FDA to Adopt Single-trial Default Policy: Implications for Biopharma and Vaccine Innovation

The U.S. Food and Drug Administration (FDA) has announced a significant shift in its drug approval standards, moving away from the long-standing expectation that sponsors generate two independent pivotal clinical trials to support approval. Under the new policy laid out by FDA Commissioner Dr. Marty Makary and Dr. Vinay Prasad of the Center for Biologics Evaluation and Research, the agency will generally treat a single well-designed and controlled clinical study - backed by confirmatory evidence - as the default basis for demonstrating “substantial evidence” of efficacy and safety. This marks a departure from decades of regulatory practice. 

In a piece published this week in The New England Journal of Medicine (paid access required), Makary and Prasad wrote that the historical “two-trial dogma” - rooted in interpretations of 20th-century law - no longer reflects modern scientific and statistical capabilities. They argued that one robust study, combined with mechanistic or supportive evidence, can provide sufficient confidence in a drug’s therapeutic benefit.  

For biopharmaceutical companies, the shift to a single-trial default offers multiple potential benefits: 

• Faster timelines and lower costs: Running two large Phase III trials remains one of the most expensive and time-consuming elements of drug development. Accepting one pivotal trial can shorten clinical programs and reduce budgetary burdens.  

• Accelerated access for patients: With fewer duplicative trials required, effective therapies could reach patients sooner, particularly for diseases where enrolling large, confirmatory studies can be challenging.  

• Strategic flexibility: Sponsors may be able to focus resources on richer trial designs or adaptive approaches that provide deeper insights into efficacy signals without repeating similar confirmatory studies.  

Some analysts even suggest that less onerous evidence standards could enhance R&D investment by lowering regulatory risk and improving sponsor confidence in development strategies. 

For vaccines and complex biologics, the implications are nuanced. Traditional vaccine development - especially for broad public immunization - has relied on multiple trials or confirmatory endpoints (such as immune correlates of protection) to build confidence in both safety and efficacy. While the single-trial default could apply to many therapeutic biologics, some experts suggest that vaccines may still warrant stronger confirmatory evidence or continued dual-trial expectations because of their use in healthy populations and the high bar for public confidence. 

Indeed, a dual-policy discussion emerging from regulatory circles highlights a potential split: while many small-molecule drugs and certain biologics may qualify for single-trial approval, vaccines might still face randomized controlled trials or higher evidence expectations to ensure broad safety assurance prior to licensure. 

Despite the potential benefits, the new policy has stirred debate among regulators and industry stakeholders. Critics argue that reducing the default to one trial could risk overreliance on a single dataset that may not fully uncover rare adverse events or confirm consistency of effect - particularly for novel modalities or complex immunologic responses. 

Moreover, the FDA has been careful to emphasize that sponsors may still need additional studies or strengthened confirmatory evidence depending on context, and the agency retains discretion to require more data when warranted. 

The shift to a single-trial default reflects broader FDA efforts to modernize its regulatory framework and align approval standards with advances in clinical science and statistical design. For the biopharma sector - especially developers of transformative therapies and next-generation vaccines - this policy could reshape clinical development planning, investment decisions, and timelines for bringing new medicines to patients. As implementation unfolds over the next several months, companies, regulators, and investors alike will be watching closely for guidance on how this new standard is applied in practice.