A note on zelen randomization

LETTERS TO THE EDITOR A NOTE ON ZELEN RANDOMIZATION: ATTITUDES OF PARENTS PARTICIPATING IN A NEONATAL CLINICAL TRIAL I wish to congratulate Snowdon, Elbourne, and Garcia on their interesting and useful study [1]. However, I do feel that their conclusions (that patients, on balance, prefer conventional consent procedures) are unwarranted by the data. This and other points of interest are discussed below. A Zelen “single consent” trial is only potentially useful, ethically and statistically, if one treatment arm is routine, while the other is experimental and so not available routinely, but is widely seen as probably superior and hence preferable. In these circumstances there is no ethical or other requirement for personal equipoise of clinicians or patients; indeed if many patients were expected to be equipoised, a Zelen trial would not be a serious contender. The problem highlighted in Snowdon’s study, for those randomized to the experimental arm in a Zelen trial, of having to choose between experimental and routine treatments, is thus not likely to be difficult in practice. In any case, the option of withdrawing from the trial exists at any stage, so the same choice (and problem) is present if conventional randomization is used. Those few patients in the experimental arm of a Zelen trial who might be near equipoise, and find the prospect of a computer “choosing” the treatment comforting, could be offered this service. The group of people which may well have suffered most from conventional randomization in the ECMO trial studied by Snowdon are those parents whose child was randomized to routine management, and subsequently died. These parents had the potential availability of a probably superior experimental treatment “dangled” in front of them, but in the end found that it was not available to them after all. They may well feel that the experimental treatment could have saved their child. These parents had, possibly, the most to gain from a Zelen trial, which has as its principal advantage the avoidance of the provision of such “dangerous information.” But, for perfectly understandable ethical reasons these same bereaved parents were not included in Snowdon’s study. Nevertheless, in my view their absence makes it impossible to arrive at even a tentative conclusion about whether the parents, as a group, would have preferred a Zelen trial. My limited understanding of the literature on those who have suffered adverse outcomes, e.g., the bereaved, is that, if approached sensitively, many are helped by discussing related events and their feelings, so that there may in fact be no “ethical-no-go-zone” preventing research in this area. Some individuals might also draw comfort from the knowledge that they would be contributing to making future medical research more ethical. As several study participants pointed out, it is quite likely that knowledge of a Zelen trial would come to public attention some years later, and that those Controlled Clinical Trials 20:569–572 (1999)  Elsevier Science Inc. 1999 655 Avenue of the Americas, New York, NY 10010

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Letters to the Editor

in the routine treatment arm (or their relations) might be informed, or realize, that they had participated. Thus, even a Zelen trial cannot guarantee avoidance of exposure to “dangerous information.” A third option might be worth consideration. This is randomization without consent followed immediately in both arms by brief information about the trial, full information about the choices actually available (given the arm to which randomized), consent to whatever treatment is chosen, and consent to (nonroutine) follow-up. This may be better than either a Zelen or a conventional trial, as it can avoid offering any false hope of the experimental treatment to those randomized to conventional treatment, while avoiding the need for economy with the truth on the part of clinicians. An important aspect to this is that, in reality, treatments are rarely completely unavailable, even if experimental. If enough money or political clout is available to the patient, the treatment may also “magically” become available. Supplying the patient with limited information at the time gives patients the option of pursuing this possibility if they so desire. Whether the design described in this paragraph, which one might label an “open Zelen trial,” would be ethically preferable to “closed Zelen” and conventional trials requires field research as to which of the alternatives is least damaging to those affected. Some of the participants thought those in the routine treatment arm had an absolute right to be informed of the trial, although they recognized that the public are not informed on most other occasions when data relating to them are used — or indeed when policy decisions that (might) affect them are made. This raises some fundamental questions: if a patient’s treatment is not affected by a trial, and if only routine information is collected, is that patient’s informed consent necessary? Insisting that patients have a right to refuse to participate can, in some circumstances, lead to apparent violation of the researcher’s “rights.” For what is it, exactly, that these patients are denying in order to realize their refusal — either the act of randomization, or the use of routine data. But randomization that does not affect treatment is surely not the patient’s concern (it is something, if you like, that the researcher can do in the privacy of his or her own home!). An extreme example helps to illustrate the point: at this very moment I might be selecting people on the U.K. voting register (which is publicly available) to be prayed for (by myself). All the participants are to be tagged, so that I am informed if they die. (This is a public service provided by the registrar for births and deaths, at a cost.) This is surely my affair, and not something I need consent for? But I can just as easily randomize people to be prayed for or not; this is now a randomized trial, but still surely my affair? Suppose I now propose to offer the people for whom I am not praying a free health check. The trial might now be regarded as clinical, and as subject to changes required by an ethics committee. But the situation has not changed one iota for those in the “prayed-for” arm; so why should my proposals for them be subject to the desires of an ethics committee which might, for instance, insist on consent being obtained for all “participants”? David A. Braunholtz Senior Research Fellow Department of Public Health and Epidemiology

Letters to the Editor

571 Birmingham, UK PII S0197-2456(99)00036-7

REFERENCE 1. Snowdon C, Ebourne D, Garcia J. Zelen randomization: Attitudes of parents participating in a neonatal clinical trial. Control Clin Trials 1999;20:149–171.

REPLY We thank Dr. Braunholtz for his interest in our qualitative work looking at the views of those who actually participate in trials, rather than opinions expressed by nonparticipants. We did not say, however, that patients on balance prefer conventional procedures. What we did conclude was that parents in this study were evenly divided for and against the Zelen method but that, contrary to expectations, those in the conventional management arm were more likely to be in the latter group. We do agree with Dr. Braunholtz that this empirical work needs to be extended to a population who suffered an adverse outcome. In this particular study, although some 28% of the infants were classified as impaired or disabled at one year, no bereaved parents were contacted from either trial arm. The reasons for this have been given more fully in previous papers [1, 2], and were beyond our control. Partly to remedy this important gap in the literature, our current research in other neonatal trials does include interviews with bereaved parents, but it is too early to know whether their conclusions will differ from those with surviving children. Dr. Braunholtz mentions the possibility of giving information to all participants after randomization. We cannot currently address these theoretical conjectures empirically, but an analogous situation has arisen in another component of our ongoing research program. In this, not only are parents (and staff) interviewed as in the ECMO study, but also the clinician’s request to the parent for informed consent to enter the trial is tape-recorded in certain centers. For this part of the qualitative study, both the Multicentre and the Local Research Ethics Committees have approved a procedure whereby the clinician only asks briefly for oral consent before tape recording the informed consent discussion (in which full oral and written information about the trial is provided); further information about the qualitative study is given in a written form only afterward. This is because at a time when a baby is seriously ill and decisions about randomized treatments need to be made quickly, it was considered inappropriate and impractical to also ask for fully informed written consent about tape-recording, especially when full information would have to mention the trial before the parents had yet been introduced to the topic. After the information has been given, the parents can then decide without pressure of time whether they wish the tape to be used and whether they wish to be interviewed at some future point. This analogy to a Zelen design should not be stretched too far, however, as randomization as the basis of a decision to intervene is not present, and both options — to use or not to use the tape or to be followed up in an interview — are equally available. These issues are also germane to Dr. Braunholtz’s final theoretical example. In summary, our previous and current research, like other qualitative studies [3], seeks to explore in some depth a variety of concepts which arise out