Pre-randomisation consent (Zelen’s method)

Background Most individually randomised trials ask patient CONSENT before randomisation. There are problems with asking for consent some scientific others ethical.

Consent problems - Scientific Asking consent means refusal by a proportion of the population, which limits the generalisability of study. Consent also alerts patient to trial potentially leading to Hawthorne effects or resentful demoralisation. Sometimes getting consent is simply not possible.

Pre-randomisation consent Two different types of pre-randomisation consent. Some trials cannot refuse allocated intervention. Other trials use Zelen’s method where consent to treatment can be withheld.

No Consent Trial of income sanctions for childhood immunisation. Families were randomised to have income supplements reduced if they did not get their children immunised. Cannot refuse consent to the sanction, which is the intervention. Similarly for cluster trials.

Zelen’s method Zelen’s method allows refusal of the intervention. This introduces DILUTION effects as people cross over to the other treatment.

Consent problems -Ethical Whilst NOT asking consent is usually seen as UNETHICAL sometimes it has been justified as being more ethical. Example - an early ECMO trial used Zelen’s method because it was felt to be unethical to ask very distressed parents consent. O’Rouke. Pediatrics 1989;84:957.

Consent problems - feasibility Sometimes it is not feasible to ask consent at the time randomisation is required. Example, a trial of allocating confused elderly used Zelen’s method as relatives were unavailable to give proxy consent.

Consent problems - administrative The requirement for doctors to ask for consent can reduce or slow recruitment to trials. Also Zelen felt a clinicians might compromise patient doctor relationships by admitting that they did not know which treatment to recommend. Because of these issues Marvin Zelen proposed the ‘randomised consent method’.

Randomised Consent Zelen argued that for patients allocated to ‘conventional’ therapy there was no need to get consent as patients would get standard therapy anyway. Consent for treatment only is required. Consent from patients allocated to the new treatment only and this is consent for treatment.

Two versions There are two versions of Zelen’s method - the original method, known as the single consent design or later the double consent approach. In the first only patients allocated to the novel treatment are asked for consent to treatment, which can be refused. In the second both groups are asked for consent to treatment.

Zelen’s single consent method

Applications Zelen’s method has commonly been used in screening programmes where people are randomised without consent to be invited to be screened or not. Follow-up is often done ‘at a distance’ through, for example, cancer registeries.

Colorectal Cancer Screening Harcastle et al. Randomised nearly all the middle aged male population (45-74) in Nottingham to be screened for early signs of colorectal cancer or act as controls. Zelen’s method was used in order to gain ‘pragmatic’ estimates of the effect of screening on a population. Hardcastle Lancet 1996;348:1472-77.

Colorectal Cancer In the Harcastle trial patients in the control arm were allowed unlimited access to diagnostic and treatment facillities for bowl cancer at their own or GP’s request. Of 76,000 men offered screening 60% accepted. This lead to a 15% reduction in bowl cancer deaths.

Advantages or Disadvantages? Had Hardcastle used a ‘standard’ method of RCT then this would have resulted in less dilution bias BUT would not have given a pragmatic estimate of the effects of cancer screening. Also some participants would have excluded themselves from the control group, which may have made the trial less generalisable.

Screening – What is the question? If the question to be answered is: What is the effect of introducing a bowl cancer screening programme? Zelen’s method gives the best answer. If the question is: What is the effect of giving bowl cancer screening to people who want screening? ‘Normal’ consent methods are best.

Practical Considerations Dey et al used Zelen’s method because of practical reasons. They wished to evaluate a ‘one stop’ breast clinic. To ask consent before allocation would have been difficult as women would already be at the clinic and the clinicians required notice for diagnostic tests. Dey et al. BMJ 2002;324:1-5.

Disadvantages - Ethical Many ethics committees and researchers are opposed to Zelen’s method because of non-consent. BMJ debated this issue and decided to still publish Zelen’s trials despite some ethicists recommending not to publish. As in all things Zelen’s method is ethical and unethical depending on the circumstances.

Ethics If consent is impracticable: Is it more or less ethical to offer an unevaluated treatment than offering a treatment without consent where the patient has at least a 50% chance of getting the safer treatment.

Disadvantages - Scientific Major scientific problem is through dilution bias, particularly with the double consent method. Cross over into the opposing group will dilute any treatment effect and make it harder to observe a difference. A review of Zelen’s trials in cancer treatments concluded cross-overs were a serious problem in many trials. Altman et al. Eur J of Cancer 1995;31A;1934-44.

Disadvantages Because of the threat of cross over one may need larger sample sizes to cope with dilution effects, which can increase the cost of duration of the trial. Outcome collection may alert patients to the trial which could result in WORSE demoralisation.

Systematic review Adamson et al, have reviewed 43 trials published since 1990 using the Zelen approach. Most of the trials used the method to avoid the introduction of bias (e.g., Hawthorne effect) NOT to enhance recruitment. Low cross-over (median 6%). Adamson J, Cockayne S, Puffer S, Torgerson DJ. Submitted.

Future of Zelen’s method Probably useful for ‘pragmatic’ trials of screening. May be useful for other treatments on occasions. May not be worth, generally, overcoming the ethical barriers to its use. HOWEVER, cross over is relatively low.

Summary Pre-randomisation consent is useful in some circumstances. Zelen’s method offers a number of potential advantages, particularly for ‘screening’ type trials. It shouldn’t be undertaken if there is the potential for high cross over rates.