From the Division of General Medicine, College of Physicians and Surgeons, Columbia University (Drs Pablos-Méndez, Barr, and Shea), and the Division of Epidemiology, Columbia University School of Public Health (Drs Pablos-Méndez and Shea), New York, NY.
Prerandomization run-in periods are being used to select or exclude
patients in an increasing number of clinical trials, but the implications
of run-in periods for interpreting the results of clinical trials and applying
these results in clinical practice have not been systematically examined.
We analyzed illustrative examples of reports of clinical trials in which run-in
periods were used to exclude noncompliant subjects, placebo responders, or
subjects who could not tolerate or did not respond to active drug. The Physicians'
Health Study exemplifies the 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
periods to exclude patients who do not tolerate or do not respond to the study
drug. The reported results of these studies are valid. However, because the
reported results apply to subgroups of patients who cannot be defined readily
based on demographic or clinical characteristics, the applicability of the
results in clinical practice is diluted. Compared with results that would
have been observed without the run-in period, the reported results overestimate
the benefits and underestimate the risks of treatment, underestimate the number
needed to treat, and yield a smaller P value. The
Cardiac Arrhythmia Suppression Trial exemplifies the use of an active-drug
run-in period that enhances clinical applicability by selecting a group of
study subjects who closely resembled patients undergoing active clinical management
for this problem. Run-in periods can dilute or enhance the clinical applicability
of the results of a clinical trial, depending on the patient group to whom
the results will be applied. Reports of clinical trials using run-in periods
should indicate how this aspect of their design affects the application of
the results to clinical practice.
Pablos-Méndez A, Barr RG, Shea S. Run-in Periods in Randomized TrialsImplications for the Application of Results in Clinical Practice. JAMA. 1998;279(3):222-225. doi:10.1001/jama.279.3.222