Zelen Randomization

Zelen Randomization: Attitudes of Parents Participating in a Neonatal Clinical Trial Claire Snowdon, MA, Diana Elbourne, PhD, and Jo Garcia, MSc Medical Statistics Unit, London School of Hygiene and Tropical Medicine, University of London (C.S., D.E.); Centre for Family Research, University of Cambridge (C.S.); and National Perinatal Epidemiology Unit, University of Oxford, Radcliffe Infirmary, United Kingdom (D.E., J.G.)

ABSTRACT: Recruitment to randomized controlled trials can be difficult for all parties involved. An alternative to the standard process has been suggested for trials in which the control group receives standard treatment or nontreatment. In this approach (the Zelen design), randomization precedes consent, which is only sought from those allocated to the experimental arm of a trial. The control group is thus unaware that randomization has taken place. As a controversial method, this approach has been often suggested but rarely used. Here we describe how 44 parents recruited to a difficult neonatal trial that used conventional randomization reacted to the idea of Zelen randomization. The arguments they gave for and against the method pertain to four areas: the giving or withholding of information, the effect on decision making, the use of data without parental knowledge, and the long-term impact for parents. The parents were evenly divided in accepting or rejecting the method. Further analysis showed that those rejecting Zelen randomization were more likely to be parents of infants allocated to the control group. This suggests that those from whom consent would not be sought, the group that this approach is primarily meant to protect, are most likely to find it unacceptable. Controlled Clin Trials 1999;20:149–171  Elsevier Science Inc. 1999 KEY WORDS: Informed consent, randomization, ethics, clinical trials, attitudes, interviews

INTRODUCTION The giving of informed consent is a prerequisite to participation in most randomized clinical trials (RCTs). In theory, it is appropriate and desirable that consent is given; in practice, informing a person fully about medical uncertainty and about the random allocation of treatment can be difficult and distressing for all parties involved. These inherent difficulties are further exacerbated in specialties where patients or their proxies are already experiencing a high degree of emotional strain. Discomfort with the process of consent can lead to Address reprint requests to: Ms. C. Snowdon, Centre for Family Research, University of Cambridge, Free School Lane, Cambridge CB2 3RF. Received December 30, 1997; accepted September 7, 1998. Controlled Clinical Trials 20:149–171 (1998)  Elsevier Science Inc. 1999 655 Avenue of the Americas, New York, NY 10010

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Figure 1 Conventional randomization.

poor rates of participation among professionals and therefore slow or inadequate rates of accrual of patients [1–6]. Fully informed consent in some circumstances has been described as “needlessly cruel,” with a statement that “attempts to gain the ‘informed’ participation of patients in randomized clinical trials are already doing harm in many individual cases [7].” Problems with consent therefore have serious implications for the success of RCTs, for professional morale, and also for the well-being of the participants. Zelen addressed these difficulties by proposing a controversial departure from the conventional approach [8–12]. Ordinarily, a clinician informs potential participants about a trial, and if consent is given, randomization follows. If consent is withheld, the standard treatment options (including no treatment) will usually be offered (Figure 1). In Zelen’s design, the clinician randomizes before asking for consent, if asking for consent at all. Consent, where sought, is for the randomly allocated treatment and for trial participation but not for randomization. This method has been termed variously randomized consent design, prerandomization design, and postrandomization design. In this article, we use the term “Zelen randomization.” Two types of Zelen designs exist: “single consent” and “double consent.” In the single-consent design, the patients allocated to the control arm of the trial are not asked for consent—they simply receive the standard treatment without mention of the trial. Clinicians ask those allocated to the experimental arm of the trial whether they consent to receive the experimental treatment. If they decline, they may be receive the standard (or another) treatment (Figure 2). The double consent design differs in that the patients allocated to the control arm are asked for consent for the standard treatment and those among them who decline may receive the experimental (or some other) treatment. Those allocated to the experimental arm are asked for consent for experimental treatment. If they decline, they may receive standard (or some other) treatment (Figure 3). Zelen’s designs are limited in that they are applicable only to certain trials. The single consent design is suitable only when the experimental treatment is

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Figure 2 Zelen randomization, single-consent design.

compared with a best-known standard treatment. For a treatment to be considered experimental, it is unlikely to have been fully evaluated. So in this study, we concentrate on the situation in which the experimental treatment is only available within the trial, although the double consent design is suitable only when the experimental treatment is also available outside the trial. Trials that use the Zelen approaches cannot be “blind” because the clinician is made aware of the treatment allocation to approach patients for consent to receive that specified treatment [13]. An assessment can, however, be made blind to allocation. Finally, trials requiring the active cooperation of the patient in a nonstandard protocol or follow-up are inappropriate when patients have not consented to participation. Although there has been wide discussion of Zelen randomization, only a few trials are known to have used it, and most were conducted in the United

Figure 3 Zelen randomization, double-consent design.

