumulating data by a committee whose members have no vested interest in the trial. While the conduct of vaccine trials in developing countries is challenging for many reasons, lack of funding is not an acceptable reason for a study not to have a data monitoring committee. If anything, the multidimensional vulnerability of trial participants in developing countries renders the need for such oversight more pressing.
Competing interests: The author has completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that all authors had: (1) No financial support for the submitted work from anyone other than their employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; (4) No Non-financial interests that may be relevant to the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.
Cite this as: BMJ 2010;340:c1373