A System Under Correction—But Still Under Pressure: Confidence in the FDA Lags Even as Cancer Drug Standards Tighten

The U.S. Food and Drug Administration is no longer operating in the same mode that defined oncology drug approvals over the past decade. After years of expanding access through accelerated pathways, the agency is now tightening its approach—requiring stronger evidence earlier and taking a more active role in confirming clinical benefit.

But this shift comes at a complicated moment.

Clinician confidence remains under pressure, even as regulatory standards become more stringent. The issue is no longer simply about whether drugs are approved too quickly. It is about how uncertainty is managed in a system where scientific progress is accelerating faster than long-term evidence can be generated.

Withdrawals and Data Reveal Systemic Gaps

The scale of the challenge is now clearer.

Across oncology, approximately 200 indications have been approved through accelerated pathways, and more than 30 have been withdrawn—most within the past five years. Analyses published in JAMA suggest that over half of these approvals fail to demonstrate clear clinical benefit after extended follow-up.

• Melphalan flufenamide (Pepaxto): This drug was initially granted accelerated approval based on a surrogate endpoint (Overall Response Rate) in the HORIZON study. However, the confirmatory OCEAN trial (NCT03151811) revealed a significant safety signal. While it met its primary goal of improving Progression-Free Survival (PFS), the data showed a detrimental effect on Overall Survival (OS)—meaning patients on the new drug actually died sooner (19.8 months) than those on the older comparator, pomalidomide (25.0 months). This “divergence” between tumor shrinkage and actual survival led to a high-profile FDA withdrawal in 2024, as the agency determined the drug’s risks outweighed its benefits.
• Infigratinib (Truseltiq): Approved for a specific niche of bile duct cancer (FGFR2+ cholangiocarcinoma), this drug faced a different structural failure. Its approval was contingent on the Phase 3 PROOF trial, which was designed to move the drug into “first-line” treatment. However, the sponsor voluntarily withdrew the indication in 2024 not due to safety, but because they could not recruit enough patients. This “recruitment failure” highlights a systemic gap: once a drug is available via accelerated approval, patients are often reluctant to enroll in a randomized trial where they might receive the “standard” treatment instead of the new drug.

These cases highlight a recurring issue: early data can appear compelling in small or highly selected patient populations, but may not hold up under broader, more rigorous testing.

Regulatory Shift: From Expansion to Correction

In response, the FDA has begun to tighten its oversight.

New guidance introduced in 2025 requires confirmatory trials to be “well underway”—meaning actively enrolling—before an accelerated approval is even granted. This shift is a direct application of the Food and Drug Omnibus Reform Act (FDORA), which strengthens the agency’s ability to withdraw indications when evidence fails to materialize.

This correction is increasingly driven by Project Optimus, a landmark initiative that marks a paradigm shift in drug development. By 2026, the industry has largely moved away from the traditional “Maximum Tolerated Dose” (MTD) model—which often resulted in drugs being too toxic for long-term use—toward finding the “Optimal Dose” early in the trial process. This structural change aims to prevent late-stage failures by ensuring efficacy and safety are balanced long before the confirmatory stage.

The shift is already visible in approval decisions. In 2026, the FDA declined to approve therapies from Replimune and Atara, citing insufficient trial design and inadequate evidence of efficacy. These decisions suggest a move toward filtering uncertainty before approval, rather than relying on post-market correction.

Why Confidence Still Hasn’t Recovered

Despite these changes, clinician confidence continues to decline.

• Entrenched Uncertainty: When drugs are approved based on early data, physicians must make treatment decisions before long-term outcomes are known. Even if a drug is later withdrawn, it may already have been used in patients for years.
• Inconsistency: As standards evolve, trial designs that were once acceptable may no longer meet regulatory expectations. This creates uncertainty about what level of evidence is required.
• Communication Gaps: Around 42% of clinicians report that changes in FDA communication negatively affect practice, suggesting that even scientifically sound decisions are not always clearly conveyed.
• Surrogate Endpoints: The system continues to rely on measures like PFS and ORR. While necessary for speed, these do not consistently predict overall survival, creating an inherent tension between early access and long-term certainty.

This combination of factors creates a compounding effect where regulatory speed and clinical reality are fundamentally misaligned. When the FDA utilizes surrogate endpoints like PFS and ORR, they prioritize the “biological signal” of a drug’s activity to provide early access, yet according to FDA’s Project Confirm, these markers often fail to translate into OS or improved quality of life. This creates a “validation gap” where the inconsistency of evolving standards meets a communication breakdown, leaving close to half of clinicians struggling to interpret whether a “dangling” approval is a breakthrough or a future withdrawal. Consequently, the entrenched uncertainty in daily practice isn’t just about the data itself, but about the lack of a clear, unified framework that tells a physician if the drug they are prescribing today will still be considered effective tomorrow.

A Rapidly Expanding Oncology Landscape

The pace of oncology innovation continues to accelerate. The FDA approved approximately:

• 83 oncology drugs and indications in 2023: Including 13 novel drugs and 70 supplemental approvals.
• Moving to 89 oncology drug and biologic product approvals in 2024: Driven by a surge in cell therapies and bi-specific antibodies.
• 58 novel drugs and biologics in 2025: Comprising 46 CDER and 12 CBER approvals; oncology represented 28% of these approvals, with half designed for rare diseases.

This growth reflects advances in immunotherapy, antibody-drug conjugates, cell therapies, and precision medicine. But it also increases complexity. Modern cancer drugs are no longer developed for a single disease; one therapy may be tested across multiple tumor types, biomarkers, and lines of treatment. Each expansion introduces new variables—and new uncertainty.

As a result, approvals are increasing faster than the time needed to fully confirm their long-term benefit.

A System Learning in Real Time

The FDA is not stepping back from innovation. It is adjusting how it manages risk in a rapidly evolving field.

The shift toward stricter standards, earlier confirmation, and the dose-optimization framework of Project Optimus reflects a recognition that speed alone is not enough. But the transition also exposes the uncertainty that has already entered clinical practice. The central challenge now is not just scientific—it is structural. The system must determine how to balance early access with reliable evidence, in a landscape where both the volume and complexity of new therapies continue to grow.

Until that balance is more clearly defined, confidence in the system is likely to remain under pressure—even as oncology itself continues to advance.

Author

Bernice Lottering