Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies:...

The validity, importance and relevance of randomized controlled trials depend on identifying an appropriate target population, ensuring adequate power, careful attention to the details of randomization and blinding, and selection of an endpoint that is important to the target population. With efficacy trials more than effectiveness trials, additional constraints are needed to reduce the variability that is typical of clinical practice: a narrowly defined sample, unvarying pre-randomization procedures and post-randomization treatments and follow-up that are as identical as possible for all patients. Efficacy trials comparing ovarian stimulation protocols should have strict protocol definitions, specific concomitant medications and minimal variability between centres with respect to stimulation goals and dose adjustments. Additionally, there should be narrowly defined criteria for administration of chorionic gonadotrophin, type of luteal support, embryo transfer and freezing policies. The goal of efficacy trials is to minimize the variability that is extrinsic to the comparison. When efficacy has been proven, effectiveness trials are needed to determine whether the effect of the new intervention is robust in the variability of typical clinical settings.