title: Assessment of audit methodologies for bias evaluation of tumor progression in oncology clinical trials.
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.
authors.affiliation: Division of Biometrics V/Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Huanyu
authors.initials: H
authors.lastname: Chen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Lori E
authors.initials: LE
authors.lastname: Dodd
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
mesh_terms: D000465:Algorithms; D015982:Bias; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000473:pathology; D054869:Clinical Audit / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination / Q000379:methods*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017063:Outcome Assessment, Health Care / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012509:Sarcoma / Q000188:drug therapy / Q000473:pathology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; C515074:ridaforolimus; D000068338:Everolimus; D020123:Sirolimus