FDA Drops Two-Trial Dogma: Historic Policy Shift Could Accelerate Drug Approvals and Transform Biotech Development
In what may be the most significant regulatory development for biotech in a decade, the FDA announced on February 18, 2026, that it is abandoning its long-standing expectation of two pivotal clinical trials for new drug approvals. Moving forward, the agency will require only one adequate and well-controlled clinical trial supported by confirmatory evidence, marking a dramatic shift that could accelerate drug development timelines and reduce costs across the industry.
The policy change, unveiled by FDA Commissioner Marty Makary and CBER Director Vinay Prasad in a New England Journal of Medicine article, represents the culmination of evolving scientific understanding and regulatory philosophy. The decision has already prompted at least one high-ranking FDA official to resign in protest, underscoring the controversial nature of this fundamental shift in drug approval standards.
The End of a 60-Year Standard
The two-trial requirement dates back to the early 1960s, when Congress mandated "adequate and well-controlled investigations" before new drugs could receive approval. For decades, the FDA interpreted this language as requiring at least two independent studies, a safeguard designed to reduce the risk that a single positive trial was merely a statistical fluke.
However, Makary and Prasad argue that modern drug development has evolved far beyond the crude trial-and-error approaches of the 1960s. Today's therapies are typically supported by detailed mechanistic science, sophisticated biomarker data, and increasingly advanced trial designs that provide multiple layers of evidence beyond simple replication.
"In this setting, over-reliance on two trials no longer makes sense," they 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."
What Constitutes Confirmatory Evidence
Under the new framework, the single required trial must be accompanied by confirmatory evidence, which can include mechanistic data, results in related indications, animal model studies, class effects, real-world evidence, or in some cases, a second trial. This approach recognizes that biological plausibility and supporting data can provide confidence in efficacy without requiring duplicative pivotal studies.
The shift in focus will emphasize trial quality over quantity, with reviewers concentrating on factors including magnitude of effect, appropriateness of control arms, endpoint selection, statistical power, blinding protocols, handling of missing data, biological plausibility, and alignment with intermediate biomarkers.
Industry Impact and Market Response
The implications for biotech companies are profound. Every Phase 2/3 biotech with one clean pivotal study is now potentially approvable, collapsing development timelines, reducing costs, and decreasing risk for both companies and their acquirers. This change comes at a time when Big Pharma is sitting on $2.1 trillion in available capital while facing a $200 billion patent cliff, creating ideal conditions for increased M&A activity.
Dr. Janet Woodcock, who led the FDA's drug center for roughly two decades before retiring in 2024, endorsed the scientific reasoning behind the shift. "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," she noted.
Woodcock emphasized that oncology and rare diseases have already largely operated under single-trial flexibility, suggesting the greater impact will be on drugs for more common conditions that historically were expected to meet the two-study benchmark.
Addressing Safety Concerns
Critics worry that reducing the evidentiary standard could compromise patient safety, but Makary and Prasad reject this characterization. They argue that two poorly designed trials do not guarantee valid conclusions, and that concentrating review resources on a single rigorous, well-designed study may actually strengthen regulatory scrutiny.
"Without examination of the quality of a study, two trials may even provide a false assurance," they wrote, emphasizing that the new approach prioritizes scientific rigor over arbitrary numerical requirements.
Broader Regulatory Philosophy
This policy change reflects Commissioner Makary's broader initiative to streamline FDA operations since arriving at the agency in April 2025. Previous reforms have included the National Priority Voucher Program and offering one-month reviews for drugs deemed to serve "national interests."
The FDA has possessed explicit statutory authority to approve drugs based on a single adequate and well-controlled study combined with confirmatory evidence since 1997, but the agency has historically maintained the two-trial expectation as an informal standard. The new policy formalizes what has been possible but rarely utilized.
Looking Ahead
Both Makary and Prasad expect the change to spur "a surge in drug development," potentially accelerating the availability of new treatments for patients while maintaining appropriate safety standards. For an industry that has long struggled with lengthy development timelines and high failure rates, this regulatory shift could represent a fundamental improvement in the risk-reward equation for drug development.
As biotech companies and investors digest the implications of this historic change, one thing is clear: the FDA's decision to abandon the two-trial dogma marks the beginning of a new era in pharmaceutical regulation, one that prioritizes scientific sophistication over regulatory tradition. The ultimate test will be whether this approach can deliver on its promise of faster access to effective treatments without compromising the safety standards that protect patients.
