FDA Commissioner Makary and Deputy Prasad Announce End of Two-Trial Drug Approval Standard in NEJM — Most Significant FDA Safety Change Since 1962

On February 18, 2026, FDA Commissioner Marty Makary and Principal Deputy Commissioner Vinay Prasad published a “Sounding Board” article in the New England Journal of Medicine titled “One Pivotal Trial, the New Default Option for FDA Approval – Ending the Two-Trial Dogma,” announcing that the FDA would no longer require two independent controlled clinical trials as the default standard for new drug approvals. Instead, the default would be one “robust pivotal trial” plus unspecified “confirmatory evidence.” The change represents the most significant weakening of FDA drug safety standards since the Kefauver-Harris Amendment of 1962 established the two-trial requirement in response to the thalidomide crisis.

The Two-Trial Standard and Its Origins

The requirement for “adequate and well-controlled investigations” (plural) was established by the 1962 Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act, passed in the wake of the thalidomide disaster that caused severe birth defects in thousands of children worldwide. The FDA interpreted the statutory language as requiring at least two independent clinical trials demonstrating safety and efficacy – a standard grounded in basic scientific epistemology: a finding must be independently replicated to be considered reliable.

The two-trial standard was specifically designed to prevent a sponsor from “being lucky once.” Two independent pivotal trials dramatically reduce the probability that a drug is approved based on statistical anomalies, hidden biases, or unreplicated results. For 64 years, this requirement served as the foundational safeguard of the American drug approval system.

What Changed

Makary and Prasad argued that “technological advancements” in clinical trial design – adaptive trials, Bayesian statistical methods, real-world evidence – meant that a single well-designed trial could provide equivalent confidence. They framed the change as ending an outdated “dogma” that unnecessarily delayed patient access to new treatments and inflated drug development costs.

The new policy applies across drug approval pathways, including breakthrough designations, accelerated approvals, and priority review. Makary and Prasad stated that the FDA “may at times still require two studies” but that one pivotal trial would be the new default.

Rationale vs. Reality

The stated rationale – lowering development costs and speeding access – aligns precisely with pharmaceutical industry lobbying priorities. The actual effect is to:

1. Halve the evidentiary bar for bringing drugs to market
2. Reduce sponsor costs by eliminating the need for a second confirmatory trial (average cost: $50-100 million per trial)
3. Shift the burden of discovering safety problems from pre-approval trials to post-marketing surveillance of patients already taking the drug
4. Weaken the FDA’s leverage to demand rigorous evidence from sponsors

The promise of “confirmatory evidence” outside a second controlled trial is inherently weaker: real-world evidence, observational data, and post-marketing studies lack the controls necessary to establish causal relationships with the rigor of randomized controlled trials.

Publication as Policy

The decision to announce a fundamental policy change through a journal article rather than through formal rulemaking – with its requirements for public comment, Congressional oversight, and judicial review – was itself significant. By publishing in NEJM rather than the Federal Register, Makary and Prasad bypassed the Administrative Procedure Act’s requirements for notice-and-comment rulemaking, making a sweeping regulatory change without democratic accountability.

Historical Pattern

The change follows a well-documented pattern of FDA regulatory erosion driven by pharmaceutical industry capture:

• 1992: Prescription Drug User Fee Act makes FDA financially dependent on industry fees
• 1997: FDA Modernization Act accelerates approval pathways
• 2004: Vioxx withdrawal reveals FDA suppressed safety data on a drug that caused an estimated 28,000 heart attack deaths
• 2012: FDA Safety and Innovation Act expands accelerated approval
• 2026: Two-trial standard eliminated

Capture Significance

The elimination of the two-trial requirement is regulatory capture in its purest form: a safety standard designed to protect patients was removed because it imposed costs on the industry the FDA is supposed to regulate. Makary and Prasad’s framing – that the change would lower drug prices by reducing development costs – inverts the agency’s statutory mandate. The FDA exists to ensure drugs are safe and effective before they reach patients, not to minimize the cost of proving safety and efficacy. The fact that two pharmaceutical-industry-aligned officials could unilaterally weaken a 64-year safety standard through a journal article, without Congressional action, public comment, or judicial review, demonstrates how thoroughly the agency’s protective function has been subordinated to commercial interests.