RUN-IN PERIODS IN RANDOMIZED TRIALS - IMPLICATIONS FOR THE APPLICATION OF RESULTS IN CLINICAL-PRACTICE

Prerandomization run-in periods are being used to select or exclude pa tients in an increasing number of clinical trials, but the implication s of run-in periods for interpreting the results of clinical trials an d applying these results in clinical practice have not been systematic ally examined. We analyzed illustrative examples of reports of clinica l trials in which run-in periods were used to exclude noncompliant sub jects, placebo responders, or subjects who could not tolerate or did n ot respond to active drug. The Physicians' Health Study exemplifies th e use of a prerandomization run-in period to exclude subjects who are nonadherent, while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in perio ds to exclude patients who do not tolerate or do not respond to the st udy drug. The reported results of these studies are valid. However, be cause the reported results apply to subgroups of patients who cannot b e defined readily based on demographic or clinical characteristics, th e applicability of the results in clinical practice is diluted. Compar ed with results that would have been observed without the run-in perio d, the reported results overestimate the benefits and underestimate th e risks of treatment, underestimate the number needed to treat, and yi eld a smaller P value. The Cardiac Arrhythmia Suppression Trial exempl ifies the use of an active-drug run-in period that enhances clinical a pplicability by selecting a group of study subjects who closely resemb led patients undergoing active clinical management for this problem. R un-in periods can dilute or enhance the clinical applicability of the results of a clinical trial, depending on the patient group to whom th e results will be applied. Reports of clinical trials using run-in per iods should indicate how this aspect of their design affects the appli cation of the results to clinical practice.