Abstract
The evolution of chemistries and instrument platforms for next-generation sequencing has led to sequencing of genomic variants in both tumor biopsies as well as in circulating tumor cells (CTCs) and cell-free DNA liquid biopsies. The transition of these analytical platforms into clinical ones has led to challenges in product development as well as regulatory strategies for the approval of diagnostic products with these platforms. Regulatory strategies for liquid biopsy diagnostics depend on a framework that has been developed over the past few years by the US Food and Drug Administration (FDA). This framework includes both guidances that cover enrichment biomarkers and companion diagnostics, as well as regulatory approval precedents, which can be used to design regulatory strategies for new liquid biopsy diagnostic products. However, the regulatory paths for these liquid biopsy diagnostics can also be tortuous, as is the example of CTC-platform liquid biopsies. The ultimate success of regulatory pathways of liquid biopsy diagnostics has been driven by the incremental value of FDA approval for Clinical Laboratory Improvement Amendment (CLIA)-developed tests and by the inherent complexity of these diagnostics, which are practical barriers for the widespread replication of these tests throughout CLIA laboratories. The framework for FDA approval of sequence information from these liquid biopsies has been focused on single-site approvals of diagnostics where sequencing information is considered at different diagnostic risk levels, ranging from novel or follow-on companion diagnostics to variant calls in genomic targets considered independently valuable for therapeutic decision making.