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States [for reviews, see 12, 14, and 15]. Some use cluster randomizations [e.g., see 16], and we do not list these here. Most are in the field of cancer [17–31], but there are also examples from osteoarthritis [32] and neonatology [33, 34]. Zelen randomization has ethical and statistical advantages and disadvantages. Its appeal lies in the fact that in difficult circumstances a clinician need not ask for consent for the trial or for randomization, only for treatment. When stress levels are high, such simplification could ease both information giving and decision making. It might also improve rates of accrual, and therefore statistical power, in trials in which recruitment might be difficult. This might be because it leads to options that could be more acceptable to some patients and clinicians, but mainly because its design is weighted to include those who might otherwise have refused. In a conventional trial, all consenting patients are followed-up in an intention-to-treat-analysis; that is, they are analyzed in accordance with their allocation, regardless of whether they actually go on to receive the allocated treatment [35]. In Zelen’s designs, all randomized patients are followed on an intention-to-treat basis. All data are therefore appropriate for analysis as, in both of Zelen’s designs, trialists may analyze data even from those who decline the offered treatment. Concerns about Zelen randomization arise from the fact that consent for randomization is not given in advance by any patients and that consent for treatment on protocol is not given by all. A proportion of the patients remain unaware of their role and are automatically included in the trial. The remainder have no explicit option to refuse to participate. Although it is widely accepted that patients whose data are used in epidemiologic studies are not necessarily informed of their roles in research, the acceptability of research without consent is less clear for RCTs. Of particular concern is the fact that not all patients are told that their treatment is chosen by chance [36, 37]. Moreover, there may be statistical concerns over bias. If, for instance, the experimental group of patients are required to attend for more follow-up than the control group, their relapses may be detected sooner. Lack of blinding may cause differential provision of concomitant treatments and/or differential recruitment into the two treatment arms. The largest statistical problem may be a reduction in power where an intention-to-treat analysis is used, the very concern that Zelen randomization aims to address. Power may be lost because of a dilution effect if a large proportion of patients reject their allocated treatment (termed crossover or transfer). Theoretical and empirical studies have shown that reduction in power resulting from crossover can be considerable, and the problem is compounded if the extent of dilution differs between the two trial arms [38–40]. Because trialists cannot usually know the extent of crossover in advance, sample size calculations can be underestimated. Although ethicists and statisticians have discussed the use of Zelen randomization, an important perspective is clearly missing from the debate: that of the participants themselves. Although studies have considered the views of healthy volunteers, [41] no evidence has yet demonstrated how those with experience of trials feel about the Zelen approach. This article describes the responses to Zelen randomization from parents who had consented for their critically ill infants to participate in a conventional

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neonatal trial in which informed consent preceded random allocation of treatment. RCTs in such circumstances are of particular interest, because they inevitably involve persons who are extremely stressed. Parents are not only concerned for the well-being of their sick infants but are often within days or even hours of their birth and any associated traumas. They may be physically exhausted or deprived of sleep, and the mothers may be experiencing the effects of pain-killing or sedative drugs. Some have argued that consent for neonatal trials is not only difficult to obtain but may be inadequate, amounting to “an elaborate ritual” [42] or a “sham” [43]. In such a context, Zelen’s approach has been seen as appropriate [43]. THE UK COLLABORATIVE TRIAL OF EXTRA CORPOREAL MEMBRANE OXYGENATION The UK Collaborative Trial of Extra Corporeal Membrane Oxygenation (The ECMO Trial) compared two methods of life support for mature neonates with acute but potentially reversible respiratory failure. The infants recruited to the trial were at high risk of death. At randomization they were already in a neonatal intensive care unit and receiving ventilatory support (“conventional management” or CM), one of the two methods the trial evaluated. Researchers compared CM to oxygenation of the blood via an external circuit (ECMO). Treatment using ECMO usually involved transportation of the infant, sometimes by air ambulance, to one of five specialist centers. As an unevaluated treatment, neonatal ECMO was only available within the trial. Discussion of procedures for recruitment involved parents’ groups at an early stage of considering the trial. These discussions included the possibility of Zelen randomization, especially because the two previous trials that had been conducted in the United States had used it [33, 34]. As these trials had been small and unusually designed in other ways, the findings were not easy to interpret. The ECMO trial team decided to use conventional recruitment, with consent preceding randomization. Recruitment took place from January 1993 to November 1995 in over 80 centers. Of the 185 trial infants involved, 101 survived to 1 year. Of those who died, 30 were allocated to ECMO and 54 to CM. Among the survivors, one infant in each treatment arm was severely disabled, as assessed at 1 year of age [44, 45]. A number of parents of surviving infants took part in the qualitative interview study reported here. Sample A pilot study for the Zelen randomization research was carried out by telephone with eight parents (one man and seven women) of seven infants involved in the ECMO trial. These parents had participated in an earlier study assessing their responses to the trial more generally [46]. The description of Zelen randomization and the proposed questions for the main study underwent only minor modifications after the pilot study, and so we report the views of these parents along with the main sample. The questions about Zelen randomization were not the primary research interest for this study. We selected the sample with another research question

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in mind, namely, how the participants responded to the results of the ECMO trial [47]. The results showed that infants who received CM were less likely to survive, a finding that could have distressed some patients. We therefore needed to handle the study of parents’ views of the results as carefully as possible. The primary research question necessarily shaped the sample in an important way in that only those parents of surviving infants who had indicated at an earlier point in the trial that they wished to see the results were included in the study. Parents of 71 of 95 surviving infants had indicated that they wished to receive a copy of the findings. Practical constraints meant that not all of these parents could be asked to take part in the study. Invitations to join the study were dispatched in small waves, starting with those more recently recruited to the trial, until the target of 20 interviews was reached. Other selection criteria were that a member of the trial staff who knew something of the circumstances of the families did not object to their inclusion, and that, for practical reasons, English should be their first language. In total, parents of 33 surviving infants were contracted. Parents of 20 infants accepted, parents of 5 declined and parents of 8 did not reply, giving a positive response rate for this group of 61%. The 20 in-depth interviews were carried out with parents resident in England, Scotland, Wales, and the Republic of Ireland. In all interviews, both parents were present. We excluded from our analysis data from two cases (in both of which the babies were allocated to CM). The researcher judged during the interviews that these parents were insufficiently aware of randomization and their own role within the trial for the questions about Zelen randomization to be meaningful, and so these questions were omitted. The pilot and main study data combine to give a valid sample of 25 women and 19 men (parents of 25 infants). The women were aged from 25 to 41 years (mean 31); the men were aged from 28 to 48 (mean 34). The interviews were held at variable times after recruitment to the trial: the youngest infant was 69 weeks old and the oldest 234 (median 121). The disability status of the 25 infants, as measured for the trial at 1 year, was that none was severely disabled; five had signs of impairment and disability not classed as severe; two had an impairment without disability, and the remaining 18 had no signs of impairment or disability. In the trial, 10 infants represented had been allocated to continue with CM and 15 to transfer for consideration for ECMO (in two cases the infants were actually managed conventionally after transfer to an ECMO center). References to each set of parents in the text are followed by [CM] or [E] to indicate their infant’s allocation. All names are pseudonyms. Methods The interviews took place from December 1996 to September 1997. They were carried out by one of the authors (C.S.) either in the parents’ own homes (n 5 17) or by telephone (n 5 9; eight pilot, one main study). All were tape recorded with the parents’ permission. The interviews had a chronologic structure, following the sequence of events from birth to the 1-year follow-up for the trial. A chronologic approach helped parents tell their stories naturally rather than responding to an obviously predefined list of questions. The fully transcribed interviews were analyzed using a textual analysis computer package, Atlas-ti [see 48].

