The FDA should not change its mind last minute

In which Ruxandra explains why the consequences of the FDA's RTF to Moderna extend far beyond the current vaccine program

I often say that in drug development, lack of regulatory clarity and consistency can be more damaging than regulation itself. Clear rules, even when stringent, can be understood and navigated. But unclear or constantly shifting expectations can be much harder to efficiently deal with.

That uncertainty doesn’t just slow individual programs, but also reshapes behavior across the biotech ecosystem in a negative way. Lack of regulatory clarity fosters a culture of defensive decision-making, where companies avoid innovative clinical development strategies and default to more conservative, expensive paths simply because they lack confidence in how the FDA might respond. Over time, this dynamic drives up trial costs, prolongs timelines, and ultimately reduces the number of truly innovative therapies that reach patients.

Unfortunately, a decision made by the FDA very recently threatens to make an already existing problem even worse.

Today, the U.S. Food and Drug Administration issued a refusal-to-file letter to Boston-based biotech Moderna regarding its Phase III trial for an mRNA influenza vaccine in adults 50 and older. The letter was signed by Dr. Vinay Prasad, the head of CBER (Centre for Biologics Evaluation and Research)—an unusual move at this stage of the process, suggesting the decision was not routine.

A refusal-to-file (RTF) letter means the FDA has determined that a company’s application is not sufficiently complete or adequate to even begin formal review. It halts the approval process before any full evaluation of safety and efficacy takes place, forcing the sponsor to address the cited deficiencies and resubmit.

The justification offered by the FDA is that Moderna used the wrong comparator in adults over 65. Specifically, the agency argues that because higher-dose or adjuvanted influenza vaccines are recommended for older adults, Moderna’s use of a standard-dose comparator rendered the trial not “adequate and well-controlled.”

If that requirement had been clear from the outset, this would be an unremarkable story about trial design. Companies adapt to clear standards and requirements from regulators all the time. But Moderna’s CEO, Stéphane Bancel, says the FDA had previously signaled that a licensed standard-dose comparator would be acceptable—and has only now changed its position after the trial was completed. If that is accurate, it would mean that roughly $750 million—what the New York Times reports the trial cost—was effectively committed under regulatory assumptions that no longer hold.

Adding to the confusion, entrepreneur Dr. Jing Liang noted on X that publicly available trial data appear to show Moderna conducted analyses involving higher-dose comparators in older adults. If accurate, it would raise further questions about the basis for issuing a refusal-to-file letter in the first place.

No matter which account ultimately proves correct, this episode leaves us with two uncomfortable possibilities. If the FDA changed its regulatory position after years of clinical development, that reinforces a persistent concern about regulatory inconsistency. If, alternatively, Moderna met the agency’s highest level of stated expectations, actually did use a high-dose comparator and still received a refusal-to-file letter, the implications are even more serious, raising questions about transparency and internal coherence at the agency.

In this post, I will focus on the “least bad” scenario—that the FDA revised its stance on a trial design it had previously indicated was acceptable. Even that interpretation carries consequences far beyond a single influenza vaccine. When regulatory expectations shift late in development, companies internalize the lesson and design more defensively, avoid innovative comparators and add layers of redundancy. Over time, this entrenches a culture of safetyism and regulatory aversion. Sponsors begin optimizing not for better science, but for minimizing the chance of procedural surprise. In time, this leads to a ballooning of costs.

Why regulatory inconsistency is bad

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Even if we assume the “least bad” scenario—that the FDA has indicated a lower-dose comparator would be acceptable—it still reinforces one of the agency’s most persistent structural problems: regulatory inconsistency and opacity.

Translating science into a clinical product already takes more than a decade and billions of dollars and only about 10% of drug development programs succeed. Most of that time and capital is spent in clinical development—running trials, scaling manufacturing, and interacting with the FDA. Yet over a 10+ year program, a company may have only three to five formal milestone meetings with regulators. Those meetings determine pivotal trial design, endpoints, manufacturing standards, and statistical plans.

Given that formal meetings with regulators are limited and FDA guidance is often broad and caveated, companies therefore make pivotal decisions under real uncertainty. And when the stakes involve hundreds of millions of dollars and years of work, the rational response is caution. This is what Adam Kroetsch meant when he said that “vague regulation breeds safetyism.” Sponsors layer on extra monitoring, avoid novel trial designs, and default to conventional manufacturing processes even when more efficient technologies exist. Each individual decision makes sense. Collectively, they make drug development slower and more expensive.

The slow adoption of risk-based monitoring (RBM) is a clear example of the downsides of regulatory opacity. RBM focuses oversight on the highest-risk elements of a study and could reduce trial costs by up to 30% without compromising safety or data integrity. The FDA has encouraged its use for years. Yet, despite this clear advantage, adoption remains uneven. Surveys show that sponsors hesitate because they worry regulators may not accept RBM in practice—even if official guidance supports it.

The same fear-driven conservatism appears in other areas of trial design. One study found that roughly one-third of data collected in clinical trials may be redundant. Sponsors collect this data due to mistakenly believing this is what regulators might ask for. That redundancy translates directly into higher costs, and longer trial timelines.

It’s trying to solve the problem of regulatory opacity, which has such a negative downstream impact on innovation, that has led me to launch, with OneDaySooner, the openFDA Fund—a centralized repository of past regulatory interactions designed to bring greater transparency to the often opaque FDA decision-making process.

The future

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Unfortunately, this is not the first late-stage reversal under the current FDA. In November 2025, biotech company uniQure announced that the FDA had reversed its prior position on the company’s gene therapy AMT-130 for Huntington’s disease. Although the agency had previously indicated that Phase 1/2 data—compared against an external natural history control—could support a Biologics License Application (BLA) under the accelerated approval pathway, it now determined that the existing data are insufficient for submission.

The shift came despite promising results showing statistically significant slowing of disease progression and supportive biomarker improvements. CEO Matt Kapusta expressed surprise, noting that the feedback represented a “drastic change” from guidance provided in late 2024.

The current FDA leadership has openly acknowledged growing competitive pressure from China and has put forward a number of thoughtful proposals to modernize the regulatory framework. But reform does not end at changing rules. These rules must also be predictable. Regulatory clarity and consistency are foundational and as important as the quality of the regulations themselves. For the sake of the US biotech ecosystem, I hope that the FDA will reverse course in what seems a trend towards decreased regulatory consistency and clarity.