Expert recommends alternative approaches to substitute for randomized trials for COVID vaccines

Lance Shea, a partner with Foley Hoag, says manufacturers should explore using artificial intelligence (AI) trials, Bayesian trials, adaptive trials, and other innovative methods to demonstrate the safety and effectiveness of new COVID-19 vaccines for low-risk groups. He recommended the alternative methods to traditional randomized trials in order to comply with the US Food and Drug Administration's (FDA) new framework for vaccine evaluation.

Shea told attendees at a Food and Drug Law Institute (FDLI) meeting on 21 August that the agency may be receptive to the approaches “because it plays to this evidence-based mindset of the commissioner and the center director” of the Center for Biologics Evaluation and Research (CBER).

A panel of legal experts joined Shea to discuss the implications of the administration’s new vaccine framework, which was released in May 2025. One panelist was highly critical of another element of the administration’s vaccine policy, which cuts all government funding for mRNA research for COVID-19 vaccines, arguing that the decision lacks a solid scientific foundation.

CBER Director Vinay Prasad and FDA Commissioner Marty Makary published an article in the New England Journal of Medicine (NEJM) in May outlining their framework for evaluating COVID-19 vaccines. Under the revised policy, COVID-19 vaccines will be evaluated primarily for people aged 65 and older, and for those younger individuals with one or more risk factors, such as asthma, cancer, diabetes, obesity, or a history of smoking.

For those without any of these risk factors, COVID-19 vaccines will need to undergo randomized, controlled trials (RCT) to demonstrate safety and effectiveness. (RELATED: FDA unveils new COVID-19 framework, restricting shots to elderly and high-risk people, Regulatory Focus, 20 May 2025).

Eva Temkin, a partner at Arnold & Porter, served as the moderator and asked the panelists to discuss the implications of the new framework on companies developing new COVID-19 vaccines.

Jesse Goodman, a professor of public health at Georgetown University and a former chief scientist at FDA, said that the policy is “unusual” in that it was developed for low-risk groups “in the absence of a safety problem and in the absence of an effectiveness problem.”

Shea said, however, that manufacturers have options for getting approval for vaccine products for low-risk populations.

“Doctors Prasad and Makary are evidence-based physicians,” said Shea. “They have been focused on EBM [evidence-based medicines], and that drives their decisions on regulatory design making.”

He added that “to meet these goals, [manufacturers] need evidence to fulfill their vision of COVID-19 vaccines for the low-risk groups.” He also said that instead of using expensive RCTs, companies can use augmented trials, adaptive trials, Bayesian-coupled trials, and AI-coupled trials to demonstrate safety and effectiveness.

Role of RWE in vaccine policy

Temkin asked the panelists to elaborate on the role of real-world evidence (RWE) and AI, and whether such tools could be used as alternatives to RCTs in answering questions on safety and effectiveness in low-risk populations, given Commissioner Makary's increased focus on leveraging RWE.

”The more we know about the drug in the current population and what the confounders are for the specific vaccine to get the approval for the low-risk population, the more you can use RWE, machine learning, and AI to help build that new solution to answer safety and effectiveness questions better,” said Shea. “It would seem to fit in the framework of EDM-driven medicine for CBER and FDA.”

In response to a question from Temkin about whether the policy requiring randomized trials for low-risk individuals regarding vaccines could also apply to other products, Shea and others stated that it is uncertain if this new requirement for RCTs in low-risk individuals will be used to support approvals in other areas.

”The NEJM article is all about the COVID-19 vaccine, and that is what I have had my thoughts around,” said Shea. ”They said in the article that the [measles, mumps and rubella (MMR)] vaccine was safe and effective, and they were behind those, so I don’t know the extent to where this framework for covid vaccines will be applied to the more seasonal vaccines.”

Barda stopped funding mRNA research

Temkin asked the panelists for their thoughts on the administration’s announcement earlier this month that it was cancelling $22M worth of investments in mRNA vaccine development at the Biomedical Advanced Research and Development Authority (BARDA).The decision was based on concerns from Health and Human Services (HHS) Secretary Robert Kennedy Jr., who said there is insufficient data that the mRNA vaccines prevent upper respiratory infections like COVID-19 and influenza.

Goodman disagreed with the move to cancel the contracts and said the decision to cancel the contracts were made by high-ranking government officials, and not scientific experts.

“The overwhelming majority of the global scientific community, not just people involved in mRNA work, feel like right now it is a very important platform technology and that there are ways it can be approved,” said Goodman.
He said that the termination of the contracts by BARDA puts the US at risk and expressed concerns about the government's plan to use "a very old technology, an inactivated vaccine," for countering COVID-19 threats and questioned why it was being considered, noting that it could leave the country “at risk” of outbreaks.

Will Waters, a healthcare attorney with Becker, Epstein and Green, agreed with Goodman and said that it seemed the scientific process was being politicized. He also said that his firm has been tracking mRNA bills at the state level.

“Some states want to ban it and some states do not….some cancellations are arbitrary and capricious and these decisions are not based on science,” said Waters.

Expert recommends alternative approaches to substitute for randomized trials for COVID vaccines

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