The Zelen Design May Be the Best Choice for a Heroin-Provision Experiment

doi:10.1016/S0895-4356(99)00009-8

Journal of Clinical Epidemiology

Volume 52, Issue 6, June 1999, Pages 503-507

https://doi.org/10.1016/S0895-4356(99)00009-8 Get rights and content

Abstract

Recently, the Dutch Parliament agreed upon the conduct of a randomized clinical trial on the effects on heroin provision on general health and psychosocial and criminal behavior in long-term addicts. Previous studies failed to establish the effects beyond reasonable doubt. The main reasons why previous trials failed are massive dropout or noncompliance in the control group. Designing a new heroin-provision trial, we concluded that the Zelen design provides the best guarantee for obtaining valid study results. Compared with the traditional design, the Zelen design probably reduces noncompliance and dropout considerably, thus increasing validity. Depending on the study population, the Zelen design may reduce study precision. However, in a trial aimed at badly integrated addicts, the Zelen design can be conducted without loss of precision because baseline measurements will only weakly correlate with effect measurements. The arguments favoring the Zelen design may be generalized to trials in which the experimental treatment is highly attractive to the study participants. However, the use of the Zelen design precludes blinding of participants who receive the experimental treatment. We argue that the conduct of studies that predictably tend to produce invalid results is ethically dubious. The ethical problem of studying participants without their consent can be solved by a slight modification of the Zelen design in which the sampling of a control group is postponed. Both the traditional and the Zelen design can imply ethical problems. Both designs can be ethically justifiable and should not be rejected on a priori grounds.

Introduction

In agreement with the advice of the Health Council, the Dutch Parliament agreed upon a medical experiment regarding the effects of heroin provision for long-term heroin addicts 1, 2. The main hypothesis is that provision of heroin, in addition to available standard treatment, decreases the harm caused by drug dependence. The outcome measures, in hierarchical order, will be general health and psychosocial and criminal behavior of long-term heroin addicts. Previous studies suffered particularly from high drop-out and noncompliance rates in the control group 3, 4, 5 or did not use a control group [6]. Therefore, these studies have been insufficiently informative with regard to the effectiveness of heroin provision. We set out to design an alternative study that would address this pragmatic question and would be less susceptible to drop-out and noncompliance while retaining the usual experimental rigor. In The Netherlands, standard treatment for long-term drug addicts is delivered by health services and consists of methadone maintenance and social aid.

Section snippets

The traditional design versus the zelen design

Previous trials 3, 4, 5 were conducted as traditional randomized trials in which addicts’ consent was obtained before randomization. Addicts who were randomized to a no-heroin provision control group had a clear reason to be disappointed, complied badly, dropped out in large numbers, and, in this way, adversely affected the trials’ validity. Thus, the challenge is to design a study in which disappointment leading to disruptive behavior is avoided. In a design that is known as the Zelen design,

Dropout and noncompliance

Potentially, the most serious threat to the comparability of treatment groups is dropout leading to incomplete data collection and missing data on effect measurements. A study’s internal validity is reduced if the addicts who drop out are prognostically different from the addicts who complete the study and the drop-out rates differ between the treatment groups.

Noncompliance is another factor that may reduce a trial’s validity. Addicts may either reject their allocated treatment or may take

Validity and precision

In the preceding section, we argued that the chances of obtaining valid results in a heroin-provision trial are probably higher with the use of the Zelen design than with the traditional design. However, the use of the Zelen design precludes taking nonstandard measurements in the control group at baseline. In this section, we qualitatively discuss the implications this has for the trial’s precision. Note also that the points 1 and 2 in the preceding list are likely to reduce the trial’s

A heroin provision experiment in badly integrated addicts

The attractiveness of the intervention implies that many heroin addicts will volunteer for heroin provision. So, in the traditional design, the addicts in the control group will be frustrated after being refused the desired intervention. Theoretically, in the Zelen design there will be no frustration; however, in practice some addicts in the control group, being aware of the experiment, may demand participation in the provision group, which will then be denied. This may cause disappointment and

Ethical considerations

In clinical medicine, both the Zelen design and the traditional design have been the subject of ethical scrutiny and controversy [9]. In both designs, the physician–patient relationship can be adversely affected because of the physician’s preference for one of the treatments [13]. However, in the traditional design, this relationship may be under even greater pressure because patients know that treatment allocation is purely a matter of chance [14]. In addition, sometimes, complex information

Conclusion

We have focused on the use of the Zelen design in a heroin-provision experiment in badly integrated long-term addicts. However, we think that our design considerations have a wider applicability. In this final section, we describe these considerations more generally.

