Review
Review of randomised trials using the post-randomised consent (Zelen's) design

https://doi.org/10.1016/j.cct.2005.11.003Get rights and content

Abstract

Background

In 1979, Zelen described a trial method of randomising participants before acquiring consent in order to enhance recruitment to clinical trials. The method has been criticised ethically due to lack of consent and scientifically due to high crossover rates. This paper reviews recent published trials using this method and describes the reasons authors gave for using the method, examines the crossover rates, and looks at the quality of identified trials.

Methods

Literature review searching for all citations to the relevant Zelen's papers of trials published since 1990 plus inclusion of trials from personal knowledge.

Results

We identified 58 relevant trials. The most common justification for the use of Zelen method was to avoid the introduction of bias (e.g., to avoid the Hawthorne effect). Few trialists had explicitly used the design to enhance participant recruitment. Most trials (n = 41) experienced some crossover from one group to the other (median crossover = 8.9%, mean = 13.8%, IQR 2.6% to 15%) although this was usually within acceptable limits.

Conclusion

The most important reason stated by authors for using Zelen's method was to limit bias. Zelen's method, if carefully used, can avoid ‘resentful demoralisation’ and the Hawthorne effect biasing a trial. Unlike a previous review, we found that crossover was not a problem for most trials.

Section snippets

Background

In most randomised controlled trials (RCT) consent to both treatment and a random allocation is sought from participants before randomisation (Fig. 1). There are, however, a number of exceptions. In cluster trials, where groups of people are randomised (e.g., members of a GP practice) often only treatment consent is obtained. For individually randomised trials, Zelen proposed two modifications to the usual practice of gaining consent before randomisation in the individually randomised RCT:

Definition of ‘Zelen's method’

In Zelen's method the option to refuse the allocated treatment, in at least one arm, is always present. Some studies, whilst using randomisation without consent, cannot be considered to be using ‘Zelen's method’ as it is not possible to refuse consent to any of the allocated treatments. For example, a study by Kerpleman and Gunn sought to evaluate the effect of income sanctions on childhood immunisation rates [11]. In that study consent for randomisation was not sought but this study could not

Results

There were 288 citations to Zelen's papers published on or since 1990 on April 2005. Of these citations, 51 were identified as being relevant RCTs. From personal knowledge, we also were aware of 7 trials that essentially used Zelen's method but did not cite these papers.

Of the 58 included trials, 45 were of the single consent method. The trials evaluated a mixture of treatments; we defined these as follows: 8 were screening trials; 13 were surgical trials; 12 were drug studies; 15 were ‘service

Discussion

We have reviewed 58 trials that have used one of the two versions of Zelen's design. Interestingly, the primary explicit reasons for the use of the design was not to enhance participant recruitment, rather it was to reduce bias.

Conclusion

This review has shown that most studies that have adopted Zelen's idea of pre-randomisation have used it to avoid certain biases that are inherent when trialists undertake non-placebo controlled trials rather than for enhancing recruitment. Zelen's method seems to have been used in screening trials to give a more ‘pragmatic’ estimate of the effects of screening when implemented on a population basis. Crossover rates, which have been seen as an important statistical limitation of the design, did

Acknowledgements

We thank Professor Diana Elbourne for her helpful comments.

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