Dora Vallejo – Ardila, Senior Medical Monitor/ Clinical Research Physician at Avance Clinical, shared a post on LinkedIn:
“The FDA-AACR Journals workshop in September 2025 delivered transformative insights into novel oncology endpoint development, emphasizing data-driven regulatory strategies that fast-track innovation while safeguarding patient benefit and trial integrity.
Novel endpoints address the urgent need for faster access to groundbreaking cancer therapies, allowing for drug approvals based on surrogate markers reasonably likely to predict clinical benefit in settings where waiting for long-term survival data may delay treatment advances. These endpoints—such as minimal residual disease (MRD), pathological complete response (pCR), and circulating tumor DNA (ctDNA)—can expedite drug development, especially in cancers with high unmet needs.
1. Evidentiary Criteria and Validation:
For regulatory acceptance, the FDA expects robust clinical and statistical evidence showing that a novel endpoint strongly correlates with meaningful patient outcomes such as progression-free survival (PFS) and overall survival (OS).
2. Workshop experts considerations:
– The importance of patient-level and trial-level surrogacy validation.
– Meta-analyses across diverse trials increase reliability.
– Caution against using endpoints as surrogates in populations or treatments significantly different from those studied.
3. Case Studies Driving Change:
- Multiple Myeloma: MRD is prognostic but not yet a validated surrogate for regulatory approval. Strong individual-level associations exist between MRD-negativity and PFS/OS, but trial-level correlation is weaker, underscoring the need for more evidence before full endorsement.
- Early Breast Cancer: pCR correlates with individual prognosis, especially for aggressive subtypes like triple-negative disease. However, trial-level surrogacy with long-term endpoints remains limited, so regulatory approvals require a totality-of-evidence approach.
- Colon and Lung Cancer: ctDNA MRD post-treatment is emerging as a sensitive biomarker for recurrence risk and treatment response, but standardization and further studies are needed to support its regulatory use as a primary endpoint.
4. Balancing Risk and Innovation:
Adoption of novel endpoints may expedite access and development but introduces the risk of approving therapies lacking long-term effectiveness or safety, as seen in historic cases (e.g., the CAST arrhythmia trial).
5. Early engagement with regulatory bodies:
Anchoring novel endpoints to established measures and confirmatory trials.
6. Best Practices for the Future:
– Prioritize endpoints that matter to patients and reflect meaningful benefit.
– Anchor novel endpoints to clinical outcomes, ensuring global access and efficiency.
– Recognize that endpoint development is iterative—clinical validation and risk mitigation must evolve with scientific advancements.”
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