Single-trial approvals are raising the bar on trial design and execution. The new paradigm is pushing sponsors to plan earlier, step up their data and risk‑based quality management and use modeling and AI to generate one compelling, regulator‑ready evidence package.
In the wake of the recent FDA decision to move from a requirement of two pivotal trials to one for new drug applications, sponsors now face higher stakes. They include maintaining patient safety and enabling stronger risk and data collection and management strategies.
Rather than lowering the scientific bar, regulators now expect one “bulletproof” trial rather than two less conclusive ones, said Vera Pomerantseva, director of product management for risk-based quality management at eClinical Solutions.
Other regulators, such as the European Medicines Agency, have accepted single registrational studies, said Pomerantseva. FDA’s move accelerates patient access without compromising safety or efficacy, she added.
The FDA’s stance is both an evolution and a fundamental shift, said Oxana Iliach, senior director of regulatory strategy at Certara. While single pivotal trials have long been accepted in rare diseases, the greater change is showing impact in one study on disease progression and curative potential for more common conditions.
Better Data Collection
A key takeaway of the policy shift is for sponsors to “plan, plan, plan” and engage regulators early and consistently to ensure adequate efficacy and safety data is generated for that single pivotal trial, Iliach said.
Lessons can be cultivated from rare disease and cell and gene therapy programs in terms of planning early across nonclinical pharmacology, toxicology and first-in-human studies to feed data into that one pivotal trial, Iliach said. Companies can better characterize pharmacokinetics and pharmacodynamics across healthy volunteers and patients, showing how the body affects the drug and vice versa, and transparently documenting input data, model construction and outputs.
Transparency is crucial, Iliach and Pomerantseva agreed, across data sources, assumptions, and the extent to which models reflect real-world therapy use and potential drug–drug interaction scenarios. Modeling and simulation should be embedded strategically across development to bridge clinically tested and untested scenarios, Iliach added.
Elevated Risk Management
Risk management becomes an even higher priority under single-trial designs, Pomerantseva said, noting the evolution of guidance, including ICH E6(R3), and describing risk-based approaches as a “must have” rather than optional. The final version of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human UseE6(R3) guideline came into effect in January 2025.
Sponsors must distinguish proactive and reactive elements of risk management, as well as link proactive Quality by Design principles to protocol review during development. They should also perform risk assessments before finalization and ensure operationally executable designs (in terms of endpoints, population demographics and trial sample size) that support strong evidence and safety, Pomerantseva said.
Ultimately, there is a need for ongoing, real-time oversight of potential data and inconsistencies, monitoring unexpected events and ensuring portfolio-level oversight across studies. This can ensure sponsors can demonstrate full control of trial execution and data validity, Pomerantseva said. Historically, siloed data review across R&D functions have led to gaps and inefficiencies, but in the single trial paradigm, this can no longer happen.
Artificial intelligence (AI) can assist tremendously in processing large datasets rapidly, summarizing information and supporting stronger evidence bases through larger trials and integration of real-world evidence (RWE), Pomerantseva said. FDA has embraced RWE and suggested that AI and advanced statistics can unlock data insights that support efficacy and safety evidence under the single-trial paradigm, she added.
You can hear more on this week’s Denatured podcast episode.
