FDA Signals Shift Toward a One-Trial Default for Drug Approval

In a recent New England Journal of Medicine commentary (Link), FDA Commissioner Dr. Marty Makary and Deputy Director Dr. Vinay Prasad outlined a significant evolution in the agency’s evidentiary framework for new drug approvals. The FDA is moving away from the long-standing expectation of two adequate and well-controlled studies and toward a default position of one robust pivotal trial supported by confirmatory evidence.

As stated in NEJM: “Going forward, the FDA’s default position is that one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorization of novel products.”

Importantly, this does not alter the statutory requirement for “substantial evidence of effectiveness.” Rather, it reflects a modernization of how such evidence may be assembled and interpreted in light of advances in trial design, statistical methods, biomarkers, and real-world data.

Potential Advantages

A single high-quality pivotal study, when rigorously designed and supported by confirmatory data, may accelerate development timelines and reduce unnecessary duplication of trials. This approach could be particularly meaningful in therapeutic areas with high unmet need, rare diseases, or operationally complex programs. It may also allow sponsors to allocate resources more efficiently while maintaining scientific integrity.

Considerations and Risks

At the same time, reproducibility has long been a cornerstone of regulatory science. Two independent trials historically provided a safeguard against chance findings or design-specific bias. Under the new framework, greater emphasis will fall on trial quality, statistical robustness, endpoint selection, and the strength of supportive evidence. Clear regulatory alignment early in development will be essential. Stakeholders, including payers and clinicians, will likely scrutinize how confirmatory evidence is defined and applied in practice.

At Cromos Pharma, we view this development as an important evolution in regulatory thinking. It underscores the need for thoughtful, strategically designed clinical programs that prioritize rigor over redundancy. As the landscape adapts, careful planning, early FDA engagement, and disciplined execution will remain critical to ensuring that speed does not come at the expense of confidence in the data.

We welcome discussion on how this shift may influence clinical development strategy across therapeutic areas.