Experimental therapies treating rare diseases have always faced a challenging road to reaching the people who need them. While the Food and Drug Administration has said it is moving ahead with new protocols to speed approvals, the agency has faced increased criticism in recent months that in practice it is standing in the way of getting these treatments to patients, as scientific and political pressures, and staff losses, are impacting the agency’s approach to standards and regulatory requirements.
Much of the criticism has been directly focused on FDA Commissioner Marty Makary.
“The problem is that the commissioner is replacing standards of safety and efficacy with fear and favor,” Congressman Jake Auchincloss (D–MA) said to CNBC’s Becky Quick at the CNBC Cures Summit in New York City on Tuesday.
Auchincloss added that Makary’s actions are “undermining patient confidence in the therapies that come to market, and that is undermining the ability of innovators to bring medicines to market with confidence.”
Rick Santorum, the former Republican senator from Pennsylvania who initially supported Makary’s appointment to the FDA, said at the CNBC Cures Summit that what Makary is saying doesn’t match what the FDA is doing. He said Makary is “regulating by press release.”
“Sure, Trump thinks things are going great, but it’s not what’s happening on the ground,” he said. “The agency is in a bit of chaos,” he added.
The Trump administration has looked to take a position that it would fight against rare diseases and find new innovative treatments. However, many in the rare disease community, as well as pharmaceutical firms, have been critical of the FDA’s approach, especially regarding the flexibility provided to these rare disease treatments compared to others. Many pharmaceutical company executives, physicians, and patient advocates all recently took part in a Senate hearing on how FDA bureaucracy is halting innovation.
“It’s hemorrhaging people, it’s not going to be able to keep up with the approvals, you’re going to see more delays,” Santorum said at the CNBC Cures event, adding that this is “not what [President Donald Trump] has intended to do.”
On Monday, UniQure, which has been working on an experimental gene therapy for Huntington’s disease, disclosed that the FDA said the data collected in its studies did not provide the evidence of effectiveness required to support a marketing application, and requested the company conduct another study.
In a statement, UniQure CEO Matt Kapusta said that “While we did not reach alignment on a submission pathway based on the Phase I/II data, we believe the totality and durability of our data warrant continued substantive dialogue regarding how the FDA’s stated commitment to regulatory flexibility may be appropriately applied in this setting.”
About 41,000 people in the U.S. are living with Huntington’s disease and more than 200,000 are at risk of inheriting it, according to data from the Huntington’s Disease Society of America.
Former FDA Commissioner and Pfizer board member Dr. Scott Gottlieb said during the CNBC Cures Summit panel that approval decisions when it comes to rare disease treatments are situations where “data sets are imperfect, you’re dealing with small trials, [and] you’re dealing with randomization against natural history studies rather than placebo-controlled trials.”
“It’s sometimes hard to discern a clear benefit in some of these circumstances,” he said. “It requires a lot of judgement on the part of the review staff, it requires the involvement of senior staff who have a lot of experience looking at these kinds of clinical trial constructs, and senior staff who are going to be willing to make accommodations in certain circumstances, and the willingness to embrace a degree of uncertainty.”
Over the last two years, the FDA has experienced significant staff reductions, with major departures being felt in the Center for Drug Evaluation and Research department.
‘Continuing to lose that caliber of personnel’
“When you lose the folks who have been doing this a long time, as they have, and they’re continuing to lose that caliber of personnel, it starts to impact review decisions,” Gottlieb said. “Part of it could be driven by the orientation of some of the people currently leading these centers, and part of it is just a loss of the very senior folks who have in the past intervened in some of these decisions to try to drive them over the finish line. I saw those circumstances come up when I was at the agency, and the people who were always engaged in that kind of engagement are now gone.”
Regarding that loss of expertise, Gottlieb said that the FDA’s oncology review staff had previously been about 100 people. Currently, the staff is headed below 60 people. “That is a palpable loss of qualified reviewers, and I can tell you, the people who’ve left the oncology review staff are some of the more senior reviewers,” he said.
Gottlieb said it will likely have an impact on complete response letters, which are the communications that the FDA sends to drug applicants when its review cycle is complete, but the product cannot be approved in its current form, outlining what needs to be fixed in order for approval.
In 2024, the FDA approved 20 drugs through an accelerated approval process. Last year, only nine were approved on the same pathway. “That’s a pretty big drop off in just a year. You’re seeing the effects of the loss of experienced review staff play out in these circumstances,” Gottlieb said.
Santorum also pointed towards the leadership of Vinay Prasad, who serves as the agency’s biologics and vaccines head. Santorum said that Prasad “has a long history of not supporting accelerated approval.”
“You have someone who’s running one of the departments who’s a long critic of this, and now you’re seeing the results,” he said.
On Monday, Pfizer CEO Albert Bourla said at the TD Cowen healthcare conference that Prasad has been disregarding the advice of the FDA’s scientists.
“I think the current director is not following the recommendations of his staff,” Bourla said.
Last month, the FDA’s Center for Biologics Evaluation and Research refused to review Moderna’s mRNA-based flu vaccine, then reversed course a week later after the company amended its application. Internal staff reviewers had supported moving forward with the application initially, according to a Stat report.
Makary, when asked during a CNBC appearance in February about the shifts in decisions, said that the FDA’s new approach of detailing why a drug has not been accepted has resulted in “a bit of an effort to find a boogeyman to account for certain products that were not approved.”
He also outlined the FDA’s proposed new system for approving customized drugs and therapies for rare diseases, which in addition to creating a new pathway for bespoke therapies that have only been tested in a handful of patients due to the challenges of conducting larger studies, would also create a standardized process for authorizing experimental treatments and, importantly, offering companies the possibility of commercializing them.
“The system has been set up for common diseases and not rare diseases,” Makary said.
Auchincloss argued that public debate and criticism of the FDA’s recent regulatory decisions are now undermining the agency’s core mission to provide clear, confident approval pathways for novel therapies.
“I think Makary and Prasad both need to be fired immediately, and the administration needs to come to Congress with individuals that can get bipartisan support so that we can start to put a floor underneath the FDA,” he said.
Gottlieb, who noted during the panel discussion that he and Makary “go back a long way,” said when he was commissioner Trump was “extremely focused” on advancing rare disease treatments.
“There is a disconnect right now between what we see playing out in the marketplace, what innovators are feeling, and what I think the aspirations are of the president,” he said.