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Figure 4 Description of postrandomization consent.

The discussion of Zelen randomization came at the end of the interview. The interviewer read aloud the single consent method, as shown in Figure 4, to ensure that all interviewees should receive the same basic information. For clarity, the description outlined first the usual recruitment procedure for the ECMO trial and then the way in which recruitment would have differed had Zelen randomization applied. This description thus reminded parents of the actual process and highlighted the ways in which the two approaches would have differed. The interviewer asked whether any parts were unclear and reread them if necessary. Although it is not possible to say accurately how well parents understood the concept of Zelen randomization, the interviewer explained and clarified further when she sensed uncertainty. The interview proceeded only when parents said they believed they understood the method. The interviewer asked the parents to assess the notion of Zelen randomization in the light of their actual experiences of taking part in a trial (albeit with conventional randomization). She asked the parents of infants allocated to ECMO to think about the issue as if they had been asked for their consent for their infants to be considered for ECMO, whereas she asked the parents of infants allocated to CM to think about the issue as if they had not been approached for consent. The parents expressed their views from these perspectives but also frequently gave their opinions on the likely impact of Zelen randomization for those in situations different from their own. Results The issue of Zelen randomization engaged the interests of the parents and often aroused strong views. All but three parents expressed an opinion on its use. When accepting or rejecting it, they gave reasons spontaneously and not

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in response to predefined options. Most parents considered the ethical and practical issues. The opinions of some reflected a belief in a general right to information, whereas those of others were firmly grounded in personal experience. In some interviews, parents unequivocally supported or rejected the approach. Others arrived at their views more gradually as various points were discussed. As discussion proceeded and the feelings of both members of a couple were elicited, views were sometimes modified. Commonly, a parent would express a clear view along with sympathy with the opposite position. For instance, those rejecting Zelen randomization often appreciated the aim of easing a difficult situation. To reflect the full and multidimensional discussions that often took place, we present the data in such a way as to show parents’ arguments for and against Zelen randomization. The opinions revolve around the method’s impact on information giving and decision making, around the use of data, and around the longer term effects. We present the final acceptance or rejection of Zelen randomization separately. Impact on information giving Argument for Zelen randomization: it offers protection from dangerous information. There was a strong theme in the data that the essential value of Zelen randomization was the avoidance of emotionally dangerous information. Parents perceived several different areas of danger, in the light of the particular aspects of the trial that they had personally found most difficult. The chief dangers or difficulties posed by particular items of information lay in their potential to disrupt; to cause fear, anger, or regret; and to impede coping both at the time offered and later. The various items of dangerous information presented by the parents were that an alternative treatment would be available but possibly unobtainable (i.e., the threat of no additional treatment), that the potentially life-changing decision about treatment would be made by a computer, and that infants allocated to CM would not receive the alternative treatment (i.e, the realization of the threat of no additional treatment). Knowledge of an alternative treatment. Infants enrolled in the ECMO trial were critically ill and already receiving CM at the time of randomization. Randomization was between continuing with CM or transferring for consideration for ECMO. Not surprisingly, parents who had seen their infants either fail to progress or actually deteriorate on CM often believed that ECMO offered an important alternative. It was not unusual for parents to say that their doctors also saw ECMO as their infants’ last or only chance. In such circumstances it is difficult to avoid a perception that the experimental treatment is the only hope, and those interviewed for this and an earlier study certainly expressed a strong preference for ECMO at the time of consent. One parent, Jim [CM], argued that simply the knowledge of the existence of an alternative inevitably encourages preferences: “as soon as somebody mentions they’re trying something else, it means they’re trying to improve what they’ve actually got at the present moment.” Similarly, Rose [E] felt that it was “obvious” that their doctors saw randomization as a means to access an alternative treatment, needed because “they didn’t see much hope” with the conventional treatment.

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In such circumstances, the wait to find out which treatment an infant will have can be extremely stressful, as Valerie and Jim [CM] described: Valerie: You’re sitting there and . . . you’re on tenterhooks, like every time the phone rang you thought it was them . . . coming back to tell you what she was gonna get. Jim:

It was a long fifteen minutes. (Valerie: Oh aye!) I mean you thought it was sort of hours, you know, waiting, but it was only fifteen minutes, but having to wait for a decision like that when you know time’s against her anyway. I mean we were just waiting, waiting, waiting, come on, hurry up, phone rings, hope it’s them, hope it’s them!

