Lead
The Food and Drug Administration announced a policy shift that makes one rigorous clinical trial the agency’s default standard for approving new drugs and novel health products, a change disclosed in a New England Journal of Medicine commentary by FDA Commissioner Dr. Marty Makary and deputy Dr. Vinay Prasad published Wednesday. The move is intended to shorten review timelines and boost development of new medicines. Agency leaders say the change reflects advances in trial design and evidence tools; they predict a surge in drug development. Critics and some career regulators say the practical effects will depend heavily on how the policy is implemented.
Key Takeaways
- The FDA will make a single pivotal trial the default for new drug approvals, a departure from the decades-old two‑trial convention first applied after 1960s legislation.
- Makary and Prasad set out the change in a New England Journal of Medicine piece published Wednesday and argued modern methods can replace routine replication testing.
- About 60% of first‑of‑a‑kind drugs approved annually over the last five years were already cleared on the basis of a single study, according to agency trends cited in the announcement.
- The policy is expected by its proponents to accelerate access and trigger more development activity, though exact timelines for broader adoption were not specified.
- Former longtime drug center chief Dr. Janet Woodcock said the change formalizes a trend already used for many cancer and rare‑disease approvals; she led the center for roughly 20 years and retired in 2024.
- The announcement follows other Makary directives, including mandated AI use by staff and expedited one‑month reviews for products deemed in the national interest.
- The agency’s approach remains more restrictive in some areas: the vaccine office recently requested an additional trial from Moderna for a new mRNA flu shot and will now review the revised submission.
Background
The two‑study standard dates to the early 1960s, when Congress required the FDA to base approvals on “adequate and well‑controlled investigations.” Historically, the agency interpreted that statutory language as support for at least two independent trials with substantial patient numbers and follow‑up. The second trial served as replication — a safeguard against chance results in the first study.
Starting in the 1990s, the FDA began accepting single‑trial approvals more often for rare or life‑threatening conditions where enrolling large numbers is infeasible. Laws passed in recent decades directed regulators to be more flexible for serious or hard‑to‑treat diseases; as a result, roughly 60% of first‑in‑class approvals in recent years used one pivotal study. Makary, who became commissioner after joining the agency last April, has pursued several procedural changes aimed at shortening review timelines.
Main Event
Makary and Prasad declared in their NEJM commentary that the agency’s “default position” will shift to requiring one trial for many new drugs and novel health products. They argued that modern trial designs, improved biomarkers, real‑world evidence, and statistical methods can provide assurance of benefit without the routine need for a second confirmatory trial. The commentary framed the change as aligning regulation with contemporary science and efficiency goals.
Officials said the policy is not an across‑the‑board elimination of replication but a recalibration: additional studies, post‑market evidence collection, or other safeguards will still be used where uncertainty remains. The leaders predicted the change would stimulate drug development by reducing time and cost barriers, potentially bringing therapies to patients more quickly.
However, internal tensions are visible. The FDA’s vaccine branch — which Prasad oversees — last week initially declined Moderna’s application for an updated mRNA influenza shot because of an insufficient trial; the agency reversed course to review the application after Moderna agreed to an extra study in older adults. Separately, Prasad has requested more data for several gene therapy and biotech submissions, a dynamic that has unsettled some industry investors and observers.
Analysis & Implications
Shifting to a one‑trial default could lower development costs and shorten timelines, which proponents say will increase innovation and patient access. For large, common‑disease markets that previously required multiple trials, sponsors may face faster regulatory timelines and earlier launches. Investors may view the policy as supportive of biotech pipelines that previously faced protracted confirmatory requirements.
But a default one‑trial stance raises tradeoffs. A single trial, even if large and well controlled, provides fewer independent confirmations of efficacy and safety than two separate trials. Regulators may need to rely more on post‑market surveillance, conditional approvals, or stricter labeling to manage residual uncertainty. That will require stronger real‑world data systems and clearer enforcement of post‑marketing study commitments.
The policy also risks uneven application across product types. Vaccines, gene therapies and other biologics present unique safety and durability questions; recent FDA decisions to require extra evidence in some of those areas show that the agency is not adopting a uniform relaxation. Implementation choices — including the use of supplemental trials, statistical criteria, and real‑world data acceptance — will determine whether patient safety and public trust are preserved as approval speed increases.
Comparison & Data
| Era | Typical Standard | Where Single Trials Used | Recent Single‑trial Share |
|---|---|---|---|
| 1960s–1990s | Two adequate, well‑controlled trials | Rare exceptions | Low |
| 1990s–2020s | Flexible: single trial accepted for rare/fatal diseases | Cancer, rare diseases | ~60% of first‑of‑a‑kind drugs (last 5 years) |
| 2020s (announced) | Default to one pivotal trial; supplemental evidence as needed | Expanding to more common diseases | To be determined |
The table summarizes how the practical standard has evolved: the two‑trial expectation has eroded over decades, and single‑trial approvals already dominate many first‑in‑class approvals. The new default may expand single‑trial use into areas previously held to higher replication standards, but the magnitude of change will depend on guidance documents and enforcement practices that remain to be released.
Reactions & Quotes
Regulatory veterans and industry watchers offered mixed responses. Supporters emphasize scientific progress; skeptics stress that policy details matter for safety and predictability.
“The scientific point is well taken: as biology and disease understanding improves, two trials are not always required,”
Dr. Janet Woodcock, former FDA drug center director (career regulator)
Woodcock noted the agency has already accepted single trials for many serious conditions and said the new policy formalizes that trend, while warning that clarity on implementation is necessary. Industry groups welcomed steps to reduce barriers but asked for explicit guidance on when a single trial will be sufficient.
“Overreliance on two trials no longer makes sense in many settings,”
Dr. Marty Makary & Dr. Vinay Prasad (FDA commentary)
Makary and Prasad framed the change as modernizing standards and accelerating patient access. Public health advocates and some scientists cautioned that removing an expectation of replication increases reliance on post‑market monitoring and on robust trial design.
Unconfirmed
- Exact implementation details and the formal guidance timeline for the one‑trial default have not been released by the FDA and remain unconfirmed.
- It is not yet clear how the policy will apply across biologics, vaccines, gene therapies and other complex products; recent vaccine actions suggest differential treatment.
- The magnitude and timing of any predicted “surge in drug development” are projections by agency leaders and are not yet supported by independent data.
- Whether the shift will materially change approval rates for common chronic diseases versus rare or life‑threatening conditions remains to be demonstrated.
Bottom Line
The FDA’s shift to a one‑trial default for many new drug approvals formalizes trends already visible in rare and oncology approvals and signals a regulatory emphasis on speed and flexibility. Proponents argue this will lower costs, shorten development timelines and expand patient access to new therapies. Opponents and cautious observers warn that greater reliance on single trials increases the importance of rigorous trial design, transparent post‑market surveillance, and enforceable commitments for follow‑up studies to manage residual uncertainty.
Implementation will determine the policy’s net effect. Clear guidance on acceptable trial designs, statistical thresholds, and the role of real‑world evidence will be essential to preserve public trust while delivering the faster approvals policymakers seek. Stakeholders should watch forthcoming FDA guidance and real‑world enforcement actions to assess whether the change improves timeliness without compromising safety and efficacy standards.