FDA Solid Tumor Approvals Shift Toward Surrogate Endpoints

Key Takeaways

• In FDA adult solid tumor indication approvals, overall survival became less common as a primary endpoint.
• Surrogate endpoints became more common, and response rate overtook progression-free survival as the leading surrogate.
• Single-arm pivotal trials supported more approvals, while randomized trial support became less common.
• Regular approval remained the predominant pathway, even as surrogate endpoints became more common among regular approvals.
• Senior author Bishal Gyawali interpreted the shift as a concern about evidence quality and questioned whether accelerated approval was being used often enough.

What does US Food and Drug Administration (FDA) approval establish for a medicine treating an adult solid tumor? A trial measuring overall survival addresses a different question from one measuring tumor response. Randomized and single-arm trials also provide different evidence about a medicine's effects. For oncologists interpreting an indication, the endpoint and trial design shape what is known at authorization. Investigators examined how those features varied across approvals over time.

Shkabari and colleagues’ JAMA analysis examined 385 unique FDA adult solid tumor indication approvals dated 2006 through 2025. Using FDA approval notifications and Drugs@FDA, the investigators included original and supplemental indications; supplemental indications outnumbered new drugs. Each indication approval counted separately, including distinct indications for the same medicine within one cancer type. The investigators grouped approvals into four successive five-year periods. They excluded hematologic and pediatric indications, diagnostics, biosimilars, generics, reformulations, and dose changes. They tracked primary efficacy endpoints, pivotal trial design, and regular versus accelerated approval, not patient-level outcomes.

From 2006–2010 to 2021–2025, overall survival (OS) as a primary endpoint fell from 40% to 18.7% of approvals. Surrogate primary endpoints rose from 60% to 81.3%. Response rate as a primary efficacy endpoint rose from 10% to 42.6%, becoming the most common surrogate. Progression-free survival (PFS) changed little over the same period. Across the full analysis, surrogate-backed approvals outnumbered OS-backed approvals.

Support from single-arm pivotal trials rose from 12.9% to 37.2% between the first and last periods, while randomized trial support fell from 87.1% to 62.8%. These shifts describe pivotal trial design over time. Across all periods, regular approvals accounted for 72.7% versus 27.3% for accelerated approvals. Surrogate endpoints also became more common among regular approvals. The approved treatment mix shifted away from chemotherapy toward immunotherapy, targeted agents, and antibody–drug conjugates.

The findings apply to FDA adult solid tumor indications, not hematologic or pediatric approvals. This cross-sectional comparison of approval evidence does not establish whether survival or other patient outcomes changed. Gyawali interpreted the greater reliance on surrogates and single-arm studies as a concern about declining evidentiary quality. He also questioned whether accelerated approval was used as often as expected when regular approvals rested on such evidence.

For Gyawali, the unresolved regulatory question is whether the pathway chosen for an indication adequately reflects the evidence available at approval. These approval trends cannot determine the consequences for patients.

Clinician Questions

What confirmatory evidence is required after accelerated approval of a drug for an adult solid tumor?

FDA accelerated approval for a medicine treating adults with solid tumors requires confirmatory studies to demonstrate clinical benefit. If benefit is not demonstrated, the FDA can take steps to remove the therapy from the market. Gyawali's concern is that regular approval upfront on surrogate or single-arm evidence does not carry that accelerated-approval confirmation requirement.

How are different treatment-line indications for the same adult solid tumor drug counted in FDA approval trends?

Different FDA-approved indications of the same medicine within the same adult solid tumor type count as separate indication approvals. First-line and later-line uses are an example, even when they involve the same drug and cancer type.