Drs. Prasad and Makary discuss the reasons for changing the safety label on mRNA COVID vaccines
A good start. But the data they are using are not comprehensive. For identifying rates of myocarditis, you need *active* surveillance of vaccinees with EKGs, echocardiograms and cardiac MRIs
I have bolded important points, and added comments.
https://jamanetwork.com/journals/jama/fullarticle/2836670
US FDA Safety Labeling Change for mRNA COVID-19 Vaccines
Vinay Prasad, MD, MPH1; Martin A. Makary, MD, MPH1
JAMA
July 14, 2025
doi: 10.1001/jama.2025.12675
On June 25, 2025, the US Food and Drug Administration (FDA), in conjunction with manufacturers, added class safety warnings for myocarditis and pericarditis to COVID-19 messenger RNA (mRNA) vaccines’ prescribing information. The new warning expands knowledge regarding the age range and severity of myocarditis, noting that the estimated unadjusted incidence of myocarditis and/or pericarditis was approximately 27 cases per 1 000 000 (or 1 in 37 000) in males aged 12 to 24 years for the 2023 to 2024 formula of mRNA COVID-19 vaccines, and that “at a median follow-up of approximately 5 months post-vaccination, persistence of abnormal cardiac magnetic resonance imaging (CMR) findings that are a marker for myocardial injury was common.” The data do not allow disambiguating risk by manufacturer. [Oddly, this estimated rate has no footnote to tell us what data were used to calculate it. Other studies suggest the rate could be 15 times higher.—Nass]
This action follows new data from a multi-institutional, retrospective study sponsored by the FDA.1 That study included 333 patients hospitalized with myocarditis after receiving a COVID-19 vaccine, in whom no alternative etiology was considered plausible. The median age was 16 years, and 96% presented with chest pain with a mean onset of 3.2 days after vaccination. Notably, 82% (177/216) of vaccine-associated myocarditis cases evaluated by cardiac magnetic resonance imaging had late gadolinium enhancement (LGE). LGE is associated with worse outcomes in other cardiac disease states2 and for patients with myocarditis.3 Although not all cases were clinically severe, 2% of patients (6/331) received inotropic support.1[This means they had severe heart failure—Nass]
Most concerning, over a median follow-up of 159 days, 60% of individuals (98/161) with initial LGE had persistence and a minority (5% [5/98]) had worsening LGE and symptoms. A total of 4% of patients (11/272) continued to have arrhythmias at a median follow-up of 31 days and 2% required antiarrhythmic medications. These findings raise questions about the benefit-risk assessment for COVID-19 vaccination in healthy male adolescents and young adults.
The FDA’s sponsored findings corroborate and extend earlier reports. A 2022 study by the US Centers for Disease Control and Prevention (CDC) performed a phone survey of more than 500 individuals aged 12 to 29 years with vaccine-induced myocarditis reports submitted to the Vaccine Adverse Event Reporting System. CDC authors found that approximately 20% of patients with postvaccination myocarditis were admitted to intensive care on initial presentation. [Serious adverse events are supposed to trigger a request for medical records, not just a phone call from CDC contractors.—Nass] At 90 days’ follow-up, more than 30% had still not been cleared for physical activity and approximately 25% were still being prescribed daily medications to treat their myocarditis. A 2024 study from France considered patients hospitalized with myocarditis within 7 days from receipt of vaccine with a median age of 25.9 years.4 Authors found 3.2% of patients (18/558) required rehospitalization for myopericarditis within 18 months, noting 1 attributable death in this group.
The history of vaccine-associated myocarditis reflects missed opportunities for safety mitigation. The first report of myocarditis after mRNA vaccination occurred in February 2021 in Israel, a country that rapidly vaccinated its population using the Pfizer mRNA vaccine. Yet the link between COVID-19 vaccination and myocarditis was not immediately accepted, and, as late as April 2021, the then-CDC director stated that she had not observed a potential causal link between vaccination and myocarditis despite millions of doses. [That is because the US cases were covered up by CDC. The VAERS contractor informed CDC in February of an unexpected increase in US myocarditis cases, I have been told on good authority.—Nass]. Early reports found rates as high as 300 per 1 000 000 among young men receiving dose 2 of the Moderna product5 or approximately 1 in 3000 among those at highest risk—young, postpubescent men.6 Eventually, the CDC would acknowledge that peak rates of myocarditis in young men observed through passive collection, likely underestimating true incidence, were as high as 100 per 1 000 000. The US was generally slow to act upon this safety concern, trailing other nations in mitigation strategies, such as increasing the time between the first 2 doses to reduce the risk of myocarditis.7
Acknowledging the risk of myocarditis by April 2021 would have important regulatory implications for pending age expansions. On May 10, 2021, the FDA expanded emergency use authorization of the Pfizer COVID-19 vaccine to persons between the ages of 12 and 17 years. Congressional investigation reveals the FDA commissioner, Center for Biologics Evaluation and Research director, and CDC director repeatedly expressed hesitation about issuing a warning about myocarditis in the month of May. On June 25, 2021, after the emergency use authorization in adolescents, the FDA issued a safety communication on myocarditis and pericarditis. [In other words, the CDC covered up the myocarditis cases until it got the ACIP to approve the vaccine for 12-17 year olds, which just happened to be the group with the highest rates of myocarditis, and benefited the least, if at all, from the vaccines. Then it admitted myocarditis was a side effect, but few learned of its admission as teens were vaccinated rapidly.—Nass]
Perhaps due to self-selection or a longer delay between doses, subsequent boosters appear to have had lower rates of vaccine-associated myocarditis. Sharff et al found a rate of 1 in 10 000 for the first (fall 2021) COVID-19 booster. Some analysts argue that these rates of myocarditis nevertheless exceed potential vaccination benefits5,8 and have been critical of vaccine and booster mandates in male adolescents and young adults aged 12 to 29 years. The 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. The FDA’s swift action in providing a class Safety Labeling Change (SLC) should not be seen as a final resolution of this concern. The FDA will continue to monitor vaccine safety and may take additional SLC actions as warranted. We highlight the following 4 key lessons from this event.
