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

• Published in: Journal of clinical oncology Vol. 26; no. 22; pp. 3791 - 3796
• Main Authors: DODD, Lori E, KORN, Edward L, FREIDLIN, Boris, JAFFE, C. Carl, RUBINSTEIN, Lawrence V, DANCEY, Janet, MOONEY, Margaret M
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.08.2008; Lippincott Williams & Wilkins
• Subjects: Antineoplastic Agents - therapeutic use; Bias; Biological and medical sciences; Clinical Trials, Phase III as Topic - economics; Clinical Trials, Phase III as Topic - methods; Cost-Benefit Analysis; Disease Progression; Disease-Free Survival; Double-Blind Method; Humans; Medical sciences; Neoplasms - drug therapy; Neoplasms - mortality; Randomized Controlled Trials as Topic - economics; Randomized Controlled Trials as Topic - methods; Reproducibility of Results; Statistics in Oncology; Time Factors; Treatment Outcome; Tumors; Phase III trial; Chemotherapy; Treatment; Cancerology; Bibliographic review; Progression free survival
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.16.1711

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.