title: Model free audit methodology for bias evaluation of tumour progression in oncology.
abstract: Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Euan
authors.initials: E
authors.lastname: Macpherson
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Smith
authors.affiliation: University of Bath, Bath, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jennison
mesh_terms: D015982:Bias; D002986:Clinical Trials as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D018401:Sample Size
keywords: independent review; oncology; progression; sample