Hum. Reprod. Advance Access originally published online on April 14, 2008
Human Reproduction 2008 23(6):1472; doi:10.1093/humrep/den116
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LETTERS TO THE EDITOR |
Ethical recruitment of patients for PGS trial
1 Centre for Reproductive Medicine, Barts and The London NHS Trust, 2nd floor, Kenton and Lucas Block, West Smithfield, London, UK 2 Institute of Health Sciences Education, Queen Mary's School of Medicine and Dentistry, University of London, London, UK 3 Academic Unit for Human Science and Medical Ethics, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK
4 Correspondence address. E-mail: ariel.zosmer{at}bartsandthelondon.nhs.uk
Ankum et al. (2008)
, members of a Data Safety and Monitoring Committee (DMC), defended their decision to allow investigators to continue to recruit patients for a study comparing conventional IVF against IVF plus preimplantation genetic screening (PGS) (Mastenbroek et al., 2007) in the face of masked interim data showing superiority of treatment A over treatment B (P = 0.02). They argued that if the study had been stopped for negative effect of PGS despite not reaching the preset threshold (P = 0.0052), the trial would have been dismissed by protagonists of PGS as having insufficient statistical power.
We note that the thresholds set by the DMC for stopping the study suggest that it gave equal weight to benefit and harm. This explains its decision to leave the interim data masked. Moreover, there is a strong impression that the study (Mastenbroek et al., 2007) took its point of departure to be the hypothesis that PGS affords benefit. We have some ethical reservations regarding both the decision to set symmetrical criteria for early termination of the study as well as the appropriateness of the DMC's justification for its decision in the case at issue.
It has been recommended that all randomized trials should be prepared for results with trends in either direction irrespective of how unlikely a negative trend may seem at the outset, and that a lower level of evidence should generally be required for early termination of trials due to negative trends, in particular when prior evidence of benefit is weak (DeMets et al., 1999).
We note that both the DMC (Ankum et al., 2008) and the investigators (Mastenbroek et al., 2007) stress that there was no prior evidence of benefit of PGS, at least as far as the primary and secondary outcomes of the study were concerned. Against this background, we wonder why the DMC set symmetrical thresholds for early termination of the study.
The Declaration of Helsinki states that—'in medical research on human subjects, considerations related to the well-being of the human subject should take precedent over the interests of science and society' (World Medical Association, 2004). It is our feeling that in setting symmetrical thresholds the DMC gave the interests of ‘science and society’ similar, if not greater, weight than to those of the study subjects. Equally, in justifying its decision it gave insufficient consideration to the obligation set by the Declaration of Helsinki. Considerations such as ‘convincing protagonists of PGS’, or even ‘the benefit to future patients’, should not be allowed to overshadow the interests of patients participating in clinical trials.
Finally, the information provided in both articles suggests that the institutional review boards and the Central Committee on Research Involving Human Subjects in the Netherlands may not have been aware of a planned interim analysis, let alone its details. Indeed, the DMC was established at the launch of the study (Ankum et al., 2008), and the interim analysis was planned two months thereafter (Mastenbroek et al., 2007). It is unclear how these institutions could have exercised their duty to protect the interests of the research subjects in the absence of such pertinent information.
References
Ankum WM, Reitsma JB, Offringa M. IVF with preimplantation genetic screening, a promising new treatment with unexpectedly negative health outcomes: the Hippocratic role of data monitoring committees. Hum Reprod (2008) 23:1–3.
Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NEA, Arts EGJM, de Vries JWA, Bossuyt PM, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med (2007) 357:9–17.
DeMets DL, Pocock SJ, Julian DG. The agonising negative trend in monitoring of clinical trials. Lancet (1999) 354:1983–1988.[CrossRef][Web of Science][Medline]
World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. (2004) Tokyo. Para A(5).
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