A powerful impetus behind the rise of the 'megatrial' (a large, simple, usually multi-centred randomized controlled trial analysed by 'intention to treat') has been the desire for ever-increasing precision in the measurement of therapeutic effectiveness. However, the demand for precision has been allowed to override other and more important methodological considerations. Megatrials have progressively abandoned the pursuit of scientifically rigorous experimentation, valid measurement and optimal epidemiological sampling in favour of recruiting and processing large number of subjects. This is a mistaken strategy which leads inevitably to error, because investigators are seeking a primarily statistical, rather than clinically or scientifically relevant, notion of exactness. We are now in a position to describe a clinical research strategy which offers many advantages over a megatrial-led approach. Research should be planned with an awareness that the validity and applicability of estimated is more important that their numerical precision, and that this requires both and unselected denominator population database of all incident cases, and maximally controlled randomized trials and other studies. The Population-Adjusted Clinical Epidemiology (PACE) strategy is suggested as exemplifying the twin principles of clinically useful research: rigorous science and representative epidemiology.