Explaining FDA's Position: My Take on Prasad and Makary (Updated)

Reconciling Scientific Integrity with Regulatory Reality. Let me Explain.

“The FDA is now saying: Here are restricted groups we will likely approve your products for, now show it is effective and safe in those groups.”

Plus, remember: Medically frail infants are being injected now without proper regulation.

When the FDA released its new framework for COVID-19 vaccine policy via a “Sounding Board” article in the New England Journal of Medicine, authored by Dr. Vinay Prasad and Dr. Marty Makary, it marked a sharp pivot away from the all-ages-for-all-times universal booster doctrine that has dominated U.S. policy for the last three years.

Predictably, the move was met with confusion and criticism from establishment voices, as reflected in Kristina Fiore’s recent article in MedPage Today. Critics such as Dr. Paul Offit and Dr. Kathryn Edwards expressed concern about ethical trial design, presumed efficacy, and procedural irregularities. Yet their critiques miss key elements of the FDA’s position—and ignore the deeper structural problems in how we’ve previously evaluated vaccine efficacy and safety.

Let’s unpack what Prasad and Makary are really doing here, and why some of the loudest complaints are aimed more at preserving a fragile narrative than at protecting public health.

The Shift to Risk-Based Policy: Long Overdue

For years, critics of the “vaccinate-everyone-every-six-months” model have argued that the evidence simply doesn’t support universal boosting—especially in young, healthy individuals. European regulators acknowledged this early on, shifting to risk-stratified strategies. The U.S., however, held the line, often citing population-level benefits despite rapidly waning immunity, immune imprinting, and evidence of negative efficacy post-infection in some cohorts.

Now, under the new FDA framework, COVID-19 vaccine approvals for low-risk individuals will require randomized controlled trials (RCTs) with inert placebos and long-term outcomes—something long demanded by independent scientists. Meanwhile, high-risk groups (e.g., the elderly, immunocompromised) will be eligible under immunogenicity-based approvals, with post-marketing safety studies still required.

This may seem like a compromise, but it’s far more radical than the critics let on.

“For all healthy persons — those with no risk factors for severe Covid-19 — between the ages of 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. Insofar as possible, when approving a Covid-19 vaccine for high-risk groups, the FDA will encourage manufacturers to conduct randomized, controlled trials in the population of healthy adults as part of their postmarketing commitment.”

Can you imagine FDA saying that under Marks? I cannot.

Immunogenicity ≠ Effectiveness — So Why Approve Based on It?

Here, Prasad and Makary walk a line between pragmatic regulation and institutional continuity. Immunobridging is not the gold standard—it’s a regulatory workaround. They know this. Prasad, in particular, has been critical of surrogate endpoints in oncology and COVID alike.

But by pairing immunogenicity-based approvals with mandatory postmarketing studies and demanding RCTs in the 50–64-year-old group, they’ve made it clear that the burden of proof is shifting—finally—back toward outcomes.

This matters. It puts industry on notice: Show us the data, not just the antibody titers.

The Lyons-Weiler/Fenton Effect: Still Ignored, Still Relevant

Strikingly absent from both the FDA’s new framework and the MedPage Today coverage is any recognition of a core methodological failure that underlies perhaps every prior estimate of COVID-19 vaccine efficacy: the Lyons-Weiler/Fenton Effect, aka, the Case Counting Window Bias.

This bias occurs when vaccine trials or observational studies exclude cases in the immediate post-vaccination window—often 7 to 14 days—while assigning those same cases to the unvaccinated comparison group. The result? Grossly inflated efficacy, underestimated risk, and fundamentally flawed ethics calculations.

Prasad knows this. He discussed it publicly when Peter Doshi and colleagues published on it. Yet in his new role at the FDA, he hasn’t addressed it directly. That silence is troubling—but it doesn’t invalidate the broader direction of the new policy.

What it does mean is that none of the prior data on which vaccine mandates and universal recommendations were based should be taken at face value. If we ignore the counting window bias, we’re building on sand.