Zelen randomization removes the waiting time, something that appealed to Hugh [CM]. Lee [E] also felt the advantage of removing this particular stressor. He found this time difficult, precisely because he was told that ECMO “probably is the best option.” Knowledge of randomization. Some parents found the knowledge that their infants’ treatments would be determined by a computer disconcerting, if not upsetting. Liz [E] was against randomization and believed that it would complicate an already difficult situation as so much would seem to depend on the allocation: “Not are you only faced with your daughter’s death but you’re faced with knowing for the rest of your life that the computer made that decision.” Rose [E] believed that the whole nature of a trial is undermining in such stressful circumstances. She argued not that there should be no trials but that informing parents about them might possibly be inappropriate, in part because of the nature of the treatment decision: I think being totally informed about the trial isn’t always a good thing either . . . . Initially it feels like it’s just practice or research or you know they’re just doing things for the sake of figures and numbers. I know obviously they have the baby’s welfare at heart but the very word “trial,” and then the fact that a computer decides is making it all the more clinical, clinical and very unreal, and almost leaving a very big major decision to a piece of apparatus that’s plugged in is just completely wrong.

Knowledge of allocation. Zelen randomization offers the opportunity for parents to be spared the knowledge that another, potentially life-saving, treatment is possible and available but not for their own infants. As shown earlier, merely the threat of not gaining access to ECMO created difficulties for parents. For those whose infants were allocated to CM, this possibility became real. Jim [CM] described the process of information and allocation as “somebody builds your hopes up and then drops you like a ton o’ bricks.” Because nothing actually changes for these parents, this process could seem “pointless” (Valerie [CM]). Martin [E] implied that randomization was a form of deciding which of several infants should be given a treatment in the context of scarce resources. He was not the only parent to draw such a conclusion [46]. Parents who hold this view believe that introducing the possibility and then the impossibility of treatment is inconsiderate. Martin preferred the idea of Zelen randomization,

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arguing that “at least you’d not be offered it first and then refused.” Anna [E] believed similarly that “it would make it harder knowing that she could have this treatment and she couldn’t get on it.” Frequently, parents described allocation to CM as a form of rejection. Janet [CM] argued that it is difficult to have a sense of perspective at the time: Your mind isn’t able to cope . . . [and] it feels like a rejection when you’re told your baby isn’t going, it does feel like a rejection, and you can only reflect when things are a lot more calm.

Hilary and John [CM] believed that hope for their daughter was actually slipping away when she was assigned to CM. John describes how knowing of the existence of another treatment complicated his experience: I remember when they told us she wasn’t going to have the ECMO treatment and how we felt then. That’s when we started to, you know, you could see that she was getting worse and of course not going to have this treatment that’s so successful in America, then that’s when alarm bells started to ring . . . and then seeing her get worse. I thought well, hold on, you know, if she’d been on this ECMO would this be different?

Argument against Zelen randomization: It is a deprivation of essential information. The counterargument was that Zelen randomization would deprive parents of information to which they have a right. However difficult such knowledge might be, some parents believed they ought to be told about the trial at the time of randomization. Ellen [E] believed that protection was not a real benefit, saying categorically, “I don’t think you are protecting them though. You’re just not informing them.” Some interviewees thought it inappropriate deliberately to withhold information from parents, judging it simply important to know what was happening. For instance, Valerie [CM] said, “it’s your baby, you want to know if they’re doing something.” Andrea [E] argued, “I would want to know what all my options were up front,” and Gail [CM] commented: “I’m somebody who thinks that you should know everything that’s going on, and if your child’s health is going to be part of some trial, that you should know about it.” Mary [E] believed the information that they were part of a trial was important in its own right: I can understand that [for] parents who aren’t randomized on to ECMO it would be a great disappointment. It would have been terrible for us because we did feel like it was her last hope but I still think we would have liked to have known and to have been part of the project.

Information gathering can be an important coping mechanism, and some parents, such as Russell [E], wanted every piece of available information. Understanding the problem could help them gain some sense of control. They talked with great appreciation about how valuable it had been to have their questions answered, sometimes over and over again if they had been unable to absorb certain details. Some had also valued the answers they had received, such as Grant [E], who had said to his child’s doctor, “I want it straight, I want it blunt.” Those who valued information objected to the deliberate withholding

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of details of the trial and characterized the Zelen approach as “underhand” (Tina [E]), “morally wrong” (Lorna [CM]), not “ethically right” (Adam [E]), and not “very fair” (Sandra [CM]). Liam [E] argued that not informing those in the control group would be discriminatory: “I say that you’re really discriminating . . . against that branch of the trial and that you’re depriving them of the information, depriving them of knowledge.” Some also perceived a wider consequence of Zelen randomization: the creation of a climate of suspicion, in which parents could not trust those on whom they had to rely. Neil [CM] described Zelen randomization as occurring “behind the parents’ back” and believed it had implications for the way doctors would be seen: They are kind of messing around with your child’s life a bit, whereas I think the way we had it, which was quite up front, face to face with the doctor, him explaining what it was about, was a more honest approach and you know exactly what you’re dealing with.

