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Project team received a FDA post-approval request to submit integrated safety analyses and supporting data from an adequate number of patients enrolled in clinical trial(s) designed to characterize the risk of fractures and its sequelae in patients exposed to entrectinib with reasonable precision; to identify risk factors for development of these sequelae; and to support labeling recommendations to mitigate the risk of skeletal fractures.
SABER inquiry due to FDA request via Safety Strategy Leader & coordinated with pRED PS nonclinical safety rep.
Bone scientific sub-team provided bone biomarker strategy for pediatric and adult populations in combination with standard imaging and growth assessment endpoints.
Strategy: Tailored safety biomarker strategy based on known biomarker biology, non-published data from FDA, and comprehensive clinical trial review publication.
Assay: Identified preferred central lab after careful vetting and review of analytical validation documents among labs; aligned with global procurement.
Operations: Supported clinical biomarker operations to smoothly integrate and operationalize the strategy into the protocol
Data Solution: Biostats provided unique approach to support the hypothesis; Virtual lab working with Dev Sci informatics to integrate bone biomarker data into QUASAR.
Timely and scientifically robust response to post-approval Health Authority request.
Use new normalization and new biomarker indices approach as part of multivariate statistical approach.
Immediately relevant strategy and assays for aRSPO3 and TREM2 nonclinical and Alectinib clinical programs.
Given the unknown mechanism of toxicity, a comprehensive approach was considered including resorption, formation and regulator biomarkers acting as at a paracrine and endocrine level.
Reference data in pediatrics is needed, but more well established in adults.
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