FDA will now approve new drugs with one clinical trial instead of two, reversing a 60-year standard

On February 18, 2026, FDA Commissioner MMMarty Makary and Center for Biologics Evaluation and Research (CBER) Director VPVinay Prasad co-authored a perspective article in the New England Journal of Medicine titled 'Rethinking the Standard for Drug Approval.'

The article announced that FDA would default to requiring only one pivotal clinical trial — plus 'confirmatory evidence' — for new drug approvals, replacing the longstanding expectation of two independent pivotal trials. Announcing regulatory policy through a journal article rather than through formal notice-and-comment rulemaking under the Administrative Procedure Act was itself unprecedented; Yale law professor JRJoseph Ross noted FDA 'skipped the formal public comment process that is supposed to accompany major regulatory changes.'

The two-trial standard traces to the 1962 Kefauver-Harris Drug Amendments, passed by Congress after thalidomide caused severe birth defects — including limb malformations — in thousands of children across Europe. The 1962 amendments required drugs to be proven 'effective' through 'adequate and well-controlled investigations' — plural.

FDA interpreted 'investigations' to mean at least two independent controlled trials, ensuring that one favorable statistical result couldn't be attributed to chance.

The standard has governed drug approvals for 64 years, through administrations of both parties. Congress revisited the standard in the FDA Modernization Act of 1997, which explicitly authorized FDA to approve drugs based on one trial 'plus confirmatory evidence' when the evidence is 'sufficient' — but FDA had never made one trial the default rather than an exception granted case-by-case.

Under the new framework, the primary trial must be a well-designed randomized controlled trial demonstrating statistically significant efficacy on a clinically meaningful endpoint. 'Confirmatory evidence' — which can substitute for the second independent trial — now includes: biomarker data (surrogate endpoints that correlate with the desired clinical outcome); animal model evidence; data from related drugs in the same mechanistic class; real-world observational data from health records; and data from the same drug approved for a different condition. The FDA article did not specify what weight each type of evidence would carry or how agency reviewers would weigh a single positive trial against weak confirmatory evidence — leaving those determinations to case-by-case review.

Dr. RPRichard Pazdur — who ran FDA's Office of Oncology Products for 26 years (1999–2025) and had approved more cancer drugs than any other individual in FDA history — resigned in protest on February 17, 2026, the day before the NEJM article published. In an interview with STAT News, Pazdur described being handed a press release with a quote attributed to him endorsing the policy change and being asked to simply agree to it.

'I was told to sign off on something I fundamentally disagree with,' he said. 'I have spent my career trying to make sure patients get drugs that actually work.

This policy could lead to patients receiving drugs that appear to work but don't.' His resignation was the most striking institutional signal that the change represented a genuine departure from FDA scientific norms.

The FDA's own internal analysis — referenced but not published in the NEJM article — estimated that a one-trial standard would reduce average drug development timelines by 2–4 years and reduce the cost of bringing a new drug to market by $300–$500 million. Makary cited these estimates in congressional testimony the following week, arguing the savings would be passed on to patients through lower drug prices and faster access. Critics noted that cost savings accrue primarily to pharmaceutical companies, not directly to patients — and that the FDA's internal analysis was not peer-reviewed or made publicly available for independent assessment.

Harvard Medical School professor AKAaron Kesselheim — who directs the Program on Regulation, Therapeutics, and Law — called the policy 'a ratcheting down of FDA evidence standards that could allow insufficiently tested drugs onto the market.' He pointed to the history of single-trial approvals under the 1997 exception: 'When FDA has approved drugs based on one trial in the past, we've seen high-profile failures — drugs that looked effective in one trial and turned out not to be when tested more broadly.' Specific examples include: Aduhelm (aducanumab), approved in 2021 for Alzheimer's under an accelerated approval mechanism over the objections of an FDA advisory committee, which showed limited clinical benefit and cost $56,000 per year; and multiple oncology accelerated approvals subsequently withdrawn when confirmatory trials failed.

The policy change is expected to most significantly affect three drug categories: rare diseases (where small patient populations make two-trial designs difficult); cancer (where accelerated approval under surrogate endpoints is already common); and neurology/psychiatry (where clinical trial design is complex and regulatory precedents are contested). Critics express particular concern about the psychiatric drug category — where placebo effects are large, trial design is especially challenging, and the history of post-approval drug failures after promising Phase III results is extensive. Proponents argue that for rare diseases — where a 'second trial' might not be feasible with only a few hundred affected patients globally — the change appropriately adapts the standard to reality.

Congress has oversight authority over FDA's drug approval standards through the Food, Drug, and Cosmetic Act. The two-trial standard was never codified in statute — it was FDA's regulatory interpretation of 'adequate and well-controlled investigations.'

Congress could pass legislation requiring two trials, overriding Makary's policy shift.

Senate HELP Committee Democrats introduced the 'Drug Approval Integrity Act' on March 1, 2026, which would write the two-trial standard into statute for drugs with annual revenues over $500 million — a threshold designed to capture blockbuster drugs while preserving flexibility for rare disease approvals. The bill had no Republican co-sponsors as of February 2026.