Russell [E] thought it a compromise that was “kinder but less honest.” He thought it would undermine trust in hospitals and the medical profession as a whole, commenting: “It does cast a shadow over everything that you’re told in a hospital and is that right?” Tina [E] believed it would be detrimental to her relationship with staff: “Whatever the outcome, I think I would feel, if they’d kept that from me, what else have they kept from me? . . . I’d find it very hard to trust the people that were involved.” Lorna [CM] felt similarly: “As much as it protects the parents from getting involved into all the worries and all the ins and outs of the trial, it’s the other side, the hiding information starts to come into my mind.” Impact on decision making There were two very different perceptions of the impact of Zelen randomization on decision making, which derived from parents’ focus either on the control or on the experimental group. For those focusing on the control group, the Zelen approach appeared to remove a decision. For those focusing on the experimental group, one decision replaced another. Lorna [CM] made this latter point in the first pilot interview of the study. She argued that parents in the experimental group would effectively be given a choice between treatments as they were offered the option of ECMO and trial participation, or turning down the trial and continuing with CM. We incorporated this issue into the study and put it to the rest of the parents. Argument in favor of Zelen randomization: Parents would not have to decide whether or not to accept randomization. The decision to take part in the trial and to accept randomization had not been particularly easy for many of the parents. If parents saw the trial as their infants’ last or only chance, they commonly represented it as having constituted great personal responsibility, even if they had made it very quickly. The decision was burdensome and some would have preferred to avoid it. Zelen randomization was attractive to two of the parents, Duncan [E] and Helen [CM]. Helen believed that it would have simplified her

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family’s situation: “At least the parents haven’t got to make that decision, that big decision, do we go for it or don’t we? Somebody else is making that decision for you.” Argument against Zelen randomization: Parents have a right to make a decision. Although parents would not be able to choose which treatment their children would have, some argued unequivocally that the decision about trial entry and permission for randomization should still be theirs. Hilary [CM] argued that in not knowing about the trial and randomization, parents are denied the chance to exercise their responsibilities for their children: I mean, it was our child and we had to make that decision, hard as it was, and much as we didn’t want to do that. . . . You’re taking that choice out of their hands by not telling them in a way. . . . We knew the facts and we were told to make a choice, so it was our choice to do that. You’re taking that away to a certain extent because you’re not telling anyone unless they actually get on to the trial.1

John’s [CM] description of the time when they learned their daughter would not have ECMO is quoted above. It was then that “alarm bells started to ring.” Despite his difficulties, he too did not believe he would have preferred not to know about ECMO and the trial at all: John:

Very difficult, isn’t it really, very difficult for everybody. I think the way they told us was best, don’t you?

Hilary: Yes. John:

Give you that choice and then you can live with that. We made the choice and we had to live with it. If things had gone against us then, we could handle that, but not to be given that, not to be told. . . . (John shook his head and did not finish his sentence).

Tina [E] stated clearly that she and her husband had had a difficult time but did not see Zelen randomization as the answer: It was very hard the way it was done, but I’m not sure if it’s . . . I’m not sure that not telling parents until after they’ve made the decision is right either because parents have the right to know if someone is making a decision behind their back. I mean as hard as the decision was to make I’m glad that I actually had the chance to make the decision. . . . I would want to know what was actually going on even if . . . my baby stayed on a ventilator. If I was in a trial I would want to know I was in a trial.

Argument in favor of Zelen randomization: Parents in the experimental group would have an opportunity to make a decision about treatment. Views on the shift in the nature of decision making for those in the experimental group were given by 20 parents, 6 of whom merely indicated the choice they would have made. All except Angela [E] said they would have chosen ECMO. 1 It was common for parents to use the term “trial” and ECMO interchangeably or to believe that infants allocated to CM were not part of the trial.

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Moira [CM] believed that, despite the difficulties, parents should be able to choose treatment themselves. Ellen [E] would have welcomed the opportunity to have made that choice, even in the face of uncertainty: I think it would have been nice to have had a choice, just because that was one of the things I found difficult, the fact that the final decision was out of my hands. It wouldn’t have made the decision any easier though, I suppose, because you don’t know the results of ECMO and conventional treatment. You’re still making a blind decision.

Tina [E] argued that the decision might be easier for parents if it were a straightforward choice between accepting or rejecting ECMO but went on to reject any possible benefit as it is outweighed by the withholding of information from some parents: I would hate to find out that I had been in a trial . . . however hard the decision was to make about putting him forward for the randomization by the computer as opposed to making a straightforward yes or no decision. I realize that would have been easier at the time but I still think I would have felt very angry to have been in a trial and to have found out after the event.

Russell [E] and Duncan [E] both thought that decision making after randomization might be easier because they believed the doctors would not maintain a neutral stance in these circumstances. This would not necessarily be the case because the condition of equipoise (uncertainty) would still pertain. Russell and Duncan, however, perceived neutrality not as a response to uncertainty but as a means of protecting parents whose infants might be subsequently allocated to CM from the certainty that ECMO is the better treatment. In this model, there would be no need for neutrality, because ECMO would be readily accessible to the parents who were asked to make a choice. Duncan said: They might try to sell ECMO more to you, you see, because the way it was given to us, they weren’t allowed to show a bias towards ECMO, and there was like a witness with the consultant to make sure he was unbiased, but if our doctor had the ECMO and was to have told us about the ECMO, he would have sold it to us more forcefully.

Frank [CM] drew attention to a possible complication that can arise when participants can choose the treatment, the dilution effect mentioned earlier: “If the trial had been run, as in the second method there, and we’d have been offered ECMO and hadn’t taken it . . . is that not gonna disrupt the . . . results?” Argument against Zelen randomization: Parents in the experimental group would face a difficult decision. Lorna [CM], who had immediately pointed to this crucial way in which Zelen randomization would change the nature of consent, argued that the experience would be more rather than less complicated. She believed that if parents were told that their infants had already been allocated to ECMO, their situation would not necessarily be easier than with conventional consent before randomization: Then you are really making a decision. Yes, you’ve got ECMO, but if you don’t want it you’ve got conventional treatment, then they really are making

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a decision, whereas we found it quite a relief to put that decision on the randomization of the computer. That helped us live with what might have happened at that time. It took that feeling away that we were deciding the fate of what could happen.

