The U.S. Food and Drug Administration's recent decision to allow a single pivotal trial for new drug applications, instead of the previous requirement for two, is prompting sponsors to strengthen their approaches to patient safety, data collection, and risk management. The change was discussed by industry experts on Mar. 10.
The move is significant because it increases the importance of each individual trial, requiring that it be robust enough to support regulatory approval on its own. Vera Pomerantseva, director of product management for risk-based quality management at eClinical Solutions, said regulators now expect one “bulletproof” trial rather than two less conclusive ones.
Pomerantseva also noted that other agencies such as the European Medicines Agency have already accepted single registrational studies. She said the FDA’s policy accelerates patient access without compromising safety or efficacy.
Oxana Iliach, senior director of regulatory strategy at Certara, described the FDA’s stance as both an evolution and a fundamental shift. While single pivotal trials have been common in rare diseases, Iliach said the greater change is demonstrating impact in one study for more common conditions.
Iliach emphasized that sponsors should “plan, plan, plan” and engage with regulators early to ensure adequate efficacy and safety data are generated from a single pivotal trial. She suggested learning from rare disease programs by planning across nonclinical pharmacology and toxicology studies to inform the main trial. Transparency in data sources and modeling assumptions is crucial throughout development.
Risk management has become even more important under this new approach. Pomerantseva highlighted updated guidance such as ICH E6(R3), which came into effect in January 2025, describing risk-based approaches as essential rather than optional. She advised sponsors to distinguish between proactive and reactive elements of risk management and link Quality by Design principles directly to protocol review during development.
Ongoing oversight of potential data inconsistencies and unexpected events is necessary to demonstrate full control over trial execution and data validity. Pomerantseva pointed out that artificial intelligence can help process large datasets quickly and support stronger evidence bases through larger trials and integration of real-world evidence (RWE). She added that the FDA has embraced RWE and suggested AI can unlock insights supporting efficacy and safety under the single-trial paradigm.
The broader implications of this policy shift include faster patient access to new therapies but also increased responsibility for sponsors to ensure their trials are comprehensive enough for regulatory approval.
