Current problems and future challenges in randomized clinical trials.

AS HISTORIANS review the advances of therapeutic science in the second half of the 20th century, one of the outstanding methodologic achievements will sure- ly be the use of evidence from randomized trials to show the efficacy of new therapeutic agents.With this type of evidence, clinicians and patients can now be reasonably reassured, for the first time in medical history, that a new treatment actually does what is claimed for it.Scientific problems in comparing therapy.Although the concept of randomized assignment was developed in the 20th century, the idea of controlled comparisons of therapy dates back to antiquity.A comparative trial of two diets was reported in the Book of Daniel'; citrus fruits were compared with five other agents when James Lind2 treated scurvy in 1747; early and late bloodletting were contrasted in 1835 by Pierre Louis;3 and many of the new therapeutic agents introduced in the first half of the 20th century received documented comparison with older agents.'7The comparisons, however, usually had four fea- tures that were scientifically unattractive.One obvious problem was that the comparisons were often noncon- current.Although the results would be presented as a contrast of newer treatment vs older treatment, the newer treitment was often given in a newer era to patients identified with newer diagnostic methods and