The Zelen design as an alternative for the traditional randomized design should be considered if: (a) the experimental intervention is highly attractive for all potential participants, and (b) the control group will receive standard

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Cited by (16)

The adapted Zelen was a feasible design to trial exercise in myeloma survivors
2020, Journal of Clinical Epidemiology
Citation Excerpt :
Five researchers of the MASCOT team attended the ethics meeting, including a myeloma consultant (KY), behavioral scientists (AF and RB), a senior physiotherapist (BP), and the trial statistician (AH). This design can evoke strong emotions and rejection from ethicists and researchers [20], and we believe that the attendance of our diverse team providing the rationale behind the design helped mitigate a lengthy review. Overall, 313 patients were invited by post to take part in the lifestyle cohort study.
We used a method rarely seen in cancer behavioral trials to explore methods of overcoming difficulties often seen in randomized controlled trials. We report our experiences of the adapted Zelen design, so that other researchers can consider this approach for behavioral trials.
The adapted Zelen design was used to explore the effects of exercise on multiple myeloma patients fatigue, quality of life, and physical outcomes. All participants consented to an observational cohort study of lifestyle factors but were unaware of subsequent randomization to remain in cohort only group or be offered an exercise intervention requiring second consent.
There was lower than expected uptake to the exercise offered group (57%), so the length of recruitment increased from 24 to 29 months to ensure power was reached. At enrollment, patients were unaware of the potential increased commitment, and as a result, 62% of participants allocated to the intervention declined because of the extra time/travel commitment required. This emulates clinical settings and suggests improvements in intervention delivery are required. Our findings suggest that the adapted Zelen design may be useful in limiting dropout of controls due to dissatisfaction from group allocation, or contamination of control arm.
Future use of this design warrants careful consideration of the study resources and recruitment time frames required but holds potential value in reducing contamination, control group dissatisfaction, and resulting dropout. Adapted Zelen design reduces selection bias and therefore gives clinicians a better understanding of acceptability in clinical settings. Future studies should evaluate control group experiences of the design and formally record contamination throughout the study to confirm its acceptability.
Details about informed consent procedures of randomized controlled trials should be reported transparently
2019, Journal of Clinical Epidemiology
Indications and requirements for the use of prerandomization
2009, Journal of Clinical Epidemiology
Citation Excerpt :
However, more and more investigators are becoming aware that the conventional design, in which informed consent is obtained in all participants before randomization, is not the panacea for all research questions, because in certain situations, information in the reference group about the experimental intervention could lead to serious protocol violations. Therefore, in the last two decades, several investigators applied prerandomization designs to counter this contamination problem, questioning the absolutism of the conventional design [1–4]. The term prerandomization implies that the randomization takes place before seeking informed consent.
Although in effectiveness studies, the conventional randomized trial, in which informed consent is obtained before randomization, is the first choice, this design is not the panacea for all research questions. To counter contamination problems, prerandomization designs might be an alternative. Prerandomization implies that the randomization takes place before seeking informed consent, and because of this, prerandomization designs are controversial among ethicists, health lawyers, methodologists, and clinicians. However, in the Netherlands, these designs are becoming more accepted since the Dutch State Secretary of Health, Welfare and Sport decided that, under certain circumstances, prerandomization is admissible and not in conflict with the law.
Based on well-defined indications and requirements, guidelines for the optimal application of prerandomization designs are presented. Designs in which prerandomization is used are outlined; methodological considerations useful when conducting trials using conventional designs or prerandomization designs are discussed, in addition to ethical and judicial aspects.
In certain situations, prerandomization designs have an essential contribution to achieve evidence-based medicine. Banning prerandomization a priori implies that information about the effectiveness of numerous public health and medical interventions will not be forthcoming. Therefore, every design should be based on a balance between maximizing the potential for patient autonomy and minimizing the bias caused by contamination. This balance cannot be reached by formulating general rules, but an independent group of experts, like members of research ethics committee (REC), should decide whether this balance is acceptable.
Randomized consent designs in randomized controlled trials: Systematic literature search
2006, Contemporary Clinical Trials
Three types of randomized consent designs are distinguished and ranked according to the extent to which participants are informed about treatment options: single-consent (those in the experimental group learn about their assigned treatment), incomplete-double-consent (all participants learn about their assigned treatment), and complete-double-consent (all participants learn about all treatments studied). All are methodologically, ethically, and judicially controversial. Even so, their use is justified if blinding is deemed necessary, but impossible to achieve by sham procedures (placebo), and experimental treatment seems attractive to potential participants.
The aim of this study is to give a comprehensive overview of the use of randomized consent designs. Data sources are MEDLINE (1/1977-2/2003), EMBASE (1/1984-2/2003), PsycINFO (1/1996–2/2003), the Cochrane Library, and the Science Citation Index database.
