Makary’s ‘Conditional Approval’ Pathway for Rare Diseases Poses More Questions Than Answers

While the FDA under HHS Secretary Robert F. Kennedy Jr. might seem to be worlds different than the FDA of 2024, the agency still seems to be prioritizing expediting treatments for rare diseases, particularly ultrarare conditions.

As head of the FDA’s Center for Biologics Evaluation and Research (CBER) until his abrupt resignation at the end of March, Peter Marks was a passionate advocate for regulatory flexibility for rare disease therapies. In fact, Marks came under fire for his June 2024 decision to grant full approval to Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy Elevidys, overriding the recommendation of FDA advisors.

Now, it appears that newly minted FDA commissioner Marty Makary wants to take up the baton. In an interview last month with former Fox News journalist Megyn Kelly, Makary unveiled plans for a new regulatory pathway for rare disease drugs, allowing for their conditional approval based on a “scientifically plausible mechanism.”

The proposed pathway—about which Makary has yet to provide further details—could enable conditional approval for drugs targeting rare diseases without data from a randomized, controlled clinical trial. Patients would then be followed under a surveillance system to allow the FDA to draw conclusions as soon as meaningful data emerge, according to a Department of Health and Human Services spokesperson.

It could be a boon for patients and biopharma companies, potentially removing some of the barriers to innovation that exist for rare disease drug development, including trial recruitment difficulties and low return-on-investment owing to sometimes minuscule patient populations. It could also breathe new life into the cell and gene therapy space—whose focus largely falls on these rare targets.

“You can’t expect the companies to do a randomized, controlled trial; you’ll kill innovation. You’ll kill investment in those innovative ideas,” Makary said during the interview with Kelly.

Marks, too, has spoken out in favor of alternative clinical trial designs, including single-arm trials, for certain gene therapies for rare diseases. “There are many rare diseases affecting dozens to a few hundred individuals in the United States where the concept of trying to do a randomized trial is very challenging at best and impossible at worst,” he told BioSpace last year.

But is such a conditional approval pathway feasible? According to experts who spoke with BioSpace, maybe—but there are a number of challenges to overcome, including legal concerns over safety and the question of whether insurers would reimburse for therapies in the absence of strong clinical data of efficacy. There could also be dissent from the new CBER head, Vinay Prasad, who has voiced concern over the FDA’s current accelerated approval process, particularly in terms of confirmatory trial delays and efficacy.

“It’s a little bit sketchy at this point in terms of knowing exactly what it’s going to look like,” Daniel Kracov, partner and chair of the Global Life Sciences Industry Practice at Arnold & Porter, told BioSpace of the proposal.

Kracov added that the FDA cannot enact this pathway alone. “At the end of the day, this would require legislation,” he said. “I don’t think FDA can simply do this.”

In an email to BioSpace, an HHS spokesperson declined to elaborate on Makary’s comments.

Kracov has a long history in the rare disease space. He has worked on issues related to the Orphan Drug Act, which was originally passed in 1983 to incentivize the development of drugs for rare diseases.

The idea for a conditional pathway for rare disease drugs is not new, he said, noting that former acting FDA Commissioner Janet Woodcock has also advocated for such an initiative. In 2016, Woodcock overruled FDA staff in her 2016 approval of Sarepta’s Exondys 51 for DMD—a company and a rare disease that have become synonymous with this movement.

At a 2024 workshop intended to address barriers to ultrarare therapy development, Woodcock noted a “mismatch” between current FDA approval standards and the realities of drug development for ultrarare diseases. “We’ve had accelerated approval. We’ve had regulatory flexibility. We’ve had one trial and confirmatory evidence. But basically, at the end of the day, the evidentiary standard is supposed to be that standard of adequate and well-controlled trials,” she said, according to BioCentury.

Woodcock asserted that regulatory flexibility isn’t a “viable policy” and prevailed on Congress to create a new approval pathway for therapies that can’t meet existing approval standards due to small patient populations or lack of predictive biomarkers. “What we’ve seen is a lot of cognitive dissonance internally, of people being asked on one hand to enforce the standards and on the other hand to be flexible. You can be flexible, flexible, flexible, and then pretty soon you’re going to break,” she said.