Lorna’s husband Neil argued that he had always seen randomization as something helpful and positive and saw Zelen randomization as regressive. He believed that parents would face an almost impossible decision: “if a doctor had come in and said to me, ‘Right there’s ECMO treatment and traditional treatment, you choose,’ I mean, how could I choose?” Bill [CM] did not like the idea of having to make a choice either, “I think if you make the choice and you made the wrong one, in your own mind you will forever be reproaching yourself.” Andrea [E] saw randomization as preferable to the responsibility she would feel in such circumstances: “I just wouldn’t want to have to make that choice to say, whether yes you take him off conventional, or you put him on ECMO. I think randomization is better.” At the time of the interview, Angela [E] was convinced that ECMO saved her son’s life but said that when she had consented to the trial she had been very wary of it. She had been swayed by his deterioration and the confidence of the recruiting doctor. She was disconcerted to feel that she might not have made the “right” decision if she had had to make it herself: “To be perfectly honest, I didn’t know what was best for him. . . . When they told me it was an incision in the neck and he was going to be connected to a machine, my instinct said no! no! They are going to experiment on your baby!” Andrea [E] also believed the conditions at the time were not conducive to clear decision making and said, “You’re not thinking totally straight, . . . 95% of you is totally numb anyway.” Although Hilary and John [CM] had wanted to make the decision to enroll in the trial, they did not believe that it would have been better, if allocated to ECMO, to have chosen the treatment themselves. They both believed that the difficulty lay in the unevaluated nature of ECMO. Hilary likened it to a decision to take an experimental drug and John commented, “Regardless of what’s happened in America, it was still considered experimental here.” These parents believed that Zelen randomization would deny those allocated to ECMO the protection afforded by randomization. From their reactions, it is clear that Zelen randomization only benefits those who reject randomization or who view it negatively. Use of data Argument supporting Zelen randomization: Use of data is of no consequence. Some accepted that information about their infants would be used in the trial without their knowledge. Shirley [CM] stated simply: “It wouldn’t have made a difference.” The saying “what you don’t know doesn’t hurt you” was used by three parents, Duncan [E], Liz [E], and Jerry [E]. Duncan and Doug [E] both saw the information as important to the advancement of science and were not concerned about the situation. Liz, Jim [CM], and Doug talked spontaneously about other situations in which information had been recorded without a subject’s knowledge and permission and believed was not a problem:

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Liz [E]: There are all sorts of organizations out there who know about your finances. They know everything about you. You don’t know who they are or where they are. We get letters through in the mail, and we think what’s that, you know. I can’t see a problem with that. It wouldn’t harm them in any way.

Hugh [CM] thought it would not be a problem as long as the name of the infant would not be included, and Grant [E] did not believe that there was a problem in using data from children without their parents’ knowledge: I guess it’s a case of what the eyes don’t see, it doesn’t bother the mind, may be very naive, I don’t know. I . . . I . . . it wouldn’t have bothered me had they used Jonathan’s notes and things. If he had died, if it meant that it would go towards proving that maybe ECMO was right or the other way was right, if it meant saving children’s lives.

Argument against Zelen randomization: Parents have a right to permit or prohibit the use of data. In contrast to the views described above, Liam [E] distinguished between information used without permission in other contexts and in the case put to him: Maybe it happens in every walk of life. Consequently statistics are gathered about what you do. You’re on such a study and you’re unaware of that, but it seems where you have such a significant report, you’re not talking about, you know, how much people spend or watching them shopping . . . you’re talking [about] a treatment of babies, a treatment of people.

Others also rejected the idea (Lee [E], Lorna [CM], Adam [E], and Ellen [E]. The idea of using information without parental permission made Ellen uncomfortable: “You’re using people in a way . . . that’s just using information from people when they don’t know they’re being watched.” The decision to become involved in the trial did have certain benefits for parents that would have been lost through Zelen randomization. They could feel commitment to the trial and often welcomed the opportunity to be involved in follow-up. Ellen [E], Shirley [CM], and Neil [CM] mentioned the practical difficulties of getting information for the follow-up that would arise if parents did not know their infants were in a trial. Neil [CM] extended the consequences of having only limited follow-up for the trial to the qualitative interview study: I mean, at the time, fair enough, you don’t know what’s going on behind the scenes if you like, but eventually these things have a nasty habit of coming out, and from your point of view, if you want to have some further feedback from the parents, you can’t do that, because you can’t say to them, “well, look, you’ve entered into this trial but you didn’t know about it. Can you tell me how you feel about it now?”

At a later date, the ECMO trial results were announced and sent to those parents who had requested a copy. Knowledge of the outcome of the trial gave some an important sense of having contributed to medicine and to the wellbeing of other families who might benefit [47]. Crucially, this contribution had come about through an active decision rather than by default. Access to the results of the trial was not only desirable to many but was seen by Adam [E]

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as an argument against Zelen randomization: “I don’t think it’s ultimately fair on the, on the parents either to never know that they were in a trial and never know the results of it if they wanted to know.” Adam went on to make the point that Zelen randomization can also deny a parent the opportunity of an altruistic decision and the possible benefits that could have held, particularly should the infant die: “In a way, if he didn’t survive, the fact that you’d been in a trial . . . at least you’re knowing that you are actually, in a way, you are helping others. I think that’s one consolation you could have if your child didn’t survive.” Rita [E] made this point also. Long-term impact Information for trial participants can be managed after Zelen randomization in two ways. Participants allocated to the control group can be left unaware of their roles in the trial or at a later date may be informed to facilitate followup. The crucial aspect for this study would have been that parents would not have known about randomization as it was carried out. The description of Zelen randomization used in the study did not address what would have happened in the future. Argument supporting Zelen randomization: Bereaved and control-group parents may be better able to cope in the long term. Some parents addressed the fact that the current system of recruitment has implications that go beyond possible distress at the point of allocation. Parents of infants allocated to CM were often seen as more vulnerable, especially if their infants went on to die. Those attracted to the idea of Zelen randomization often believed that its value lay in the protection it offered this group from further emotional difficulties. Sophie and Ray [E] created a scenario in which a baby treated with CM was deteriorating: Ray:

I think you’d feel more upset knowing that there’s a possibility that there was something else out there they could do, but you just haven’t, you just haven’t been the lucky one.

