End of FDA Commissioner Makary’s Tumultuous Tenure Leaves Agency in Transition

FDA Commissioner Marty Makary, MD, MPH, resigned Tuesday, according to The Associated Press, just 13 months after being confirmed to lead the agency, following months of mounting pressure from pharmaceutical executives, anti-abortion activists, vaping industry lobbyists, and other political allies of President Trump.¹

The decision to remove Makary was made by Health and Human Services Secretary Robert F. Kennedy Jr. and subsequently approved by the White House, according to an administration official.

Kyle Diamantas, the agency's chief for foods and an attorney with personal ties to Donald Trump Jr., is expected to take over as acting commissioner, according to reports. A permanent replacement will require a presidential nomination and Senate confirmation.

Makary, a surgeon and health researcher who rose to prominence as a critic of public health measures during the COVID-19 pandemic, struggled throughout his tenure to manage the FDA's bureaucracy and maintain the confidence of its career staff.

Most of the agency's senior career officials resigned, retired, or were forced out during the first year of the second Trump administration, contributing to a sustained period of low morale, dysfunction, and internal frustration that frequently spilled into public view.

"He's a great doctor, and he was having some difficulty," Trump told reporters.¹

Makary introduced a string of initiatives aimed at speeding up drug reviews, including dropping certain study requirements, incorporating artificial intelligence into drug evaluations, and offering expedited reviews for medicines deemed to serve national interests.

In his resignation message, he cited 50 major FDA reforms. But pharmaceutical executives, who rely heavily on the predictability and consistency of FDA decisions, found those efforts overshadowed by internal conflicts and a revolving door of leadership that created uncertainty across the agency.

In the FDA's drug center, its largest division, six different people served as director over the course of a single year.

CRLs and trial design under a turbulent tenure

One of the most consequential areas of turbulence for the clinical research industry under Makary came with complete response letters (CRLs) and shifting expectations around trial design. Applied Clinical Trials covered this closely throughout his tenure.

In one notable transparency effort, the FDA published more than 200 CRLs issued between 2020 and 2024, offering the industry unprecedented visibility into the deficiencies that most often delay drug approvals.²

Previously, CRLs were shared only with product sponsors, limiting broader industry learning. A prior analysis had found that 85% of safety and efficacy issues cited in CRLs were not publicly disclosed by sponsors, and that in roughly 40% of cases where new clinical trials were requested, that information was not communicated in press releases. Among the published letters, 48% cited deficiencies in both safety and efficacy domains.

"For far too long, drug developers have been playing a guessing game when navigating the FDA," Makary said at the time.

But transparency efforts ran alongside a pattern of CRLs that caught sponsors off guard. In July 2025, the FDA issued CRLs to both Replimune and Capricor for therapies that had previously received breakthrough or priority designations.³

In the Replimune case, the agency cited concerns with the trial design of the IGNYTE study, concluding it did not constitute an adequate and well-controlled study.

Capricor, whose cell therapy for Duchenne muscular dystrophy-associated cardiomyopathy had advanced through review without major issues, was similarly surprised by the outcome.

"This is particularly challenging for those who have based development strategies and investments on the outcomes of meaningful communications strategies with FDA stakeholders prior to 2025," Craig Lipset, co-chair of the Decentralized Trials and Research Alliance, told ACT at the time. "It raises questions for developers today as to whether past understandings still hold true."

Vaccine policy shifts added to sponsor uncertainty

Makary's handpicked deputy, Vinay Prasad, MD, MPH, who served as the FDA's vaccine and biotech chief until stepping down for the second time in April, added another layer of complexity for clinical trial sponsors through a series of controversial vaccine policy moves.

In May 2025, Prasad and Makary co-authored an article in the New England Journal of Medicine announcing that any new COVID-19 vaccines would be required to undergo testing in placebo-controlled trials before receiving approval, with a recommended primary endpoint of symptomatic COVID-19 and a minimum six-month follow-up period. The requirement applied to low-risk populations and prompted Moderna to voluntarily withdraw its BLA for a flu and COVID combination vaccine candidate, while Pfizer faced its own timeline setbacks under the new framework.⁴

ACT spoke with Krinx Kong, chief commercial officer at Cognivia, about the operational implications at the time.

"Placebo-controlled designs often require longer follow-ups, which can prolong timelines by months or even years," Kong said. "Patients and parents may be reluctant to participate if there's a genuine chance of receiving no active protection."

Prasad also repeatedly overruled vaccine staffers on coronavirus shot eligibility and, in an internal memo, claimed without published evidence that FDA had linked COVID-19 shots to the deaths of 10 children. A dozen former FDA commissioners issued a formal denunciation of a planned vaccine approval overhaul that followed, warning it would undermine the public interest. The overhaul was never completed.

What comes next

Most of the programs Makary introduced have not gone through the federal rulemaking process required to make them permanent, leaving their futures uncertain under new leadership. Democrats in Congress have already questioned the legality of some efforts, including the expedited review program for innovative medicines.

For sponsors and CROs navigating what comes next, the transition adds another variable to an already unpredictable regulatory environment.

During the CRL coverage, Robin Bliss, vice president of strategic consulting at Veristat, told ACT that clear and direct communication with the FDA has become more critical than ever.

"Having direct and clear communication with the FDA is critical to expedite drug development and reduce risk of misunderstanding of regulatory requirements," she said.

References

1. Trump’s FDA chief is out after angering pharma CEOs, vaping lobbyists and anti-abortion activists. The Associated Press. May 12, 2026. Accessed May 13, 2026. https://apnews.com/article/fda-trump-makary-kennedy-vaccines-drugs-ef151784342c48cca3b91a829d615b5e

2. New FDA Initiative Reveals Common Reasons for Drug Application Rejection. Applied Clinical Trials. July 11, 2025. Accessed May 13, 2026. https://www.appliedclinicaltrialsonline.com/view/new-fda-initiative-reveals-common-reasons-drug-application-rejection

3. FDA Crackdown on Trial Design: What July’s CRLs to Replimune and Capricor Mean for Sponsors. Applied Clinical Trials. July 25, 2025. Accessed May 13, 2026. https://www.appliedclinicaltrialsonline.com/view/fda-trial-design-crls-replimune-capricor-sponsors

4. FDA Outlines Updated Requirement for Placebo-Controlled Trials in Vaccine Research. Applied Clinical Trials. May 21, 2025. Accessed May 13, 2026. https://www.appliedclinicaltrialsonline.com/view/fda-outlines-updated-requirement-placebo-controlled-trials-vaccine-research