FDA posts 20 page finao guidance on use of ctDNA as a biomarker in drug development.
See the 20 page PDF here:
https://www.fda.gov/media/183874/download
See an essay from Josie Hayes at Linked In here:
And subscription coverage at Genomeweb here.
"Big Three" Use Cases
The guidance encompasses "the big three" use cases - ctDNA for oncogene selection; for MRD; and for drug response. For MRD, the FDA notes that tumor-informed and tumor-naive methods have various advantages.
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FDA's Draft Guidance on ctDNA in Drug Development
The FDA's November 2024 Draft Guidance focuses on using circulating tumor DNA (ctDNA) as a biomarker in curative-intent drug development for early-stage solid tumors. It highlights key roles for ctDNA, including patient selection, molecular residual disease (MRD) enrichment, response measurement, and early endpoints in clinical trials. This framework is part of the FDA's ongoing effort to improve precision in oncology and reduce treatment toxicity for patients unlikely to benefit from therapy.
Key Points and Takeaways:
- Comment Period: The guidance allows a 60-day comment period for industry feedback.
- [About January 20]
- ctDNA in Trials:
- Can be used to select patients with specific molecular alterations, especially when tumor tissue is unavailable.
- MRD detection via ctDNA identifies patients at high risk of recurrence, enabling tailored escalation or de-escalation of therapy.
- ctDNA trends (e.g., clearance or reduction) could act as surrogate early endpoints, potentially predicting long-term outcomes like disease-free survival (DFS) or overall survival (OS).
- Validation and Standardization:
- Robust assay validation (e.g., sensitivity, specificity) is critical for regulatory acceptance.
- [For MRD] Tumor-informed (mutation-specific) and tumor-naïve (general panel) assays each have advantages and limitations, depending on the study design.
- Regulatory Synergy:
- Emphasizes harmonization between ctDNA assays and broader regulatory requirements for investigational devices.
Broader Context: FDA and MRD Testing
- The guidance builds on the FDA's 2020 Hematologic Malignancies Guidance, where MRD was validated in blood cancers. Applying similar principles to solid tumors remains a challenge due to variable ctDNA levels influenced by tumor type, stage, and biology.
- For drug development, ctDNA could complement imaging or pathological assessments, streamlining early signals of efficacy in trials.
Final Thought:
The draft highlights the FDA's cautious optimism for ctDNA as a transformative biomarker in oncology, but it underscores the need for robust clinical evidence and assay consistency before ctDNA can achieve routine regulatory and clinical utility. Experts should consider contributing comments during the review window to refine these pivotal recommendations.
