Cautious Optimism About FDA’s One Pivotal Trial Policy

Deborah Borfitz 

Earlier this year, the U.S. Food and Drug Administration (FDA) made a single pivotal clinical trial the default requirement for getting a medicine to market in lieu of the traditional two-trial mandate. It was a controversial move designed to reduce clinical development costs for drug sponsors, but it comes with the peril of potential project failure if study results aren’t rigorously defensible—or if companies fail to invest heavily in the quality of that single trial using readily accessible tools for data monitoring, artificial intelligence (AI), and biosimulation. 

The predicament has not escaped the attention of technology providers like Certara and eClinical Solutions that are now actively seeking to derisk these high-stakes trials. Certara brings biosimulation software and expert consulting to the table for predicting drug behavior and optimizing trial design, while eClinical Solutions offers a clinical data cloud platform and biometrics services to digitize and manage the flow of trial data. 

The one-trial approach has long been in vogue for oncology and rare disease indications that require faster development pathways, notes Venu Mallarapu, chief transformation and AI officer at eClinical Solutions. That it is now being applied to all trials means the margin for error is much smaller while expectations for data quality, rigor, and operational perfection have increased substantially. 

The FDA announced that one pivotal trial will now be the rule rather than the exception in an article that was published earlier this year in The New England Journal of Medicine (DOI: 10.1056/NEJMsb2517623). “This is one of the most significant changes in regulatory policy in a very long time, and I very much applaud it,” says Piet van der Graaf, PharmD, Ph.D., senior vice president of applied biosimulation at Certara, professor of systems pharmacology at Leiden University (Netherlands), and professor of pediatrics at Cincinnati Children’s Hospital Medical Center. “I would think most, if not everyone, in the industry would agree with me.” 

Reactions to the new policy have been mixed, according to Mallarapu. While some expect it to accelerate the pace of bringing new medicines to market, the “contrarian view” is that it lowers safety standards and risks introducing unreliable drugs by relying on a weakened evidence base. 

Both perspectives are valid, he adds, and the reason why sponsors need to “take stock of how things are managed internally” to identify their optimal strategy. Risk-based quality management (RBQM), a major specialty and focus area for eClinical Solutions, was “designed for just this kind of scenario.” 

Revisions to ICH E8 (General Considerations for Clinical Studies), finalized in 2021, also align well with RBQM adoption. The international guideline advocates for a shift away from a rigid, checklist-based oversight approach to a flexible and proactive risk-based one focused on quality by design. 

RBQM helps in building the process, systems, and teams for operating under the new regulatory framework, says Mallarapu. While one pivotal trial is a new standard, it is not a mandate, and the FDA may require more than a single trial if it is deemed necessary.