Assessment of Audit Methodologies for Bias Evaluation of Tumor Progression in Oncology Clinical Trials Jenny J. Zhang 1 , Lijun Zhang 1 , Huanyu Chen 1 , Anthony J. Murgo 2 , Lori E. Dodd 3 , Richard Pazdur 2 , and Rajeshwari Sridhara 1 Abstract As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion. Clin Cancer Res; 19(10); 2637–45. Ó2013 AACR. Introduction Progression-free survival (PFS) is defined as the time from randomization to either disease progression or death, whichever occurs first. When PFS is the primary efficacy endpoint of a clinical trial, the U.S. Food and Drug Administration (FDA) and other regulatory authorities have generally required a blinded indepen- dent central review (BICR) under the assumption that the investigator or local site evaluation could potentially be biased because of the subjectivity in the measurement and interpretation of PFS. However, this approach may lead to more than 30% disagreement at the patient level between the BICR and local site evaluation assessments and/or among the independent reviewers themselves. These disagreements have been attributed to a variety of reasons, including selection of different target lesions by the reviewers (1). In addition, because treatment is generally changed after local site evaluation–determined progression resulting in no further protocol-specified progression assessments before the BICR is conducted, missing data and informative censoring are limitations of BICR-determined PFS analyses that may result in biased treatment effect estimates (2). Informative cen- soring results, when patients declared to have progres- sive disease by the local site evaluation, are censored by the BICR due to lack of further tumor assessments after local site evaluation-determined progression. Note that local site evaluation assessments may include local radiographic reads and/or other clinical assess- ments. BICR radiologists are not part of the clinical trial investigation, typically do not have information about clinical assessments, and are blinded to treatment assignment. The role of BICR was first examined by Dodd and colleagues in 2008 in 6 phase III oncology trials (2), in which differences between local site evaluation and BICR did not result in different conclusions about treatment efficacy, despite relatively high discrepancy rates at the patient level. The Pharmaceutical Research and Manufac- turers of America (PhRMA) PFS Working Group con- ducted a meta-analysis of 27 trials, which showed that while discrepancies in determining the progression dates were observed on average in 50% of patients, the relative treatment effect as measured by a HR was similar when assessed by either local site evaluation or BICR (3). To further confirm these results, the FDA conducted a meta- analysis of 28 randomized, phase III trials submitted for review in consideration of approval across 9 nonhema- tologic malignant tumor types with BICR- and local site evaluation–assessed PFS results reported (4). Note that there is some overlap of the trials included in the FDA Authors' Affiliations: 1 Division of Biometrics V/Office of Biostatistics/ Office of Translational Sciences and 2 Office of Hematology and Oncology Products/Office of New Drugs, Center for Drug Evaluation Research, U.S. Food and Drug Administration, Silver Spring; and 3 Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, NIH, Bethesda, Maryland Current address for J.J. Zhang: Gilead Sciences, Foster City, California. Corresponding Author: Rajeshwari Sridhara, FDA, WO21, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Phone: 301-796-1759; Fax: 301-796-9733; E-mail: rajeshwari.sridhara@fda.hhs.gov doi: 10.1158/1078-0432.CCR-12-3364 Ó2013 American Association for Cancer Research. CCR FOCUS www.aacrjournals.org 2637 on August 27, 2021. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst March 26, 2013; DOI: 10.1158/1078-0432.CCR-12-3364