Statistical considerations for some issues in clinical bridging studies evaluating companion diagnostic devices

ABSTRACTABSTRACTAn in vitro diagnostic device (IVD) that is essential for the safe and effective use of a corresponding therapeutic product is commonly referred to as companion diagnostic device. Clinical trials using companion diagnostic devices (tests) together with therapies can yield the information necessary to address whether both products are safe and effective. A clinical trial ideally assesses safety and effectiveness of a therapy, where the clinical trial enrolls subjects based on the final market ready companion diagnostic test (CDx). However, such a requirement may be difficult to accomplish or impractical to achieve at the time of the clinical trial enrollment, due to unavailability of the CDx. Instead, clinical trial assay(s) (CTA), which are not the final marketable product, are often used in enrollment of patients in a clinical trial. When CTA is used for subject enrollment, a clinical bridging study provides a mechanism to bridge the clinical efficacy of the therapeutic product from CTA to CDx. This manuscript reviews some issues and challenges commonly associated with clinical bridging studies, including missing data, use of local tests for enrollment, prescreening before enrollment, and evaluation of CDx for low positive rate biomarkers, with particular focus on clinical trials using a binary endpoint and provide alternative statistical methodologies to assess effectiveness of CDx.KEYWORDS: Companion diagnostic (CDx)clinical trial assay (CTA)clinical bridging studysample retainmentlocal laboratory testprescreening biaslow positive rate biomarker Disclosure statementNo potential conflict of interest was reported by the authors.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.Correction StatementThis article has been corrected with minor changes. These changes do not impact the academic content of the article.