Sophie: Not been chosen . . . it definitely would have been a different kettle of fish if they’d said to you about it and then . . . come back and said, “I’m sorry, she can’t go on it anyway.” Ray:

Yeah. And then it had got to such a stage where she was maybe, God forbid, slipping away, and you’d say “well do something else.”

Sophie: Yeah. You’d be desperate for the chance to be on the trial then, wouldn’t you, and you’d know about it, but you’d know she couldn’t be on it. Ray:

I think you’d be ranting and raving really, then, wouldn’t you.

Parents saw the information as particularly difficult in cases where infants died after treatment with CM. Although parents were originally asked to consider this situation in terms of the allocation that was made for their own infants, they frequently shifted the focus instead to the bereaved parents, and imagined vividly how they would have felt themselves. Jerry [E] said: “I think

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you might be a little bit bitter in that respect, knowing there might have been something out there to save your child’s life and it wasn’t used, whether it be on the trial or not.” For Tina [E], Melanie and Lee [E], and Emma [E], the whole success of the Zelen approach hinged on never learning about the trial, an alternative treatment or randomization. Clearly, any protection offered by Zelen randomization is undermined if parents holding this opinion receive this information at a later date. For these parents, Zelen’s double consent design would simply undo any benefits that randomization without consent might offer. Argument against Zelen randomization: Parents may be upset to learn later that their infants are in a trial. Parents often raised the issue of learning about the trial later and speculated how they and others would feel. Grant [E] pointed out that if parents learned later about their child’s involvement in a trial, their reactions would be shaped by the means by which they found out. He believed that it would be acceptable to parents if it was done “properly by letter,” but his wife Rita commented that if he were in that position himself he would “probably still have gone spare.” These parents had accepted the trial and random allocation of treatment at the time of consent, but some believed that they would be angry if they were only informed retrospectively. Mary believed that if she had found out about ECMO at a later time she would have been “up in arms” and would have gone back to the consultant to demand an explanation of why her daughter had not received ECMO. Valerie [CM] said she would have “flipped.” Lorna [CM] would have wondered whether they were not told at the time “because there was something they were hiding from us. Was there something more sinister?” Andrea [E] would have been “devastated” and “gutted” had her son died on CM and she learned afterward about the possibility of ECMO: If it hadn’t been known to me, though it hadn’t been available to us . . . I think I would have been even more devastated. Again, just because—not that it’s making you any guarantees, but it’s just that extra door that I think at the time like—that you just need to do down as many avenues as you possibly can to satisfy—it’s selfish but it’s just to satisfy yourself, knowing, well, at least we did everything absolutely possible for him.

Angela [E] believed that the effort to ease the short-term situation would generate long-term problems: At the time it would be kinder to the parents . . . especially if you are going to be given a hope and then have it taken away from you, but later I think you would get very, very angry people who would somehow feel that if they had known they could have done something about it, and I think if at the time you know it is happening it just adds to the heartache . . . But if someone was to actually find out that their child was used for the trial and they weren’t even told about it or something like that, I think you would get very, very angry people, because it’s like—it’s like a wound if somebody—if you—if something reopens that later and you were to have lost a child and then find out that they had done this without your knowledge, I think you could be dealing with people’s anger then.

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All parents included in this study had been through the allocation of treatment. Even if the rationale behind randomization was not clear, all knew that access to ECMO was not guaranteed. Yet only three parents (Jim [CM], Lorna [CM], and Tina [E]) pointed out that the allocation and the outcome would not have been any different, regardless of the system used for consent. Parents of babies allocated to CM would not have been able to change the allocation. Parents may possibly believe that it would be difficult to take on board issues about allocation at a later date because they would be angry, with their focus on deprivation of a treatment rather than anything else. Acceptance and rejection of Zelen randomization After discussing at length, the parents were asked whether or not they would support the use of Zelen randomization. They were very evenly split, with 21 in favor and 20 against, 1 unable to decide, and 2 giving insufficiently clear statements to categorize. In some cases the interviewer was surprised to hear support for Zelen randomization, given earlier accounts of a need for information (Russell [E], Bill [CM], Grant [E], Rose [E], and Frank [CM]). Being of a qualitative nature, this study involves examining the views of a small group of persons in depth. Data from such studies are not usually conducive to statistical analysis. The views expressed here are, however, readily grouped into categories of support or rejection of Zelen randomization. These data are based on the treatment of each parent individually rather than in pairs, because the views within a pair were not always the same. As Table 1 shows, there were no particular differences between men and women in their views, but parents of infants allocated to CM were likelier to reject Zelen randomization. DISCUSSION Zelen randomization has been the subject of professional debate, but no attention has previously been paid to the views of those with actual experience of trial participation. The way in which parents in this study often engaged with and extended the issues involved in the subject was impressive and indicated the value of their particular perspective. Their interest was rooted in personal experience, and they empathized highly with others in similar situations. Despite the short time available for consideration of the concept, they assessed in a rounded and full way how Zelen randomization might succeed or fail. Although evenly divided in how they summed up their view of Zelen randomization, parents often appreciated both sides of the arguments. Some thought it highly disappointing and cruel to inform worried parents about a treatment that may not be possible. Because such a process was thought likely to have major ramifications for those whose infants did not survive, some saw Zelen randomization as a kinder approach. In the opposing view, by which the gathering of information is a coping strategy or access to information was considered a right, parents saw the withholding of crucial details not only as undermining but also denying the active and protective role of a parent on behalf of a sick infant. Essentially, parental views about Zelen randomization

