Keywords: Next Generation Sequencing, companion diagnostics, analytical and clinical validation
Increase in targeted therapies has resulted in the need for a single assay capable of detecting diverse biomarkers indicated for these agents. Comprehensive genomic profiling (CGP) provides such a solution, but due to the complexity and rapid advancement of the technology, statistical challenges in development and validation arise and strategical solutions have become critically important. In this presentation, I will discuss the statistical challenges and issues in the analytical and clinical validation of FoundationOne CDx, the first NGS-based comprehensive companion diagnostics (CDx) platform which interrogates 324 genes for short variants, copy number alterations, rearrangements, MSI and TMB with well-defined performance characteristics. Our analytical validation strategy with an approach of combining representative variants across platform and samples enriched for specific CDx biomarkers enables us to provide stringent validation data required by FDA for the “pan-tumor” claim. In addition, the platform is clinically validated for 8 CDx indications in 5 tumor types associated with 17 targeted therapies, either as a follow-on or novel CDx. Using statistical methods developed for external comparison studies, we are able to evaluate the device’s clinical performance without being limited by the difficulties in conducting a clinical validation trial or accessing the patient samples from the original clinical trial.