There must be a good strategic reason why the fundamental estimates of efficacy are being taken at face value; perhaps it’s easier to force new studies under new scrutiny. New rulers, new rules. People like Edwards and Offit find that frustation.

That has to be a good sign.

Offit’s Objections: Premised on Flawed Certainties

Paul Offit claims we already know enough about vaccine safety and efficacy. That’s a dangerous assumption—especially when prior trials:

• Were never even conducted on the population in question in the first place.

• Excluded early risk windows,

• Failed to stratify by prior infection and risk,

• Underpowered severe adverse event detection,

• Later trials used active comparators that masked safety signals (under the argument of “clinical equipoise”, which requires that participants will be allocated to an intervention that is not inferior to any available alternative. Under this view, placebo-controlled RCTs must not be allowed anymore when assessing novel COVID-19 vaccine candidates. This is NOT FDA’s (Prasad and Makary’s) position:

“Given that there is global equipoise about yearly boosters for the 50–64-year-old age group, we assert that this is an ideal population for future trials. The FDA’s preferred primary end point in these trials will be symptomatic Covid-19, with special attention paid to several secondary end points: severe Covid-19, hospitalization, and death. Sample-size calculations should aim to demonstrate that vaccines reduce the incidence of the primary end point with a lower confidence interval bound that is ideally above 30%. People who have had Covid-19 in the past year should not be excluded — since evidence is needed for the average American. Follow-up should extend for a minimum of 6 months to ensure that early booster gains persist. The control group could receive a saline placebo, to permit documentation of the full adverse-event profile. Ultimately, these studies alone can provide reassurance that the American repeat-boosters-in-perpetuity strategy is evidence-based.”

Offit’s argument—that it may now be unethical to not vaccinate control groups—falls apart if prior efficacy claims were based on flawed designs. Ethics require equipoise. You can’t claim to know the vaccine works in a group if the trial you’re citing excluded the most relevant time window for adverse events or counted cases unfairly. So a re-do on the science is just what the doctor ordered.

Edwards' Concerns: Procedural but Not Substantive

Dr. Kathryn Edwards laments that this new policy wasn’t routed through the usual FDA advisory processes. She’s right—it wasn’t. It was published in a journal, with no VRBPAC vote, no Federal Register comment window.

But this objection is about process, not content.

Prasad and Makary are announcing FDA and CBER’s position. They are within their rights, duties and responsibilities to do so. Along with their stated position comes their requisite expectations: Follow directions from Directors, or be reclassified and put on administrative leave. So no, they won’t defer to VRBAC and passively sit by while the rubber stamp new COVID-19 shots.

It’s worth pointing out that many of the same critics never raised a peep when the CDC ignored its own ACIP’s hesitations to greenlight bivalent boosters, or FDA’s warning on myocarditis, or when mRNA vaccines were rebranded as “safe and effective” with no supporting RCTs against new variants.

The process has been broken for years. At least now, someone is admitting that we need better data. That someone is the United States Food and Drug Administration.

The Strategic Genius: A Transparent Blueprint for Scientific Reform

Here’s the deeper read: Prasad and Makary’s FDA policy may be less about preserving Pharma’s current dominance than about undermining it from within.

Requiring RCTs in healthy people forces industry to prove it—not just gesture toward antibody curves. Because the other side of efficacy is safety. Prasad and Makary made that clear enough.

Requiring saline placebos ensures real signals won’t be masked. No non-inferiority slippery slope allowed.

Forcing trials to include people with prior COVID means Pharma can’t cherry-pick immunologically naïve subjects anymore. If you’re going to say your vaccine is safe and effective for everyone, study them all. No more intentional translational failure.

None of these moves help Pharma. They help the public.

The Rational Conclusion is: Not Perfect, But Better

No policy is flawless. Yes, the continued reliance on immunobridging in high-risk groups leaves the door open for abuse. The silence on window bias is disappointing. And the publication route bypassed institutional transparency.

But let’s be honest—this policy marks the first time in three years that U.S. regulators have even suggested that more trials are needed, that risk stratification matters, and that universal boosting may not be scientifically defensible.

