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May 20, 1998

Concerns About Run-in Periods in Randomized Trials

Author Affiliations

Margaret A.WinkerMD, Senior EditorIndividualAuthorPhil B.FontanarosaMD, Senior EditorIndividualAuthor

JAMA. 1998;279(19):1526-1527. doi:10-1001/pubs.JAMA-ISSN-0098-7484-279-19-jbk0520

To the Editor.—Nobody would disagree with Dr Pablos-Méndez and colleagues1 that nonadherence in a clinical trial adversely affects statistical efficiency.2,3 We believe, however, that these authors do not adequately consider the impact of nonadherence on the validity of a randomized trial, and hence draw inappropriate inferences about generalizability. Since patients who do not comply obtain no benefit, nonadherence in a clinical trial will produce bias in the estimation of the true efficacy.35 For this reason clinical trials use a variety of useful strategies, including a run-in period to identify and enroll subjects who will adhere. In the Physicians' Health Study,6 adherence during the run-in was the strongest predictor of adherence during the trial so prerandomization exclusion of nonadherers greatly enhanced validity. A successful run-in period in a trial enhances validity, which is a prerequisite for generalizability.

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