EDITOR—No one should argue with Peto and Baigent about the dangers of basing clinical practice on flawed “outcomes research” or isolated, undersized, randomised trials,1 but the simple megatrial may not be the ideal model for the next 50 years. Although such trials have taught us not to expect a predictable physiological response from our treatments but merely an improvement in the odds of successful outcome, the homogenising effect of large numbers may still disguise important variations in response. Attempts to explore these variations through subgroup analysis are widely condemned because of the perceived association with retrospective data dredging, so that the theoretical knowledge of clinicians and the individuality of patients are seen as increasingly less relevant to decisions about treatment.

The trials that Peto and Baigent advocate focus on hard end points, such as deaths, which may be rare in some patient groups and of limited relevance in others. The ageing of the world's …