Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?
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.
Dodd
Lori E
LE
Division of Cancer Treatment and Diagnosis, Branches of Biometric Research, Investigational Drug, Cancer Investigations, and Diagnostic Imaging, National Cancer Institute, Rockville, MD 20892, USA. doddl@mail.nih.gov
Korn
Edward L
EL
Freidlin
Boris
B
Jaffe
C Carl
CC
Rubinstein
Lawrence V
LV
Dancey
Janet
J
Mooney
Margaret M
MM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015982:Bias; D017326:Clinical Trials, Phase III as Topic / Q000191:economics / Q000379:methods*; D003362:Cost-Benefit Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic / Q000191:economics / Q000379:methods*; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents