Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?

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.

Fig 1.

(A) Demonstrates the existence of informative censoring via conditional progression-free survival (PFS) curves. The PFS curves are conditional on time of local progression. The “observed curve” plots the centrally determined progression from the time of investigator-assessed progression for the 16 patients for whom investigator-assessed progression was called before the blinded independent central review (BICR) –determined time. The “expected curve without informative censoring” is the curve that would be expected if the censoring was not informative. Curves are constructed as described in the Appendix. Data are from Yang et al. (B) Demonstrates the impact of informative censoring shown in 1A on the unconditional PFS curves. The curves plot BICR PFS with and without informative censoring. However, the “with informative censoring” curve censors cases for which BICR progression determined after local progression at the locally designated progression time.