Assessing clinical trials--restricted randomisation.

Restricted randomisation -3 is recommended when investigators want to ensure that the numbers of patients allocated to each treatment are approximately equal in the trial as a whole or in important subgroups of patients, or both. Corresponding methods, in order of increasing complexity, are the method of random permuted blocks, stratified randomisation, and minimisation. These are discussed in this article, but Zelen' has given a fuller account. He is also responsible for a new design-randomised consent4 -which is also discussed. The method of random permuted blocks is easy to use. In the trial as a whole it guarantees that the numbers allocated to each treatment are equal after every block of so many patients has entered. Stratification' by one factor (perhaps two) that is known to affect prognosis is a safeguard against a chance imbalance between treatment groups with respect to an important variable -for example, the extent of cavitation in tuberculosis or axillary node disease in breast cancer. Stratification, especially in small trials, is recommended so long as the randomisation is still simple to operate. One method is to devise a separate list for each stratum by the method of random permuted blocks-that is, consult different lists according to the extent of cavitation for a patient with tuberculosis. Stratified randomisation may also be useful in multicentre trials when it is important to avoid treatment imbalance in individual hospitals as well as in the trial as a whole. One way of doing this when there are many centres is to prepare randomisation lists for the trial as a whole, monitor the imbalance in individual hospitals, and intervene to restore the balance within a hospital before the assignments there get too far out of line. Minimisation,3 as the word implies, is a method of random assignment that minimises the marginal imbalance in the numbers of patients allocated to different treatments over several (two or more) factors known to affect prognosis, one of which may be a hospital in a multicentre study. The method avoids the limitations of stratified randomisation (see question 21) but has a similar purpose. It works this way: a measure of imbalance is calculated over the set of prognostic factors describing the new patient, who is then most probably, but not invariably, assigned to the treatment that minimises the overall imbalance. Randomised consent designs4 have a different rationale: (a) to limit the number of patients to whom a full and perhaps distressing explanation is given of the purpose of a randomised trial; and (b) to encourage doctors to participate in clinical trials. Some doctors fear that informed consent-as regulated by the Federal Government in the United States, for exampledestroys their patients' hope and confidence. These doctors refer no patients or only selected ones for inclusion in clinical trials. Zelen4 proposed that all eligible patients should be randomised to a "seek consent" or a "do not seek consent" group. The latter receives the standard treatment; the former group is asked to give informed consent to the experimental treatment. Comparison is made between groups as randomised, though the "seek consent" group will have a proportion of patients who received the standard treatment-because they so decided after the trial had been fully explained, or because their doctor elected not to confront them with a traumatic explanation. These designs are new and therefore uncommon in published reports.