Читать книгу Randomised Clinical Trials - David Machin - Страница 55

If there are only minor differences in the actual type of interventions to be compared in a randomised trial, then outcome differences are likely to be small and only a very large‐scale trial would detect any differences in efficacy even if they were truly present. What is more, even if such small differences are demonstrated by a clinical trial, they may have little clinical or research consequence. Thus, it is best (within the realms of practicability and safety considerations) if the treatment options are as different as possible so that clinically important differences may therefore be potentially established. For example, if a randomised trial is planned to test against placebo (dose d = 0) a drug (at dose d), then d should be taken as high as possible. If in such a trial no effect is demonstrated, then one may be reasonably confident that the drug is not efficacious. On the other hand, if a lower dose d/2 (say) had been chosen to compare with placebo, then a ‘no difference’ outcome may be a result of the dose chosen being too low rather than the drug being truly inactive. Thus, another key question for the design team in this context is to decide how high the dose should be whilst balancing potential efficacy against toxicity and safety issues. One may imagine the different scenarios if one were choosing the dose to include for a new analgesic if the patients are young (usually healthy) individuals as compared to establishing the value of a drug suitable for those who are terminally ill.

An extreme example of a major difference in the interventions studied, which one may imagine would have been difficult to justify, is that of the hip fracture prevention trial of Example 1.11 where the authors state the following:

In homes allocated to usual care (control group), the nominated study coordinator received brief information (10 minutes) about and demonstration of the hip protector, and two hip protectors were provided for demonstration purposes.

The intervention (intervention group) consisted of structured education of staff, who then taught patients, and provision of free hip protectors. We provided three hip protectors per resident … .

Clearly if an extreme intervention has little or no demonstrable effect, then a less extreme intervention is also likely to be ineffective. Nevertheless, one has to be cautious in pushing the extent of the intervention too far as it may be that less intervention also has the desired effect. Thus, one might be concerned, for example, that one of the components (structured education of staff or provision of three hip protectors per resident) of the intervention for elderly residents may not be essential to achieve the reduction in the hip fracture rates. As an extreme example, if cure can be achieved with dose d/2, then it would be foolish to give patients dose d. These issues have to be debated thoroughly by the trial design team.