FDA Drops Two-Study Requirement for Drug Approvals in Major Policy Shift

The Food and Drug Administration has officially abandoned its long-standing expectation that drug manufacturers conduct two pivotal clinical trials to support new drug approvals, announcing that a single adequate and well-controlled study will now serve as the agency's default standard. The policy change, unveiled by Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad in a New England Journal of Medicine article, marks one of the most significant shifts in FDA regulatory practice in decades.

Moving forward, the FDA will require only one well-controlled clinical trial supplemented by "confirmatory evidence" to approve new medications. This evidence may include mechanistic data demonstrating biological plausibility, results from related indications, animal model studies, or real-world evidence showing effectiveness in clinical practice.

"In this setting, over-reliance on two trials no longer makes sense," Makary and Prasad wrote. "In 2026 there are powerful alternative ways to feel assured that our products help people live longer or better than requiring manufacturers to test them yet again."

The End of a Sixty-Year Standard

The two-study requirement traces its origins to the early 1960s, when Congress passed legislation requiring the FDA to review data from "adequate and well-controlled investigations" before clearing new medications. For decades, the agency interpreted this statutory language as mandating at least two independent studies, preferably with large patient populations and extended follow-up periods.

The rationale was straightforward: a second study served as a safeguard against false-positive results, ensuring that initial trial findings could be replicated before exposing the broader population to a new drug. This standard became so entrenched that it acquired what Makary and Prasad describe as "dogma" status within the regulatory community.

However, the statutory foundation for the two-trial standard has been more flexible than common practice suggested. Since 1997, FDA regulations have explicitly allowed for drug approval based on "one adequate and well-controlled clinical investigation and confirmatory evidence." The agency increasingly exercised this flexibility for treatments targeting rare diseases or life-threatening conditions where conducting two large trials would be impractical or unethical.

Over the past five years, approximately 60% of first-of-a-kind drug approvals have already relied on single-study evidence, reflecting congressional directives to accelerate access for serious conditions. The new policy simply extends this flexibility to become the default expectation across all therapeutic areas.

Scientific Justification

Makary and Prasad argue that advances in biomedical science have fundamentally altered the evidentiary landscape since the two-trial standard took shape. Modern drug development employs increasingly sophisticated biomarkers, mechanistic understanding of disease pathways, and statistical methods that can corroborate efficacy without requiring duplicate pivotal trials.

"Two trials should be seen as just one of many interlocking facets of clinical credibility," the officials wrote. The FDA now evaluates not only survival outcomes but also a drug's effects on biomarkers, secondary endpoints, and biological mechanisms to "tell a complete biologic story."

The policy shift does not eliminate the FDA's discretion to require additional studies when warranted. Drugs with unclear mechanisms of action, trials relying on short-term surrogate endpoints, or medications targeting conditions without well-established biomarkers may still face heightened evidentiary requirements. The agency retains authority to demand a second study if confirmatory evidence proves insufficient.

Implications for Addiction Treatment Development

The policy change carries particular significance for the development of new treatments for substance use disorders, a field that has historically faced challenges in conducting large-scale clinical trials. Patient recruitment difficulties, high dropout rates, and the complexity of measuring outcomes in addiction research have made the two-trial standard especially burdensome for developers of medication-assisted treatment options.

Addiction treatment drug development has lagged behind other therapeutic areas, with few new mechanisms reaching the market in recent decades. Buprenorphine and extended-release naltrexone remain the primary pharmacological options for opioid use disorder despite their limitations, while no FDA-approved medications exist for stimulant use disorder. The reduced trial burden could incentivize investment in novel approaches, including psychedelic-assisted therapies, anti-addiction vaccines, and precision medicine approaches targeting specific genetic or neurobiological subtypes.

The change may also accelerate development of combination therapies and reformulations of existing medications. Rather than conducting two full pivotal trials for each new formulation, manufacturers may be able to rely on a single well-designed study supplemented by pharmacokinetic data and real-world evidence from similar products.

Industry and Expert Reactions

Wall Street analysts greeted the announcement with cautious optimism. RBC Capital Markets noted in a February 18 research note that the policy "could have meaningful readthroughs to the broader space and individual companies... improving likelihoods of drugs ultimately getting over the line and/or reducing late-stage development costs."

Former FDA drug director Janet Woodcock, who led the agency's Center for Drug Evaluation and Research for approximately two decades before retiring in 2024, endorsed the change as reflecting scientific progress. "The scientific point is well taken that as we move toward greater understanding of biology and disease we don't need to do two trials all the time," Woodcock told MedPage Today.

However, not all observers welcomed the shift. Steven Grossman, president of the policy and regulatory consulting firm HPS Group, questioned the necessity of the change given that the FDA has had statutory authority to approve based on single trials since the 1990s. "What is the problem with existing policy that requires change?" Grossman asked in a statement, noting that second studies have historically served an important confirmatory function. "I have worked on drugs and biologics that had a great first study and didn't fare as well on the second."

The policy change also contributed to the departure of Richard Pazdur, the longtime director of the FDA's Oncology Center of Excellence, who left the agency after disagreements with Makary over lowering clinical trial requirements. Pazdur had spent 26 years at the FDA and was widely respected for his role in modernizing cancer drug review.

Broader Regulatory Context

The single-trial policy represents the latest in a series of initiatives Makary has launched since becoming FDA Commissioner in April 2025. Other changes include mandating artificial intelligence tools for FDA staff, offering one-month review timelines for drugs serving "national interests," and establishing a National Priority Voucher Program to accelerate development of critical medications.

These moves reflect the Trump administration's broader deregulatory agenda, though the single-trial policy has attracted less partisan controversy than some other FDA actions. The change aligns with long-standing recommendations from some patient advocacy groups and industry representatives who have argued that excessive regulatory requirements delay access to beneficial treatments.

Critics counter that the two-trial standard, while imperfect, provided an important check on the inherent uncertainty of clinical research. They note that some high-profile drug safety issues have emerged only after larger populations were exposed to medications approved based on limited evidence, and worry that reducing evidentiary requirements could increase the risk of such outcomes.

The coming years will test whether the FDA's confidence in modern scientific methods is justified, or whether the two-trial standard served a protective function that will be missed. For patients awaiting new treatments for substance use disorders and other conditions, the policy shift offers hope for faster access—but also raises questions about whether speed will come at the cost of certainty.