FDA Announces a Single Pivotal Trial as the New Default Standard for Drug Approval

This policy change formally ends the longstanding requirement for two clinical trials that has characterized FDA drug approvals for decades. The announcement came in the form of a paper authored by Drs. Martin Makary (the FDA commissioner) and Vinay Prasad (the director of the Center for Biologics Evaluation and Research) and published in the New England Journal of Medicine (NEJM).

The Two-Trial Requirement

Historically, the FDA has relied on two clinical trials to establish credible causal evidence that a new therapy could improve clinical outcomes with acceptable safety. From a statistical perspective, and using the testing of an inert (safe but ineffective) substance as an example, a requirement for two trials reduces the chance of a Type 1 error (a false positive finding) from 250 in 10,000 to six in 10,000. However, this approach was developed in an era when biologic understanding was more limited, and drug development was less precise.

Notably, since 1997, the FDA has had statutory authority to grant marketing authorizations based on a single adequate and well-controlled study combined with confirmatory evidence, and in certain fields involving serious or hard-to-treat conditions (e.g., oncology), single-trial approvals have been in the majority. Confirmatory evidence may include mechanistic science, data from a related indication, animal models, information from other drugs of the same class, real-world evidence, or a second adequate and well-controlled study. However, uncertainty among manufacturers as to when a single trial would be accepted has persisted.

The New Default Standard

Under the new policy, the FDA’s default position is that one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis for marketing authorization of novel drug products. The NEJM paper notes that modern drug development establishes credibility in multiple ways, relying on conclusions from both statistical and biologic evidence. Today, manufacturers go to great lengths to elucidate the precise mechanism of action of their products, and the FDA considers not only a drug’s effect on patient survival, but also the biological changes that indicate how the drug works.

In order to confirm a single trial’s credibility, the FDA will carefully examine all aspects of study design, including the prespecification of a hypothesis, the nature of the controls, the size of the effect, the choice of primary endpoint, statistical power, inclusion and exclusion criteria, blinding, randomization, independent review, the handling of missing data, and many other factors.

Key Exceptions

Importantly, the FDA reserves the right to require two or more studies in certain circumstances. Thus, additional adequate and well-controlled studies may be required if the trial:

• Has an unclear, multi-pronged, or nonspecific mechanism of action.

• Affects a variable, short-term, or surrogate outcome.

• Has an underlying limitation or deficiency.

Implications for the Pharmaceutical Industry

Reduced Costs and Faster Time to Market: At present, the average time to bring a new drug to market currently exceeds seven years. The authors expect that the policy change will substantially reduce costs for sponsors and speed drugs to market. Nevertheless, estimates suggest that a single pivotal study could still cost between $30 million and $150 million, and such trials may require years to complete. Lowering capital costs for drug developers may also mitigate arguments justifying high drug prices based on research and development expenses.

Enhanced Quality Focus: The authors believe that greater attention will be paid to the quality of a single pivotal trial. Instead of prioritizing finite reviewer time reading and assessing two or more pivotal trials, the agency will focus its energies on ensuring that the one required clinical trial provides the most up-to-date and useful information for patients. This may result in heightened scrutiny of control arm quality and trial design elements.

Anticipated Surge in Drug Development: The authors expect a surge in drug development activity in response to this initiative.

Postmarket Data Collection: This reform is being implemented simultaneously with the agency’s postmarket initiative to collect robust data on all drugs and devices. Companies should anticipate continued or enhanced postmarket surveillance requirements.

Addressing Potential Concerns

In the NEJM paper, the authors address potential criticism that this new FDA policy relaxes safety and efficacy standards. They note that that even with a default requirement of two trials, the FDA has previously approved products later found to have serious safety concerns or lack efficacy. Additionally, the number of clinical studies is not a safeguard if other aspects of trial design are deficient. Erroneous conclusions may be reached even with multiple studies if the control arm is substandard, endpoints are dubious, statistical plans are generated after the fact, or the statistical power is inadequate. The authors believe that their proposal for a single robust and sound clinical trial may actually improve the FDA’s standards and reduce the risk of approval of a product later found to be deficient.

Conclusion

This policy change represents a meaningful shift in the FDA’s approach to drug approval. For pharmaceutical and biotech companies, the new default standard may offer opportunities to streamline development timelines and reduce costs. However, companies should expect rigorous scrutiny of their single pivotal trials and should be prepared for robust postmarket surveillance obligations. Early engagement with the FDA on trial design, control groups, and confirmatory evidence strategies will be essential to leveraging this new framework effectively.