The FDA has shifted from the traditional two-trial expectation to a one pivotal trial standard. Understand what changed, why it matters, and how it impacts drug approvals.
Edited and Written By: Pharmacally Medical News Desk
Assisted By: Sana Khan BPharm
Reviewed By: Pharmacally Editorial Team
The FDA has shifted its drug approval paradigm, making a single high-quality pivotal trial the new default standard rather than requiring two. This policy change, outlined in a February 19, 2026, New England Journal of Medicine article by FDA leaders Vinay Prasad and Marty Makary, aims to accelerate access to innovative therapies while maintaining rigorous evidence standards.
Policy Shift Explained
The longstanding “two-trial dogma,” rooted in 1960s regulations (the Kefauver–Harris amendments), presumed two adequate and well-controlled studies were needed for approval confidence. US law since 1997 has allowed one trial with supportive confirmatory evidence, but FDA practice often demanded two, causing sponsor uncertainty.
What the FDA announced
In a commentary published by FDA Commissioner Martin Makary and Deputy Vinay Prasad, the agency states that the default for demonstrating substantial evidence of effectiveness will be a single, well-conducted pivotal trial supplemented by confirmatory evidence where appropriate.
The authors argue that advances in trial design, biomarkers, statistical methods, and availability of high-quality external data make a single robust trial plus supportive evidence sufficient in many situations. The NEJM piece frames this as an explicit move to end the routine “two-trial dogma.”
Key Benefits
Sponsors face reduced costs, with a single trial estimated at $30–150 million versus double for two, potentially speeding drugs to patients and curbing price justifications tied to development expenses.
Makary and Prasad argue this elevates quality: concentrating resources on one superior study outperforms mediocre duplicates, amid FDA’s push for postmarketing surveillance to monitor real-world performance.
Exceptions and Safeguards
Two trials remain mandatory for drugs with nebulous mechanisms, surrogate endpoints, short-term outcomes, or trial flaws like poor controls or post-hoc analyses.
The policy extends to accelerated approvals, breakthrough designations, and priority reviews, building on precedents where single trials sufficed but clarifying application across therapies.
Analysts view it as evolutionary, not revolutionary, given prior flexibility, though critics like HPS Group’s Steven Grossman question if it weakens patient protections despite existing guidance.
Reference
Prasad V, Makary MA. One Pivotal Trial, the New Default Option for FDA Approval – Ending the Two-Trial Dogma. N Engl J Med. 2026 Feb 19;394(8):815-817. PMID: 41707146. https://doi.org/10.1056/nejmsb2517623