In news that seemed to break on Saturday, August 9, Vinay Prasad is returning to the FDA to head CBER - biologicals & vaccines. He was gone from Tuesday, July 29, to Friday, August 8.
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Timeline includes -
NYT
May 20 - Prasad published article in NEJM (Prasad & Markary) that the best approval for COVID vaccines would be for over-age-65 and younger persons with predisposing illnesses. At NEJM: Here. Immediate coverage at NYT here.
July 2 - NYT article that in fact FDA staff had endorsed open-ended approval of new COVID vaccines, but Prasad 5-page memorandum overruled staff. Here. The NYT article includes the 5-page memorandum. PDF here (dated May 16, ahead of NEJM release).
July 29 - Prasad leaves FDA. See coverage the next day at Reuters here.
WSJ
July 27 - "Digging the grave" op ed - "Prasad is a Bernie Sanders Acolyte."
July 30 - "Dancing on the grave" op ed - "Why Prasad Had to Go."
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August 4 - At conference, Dr Makary publicly invites Prasad to return to FDA ASAP. (Inside Health Policy here, and other sources).
August 5 - In my hands, Chat GPT predicted Prasad was unlikely to return, as the event lacked any clear precedents. Here.
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August 9 (Saturday) - Many sources, Prasad is back. Open access article at The Hill. WaPo and others quote HHS as saying the whole episode was "fake news."
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August 7, 2025
JAMA Network Open publishes Prosser et al. on cost-effectiveness of mRNA COVID vaccine. Here.
- Vaccine was cost-saving over age 65.
- Vaccine was $25,787 per QALY age 50-64.
- Vaccine was $115,588 per QALY age 18-49.
While one could say "That is dollars not health," the dollarized values are based on QALYs and one could have stopped and just compared net QALYs across age brackets.
It is supportive of Prasad's cut-offs that risk-benefit seems much higher over age 65.
It is alternatively supportive of broader coverage, in that younger persons still had favorable (though less strongly favorable) results.
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AI Corner
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I asked Google Notebook LM to compare the NEJM Covid article by Prasad (Prasad & Makary) with the May FDA internal memo released by NYT on the same topic.
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Here is a summary of the arguments presented in each PDF, followed by a comparison of where they particularly agree or differ:
NEJM
Summary of "2025 NEJM 0520 Prasad Makary Why COVID VAX is Bad 3p.pdf"
This article, a "Sounding Board" piece by Vinayak Prasad, M.D., M.P.H., and Martin A. Makary, M.D., M.P.H., published in the New England Journal of Medicine on May 20, 2025, critiques the U.S. approach to COVID-19 vaccination.
Key Arguments and Proposed Framework:
- Critique of U.S. Policy: The authors argue that the U.S. has adopted an aggressive "one-size-fits-all" annual COVID-19 booster program, recommending boosters for every American, unlike other high-income nations which confine recommendations to older adults or those at high risk. They reject the view that Americans are not sophisticated enough for age- and risk-based recommendations.
- Uncertain Benefit and Declining Trust: The benefit of repeat dosing, especially for low-risk persons with prior doses or infections, is uncertain. This uncertainty, coupled with declining public trust, has led to poor booster uptake (less than 25% of Americans, less than 10% for children <12 in 2024-2025 season). This has also contributed to a general decline in trust in vaccination, affecting other vital programs like MMR.
- New FDA Regulatory Framework: The FDA will adopt a new framework moving forward:
- Immunogenicity-Based Approval: Favorable benefit-risk findings based on immunogenicity data are anticipated for adults over 65 years and all persons over 6 months with one or more CDC-defined risk factors for severe COVID-19 outcomes. This group is estimated to include 100 million to 200 million Americans.
- Randomized Controlled Trial (RCT) Requirement: For healthy persons (no risk factors) between 6 months and 64 years, the FDA anticipates the need for randomized, controlled trial data evaluating clinical outcomes before Biologics License Applications can be granted.
- Preferred Study Design for RCTs:
- Ideal Population: The 50–64-year-old age group without risk factors is considered an ideal population for future trials due to global equipoise regarding yearly boosters.
