How will FDA changes reshape drug approval in 2025 and beyond?

Six weeks after a reduction in force (RIF) at the US Food and Drug Administration removed thousands of workers, signs are emerging about how the agency’s approach to drug approval may change.

The 20% RIF on April 1, which excluded drug, device, and food reviewers and inspectors, nonetheless sparked concern and speculation across the pharmaceutical industry. Former commissioner Robert Califf posted on LinkedIn, “The FDA as we’ve known it is finished.” Over 200 biotech leaders signed a letter to Senate Health, Education, Labor, and Pensions (HELP) Committee Chair Bill Cassidy (R-LA) urging the government to “quickly preserve and restore” the FDA’s core functions and avoid delays to promised drug-approval decision dates.

A little over a month later, some of those fears have materialized, but many have not. New commissioner Marty Makary says that he wants to speed up the regulatory process and bring new treatments to patients more rapidly. But the agency workforce remains in disarray, and Makary has announced a flurry of atypical decisions about vaccines—such as suggesting repeat efficacy testing for seasonal updates—that appear to be guided by the antivaccine views of Makary’s boss, Health and Human Services secretary Robert F. Kennedy Jr.

Industry observers say this year may be characterized by slower regulatory decisions, reduced informal guidance, and big questions about the future of biologics in the US. These changes will have knock-on impacts far beyond US borders, because regulators in many other countries expedite review of FDA-approved drugs.

The FDA becomes involved before any new drug molecule is tested in humans. Here’s how upheaval at the agency appears to be affecting specific points in the approval process for new drugs.

Layoffs lead to confusion

“We’re a month out, and there’s still so much confusion about what is operating and what’s not operating. It’s really frustrating,” says an employee who was fired from the FDA in the mass layoff and spoke to C&EN during the first week of May on condition of anonymity because they still hope to be called back to a job they loved.

That lack of clarity is also apparent to industry professionals. “What concerns me the most is the—let’s call it undefined—way the FDA is changing,” says retired biotech executive Ben Machielse. “I miss a plan.”

Makary, who joined the agency just after the layoffs, has made some surprising reversals since taking on his role. That includes saying emphatically in an interview that a proposed reorganization of the FDA won’t happen. Under his leadership, FDA staffers who were let go from certain positions, including ones in food safety labs and public records offices, have been rehired to fill those critical roles.

“These government agencies have been around for a long time, and they’ve grown and become complex—because helping the American people can be complex,” says the fired FDA employee, adding that they think the architects of the mass layoff did not understand what they were cutting.

Though this person supports fiscal responsibility in government, they emphasized that continuity of service is also important. The office they left has been unable to continue some of its drug safety functions but also has not communicated about that stoppage to the public.

Others echo concern about the agency’s lack of transparency. “Right now, getting communications out of the agency is really tough,” says Chad Landmon, who handles intellectual property and FDA matters as chair of the Hatch-Waxman and biologics group at the law firm Polsinelli. It’s difficult for him and his colleagues to predict how policies might change, Landmon adds.

The absence of clarity has companies and investors caught between wait-and-see mode and the need to make decisions.. “It's still very early days, and it's—a lot of this is sentiment driven rather than science driven or data driven,” says Reinout Hesselink, a regulatory consultant based in the Netherlands. People “don’t like the uncertainties,” he says.

In the past month, the FDA has missed drug approval deadlines in a few highly publicized cases. On April 23, Vanda Pharmaceuticals announced that the agency had cited the RIF in its request to a judge to delay a hearing over a Vanda drug candidate that reviewers had rejected in 2024. On April 30, the agency missed a decision deadline for a rare disease drug from Stealth BioTherapeutics; there was a previous regulatory dispute over whether the clinical trial was adequate to show the drug’s efficacy. On May 7, the agency was due to decide on a GlaxoSmithKline antibody but did not, according to Fierce Pharma.

Most notable, the FDA did not approve Novavax’s peptide vaccine for SARS-CoV-2, which Makary has insisted must be tested again for efficacy. The vaccine has been marketed since 2022 under an emergency authorization from the agency. But on a May 8 earnings call, Novavax CEO John Jacobs said, “Based on what we've received to date, formally from FDA, they're asking for a postmarketing commitment. And by definition, it's our understanding that a postmarketing commitment comes after approval.”