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Table 1 Distribution of Views of Parents According to Treatment Allocation ECMO

CM

Total

For Zelen

Emma* Eileen and Jerry Melanie and Lee Anna and Eric Julie and Martin Sophie and Ray Duncan‡ Liz§ Rose and Liam Grantk

Janet [P] Helen [P] Jim† Shirley and Hugh

21

Against Zelen

Andrea [P] Ellen and Adam Tina and Doug Mary [P] Ritak Angela [P]

Gail and Bill Hilary and John Valerie† Sandra [P] Jo and Frank Lorna and Neil [P] Moira and Dan

20

Other

Russell* Penny‡ Carl§

Total

27

3

17

44

The symbols * † ‡ § and k are used to link members of a couple where they have differed in their opinions. Parents interviewed for the pilot study (see text under Sample) are indicated by [P].

stemmed from the importance they attached to access to information, and it is precisely this variable element that makes the process so difficult to adapt to individual cases. Clearly, one cannot find out whether or not a person wants information without first alerting him or her to the fact that information is available. The feature that was so desirable for approximately half of the parents in the sample was not that they would actively have chosen not to access dangerous information but that they would have preferred not to have been aware of it at all. The concept of dangerous information was complicated and existed on both sides of the debate. It could relate to the impact of the revelation that however sick an infant may be, he or she could not access an available treatment; it could also relate to the revelation at a later time, to those in the control group, that the situation was not as it had seemed. Parents saw both approaches to consent as having consequences for those involved, both in terms of their wellbeing and in terms of their relationships with medical professionals. One might consider this research with parents to have done little to indicate how to manage such a difficult situation, given the even division in the views expressed. Perhaps this is due to the fact that, as Liam [E] pointed out, there is “no perfect answer.” Ultimately, we cannot devise a system that will incorporate the opposing views presented here. Ellen [E], for instance, argues that if her infant was allocated to CM in a trial using a Zelen randomization, she would prefer never to be informed about the trial, whereas Hilary and John

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[CM] rejected the use of Zelen randomization outright, even though they had experienced a time of thinking that their daughter would die once allocated to CM. These views cannot be reconciled. Instead, one view must take precedence over another. Several finding have emerged from this research that may further the debate. First, it became clear that Zelen randomization would not necessarily minimize stress for those allocated to an intervention group. One of the functions of randomization is to deal with equipoise. When it is not known which treatment is most beneficial (clinical equipoise), it serves to distribute fairly the unevaluated risks and benefits among participants. It removes from clinicians and potential participants the need to decide which treatment they believe will be most efficacious when there is insufficient evidence to make the choice clear. The decision each participant makes in a trial is, in theory at least, whether or not to accepted randomization and whichever treatment one is allocated to. With single-consent Zelen randomization, potential participants allocated to an experimental treatment would, however, be faced effectively with a straightforward choice between experimental treatment on protocol or standard care off protocol, despite the context of medical uncertainty. In effect, the potential participants have to make precisely the choice the trial is set up to avoid. Some parents saw this as an impossible decision. When a choice is unwelcome, the Zelen randomization itself could cause stress and difficult decision making. Second, we must look more closely at the views of those who are seen to need most protection. Zelen randomization is designed with the intention of minimizing emotional difficulty in RCTs involving standard or nontreatment, particularly for those allocated to the control group. In some circumstances, as in the ECMO trial, the standard treatment administered to the control group can be seen not as the safe, tested, and established approach, as might have been predicted, but as an inferior treatment. In this study, parents belonging to precisely the group that Zelen randomization was partly designed to protect were most likely to reject it. This happened despite the fact that these parents were also aware that the trial showed that infants who received CM were less likely to survive. If we must favor one view over another on the basis of the evidence presented here, then the arguments against Zelen randomization from this sample would seem compelling, not because they represent a majority’s view but because the dissenters are more likely to have been those in the control group. A recent editorial suggested that Zelen randomization ought to have been used for the ECMO trial [43]. In response, Meren [49] disagreed and put forward the same arguments that some of the parents in this study articulated strongly: Your argument seems to suggest the need for sensitive information practice and skilled support rather than depriving frightened and confused parents of information. . . . [T]hey, rather than the law, should decide how much information they receive—but withholding information deprives them of this particular decision and betrays their trust.

Although rejecting of the use of Zelen randomization does mean that those preferring not to be informed about a trial, if allocated to a control group, will have to face unwelcome information, it also highlights the need for attention to be paid the process of seeking consent to ease the situation as far as possible.

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CONCLUSION The subject of Zelen randomization proved to be a highly engaging topic for the parents in this study, who were divided in its acceptance or rejection. They saw a trade-off of protection and information, desirable to some, anathema to others. They also saw an opposition of the short-term benefits and longterm consequences. It became clear from their responses that Zelen randomization would create very different circumstances for participants depending on their allocation. Those who found this method, and the circumstances it would create, to be unacceptable were most likely to be parents of infants allocated to the control group. Had this system been used for the ECMO trial, these parents would not have been informed of their allocation at the time, and knowing this may have afforded them a higher degree of empathy with others in such a situation. Their particular rejection of Zelen randomization is important because their perspective is unique; although the questions are to some degree hypothetical, these parents speak from personal experience. In cases where participants perceive standard treatment as the less desirable option, Zelen randomization may well widen rather than narrow any perceived inequities between the groups in a trial. This study was funded by the Department of Health and the Nuffield Foundation and developed from research funded by the Wellcome Trust. We thank Carole Harris from the ECMO Trial office and Sally Roberts at the Centre for Family Research for their help. Our thanks also go to the parents who kindly gave the information upon which this research is based.

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