The FDA’s transition to a single-trial default for drug and biologic approvals marks a pivotal evolution in regulatory philosophy, moving away from the 1962 Kefauver-Harris dual-study precedent. For industry leadership, this shift offers a significant opportunity to accelerate speed-to-market, provided that clinical programs are built on a foundation of absolute statistical and biological rigor. However, this flexibility does not signal a lowering of the regulatory bar; rather, it intensifies the technical burden on sponsors to deliver definitive evidence within a more condensed window.
For decades, the “gold standard” for drug approval in the United States was the dual-trial requirement. Under the 1962 Kefauver-Harris Amendment, sponsors typically had to provide “substantial evidence” of effectiveness through at least two adequate and well-controlled clinical investigations. The “substantial evidence” standard was interpreted as a requirement for two adequate and well-controlled investigations to mitigate the risk of Type I errors or “fluke” results. However, as medicine moves toward precision therapies and orphan disease treatments, the FDA has increasingly embraced regulatory flexibility. Today, a single pivotal trial can serve as the cornerstone of a New Drug Application (NDA) or Biologics License Application (BLA), provided it meets specific, rigorous criteria.
However, the FDA did not grant single-trial approval lightly. According to the agency’s 2019 and 2023 guidance documents, three conditions must generally be met to justify this departure from the two-trial norm. First, a single trial must be large, multicenter, and highly persuasive. If the results are statistically “extreme” (e.g., a p-value much lower than the standard $0.05$), the FDA may conclude that a second trial would be redundant or even unethical. Second, the FDA requires confirmatory evidence to bolster the findings from the single pivotal trial. This can include, mechanistic data that presents clear proof that the drug hits its intended biological target, data from a different but closely related disease where the drug has already shown efficacy, and natural history studies comparing trial results to the documented progression of the disease without treatment. Third, the single-trial approvals have been most common for orphan drugs or treatments for life-threatening conditions with no existing therapy. In these cases, the patient population is often too small to support two full-scale Phase 3 trials.
As outlined by Commissioner Dr. Marty Makary and Dr. Vinay Prasad, the agency is now expanding the above norm for rare diseases to all indications. The agency will prioritize biological plausibility and extreme statistical significance over mere replication. The precedent set in orphan and oncology indications, where 60% of recent NMEs were cleared via a single trial, now extends to all other disease states.
Like everything in life, this policy carries its own challenges. For C-suite executives, it is critical to recognize that a single-trial pathway eliminates the “safety net” of replication. Under the traditional model, a marginal first trial could potentially be redeemed by a robust second trial. Under the new default, the burden of proof shifts entirely to the quality and depth of the initial pivotal data. To secure approval with a single investigation, sponsors must present a comprehensive evidentiary package, including:
- Mechanistic Clarity: Highly granular data from pilot and exploratory studies that confirm the drug’s pharmacological target and dose-response curve.
- Statistical Persuasiveness: A pivotal trial design that achieves high power and ideally displays an “extreme” p-value to eliminate concerns regarding reproducibility.
- Confirmatory Multi-Source Evidence: Leveraging natural history studies, real-world evidence (RWE), or validated surrogate endpoints to bolster the primary trial results.
While the “one-study” stance aims to catalyze a surge in development, the FDA remains a rigorous gatekeeper. Recent rejections of gene therapies and mRNA flu vaccines underscore that the agency will not hesitate to demand additional data if a single trial leaves any ambiguity regarding safety or efficacy. Former drug director Dr. Janet Woodcock aptly noted that “implementation will be everything.”
The risk for sponsors lies in the “grey zone” of statistical significance. If a single trial delivers positive but non-definitive results, the FDA reserves the authority to revert to a two-trial requirement or mandate extensive post-marketing (Phase 4) commitments. This creates a high-stakes environment where a failed single-trial strategy could result in significant delays compared to a traditional two-trial parallel design. Furthermore, internal stakeholders and investors may perceive the lack of a second confirmatory trial as an increased risk to long-term market stability. Sponsors must be prepared to justify their data quality not just to the FDA, but to a skeptical market that no longer sees a “second chance” in the pipeline. Reliance on a single study requires a level of trial integrity and site monitoring that leaves zero room for operational error.
While we welcome this positive change in policy where sponsors were forced to do more than one trial for products with clear benefits, it should be cautious optimism. This new era of “precision regulation” demands that sponsors move toward a strategy of singular, undeniable clinical excellence. By front-loading investment into trial design and biomarker validation, companies can navigate this faster path while satisfying the high expectations of regulators, investors, and patients alike. Success in 2026 will be defined not by the number of trials performed, but by the irrefutable quality of the evidence provided.
