FDA Conducting Benefit-Risk Modeling on Covid Vaccines

FDA is currently conducting benefit-risk modeling studies based on the evolving risk of Covid-19 severe outcomes and the long-term cardiac damage from vaccine-associated myocarditis, agency leaders say in a new JAMA article that outlines their rationale in ordering recent safety labeling change to mRNA Covid vaccines. “The FDA’s swift action in providing a class safety labeling change should not be seen as a final resolution of this concern,” FDA commissioner Marty Makary and CBER director Vinay Prasad write in the viewpoint article.

Last month, FDA approved updates to the prescribing information for Pfizer’s Comirnaty Covid-19 mRNA vaccine and Moderna’s Spikevax Covid-19 mRNA vaccine to include new safety information about the risks of myocarditis and pericarditis following their administration. The warning on myocarditis and pericarditis in the vaccines’ prescribing information has been updated to explain that the observed risk has been highest in males 12 through 24 years of age.

A new safety communication issued at the time says the update warns about (1) the estimated unadjusted incidence of myocarditis and/or pericarditis following administration of the 2023-2024 Formula of mRNA Covid-19 vaccines and (2) the results of a study that collected information on cardiac magnetic resonance imaging in people who developed myocarditis after receiving a vaccine.

In the JAMA article, Makary and Prasad outline the following four key findings from their recent vaccine safety review:

1. Vaccines can cause rare but serious adverse effects.
   While vaccines are often lifesaving, they can cause unexpected harms in certain individuals. FDA cited its pause of the chikungunya vaccine IXCHIQ — due to two deaths and multiple adverse events — as an example. Going forward, the agency will require randomized controlled trials (RCTs) to assess the benefit-risk balance of repeat Covid-19 vaccinations in healthy young populations.
2. Observational “big data” studies are critical for safety monitoring.
   Large-scale observational studies are essential to detect rare side effects like myocarditis — estimated at one in 37,000 in the highest-risk groups — that RCTs may miss due to size limitations. Despite differences between study types, real-world data will remain a core tool in post-market surveillance.
3. FDA will act quickly on emerging safety signals.
   The agency underscored its authority and readiness to take rapid action — such as updating labels, adding warnings, or restricting use — when serious safety concerns arise.
4. Higher standard required for vaccinating low-risk individuals.
   The agency emphasized it will not approve vaccines for healthy individuals under 65 — particularly adolescents and young adults — without strong RCT data showing that benefits outweigh risks. Past broad mandates may have undermined public trust, and the agency now aims to rebuild that trust with a more cautious, data-driven approach.