- Endpoints: The primary endpoint should be symptomatic COVID-19, with secondary endpoints including severe COVID-19, hospitalization, and death.
- Trial Features: Sample size calculations should aim for a lower confidence interval bound ideally above 30%. Trials should include people with past COVID-19, extend follow-up for a minimum of 6 months, and the control group could receive a saline placebo to document the full adverse-event profile.
- Balancing Competing Values: The new policy balances the need for timely approval for high-risk populations with the need for evidence in low-risk groups, acknowledging the uncertainty of benefit for healthy individuals.
- COVID-19 vs. Influenza: COVID-19 is distinct from influenza in that its vaccine-induced immunity may not require annual updates, it has summer transmission that facilitates studies, and natural immunity against severe disease appears robust.
- Commitment to Gold-Standard Science: The new FDA philosophy represents a balance of regulatory flexibility and a commitment to "gold-standard science," aiming to provide information craved by healthcare providers and the American public.
FDA Memo
Summary of "2025 FDA 0516 Prasad memo on restricted vaccine approval 5pp.pdf"
This document is a Center Director Decisional Memorandum from Vinayak Prasad, M.D., MPH, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, dated May 16, 2025. It explains CBER's decision regarding Novavax's Biologics License Application (BLA) for NUVAXOVID (COVID-19 Vaccine, Adjuvanted).
Key Arguments and Decision:
- Restricted Approval: Dr. Prasad's memo approves NUVAXOVID for active immunization to prevent COVID-19, but only for individuals 65 years of age and older, and those 12 through 64 years who have at least one underlying condition that puts them at high risk for severe outcomes from COVID-19. This is a narrower indication than Novavax's original request for individuals 12 years of age and older.
- Reasons for Restriction: CBER's decision to limit the BLA is based on several factors:
- Limitations of Submitted Data: There was an overreliance on potentially confounded observational data, and a diminishing risk of severe COVID-19 outcomes in the general American population.
- Unclear Efficacy from Immunogenicity Data: The ability to estimate clinical efficacy against novel COVID-19 variants from immunogenicity data and observational/real-world data is limited because the amount of protection conferred by an increase in neutralizing antibodies is unclear. A causal relationship between rising neutralizing antibody titers and diminished severe COVID-19 outcomes has not been established.
- Differences from Influenza: SARS-CoV-2 differs from influenza; natural SARS-CoV-2 infection provides durable protection against future severe disease and death, which may outlast vaccine-conferred protection. The viral evolution rate of SARS-CoV-2 is markedly slower than influenza.
- Observational Data Bias: Observational data supporting risk reduction from additional vaccine doses is subject to multiple biases, including the "healthy vaccinee bias," which makes it difficult to draw reliable conclusions about vaccine efficacy. This bias has been thoroughly documented for both COVID-19 and influenza vaccines.
- Decreased Risk of Severe Outcomes: The risk of severe outcomes from COVID-19 has dramatically decreased over the past four years, with the infection fatality rate estimated to have decreased approximately 10-fold. As a result, individuals previously at low risk now have minimal risk of death from COVID-19.
- Benefit-Risk Calculation Altered: Given the decreased risk of severe COVID-19, the potential for absolute benefit from vaccination has also decreased. Even rare known and unknown vaccination-related harms, such as myocarditis, now have a higher chance of outweighing potential benefits in non-high-risk populations.
- Post-Marketing Commitment (PMC): Novavax has agreed to a PMC to assess the efficacy of the product among 50- to 64-year-old individuals in a randomized controlled trial. This study aims to determine if other patient populations have a favorable benefit-risk profile, as there is "equipoise" for such a study in individuals 50-65 years of age without risk factors.
- Divergence from U.S. Policy: The memo notes that the U.S. COVID-19 vaccine schedule of recommending annual vaccinations to children and non-high-risk adults under 65 diverges from international consensus.
- Emerging Consensus: The memorandum highlights an emerging consensus in the American medical community for this approach, referencing former FDA commissioner Robert Califf's statements supporting placebo-controlled trials for updated boosters in non-high-risk individuals.
