Original Article
Indications and requirements for the use of prerandomization

https://doi.org/10.1016/j.jclinepi.2008.07.010Get rights and content

Abstract

Background and Objective

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.

Results

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.

Conclusion

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.

Introduction

Currently, evidence-based medicine is widely propagated as the reference for good clinical practice. This development involves a critical appraisal of a widening range of public health or clinical interventions. As a consequence, the need for patient-related research is growing, as is demonstrated by the increasing number of such scientific publications. In effectiveness studies, the conventional randomized trial will always be the design of first choice. 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], [2], [3], [4]. The term prerandomization implies that the randomization takes place before seeking informed consent.

Because of this deviant informed consent procedure, the position on prerandomization of medical ethicists, health lawyers, methodologists, and clinicians remains controversial, and varies from total unacceptability to acceptance under specific conditions [5], [6], [7], [8], [9], [10], [11], [12]. Unsurprisingly, there is controversy both between and within research ethics committees (REC) about when, or even whether, these designs are admissible [13].

Prerandomization is also applied in apparently less controversial designs in which clusters, such as primary care practices or schools, rather than individuals, are randomized, and obtaining informed consent from the participants after randomizing the clusters is inevitable. Another situation in which prerandomization is used is in patients who are unable to give informed consent because of a reversible process of disease, such as comatose or psychiatric patients who may be able to give consent after a period of convalescence [14], [15]. Whether this is justified and in which circumstances a temporarily proxy consent may be used is a complex issue, and the ethical and judicial ramifications are discussed elsewhere [16], [17], [18], [19]. This application of the prerandomization design is beyond the scope of this article.

In this article, we derive guidelines for the optimal application of prerandomization designs.

Preceding this, different types of prerandomization designs are outlined, and an overview of methodological differences between conventional designs and prerandomization designs is given. In the last section, ethical and judicial considerations concerning trials and informed consent are described.

Section snippets

Prerandomization designs

Box 1 shows the definitions of key concepts use in this article. In 1977, Zelen introduced the single-consent design [20], [21]. The key characteristic of this design is that, patients are randomized before informed consent is sought. The patients allocated to the experimental treatment group are approached by the investigator or clinician for informed consent. However, the patients randomized to the reference group are given the (best) standard treatment but are not approached for informed

General issues

Clinical trials should provide information about the relative magnitude of effect(s) of an experimental intervention on (disease) outcome as compared with some reference intervention(s) or policies. This information is ultimately obtained by comparing the outcomes of interest between the study groups. The difference thus calculated may be explainable by different mechanisms. First, it could be the result of the experimental intervention. Second, it could be the result of bias. Briefly, bias may

Ethical and judicial considerations

In a clinical trial, there is a balance between individual and collective ethics [33], [34]. “Individual ethics” implies that each patient should receive the treatment which is thought to be most beneficial for his condition. This is the clear aim of good clinical practice, in which the patient and his clinician decide together on the best course of action. Usually, the clinician proposes the therapy on the basis of his knowledge and experience, which is followed by the appropriate

Conclusion

In general, the use of prerandomization in study designs is underestimated. However, based on well-defined indications and requirements, prerandomization designs have an essential contribution to evidence-based medicine. Banning prerandomization a priori implies that information about the effectiveness of numerous public health and medical intervention will not be forthcoming. A number of effective interventions will not be introduced because of the lack of evidence. Furthermore, the use of

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