FDA Approval of New Drugs: One Pivotal Trial or a Chaotic Agency?

A version of this column was published in the April 2026 issue of Public Citizen’s Health Letter.

When reviewing the safety and effectiveness of new drugs before marketing approval, the Food and Drug Administration (FDA) has generally interpreted the Food, Drug, and Cosmetic Act of 1962 as requiring at least two successful randomized, double-blind clinical trials. In 1997, Congress amended the law to allow the FDA to grant marketing authorization based on one such study and confirmatory evidence, an authority that the agency has used for accelerated approval, priority reviews and sometimes for traditional approvals.[1]

In February 2026, Dr. Vinay Prasad, a senior FDA official at the time, and Dr. Martin A. Makary, the FDA Commissioner, went further, writing in an opinion article in the New England Journal of Medicine: “Going forward, the FDA’s default position is that one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis for marketing authorization of novel products.” Prasad and Makary also asserted, without citing any evidence, that: “The FDA expects a surge in drug development in response to our initiative.”[2]

The FDA announcement, meant to resolve “confusion from manufacturers regarding settings in which a single trial will be accepted,” may be considerably less impactful than it seems. First, the FDA is not really “Ending the Two-Trial Dogma” because, according to the article, “changing the default option does not mean the FDA will never require two studies.” Sound confusing? It is. Second, it is totally unknown if there will be a surge in drug development, presumably because manufacturers would spend less money and time conducting pivotal studies. Time will tell. Third, the announcement was made in an opinion article in a medical journal, not in a guidance or regulation. Is the “New Default Option” merely the personal view of the officials, or an official policy likely to have meaning after they are no longer at the agency?

Why does this matter to patients and the public? In recent months, the FDA has been all over the place on its standards for drug approvals. It has avoided public advisory committee meetings,[3] and a senior official has anonymously criticized a product in a private press conference, which is almost unheard of.[4] The academic discussion of one pivotal trial or two notwithstanding, there is little confidence that the FDA is consistent or willing to publicly stand by its decisions when there is pressure to change them.

For example, in March 2026, the FDA approved expanded use of leucovorin calcium tablets (previously marketed as WELLCOVORIN and generics) for patients with cerebral folate deficiency.[5] The planned approval, discussed in the February 2026 issue of Worst Pills, Best Pills News, substantially eroded the agency’s approval standards, the agency’s statement to the contrary in the news release notwithstanding.[6],[7] Cerebral folate deficiency is a rare neurological condition that affects the transport of folate into the brain and has autism-like features. There is no meaningful evidence, however, that cerebral folate deficiency is related to the cause of autism, although a 2025 Department of Health and Human Services press release had said the condition “has been associated with autism.”[8],[9] The evidence to support the approval was not one or two clinical trials, but published case reports and the FDA’s literature review.[10]

For other products, the situation has been completely different. The FDA refused to review a new flu vaccine because of concerns about the design of the clinical trials, then reversed its decision a few days later.[11] For rare-disease drugs, as of March 2026, the FDA had issued about 20 drug rejections or refusals in the last eight months. The agency’s actions “underscore a break from decades of general stability in the F.D.A.’s top ranks across several presidential administrations,” the New York Times reported. “It has advised companies to launch costly and complex studies that could add years to finding treatments for rare diseases with no cure.”[12] The day after the Times article was published, it was announced that Prasad, an author of the article on pivotal trials and the agency official responsible for overruling career scientists on some vaccine and drug approvals, was leaving the FDA.[13]

Regardless of the number of trials and the confirmatory evidence, the onus is on the FDA to make decisions based on scientific data about safety and effectiveness, and to do so without political interference. The agency should uphold rigorous and consistent approval standards for all new products, not pick and choose based on political, personal and scientific whims. In recent months, the FDA has been a dysfunctional and chaotic agency that scores own goals, not an effective regulator that advances the interests of patients and the public. The situation must change, and soon.
 

References

[1] Food and Drug Administration. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence; draft guidance for industry. September 2023. https://www.fda.gov/media/172166/download. Accessed March 9, 2026.

[2] Prasad V, Makary MA. One pivotal trial, the new default option for FDA approval ¾ ending the two-trial dogma. N Engl J Med. 2026(8);394:815-817.

[3] Steinbrook R. FDA advisory committees: the importance of meeting. Worst Pills, Best Pills News. December 2025.

[4] Lawrence L. As controversial decisions mount, FDA shuns public advisory meetings. STAT News. March 9, 2026. https://www.statnews.com/2026/03/09/fda-cuts-back-advisory-meetings-controversial-decisions-grow/. Accessed March 9, 2025.

[5] FDA News Release. FDA approves first treatment for patients with cerebral folate transport deficiency. March 10, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-cerebral-folate-transport-deficiency. Accessed March 12, 2026.

[6] Ibid.

[7] Steinbrook R. The FDA, autism, leucovorin and cerebral folate deficiency. Worst Pills, Best Pills News. February 2026.

[8] Department of Health and Humans Services News Release. President Trump, Secretary Kennedy announce bold actions to tackle autism epidemic. September 22, 2025. https://www.hhs.gov/press-room/hhs-trump-kennedy-autism-initiatives-leucovorin-tylenol-research-2025.html. Accessed March 12, 2026.

[9] Goldman ID, Chabner BA. Cerebral folate deficiency, autism, and the role of leucovorin. N Engl J Med. 2026;394(9):833-835. https://www.nejm.org/doi/full/10.1056/NEJMp2516268. Accessed March 9, 2026.

[10] Aaron DG, Sinha MA, Cohen IG. The FDA’s leucovorin approval ¾ a departure from evidentiary standards. JAMA. 2026;335(5):397-398. https://jamanetwork.com/journals/jama/fullarticle/2843211. Accessed March 9, 2026.

[11] Jewett C, Robbins R. F.D.A. reverses decision and agrees to review Moderna’s flu vaccine. New York Times. February 18, 2026 https://www.nytimes.com/2026/02/18/health/fda-moderna-flu-vaccine-mrna.html. Accessed March 9, 2026.

[12] Jewett C. F.D.A. faces upset over denials of new drugs. New York Times. March 5, 2026. https://www.nytimes.com/2026/03/05/health/fda-drugs-rare-diseases-rfk-jr.html. Accessed March 9, 2026.

[13] Jewett C. Divisive F.D.A. vaccine regulator is resigning. New York Times. March 6, 2026. https://www.nytimes.com/2026/03/06/health/fda-prasad-resigns.html. Accessed March 9, 2026.