Indeterminate Data and Handling for Assessing Diagnostic Performance in Imaging Drug Developments

Abstract

In diagnostic imaging drug developments, the imaging scan read data in controlled imaging drug clinical trials includes test positive and test negative. Broadly speaking, the standard of reference data are either presence or absence of a disease or clinical condition. Together, these data are used to assess the diagnostic performance of an investigational imaging drug in a controlled imaging drug clinical trial. For those imaging scan read data that cannot be called positive/negative, the “indeterminate” category is commonly used to cover imaging results that may be considered intermediate, indeterminate, or uninterpretable. Similarly, for those standard of reference data that cannot be categorized into presence/absence including uncollected or unavailable reference standard data, the “indeterminate” category may be used. Historically, little attention has been paid to the indeterminate imaging scan read data as they are generally rare or considered irrelevant though they are related to scanned subjects and can be informative. Subjects lack the standard of reference are simply excluded as such the study only reports the analysis results in subjects with available standard of reference data, known as completer analysis, similar to evaluable subjects seen in controlled trials for drug developments. To improve diagnostic clinical trial planning, this paper introduces five attributes of an estimand in diagnostic imaging drug clinical trials. The paper then defines the indeterminate data mechanisms and gives examples for each indeterminate mechanism that is specific to the clinical context of a diagnostic imaging drug clinical trial. Several imputation approaches to handling indeterminate data are discussed. Depending on the clinical question of primary interests, indeterminate data may be intercurrent events. The paper ends with discussions on imputations of intercurrent events occurring in indeterminate imaging scan read data and those occurring in indeterminate standard of reference data when encountered in diagnostic imaging clinical trials and provides points to consider of estimands for diagnostic imaging drug developments.