Eligible were studies using a randomized consent design. Cluster randomized trials were excluded. One reviewer selected and data-extracted eligible papers. A second reviewer independently data-extracted 10% of the papers. Data on country of study conduct, year of commencement, area of medicine, type of design, reason(s) for use, details on approval by a research ethics committee, the index and reference intervention, nature of endpoints, and details on collection of data were extracted. Furthermore, for each trial, the rates of non-compliance and loss to follow-up were registered by treatment arm. The three types of randomized consent designs were compared as to differences between the rates of non-compliance and loss to follow-up in the separate trial arms.
Randomized consent designs are seldom used (n = 50). When used, they have often been used in the wrong circumstances (misuse). In 65% of the studies the non-compliance in the index group is larger than in the reference group. Contrary to expectation, trials using the incomplete-double design were associated with significantly higher rates of non-compliance and loss to follow-up in the reference groups than trials employing the other two versions.
Trialists and physicians should be aware of the proper indication for the use of randomized consent designs.
Heroin maintenance treatment for chronic heroin-dependent individuals: A Cochrane systematic review of effectiveness
2006, Journal of Substance Abuse Treatment
The provision of prescribed heroin to chronic heroin-dependent individuals failing other treatments has been supported during the last 70 years on the ground that the first goal of interventions on drug users is to keep them in treatment to protect them from criminal activities and to promote social integration. To assess heroin prescription effectiveness, we conducted a Cochrane systematic review of all relevant randomized controlled trials. We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library and contacted leading researchers for ongoing studies. We found 19 eligible studies, of which 4 met our inclusion criteria (577 patients). In 1 study, patients in the heroin arm remained in treatment longer than those in the methadone arm (n = 96, RR = 2.82, 95% CI = 1.70–4.68); in 2 studies, there was no difference; and in 1 study, patients given heroin left the study earlier than those given methadone (n = 235, RR = 0.79, 95% CI = 0.68–0.90). Heroin was more effective than methadone in refraining people from using street heroin in 2 studies (n = 96, RR = 1.10, 95% CI = 0.79–1.53; n = 51, RR = 0.33, 95% CI = 0.15–0.72). In 1 study, heroin reduced the risk of being charged (RR = 0.32, 95% CI = 0.14–0.78); 2 studies showed no difference, and another 2 studies adopted a multidomain outcome enclosing criminal offense and social functioning and found improvements with heroin + methadone over methadone only. It is unclear if heroin attracts people in treatment; those in treatment use less street heroin and are likely to have less criminal activities. This review systematizes and compares studies showing some inconsistencies between their aims, their adopted outcomes, and their conclusions drawn from results.
Members of research ethics committees accepted a modification of the randomized consent design
2005, Journal of Clinical Epidemiology
Citation Excerpt :
In The Netherlands, we mailed the questionnaires to the 77 registered medical ethics committees (local research ethics committees), and to the central medical ethics committee (CCMO). The questionnaire described a fictitious study on the provision of heroin to long-term heroin addicts, which met three preconditions for the proper use of a randomized consent design [21], namely, (1) the experimental intervention cannot be blinded and is very attractive (in which situation full prior consent would evoke contamination, and differential noncompliance and dropout in the reference group); (2) no personal measurement(s) are necessary until informed consent is obtained; and finally, (3) the reference group receives standard treatment (“usual care”). A randomized consent design with informed consent for effect measurements in the reference group, indicated as randomized consent design (Fig. 1a) and the modified version, indicated as modified randomized consent design (Fig. 1b), were explained as feasible design options for this study.
The use of randomized consent designs has been subject of methodologic and ethical controversy. In most Western countries, research ethics committees make the decision as to whether a randomized consent design can be applied. The purpose of the study is to assess to what extent a randomized consent design and a modification of this design is accepted by research ethics committees, in terms of ethics, health law, and methodology.
A postal survey was conducted among members of research ethics committees in the United Kingdom, and in The Netherlands, with professional competence in ethics, (health) law, methodology, or clinical practice.
In both the UK and in The Netherlands, the modified randomized consent design appears to be statistically significantly more acceptable than the randomized consent design, with respect to ethical and judicial aspects. The overall rejection rate of the randomized consent design was 66% in the UK and 59% in The Netherlands. However, the modified randomized consent design was rejected by 47 and 41% in the two countries, respectively.
the modified randomized consent design appears to be more acceptable than the randomized consent design. To increase consistency in the way research ethics committees handle study protocols, a discussion about the use of randomized consent designs appears necessary.

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Original articlesThe Zelen Design May Be the Best Choice for a Heroin-Provision Experiment

Abstract

Introduction

Section snippets

The traditional design versus the zelen design

Dropout and noncompliance

Validity and precision

A heroin provision experiment in badly integrated addicts

Ethical considerations

Conclusion

Lancet

Lancet

Evaluation of heroin maintenance in controlled trial

Arch Gen Psychiatry

Diversifizierte Verschreibung von Betäubungsmitteln an HeroinabhängigeGrundlagen, Versuchsplan, Begleitforschung

Schweiz Rundsch Med Prax

Versuche für eine ärztliche Verschreibung von BetäubungsmittelnZwischenbericht der Forschungsbeauftragten

Das Englische System in Widnes, Merseyside. Heroinvergabe

A new design for randomized clinical trials

N Engl J Med

Original articles
The Zelen Design May Be the Best Choice for a Heroin-Provision Experiment