News & Alerts

U.S. Food and Drug Administration
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Docket Number: FDA-2024-D-5850
Issued by: Oncology Center of Excellence

To Whom It May Concern:

The National Breast Cancer Coalition (NBCC) appreciates the opportunity to comment on the U.S. Food and Drug Administration’s (FDA) Draft Guidance for Industry: Approaches to Assessment of Overall Survival in Oncology Clinical Trials (August 2025).

NBCC is a grassroots advocacy organization representing tens of thousands of advocates, researchers, and survivors across the United States and internationally. Since our founding in 1991, NBCC’s mission has been to end breast cancer through the power of action and advocacy—ensuring that research, policy, and regulation serve patients’ real needs and reflect sound scientific and ethical principles.

We commend FDA for its continuing efforts to strengthen oncology trial integrity and ensure that drug approvals are based on clinically meaningful outcomes. However, several aspects of this draft guidance would benefit from revision to ensure that patient protection, ethical conduct, and true clinical benefit remain at the center of regulatory decision-making.

1. Crossover Should Be Mandated When Later-Line Efficacy Exists

The draft guidance recommends limiting protocol-specified crossover because it can complicate interpretation of overall survival (OS). While we recognize the statistical challenges crossover introduces, NBCC believes that crossover should be required—not limited—when a therapy has already demonstrated efficacy in a later-line setting and is being studied in an earlier line of treatment.

In such cases, denying patients on the control arm access to a therapy already proven to extend or improve life is inconsistent with modern standards of ethical research and clinical practice. Trial participants should never be disadvantaged relative to patients outside the trial.

We therefore recommend the following revision to Section III.A:

• When a therapy has demonstrated survival or clinical benefit in a later-line setting and is being studied for use in an earlier line of therapy, protocol-specified crossover should be included to allow participants in the control arm access to the investigational therapy upon disease progression. Sponsors should prespecify appropriate statistical methods to adjust for crossover in overall survival analyses.

2. Overall Survival Must Be Treated as a Measure of Clinical Benefit, Not Solely a Safety Endpoint

The guidance frames OS largely as a safety measure when it is not the primary endpoint. NBCC urges FDA to reaffirm that OS remains the gold standard measure of benefit in oncology.

Labeling OS primarily as a safety assessment, risks encouraging sponsors to rely excessively on unvalidated surrogate endpoints such as response rate or progression-free survival (PFS), which often fail to predict real patient benefit.

Recommendation:

• FDA should require that overall survival be prospectively incorporated as a co-primary or key secondary endpoint in all randomized oncology trials where feasible, with a pre-specified statistical plan for efficacy assessment rather than only descriptive safety evaluation.

3. Patient and Advocate Input Must Be Incorporated When Defining “Clinically Meaningful Harm”

The draft guidance directs sponsors to pre-specify thresholds for “clinically relevant harm” but provides no mechanism for incorporating patient perspectives into these determinations.

NBCC believes this is a critical omission. What constitutes an acceptable degree of harm or uncertainty must reflect patient and advocate input, not purely statistical convention. Acceptability of risk depends on disease context, treatment goals, and quality-of-life trade-offs—dimensions best understood through direct engagement with patients and advocates.

Recommendation:

• FDA should require sponsors to obtain and document patient and advocate input when defining harm thresholds, including hazard-ratio cut-offs and acceptable uncertainty levels, to ensure that harm assessments reflect patient values and preferences.

4. Strengthen Guidance on Use of Surrogate Endpoints

While the guidance acknowledges instances where surrogate endpoints (e.g., PFS, MRD, response rate) have failed to align with OS, it does not go far enough in discouraging their overuse.

NBCC has repeatedly called attention to the problem of uninformative trials and approvals based on unvalidated surrogates that do not translate into better survival or quality of life. The final guidance should make explicit that surrogate endpoints may justify accelerated approval but cannot substitute for OS in traditional approval decisions without robust validation.

Recommendation:

• FDA should include clear language discouraging reliance on unvalidated surrogate endpoints for full approval and requiring verification of meaningful overall survival benefit or patient-reported outcome benefit as confirmatory evidence.

5. Embed Patient Engagement Throughout Trial Design and Analysis Planning

The guidance is written exclusively from a sponsor-statistician perspective. It omits reference to the role of trained patient advocates in shaping the statistical analysis plan (SAP), endpoint prioritization, or harm assessment.

This omission conflicts with the spirit of the 21st Century Cures Act and FDA’s Patient-Focused Drug Development (PFDD) framework. Trained patient advocates must have a meaningful role in defining outcomes that matter to patients, interpreting risk, and determining whether observed differences in OS are clinically meaningful.

Recommendation:

• FDA should explicitly recommend that trained patient advocates who represent a patient constituency participate in trial design, endpoint selection, and statistical analysis planning to ensure that endpoints, harm thresholds, and analytic assumptions reflect patient priorities.

Conclusion

NBCC supports FDA’s commitment to strengthening oncology trial evaluation and to ensuring that new drugs provide real, measurable benefit to patients. However, to achieve a truly patient-centered regulatory framework, the final guidance should include our above-described recommendations.

By adopting these recommendations, FDA will strengthen scientific credibility while ensuring that oncology research and drug approvals remain ethically grounded and centered on the outcomes that matter most to patients: living longer and living better.