It’s not enough. But it’s a beginning.

Prasad and Makary are playing a long, responsibility game of transparent accountability. They are forcing Pharma into a corner where they must either show the data or expose their own lack of it—and it’s a strategy worth watching.

Especially since we are ready to hold them to it.

What the Policy Doesn’t Say: Common Misreadings Explained

The NEJM article by Drs. Prasad and Makary is densely written and layered with regulatory nuance. It’s understandable that even experienced readers may misinterpret certain provisions. Here are several points that have been misconstrued, along with clarifications based on the article’s actual content.

1. Misconstrued: The policy gives blanket approval for infants to receive the vaccine without further study.

What the article actually says:

“We anticipate continued reliance on data demonstrating immunogenicity and safety as the basis for vaccine approval [in high-risk groups].”

Clarification:

The article does not authorize routine use of the vaccine in all infants. It allows potential approval only for infants who fall into clearly defined high-risk categories (e.g., with significant underlying health conditions), and (and this is the most important part): only when manufacturers provide both immunogenicity and safety data. For healthy infants, RCTs are recommended before any approval is considered.

2. Misconstrued: Immunogenicity alone is enough for FDA approval in high-risk groups.

Clarification:

The policy requires that manufacturers present evidence of both immunogenicity and safety. This dual standard maintains a threshold for protection while recognizing that, in certain high-risk populations, placebo-controlled trials may not always be feasible. But nowhere does it suggest that immunogenicity alone—without safety data—is sufficient.

3. Misconstrued: All infants are now considered “high-risk” under this framework.

Clarification:

While the list of high-risk conditions for adults includes broad criteria like obesity or depression, its application in infants is much narrower. Infants would need to have specific qualifying medical conditions—such as severe immunodeficiency, congenital heart disease, or complex chronic conditions—to be considered high-risk under this policy. Most healthy infants do not fall under this category. These are the same types of people who were excluded from clinical trials in the past— because they were so medically frail, their individual tolerance of the mRNA jabs would cause the jabs to appear risky. The FDA is now saying: Here are restricted groups we will likely approve your products for, now show it is effective and safe in those groups. And the FDA does not say they should be mandated (Important correction! “not” - Thank you, AF!). There are more chapters on that topic to be revealed.

4. Misconstrued: The article replaces or bypasses the formal FDA regulatory process.

Clarification:

Although the new framework was introduced via a NEJM article rather than through the Federal Register or VRBPAC proceedings, it does not override those processes. The article describes the FDA’s intended approach; it does not itself confer legal or regulatory approval. Formal authorizations will still go through the established channels.

5. Misconstrued: Placebo-controlled trials are no longer ethical or encouraged.

Clarification:

The article emphasizes that equipoise exists in the 50–64-year-old population and explicitly recommends RCTs with saline placebos in healthy individuals. This design element underscores the need for rigorous evaluation and does not dismiss the ethical basis for such trials.

6. Misconstrued: The policy endorses past efficacy estimates uncritically.

Clarification:

While the article does not directly critique previous studies, its proposed trial framework indirectly acknowledges shortcomings in prior designs. For example, including individuals with prior COVID-19, requiring 6-month follow-up, and specifying meaningful clinical endpoints (not just antibodies) all represent a corrective posture toward earlier assumptions. These design elements quietly but absolutely raise the bar. From the floor. There is now a bar.

Given the technical nature of the article and the regulatory complexity it addresses, it’s easy to see how well-intentioned readers might draw inaccurate conclusions. However, a close read shows that the FDA’s updated position is more conservative, not less. It restricts approval to high-risk groups with evidence of safety, calls for new trials in healthy populations, and subtly corrects the trajectory of the prior universal vaccination model.

Rather than a green light for all, the policy represents a narrowing of scope—and a return to evidence-based conditions for approval.

Disagree on any point? Did I miss a nuance you picked up? Let me know in the comments. Either way, please share the article and consider upgrading to a paid subscription. We’re still in the mix, and the bills still come in every month. You make Popular Rational possible with your paid subscription.

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