Other approval decisions appear to have proceeded normally since April. Bruce Booth, a partner at Atlas Venture, posted to LinkedIn on May 1 that companies in his firm’s portfolio have not yet experienced delays. The industry should give Makary “a chance to stabilize the organization and work with the sector to advance drug innovation,” he wrote.

But regulation of drug development begins long before the approval deadline, and uncertainty and delay could arise at many points along the way.

Preparing for review

Drug companies usually refer to FDA policies at multiple junctures as they develop their drugs, run trials, and apply for approval. But experts say that the offices that used to develop regulatory guidelines were significantly affected by the April 1 mass layoff. This apparent vacuum in technical decision-making could cause problems.

For example, companies hoping to develop a drug in the US must prepare an investigational new drug application (IND) for FDA review. The document details what a drug is and how it is manufactured, includes safety studies in animals, and lays out detailed plans for clinical studies. The agency receives between 1,500 and 2,000 INDs each year.

The data that must be included in an IND will probably change. Makary has announced plans to reduce animal safety testing in favor of newer technologies—although exactly what kind of studies would suffice as an alternative is not yet clear. And without policy offices, it is unclear who will spell out the answers.

According to Barrett Tenbarge, a partner at the law firm Faegre Drinker Biddle & Reath, the loss of experts in policy offices also muddies the implications of an executive order signed by President Donald J. Trump on Jan. 31, which requires regulators to rescind 10 regulations for every new one they introduce.

Although a central, agency-wide policy office is still operating, Tenbarge tells C&EN that “the offices of policy throughout FDA that were reportedly subject to RIFs are responsible for driving the details of new regulations and guidance documents.” If product-specific expertise no longer exists, he says, it is difficult to forecast how the agency will cut existing regulations to make way for guidance addressing new questions, as the January executive order requires.

On May 13, the HHS requested public feedback on which regulations should be cut department-wide, and launched a web portal for deregulation proposals. At least one trade group, the Alliance for Pharmacy Compounding, has already prepared a report on FDA regulations that it says are outdated or overreach the agency’s authority—and which would benefit compounding pharmacies if rescinded. But patient safety must remain paramount, according to Scott Brunner, the alliance’s CEO. In a press briefing, he said that “this blueprint is not a call for deregulation. We believe that pharmacy compounding . . . requires a rigorous regulatory framework.”

Although the approval process for generic drugs—medicines made by third parties after patent exclusivity has expired—is distinct from the process for completely new medicines, Tenbarge says the changes to industry policymaking could have ripple effects here as well. “Product-specific guidance documents are a critical tool that FDA uses to help get generic drugs to patients faster,” he says. Without clear explanations of how to prove their drugs are equivalent to the originals, generic manufacturers may waste time with incomplete applications, he warns.

Reviewers’ remit

Although the reduction in force and earlier voluntary buyouts excluded staff members who review new drugs, cuts to support staff have affected their ability to get work done, and STAT reports that many reviewers are seeking to leave the agency.

Even before filing an IND, companies sponsoring potential drugs commonly meet with regulators to ask specific technical questions, especially if their work breaks new ground. According to Hesselink, the wait time for such a meeting has stretched from 3 months to as long as 6 months in recent weeks.

Delays in these early stages could pose a serious problem for biotech firms with limited cash reserves, Hesselink says. “Most of them need to have human data as soon as possible,” he says. “You can't wait a year and a half burning your money till you get approval, and only then start your trials.” He says the slowdown could accelerate a trend to conduct first-in-human studies outside the US.

If clinical trials of a potential drug’s safety and efficacy are successful—and many are not—the drug’s sponsor can apply to sell it to patients with a new drug application or biologic license application. The submission package for either of these has to demonstrate that the drug works for patients and that it can be made safely and reliably at scale. At over $4 million, the filing fee is a significant investment for a company.

