Key takeaways
Placebo-controlled trials now required for low-risk groups: FDA will require placebo-controlled trials for COVID-19 vaccines in low-risk populations before granting full approval—adding complexity to trial design, ethics reviews, and recruitment.
New focus on clinical outcomes & longer follow-up: Trials must now measure symptomatic COVID-19 as the primary endpoint, include participants with prior infections, and follow them for at least six months.
Delays are already happening: Moderna pulled its BLA for a combo vaccine, and Pfizer faces setbacks. Sponsors should prepare for longer timelines and adopt flexible, adaptive trial strategies.
As the fall approaches and preparations for this year’s COVID-19 vaccine rollout continue, a new FDA requirement is expected to cause delays and limit who is eligible for vaccination. On May 20, FDA Commissioner Vinay Prasad, MD, MPH; and FDA Vaccine Chief Martin A. Makary, MD, MPH, authored an article published in The New England Journal of Medicine (NEJM) announcing the agency’s expected requirement that any new COVID-19 vaccines will be required to undergo testing in placebo-controlled trials.1
“Although the rapid development of multiple COVID-19 vaccines in 2020 represents a major scientific, medical, and regulatory accomplishment, the benefit of repeat dosing—particularly among low-risk persons who may have previously received multiple doses of COVID-19 vaccines, had multiple COVID-19 infections, or both—is uncertain. The American people, along with many health care providers, remain unconvinced,” Prasad and Makary wrote in the article.
FDA introduces new placebo trial requirement for COVID-19 vaccines
The new framework around COVID-19 vaccine research, regarding those with no risk factors for severe COVID-19, calls for randomized, controlled trial data evaluating clinical outcomes before Biologics License Applications (BLAs) can be granted. The requirement isn’t expected to apply to those at a higher risk of severe illness from the virus. According to NBC News, drugmakers are exempt from additional testing for those groups, which include older adults.2
Updated FDA trial guidelines focus on clinical outcomes
The NEJM article also highlights FDA’s preferred study design for these trials moving forward. The recommended primary endpoint will be symptomatic COVID-19, with key secondary endpoints including severe COVID-19, hospitalization, and death. Data should demonstrate that vaccines reduce the incidence of symptomatic COVID-19 with a confidence interval that is ideally about 30%. Additionally, people who have had the virus in the previous year should not be excluded from participating in these studies and follow-up should extend for a minimum of six months.
“Ultimately, these studies alone can provide reassurance that the American repeat-boosters-in-perpetuity strategy is evidence-based,” Prasad and Makary wrote.
In anticipation of a potential shift in the regulatory framework around vaccine trials, Applied Clinical Trials previously spoke with Krinx Kong, chief commercial officer, Cognivia, to gain insight.
In a video interview, Kong explained: “Now, if a policy shift were to mandate placebo use in all vaccine trials, even where active comparators might be more appropriate, we'd likely see significant impacts on both design complexity and timelines. First, ethics boards may push back. If an effective vaccine already exists, withholding it in favor of placebo could be viewed as unethical. This leads to delays, extra review cycles, and potential public concern.”
He continued: “Next, placebo-controlled designs often require longer follow ups, which can prolong timelines by months or even years. Lastly, these designs are frequently more difficult to recruit for, patients and parents may be reluctant to participate if there's a genuine chance of receiving no active protection. If policy does shift, having tools that can adapt trial design without compromising data integrity or patient trust will be essential.”
Moderna and Pfizer experience delays under new regulations
The industry is already seeing a response to this new framework. On May 21, Moderna, one of the largest players in the vaccine space, voluntarily withdrew its BLA for mRNA-1083, a flu/COVID combination vaccine candidate for adults aged 50 years and older.
In an official press release, Moderna stated, “The Company plans to resubmit the BLA later this year, after vaccine efficacy data from the ongoing Phase III trial of its investigational seasonal influenza vaccine, mRNA-1010, are available. Moderna continues to expect interim data from the mRNA-1010 trial to be available this summer.”3
Additionally, NBC News reported that Pfizer will experience delays. The news outlet noted that it will be “near impossible” for both Pfizer and Moderna to complete trials in accordance with the new regulations for the fall season.2
Basis for the updated vaccine testing framework
As mentioned, an update regarding vaccine trials was expected. On April 30, The Washington Post reported that US Health and Human Services Secretary Robert F. Kennedy Jr. intended to shift the way vaccines are evaluated in research.4
Prasad and Makary noted that less than 25% of Americans received boosters each year over the past two seasons. Health care workers remain even more hesitant, with less than one-third participating in the 2023-2024 fall booster program. In general, public trust in vaccine research has declined, according to the FDA leaders.
In conclusion, Prasad and Makary wrote: “These clinical trials will inform future directions for the FDA, but more important, they will provide information that is desperately craved by health care providers and the American people.”
References
1. Prasad V, Makary M. An Evidence-Based Approach to Covid-19 Vaccination. N Engl J Med. May 20, 2025. doi: 10.1056/NEJMsb2506929. https://www.nejm.org/doi/full/10.1056/NEJMsb2506929
2. Lovelace, B. Covid vaccine rollout for healthy kids and adults is likely delayed by a new FDA rule. NBC News. May 20, 2025. Accessed May 21, 2025. https://www.nbcnews.com/health/health-news/covid-vaccines-fda-trials-delay-kids-adults-fall-rcna207718
3. Moderna Provides Update on BLA Submission for Combination Vaccine Against Influenza and COVID-19. Moderna. News release. May 21, 2025. Accessed May 21, 2025. https://investors.modernatx.com/news/news-details/2025/Moderna-Provides-Update-on-BLA-Submission-for-Combination-Vaccine-Against-Influenza-and-COVID-19/default.aspx
4. Robert F. Kennedy Jr will require all new vaccines to undergo placebo testing, WaPo reports. Reuters. April 30, 2025. Accessed May 21, 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/robert-f-kennedy-jr-will-require-all-new-vaccines-undergo-placebo-testing-wapo-2025-05-01/
