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Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?

Lori E. Dodd, Edward L. Korn, Boris Freidlin, C. Carl Jaffe, Lawrence V. Rubinstein, Janet Dancey, Margaret M. Mooney

From the Branches of Biometric Research, Investigational Drug, Cancer Investigations, and Diagnostic Imaging, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD

Corresponding author: Lori Dodd, PhD, National Cancer Institute, 6130 Executive Blvd, MSC 743, EPN Rm 8140, Rockville, MD 20892; e-mail: doddl{at}mail.nih.gov

ABSTRACT

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

NOTES

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Published by the American Society of Clinical Oncology

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