Hum. Reprod. Advance Access originally published online on April 14, 2008
Human Reproduction 2008 23(6):1472-1473; doi:10.1093/humrep/den117
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LETTERS TO THE EDITOR |
Reply: Ethical recruitment of patients for PGS trial
1 Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, The Netherlands 2 Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, The Netherlands 3 Department of Paediatric Clinical Epidemiology, Academic Medical Centre, University of Amsterdam, The Netherlands
4 Correspondence address. E-mail: w.m.ankum{at}amc.uva.nl
In their response to our paper, Zosmer, Epstein and Al-Shawaf have expressed ethical reservations regarding both our decision to set symmetrical criteria for early termination of the preimplantation genetic screening (PGS) trial, as well as the appropriateness of our justification for doing so (Mastenbroek et al., 2007
; Ankum et al., 2008).
Whenever promising new treatments have already been adopted by the field and have been implemented into daily care without randomized trials justifying this course of action, a situation may arise where the question as to which treatment should be regarded as being ‘experimental’ and which one as ‘standard care’ has reversed or has even become irrelevant. Not the old type of management is the one to beat, but the new one which has already been adopted as being the new standard. This situation occurred at the onset of PGS trial, when it had already been suggested that performing IVF without PGS was unethical (Gianaroli et al., 1997, 2005; Munné et al., 1999, 2003, 2006; Kahraman et al., 2000). For this reason, we made a strong plea in our discussion paper underlining the prerequisite of having randomized data before new treatments are being adopted in general practice.
As Data Monitoring and Safety Committee (DMSC) members, we decided to adopt symmetrical criteria for early termination at the interim analysis. This equally valued direct and indirect benefits and burdens for trial participants and those for future patients and society. We acknowledge the authors' ethical reservations in these matters, and would indeed have set different criteria for early termination if the present study had not been performed as a post hoc randomized controlled trial. We strongly believe that, given these circumstances together with the O'Brien–Fleming criteria which were not met at interim analysis, continuation of the PGS trial was indeed justified (O'Brien and Fleming, 1979). Consequentially, this allowed us to speculate on various subjects, e.g. ‘convincing protagonists of PGS’ and ‘the benefit of future patients,’ without crossing the ethical borders set by the declaration of Helsinki, neither in our responsibilities as DMSC-members nor in writing our discussion paper for Human Reproduction.
We would like to stress that the situation in the PGS trial differed fundamentally from those circumstances, where a new treatment is truly experimental and has not yet been adopted in general practice. If the chance of an experimental treatment being superior crumbles as the study progresses in such a trial, it would indeed be unethical to continue, especially when vital outcomes are at stake. But even then the decision to unmask treatment allocation at interim analysis and to truncate the trial prematurely would still bear the risk of regrets later on, since interim findings may have resulted from sheer coincidence after all (Montori et al., 2005).
After publication in the New England Journal of Medicine, the final results of the PGS trial have inspired the current discussions on the status of PGS as part of IVF programs (Munné et al., 2007). This has led to a situation where new international trials on the same subject are being seriously considered in order to try and refute its findings. Only the large size of the PGS trial, the fact that differences were statistically significant and have been published in a high ranking medical journal, seem to have convinced protagonists of PGS that new trials would probably be unethical, thereby benefiting many future patients. For certain, stopping the PGS trial prematurely would have led to many more patients being exposed to PGS.
We thank the authors for their contribution to this discussion and for bringing these matters to our attention, which has given us the opportunity for this response.
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.
Gianaroli L, Fiorentino A, Magli MC, Garrisi J, Ferraretti AP, Munné S. Preimplantation genetic diagnosis increases the implantation rate in human in vitro fertilizitation by avoiding the transfer of chromosomally abnormal embryos. Fertil Steril (1997) 68:1128–1131.[CrossRef][Web of Science][Medline]
Gianaroli L, Magli MC, Ferraretti AP, Tabanelli C, Trengia V, Farfalli V, Cavallini G. The beneficial effects of preimplantation genetic diagnosis for aneuploidy supports extensive clinical application. Reprod BioMed Online (2005) 10:633–640.[Web of Science][Medline]
Kahraman S, Bahçe M, 
amli H, Ïmirzalho
lu N, Yakisn K, Cengiz G, Dönnez E. Healthy births and ongoing pregnancies obtained by preimplantation genetic diagnosis in patients with advanced maternal age and recurrent implantation failure. Hum Reprod (2000) 15:2003–2007.
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.
Montori VM, Devereaux PJ, Adhikari NKJ, Burns KEA, Eggert CH, Briel M, Lacchetti C, Leung TW, Darling E, Bryant DM, et al. Randomised trials stopped early for benefit. A systematic review. JAMA (2005) 294:2203–2209.
Munné S, Magli C, Cohen J, Morton P, Sadowy S, Gianaroli L, Tucker M, Márquez C, Sable D, Ferraretti P, Massey JB. Outstanding contribution: positive outcome after preimplantation diagnosis of aneuploidy in human embryos. Hum Reprod (1999) 14:2191–2199.
Munné S, Sandalinas M, Escudero T, Velilla E, Walsmsley R, Sadowy S, Cohen J, Sable D. Improved implantation after preimplantation genetic diagnosis of aneuploidy. Reprod BioMed Online (2003) 7:91–97.[Medline]
Munné S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, The Referring Centres PGD group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril (2006) 85:326–332.[CrossRef][Web of Science][Medline]
Munné S, Gianaroli L, Tur-Kaspa I, Magli C, Sandalinas M, Grifo J, Cram D, Kahraman S, Verlinsky Y, Simpson JL. Substandard application of preimplantation genetic screening may interfere with its clinical success. Fertil Steril (2007) 88:781–784.[CrossRef][Web of Science][Medline]
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics (1979) 35:549–556.[CrossRef][Web of Science][Medline]
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