Comparison: Agreement and Differences
The two documents, while serving different purposes, show significant alignment, particularly due to the shared authorship of Dr. Vinayak Prasad.
Points of Agreement:
- Restricted Vaccination Recommendations: Both sources strongly advocate for limiting broad COVID-19 vaccine recommendations (especially annual boosters) to older adults (typically 65+) and those with specified underlying high-risk conditions [Prasad memo: 1, 3, 4, 5, 23; NEJM article: 30, 32]. They explicitly criticize the U.S.'s "one-size-fits-all" approach that extends recommendations to healthy, low-risk individuals [NEJM article: 30].
- Need for Randomized Controlled Trials (RCTs) in Low-Risk Groups: A core tenet in both documents is the critical need for robust, randomized, placebo-controlled trials to evaluate clinical outcomes (efficacy and safety) for healthy, low-risk populations before granting broad marketing authorization [Prasad memo: 3, 26; NEJM article: 32, 34, 35, 41].
- Target Population for RCTs: Both identify the 50-64-year-old age group without underlying risk factors as an ideal population for future RCTs, citing "global equipoise" regarding the benefit of yearly boosters for this group [Prasad memo: 26; NEJM article: 34].
- Diminished Risk of Severe COVID-19: Both acknowledge the dramatic decrease in the risk of severe outcomes from COVID-19 over time [Prasad memo: 14, 19, 20]. This fundamental shift alters the benefit-risk calculation for low-risk individuals, making the potential for absolute benefit minimal [Prasad memo: 20].
- Limitations of Observational and Immunogenicity Data: Both documents express concerns about the reliance on observational data, noting biases like the "healthy vaccinee bias," and the limited ability of immunogenicity data alone to reliably predict clinical efficacy, especially against novel variants [Prasad memo: 5, 6, 7, 8, 13, 14; NEJM article: implicitly, by stating the need for RCTs focused on clinical outcomes (32, 35)].
- Distinction from Influenza: Both clearly articulate that SARS-CoV-2 differs significantly from influenza in terms of viral evolution speed and the durability of natural immunity against severe disease [Prasad memo: 9, 12; NEJM article: 37, 40].
- Transparency and Evidence Generation: Both emphasize the importance of generating robust, "gold-standard" evidence to inform future vaccine policies and provide clarity to healthcare providers and the public [Prasad memo: 27, 28; NEJM article: 41].
Points of Difference (primarily in scope and emphasis):
- Document Type and Purpose:
- The Prasad memo is an internal FDA decisional memorandum explaining a specific regulatory approval decision for a single product (NUVAXOVID BLA) based on the presented evidence. Its focus is on the rationale for that specific, restricted approval.
- The NEJM article is a published "Sounding Board" opinion piece outlining a broader "new FDA Covid-19 philosophy" and a proposed general regulatory framework for future COVID-19 vaccine approvals. It sets out a policy vision.
- Scope of Application:
- The Prasad memo directly applies its rationale to the approval of NUVAXOVID and its specific indication.
- The NEJM article lays out a general policy for all future COVID-19 vaccine approvals and booster recommendations, applicable to a wider range of products and populations.
- Discussion of Public Trust and Vaccine Uptake:
- The NEJM article explicitly addresses the issue of poor booster uptake and the decline in public trust in vaccination generally, including a "ripple effect" on vital immunization programs like MMR. It highlights this as a significant contextual factor for the FDA's new approach.
- While the Prasad memo mentions the divergence of the U.S. vaccine schedule from international consensus, it does not delve into the broader implications of declining public trust or poor uptake as a direct reason for its decision, though it aligns with the philosophy that might address such issues.
- Detail on Specific Harms/Harm-Benefit Analyses:
- The Prasad memo explicitly cites specific "harm-benefit analyses" suggesting net harm of ongoing vaccination for low-risk populations and discusses "unfavorable imbalances in rates of neurological, cardiac and thrombotic adverse events" linked to the Novavax vaccine.
- The NEJM article acknowledges that the policy "balances competing values" and that the benefit for low-risk individuals is "uncertain", but it does not detail specific harms or refer to particular harm-benefit analyses as extensively as the memo.
