Recently, Drs. Marty Makary (US FDA Commissioner) and Vinay Prasad (FDA CBER Director) authored text in the New England Journal of Medicine signifying a purported paradigm shift in the way FDA will review applications for licensure, noting that moving forward only a single pivotal trial of an investigational medicinal product (IMP) will be required. This stands counter to the broadly accepted dogma that summary of two adequate and well-controlled pivotal trials (AWCs; e.g., comparison of an IMP to an approved medicine or placebo, and blinded where feasible) are required for submission of either a New Drug Application or Biologics License Application.
Importantly, the possibility for the FDA to approve on the basis of one adequate and well controlled trial in combination with confirmatory evidence has been in place since 1997 and is regularly leveraged for rare and/or serious diseases, particularly under accelerated approval paradigms. There has also historically been success taking a one-trial approach in other therapy areas with a well-designed and justified protocol. Similarly, the FDA emphasizes that in addition to the single trial being well‑designed and well‑conducted, it must use the most relevant comparator for the US population, which may increase the need for active‑comparator designs to meet US regulatory expectations.
On the surface, this looks like a massive win for drug developers seeking approval in the US, but’s it’s fair to question the gravity of this NEJM publication for multiple reasons:
- While this publication follows a prior FDA-authored NEJM article regarding a new Plausible Mechanism Pathway, it is unclear if these thoughts will be formally promulgated in official FDA Guidance.
- Particularly given recent technological and medical advances, FDA have already been “following the science” on a case by case basis, and have recently (2023) proposed draft guidance on evidence of substantial effectiveness being derived from a single pivotal trial. This is in line with a careful perusal of 21 CFR 314 (Applications for FDA Approval to Market a New Drug), which alludes to regulatory discretion as it relates to a need for two AWCs.
- The article declines to opine on the single-trial sample size, nebulously noting only that “the FDA will carefully examine all aspects of study design with particular focus on controls, end points, effect size, and statistical protocols.”
- This stance appears to run contrary to Prasad’s well-documented opinions that FDA have acted as a “rubber stamp” for drug approvals, and that additional burdens of proof should be required for IMP licensure.
- The utility of Real World Evidence/Real World Data in regulatory decision-making has already been established.
To be clear, Makary’s and Prasad’s thoughts should be taken at face value, with the single pivotal trial approach manifesting in regulatory roadmaps and content of formal meetings between sponsors and FDA. Rather than negotiating down from two trials, sponsors may now plan from the outset around a single pivotal study representing the reality of modern drug development where originators strive for a good understanding of the mechanism of action and generate additional supportive data throughout development in order to manage risk. Further, even if not yet firmly described in regulation or guidance, it appears to be a step in the direction of simplifying the IND phase.
While this is a bold statement of intent from the FDA, as has been the case with many of FDA’s press releases over the past calendar year, we will need to see the practical implications before forming a firm opinion. How this shift will influence global development strategies remains uncertain, and safety database requirements under ICH E1 will continue to apply. Its practical impact on global drug development remains to be seen.