FDA scientists review all regulatory filings, from early requests to test a molecule in humans to meatier applications to sell a drug to the public. As few as three or as many as seven reviewers might be involved, depending on a drug’s complexity and the clinical trials its sponsor plans to carry out. Retired biotech executive Machielse says it’s not uncommon for the same principal reviewer to handle a product throughout its yearslong development cycle. The departure of such people from the agency could slow down reviews on products they cover, he adds, “because the principal reviewer knows all the backgrounds, knows the decisions which were made, and knows the product the best.”

According to Polsinelli’s Landmon, a loss of institutional knowledge could create both challenges and possibilities for drug sponsors. Although the FDA has a responsibility to apply the law consistently or else articulate the reasons for policy changes, he says companies dealing with new reviewers “may get opportunities to convince FDA to do things that maybe you couldn’t convince them to do before.”

Turbulence within the agency appears to be affecting how it applies its rules. For example, the April letter to the Senate HELP Committee reports a case in which an anonymous company received conflicting information from different members of the review team and no senior decision-maker stepped in to determine the agency’s position.

An April 16 report from biopharma analysts at Leerink Partners says the submissions at greatest risk of delay are those “where a nuanced dialogue with the FDA and drug sponsor could push an approval over the finish line.” Such filings include drugs that tackle new diseases, use novel endpoints to measure success, or produce ambiguous results in clinical trials, the report says.

Makary is moving quickly to introduce artificial intelligence tools to speed and simplify the review process. In an interview April 17, Makary said he intends to “introduce AI into the review process, to help the reviewer, to make the reviewer’s workstream much more streamlined and summarize things.”

On May 8, the agency announced that it had completed a pilot scientific review that used generative AI to “allow FDA scientists and subject-matter experts to spend less time on tedious, repetitive tasks” and would roll out the tool agency-wide by the end of June. The FDA’s media office did not reply to questions from C&EN about the AI tool that it used, for what specific tasks, and how the tool was benchmarked.

Product-specific policies

The area of greatest uncertainty may be the fate of vaccines and of more-complicated biologics.

For example, Makary has indicated a desire to move more quickly on rare disease drugs. In the April 17 interview, he said that “if there’s a rare condition . . . we may be approving drugs based on a plausible mechanism, on sort of a conditional basis.”

In an April 21 newsletter to investors, Tim Opler, managing director of the health-care group atStifel Investment Banking, recounts an unnamed drug developer’s experience at a regulatory meeting that seems to back up Makary’s sentiment. The company, which was developing a drug for children with an unspecified rare disease, presented its plan for a Phase 3 efficacy trial. Opler says, “The FDA attendees asked why the sponsor was going to do a Phase 3 at all. Why not just file for approval?”

But that gung ho approach may not hold across the board.

“There seems to be a bias towards certain products” among members of the current administration,” Machielse says. That worries him, as it may push investors to develop drugs not on the basis of unmet medical needs but on the basis of what seems less risky.

When he was active in the field, Machielse says, “The FDA never said what drugs to develop. Never.” But given agency leaders’ negative statements about vaccines, messenger RNA therapies, and weight-loss drugs, he predicts greater caution in those sectors.

Hesselink adds gene therapies and products that use CRISPR to the list of products that might be seen as riskier to pursue. “It's not clear what the risks are,” he said. “But people are risk averse simply because they can't afford delays, let alone they can't afford refusals.”

On May 6, the agency announced that physician Vinay Prasad is taking over as head of the Center for Biologics Evaluation and Research, which regulates vaccines, blood products, and cell and gene therapies. Prasad has been a fierce critic of the FDA and the pharmaceutical industry on his Substack, X, and YouTube accounts. The share prices of several vaccine makers fell on the news of his appointment—most notably the mRNA vaccine firm Moderna, which dropped 10%.

An investor note by analysts at William Blair predicts that Prasad’s appointment will continue to pressure the vaccine sector. The analysts also note a conflict between Makary’s push for faster approvals and Prasad’s criticisms of accelerated approvals, and are uncertain which will win out for cell and gene therapies, especially for rare diseases.

Prasad’s appointment, the note says, “adds another round of FDA uncertainty.”