The Future of FDA Guidance, Trial Design, and Accelerated Approvals With Matthew Hadfield, DO and Harpreet Singh, MD

Surrogate versus Survival End Points

Dr. Singh began by clarifying distinctions between end points in oncology trials:

• Overall Response Rate (ORR): Tumor shrinkage, measured by response and durability. ORR has traditionally supported accelerated approval, especially in single-arm trials for rare cancers or settings where randomized studies are impractical.
• Intermediate End Points: FDA now prefers this terminology over “surrogate” because ORR and progression-free survival (PFS) do not always correlate with OS. “Response rate does not always translate into long-term benefits,” Dr. Singh noted, referencing examples where promising early signals failed to demonstrate survival advantage once tested in randomized trials.
• Overall Survival: Still considered the “gold standard” end point, but often impractical. In diseases like prostate cancer, myeloma, or melanoma, patients live long after diagnosis and receive multiple lines of therapy, complicating the ability to isolate OS benefit within a trial’s timeframe.

Dr. Singh emphasized that while accelerated approval remains vital for early patient access, confirmatory trials must ensure that short-term benefits translate into meaningful survival.

Key Elements of the New FDA Draft Guidance

The FDA’s recent draft guidance does not fundamentally change past practices but clarifies expectations for sponsors:

1. Prespecified Planning: When OS is not the primary end point, sponsors must include protocols for capturing long-term survival and subsequent therapies. Dr. Singh highlighted that this represents “operational lift for sponsors” but is crucial to rule out harm.
2. Subgroups and Biomarkers: The agency stresses biologically plausible subgroup analysis. Past experiences with PARP inhibitors and PD-L1 inhibitors demonstrated that biomarker-negative patients frequently did not derive survival benefit, prompting restriction of indications. Dr. Singh summarized: “FDA has determined in several cases that patients lacking the biomarker do not live longer, leading to restricted indications.”
3. Trial Design Considerations: FDA advises caution with crossover and unequal randomization, which can obscure OS results. While crossover improves patient access, it complicates survival analysis. Dr. Singh explained that in KRAS inhibitor development, lack of early crossover led to “asymmetric dropout” in the docetaxel arm, undermining interpretability. She stressed that crossover decisions must be modeled and discussed with the agency on a trial-by-trial basis.
4. Analysis Framework: Guidance encourages standardized approaches for handling missing data, intercurrent events (eg, deaths unrelated to disease), and exploratory OS analyses.

Balancing Access and Rigor

Dr. Hadfield acknowledged that some in the oncology community worry that heightened scrutiny could restrict access to novel therapies. Dr. Singh countered:

• “A failed trial is not a failed drug.” Many accelerated approvals with early promise stumble in randomized settings due to design, patient selection, or operational missteps, not necessarily because the drug lacks activity.
• The accelerated approval pathway is “alive and well,” though the bar is higher now given the abundance of available therapies.
• Sponsors must accept crossover in some scenarios despite its statistical complexity. “It’s not acceptable for patients to be denied potentially life-prolonging therapy just to preserve statistical integrity,” she insisted. Instead, sponsors and statisticians should model its impact.

Both speakers agreed this tension—between safeguarding patients through rigorous end points and maintaining timely access to innovative therapies—represents the central challenge of oncology regulation today.

Key Takeaways

• FDA guidance emphasizes OS as a critical safety end point, even when not the primary trial end point. Sponsors must pre-plan for OS collection and analysis.
• Accelerated approval remains a key pathway, but confirmatory trials aligning early signals with long-term outcomes are essential.
• Biomarker-driven subgroups are central to FDA decision-making. Drugs must demonstrate meaningful benefit within biologically plausible populations.
• Crossover designs require careful planning. While ethically important for patients, crossover complicates OS analysis and requires advanced statistical strategies.
• Negative confirmatory trials do not necessarily invalidate a drug. Failures often reflect design issues rather than lack of drug activity, underscoring the importance of thoughtful trial planning and overall drug development.
• Access versus rigor is a balancing act. Regulators, clinicians, and sponsors must collaborate to ensure innovation reaches patients quickly while maintaining robust safety and efficacy standards.

About Dr. Hadfield and Dr. Singh

Matthew Hadfield, DO, is a Medical Oncologist at Brown University/Legorreta Cancer Center. He recently completed his Hematology/Oncology Fellowship at Brown University. Dr. Hadfield’s clinical and research interests are in phase 1 clinical trials and developmental therapeutics, as well as cutaneous malignancies and immunotherapy-related adverse events.

Harpreet Singh, MD, is the Chief Medical Officer at Precision for Medicine and a former Division Director of Oncology at the FDA, where she oversaw the development of multiple targeted therapies. Her extensive background also includes her role as Associate Director for Cancer in Older Adults and Special Populations at the FDA Oncology Center of Excellence, as well as a fellowship at the National Cancer Institute. Dr. Singh is recognized for her innovative contributions to drug development.