First, vaccines can have idiosyncratic and concerning adverse effects. Although many vaccines are both miraculous and lifesaving, the ability of an immunologic product to result in unforeseen and idiosyncratic harms remains real. Recently, another vaccine against a neglected tropical disease, chikungunya—IXCHIQ—was placed on pause by the FDA, an action triggered by 2 patient deaths and 15 cases of chikungunya-like adverse events.9 [Yet another example of FDA and CDC rushing through an approval of a vaccine that was not needed and inadequately studied, in which the “animal rule” was [imho illegally] invoked, despite an ongoing epidemic in Paraguay where adequate studies could and should have been conducted.—Nass]. Identifying with acceptable certainty those subpopulations in whom benefits exceed harms is fundamental to regulatory decision-making. In part because of uncertainty about the benefit-risk profile for repeat COVID-19 vaccinations in young populations without risk factors for severe disease, the FDA announced a new evidence-based framework to require randomized controlled trials (RCTs) in these populations prior to issuing further marketing approvals.10
Second, big data will always have a place in drug, biologic, and vaccine regulation. Although some critics point to discordance between RCTs and observational studies on the same clinical questions in making claims of efficacy, few dispute the need for large, well-designed and -conducted observational studies to elucidate adverse events that cannot be detected in smaller prelicensure RCTs. Our best estimates of unadjusted incidence of myocarditis in the highest-risk demographic group is 1 in 37 000 for the 2023 to 2024 formulation, the last year for which data exist. RCTs powered for clinically relevant outcomes, such as reductions in symptomatic disease—the primary end point of future COVID-19 registration and postmarketing studies—will be insufficient to ascertain with certainty an absolute harm at that incident rate.
Third, the FDA must take swift action when safety signals are found. The current SLC reflects the agency’s unwavering commitment to act at the first sign of serious harm for any product. The FDA retains broad statutory authority in cases of safety concerns, including the ability to compel warnings and precautions labeling, add contraindications, and limit approved indications. The FDA will continue to contemplate these potential SLCs based on ongoing benefit-risk modeling and discussions.
Fourth, the burden of proof must be high to vaccinate healthy people at low risk of severe disease. The FDA does not recommend nor mandate medical products, but instead authorizes specific indications for use only when there is substantial confidence that benefits outweigh risks, and ensures accurate and essential labeling information for the intended uses of the product. Once the FDA approves a regulated product, health care professionals may prescribe the FDA-approved product for an unapproved use when the clinician judges it is medically appropriate for their specific patient. That said, the FDA cannot provide marketing approval in situations where we are not confident that the potential benefit exceeds harm. Notably, for all COVID-19 vaccines going forward—both those using mRNA and protein-based technologies—the FDA does not anticipate providing market approval for healthy individuals younger than 65 years, described in our 2025 COVID-19 framework,10 in the absence of data from RCTs. Clinicians who choose to vaccinate male adolescents and young adults between the ages of 12 and 24 years should consider recent infection, absolute risk of severe disease, and risk of vaccine-associated myocarditis as some of the salient factors for clinical decision-making. [This is a clear warning to doctors that they will be subject to criticism and probably malpractice suits if they do so—Nass]
During the COVID-19 pandemic, broad, one-size-fits-all mandates were aggressively pursued, requiring vaccines in populations with potentially net-negative benefit-risk profiles. This risk-taking approach may, in part, be responsible for widespread loss of trust in public health and medicine and growing hesitancy against all vaccination. Public trust takes decades to build, but can be forfeited in a single action. The FDA’s class SLC action on mRNA products represents one step toward rebuilding that trust.