What is Zelen's design?

British Medical Journal, Feb 21, 1998 by David J. Torgerson, Martin Roland

When patients do not receive their preferred treatment in

randomised trials there may be difficulties with patient

recruitment and scientific problems with bias.[1] For

example, bias may occur when patients are aware of a new

treatment not available to them and comply poorly with

the standard treatment.

Zelen's design can address these difficulties[2 3] by

randomising patients before consent to participate has

been sought. Two types of the design exist: double and

single consent In the double consent version patients are

initially offered the treatment to which they were

randomised; however if they decline the ramdomised

treatment, they can then be offered alternative therapies--including

the experimental treatment hi the single consent

version only patients offered the experimental treatment

are told there is an alternative treatment (die control)

available. Patients randomised to the control treatment are

not allowed the experimental treatment (although they are

given unhindered access to any usual treatment facilities).

Analysis is undertaken with patients retaining their

original assignment.

Zelen's design has been much discussed and for most

therapeutic trials is probably unethical. Occasionally,

however, it has been chosen on ethical grounds. For

example, in a trial of extracorporeal membrane oxygenation

for infants with pulmonary hypertension Zelen's design

was used as it was considered preferable not to raise false

hopes among half the parents that there was a novel

treatment available for their child only to have it denied

them through the randomisation.[4]

Zelen's design may be particularly useful for evaluating

population based interventions such as screening, where it

is important to estimate the effects on a whole population.

However, if the presence of the trial is known to the non-screened

group this may artificially induce changes in that

group which may influence the results (a Hawthorne

effect). For example, in a randomised trial of bone density

screening[5] the non-screened group were not contacted at

baseline as this might have artificially increased their use of

hormone replacement therapy Had the trialists not used

Zelen's design the investigators could not have been sure of

the full unbiased impact of screening on uptake of hormone

replacement therapy.

If bias due to patients knowing they are in the "usual

care" group is to be avoided patients usually

need to be followed up for key events at a distance so as

not to alert them to the study. For example, in a

randomised trial of colorectal cancer screening cancer

events for both groups of patients were ascertained

through medical records and a cancer registry.[6] By using

Zelen's design in screening trials it is possible to achieve

more accurate estimates of population outcomes such as

cancer reduction[6 7] compared with the conventional trial

designs.

There are obvious ethical problems in using Zelen's

design to randomise patients without their consent[8]

(though treatment consent is always sought). For some

interventions, however, such as screening, this may be the

only practical design. For example, if all patients in the

colorectal cancer screening trials had been screened but

only a random half had been offered intervention, there

would have been an ethical dilemma of not offering further

investigation and treatment to control patients who

appeared to be at high risk.

Zelen's design can have other disadvantages. If the trial

requires intrusive data collection or monitoring then Zelen's

design as control patients will be aware of the study.

Given that intrusive data collection is not feasible, it may

not be possible to use restrictive inclusive or exclusive

patient recruitment criteria. Furthermore, if many patients

refuse their original treatment, this will lead to a reduction in

study power. Both these factors will lead to the need for a

large sample size.[9]

[1] Torgerson DJ, Sibbald B, What is a patient preference design? BMJ

1998;316:360.

[2] Zelen M. A new design for randomized clinical trials. N Engl J Med

1979;300:1242-5.

[3] Zelen M. Randomized consent designs for clinical trials: An update. Stats

in Med 1990;9:645-56.

[4] O'Rourke PP, Crone RK, Vacanti JP, Ware JH, Lillehli CW, Parad RB, et al.

Extracorporeal membrane oxygenation and conventional medical therapy in

neonates with persistent pulmonary hypertension of the newborn: A prospective

randomized study. Pediatrics 1989;84-957-63.

[5] Torgerson DJ, Thomas RF, Campbell MK, Reid DM. Randomised trial of

osteoporosis screening: HRT uptake and quality of life results, Arch intern

Med 1997;157:2121-5.

[6] Hardcastle JD, Chamberlain JO, Robinson MHE Moss SM, Amar SS,

Balfour TW et al. Randomised controlled trial of faecal-occult blood

screening for colorectal cancer. Lancet 1996;348:1472-7.

[7] Kronborg 0, Fenger C, Olsen J, Jorgensen OD, Sondergaard 0.

Randomised study of screening for colorectal cancer by Faecal occult

blood test. Lancet 1996;348:1467-7 1.

[8] Smith R. Wormed consent: the intricacies. BMJ 1997;314:1059-60.

[9] Altman DG, Whitehead J, Parmar MKB, Stenning SP, Fayers PM, Machin D.