Kracov agreed that to “lower the bar” and grant access to a rare disease drug may be positive but added that “there has to be a meaningful standard for the approval of products in order for payers to be willing to pay for those products.” Approving drugs based on a plausible mechanism is “about as low a standard as you could possibly get.”

Kracov said that his firm, which helps biopharma companies negotiate challenges relating to drug development, approval and marketing of products, has had difficulty convincing payers to pay for products that have been approved under the FDA’s accelerated approval pathway, “much less having a conditional approval.” This is particularly true, he said, as some of these drugs may cost $1 million or more.

Both Kracov and Eva Temkin, also a partner at Arnold & Porter, likened the pathway Makary is proposing to the Right to Try law, which was signed in 2018 by President Donald Trump and gives terminally ill patients the right to try experimental treatments not approved by the FDA. “If anything, it may be less protective of patients than the existing Right to Try mechanism,” Temkin, who previously served as acting deputy director for policy staff at the FDA’s Office of Therapeutic Biologics and Biosimilars, told BioSpace.

The Right to Try pathway requires the drug in question to have completed Phase I safety trials and be under active investigation in clinical trials, she explained. Eligibility is also quite limited, with the pathway only being open to patients with life-threatening diseases who have exhausted approved treatment options and are unable to participate in a clinical trial for the drug.

The newly proposed pathway could also present challenges in terms of assessing safety, Temkin added. “It’s very hard to imagine how adverse events could be analyzed, separated into trends. Separating the signal from the noise when you don’t even know very much about the safety or effectiveness of the drug becomes very difficult.”

However, Rob Etherington, CEO of Clene, noted that modern surveillance capabilities have evolved significantly. “With the integration of electronic health records, digital biomarkers and AI-driven analytics, postmarket surveillance is now far more sophisticated, real-time and predictive than ever before,” he told BioSpace. When paired with clear regulatory expectations and confirmatory Phase III trials, these systems “can provide early, meaningful insights while maintaining patient safety.”

Another challenge could arise if, after all of the data emerge, the drug is found not to be effective. The question would then become, “How exactly you take the drug off the market if it doesn’t prove out,” Temkin said. “You’ve seen that play out in accelerated approval. I think that’s going to also be a big question if there’s a conditional approval. Does the [FDA] then have to litigate, have to convene an advisory committee?”

Since its inception in 1992, nearly 300 drugs have been approved under the FDA’s accelerated approval pathway, the majority in cancer indications. Recently, however, some notable drugs that received accelerated approval—including Pfizer’s sickle cell disease therapy Oxbryta and Biogen and Eisai’s Alzheimer’s medicine Aduhelm—have been withdrawn or discontinued.

Finally, Kracov said it may be difficult to get buy-in from biopharma investors. “Once you head down the road with conditional approvals, how do you provide the necessary confidence to investors that they’re going to get paid for their investment over time?”

For all of its challenges, proposed pathways such as Makary’s provide a spark of hope for rare disease–focused companies and patients.

Etherington said that for a universally fatal disease like amyotrophic lateral sclerosis—often considered a rare disease, though more prevalent than many—“this approach offers significant promise.” That’s because the FDA currently approves drugs for individual indications.

“ALS and other neurodegenerative diseases often share a unifying pathogenic thread—mitochondrial dysfunction,” Etherington, whose company is developing a gold nanocrystal-based drug for ALS, told BioSpace in an email. “Yet, current FDA regulatory pathways do not readily accommodate platform therapies that target core cellular dysfunctions across multiple conditions. Commissioner Makary’s remarks suggest a willingness to move beyond rigid, disease-specific silos suggesting allowance of regulatory flexibility when robust scientific rationale and mechanistic plausibility converge.”

For biotechs like Clene, a conditional approval pathway “would provide a thoughtful and much-needed opportunity,” Etherington said.

According to Temkin, however, the idea that biopharma companies would be willing to provide drugs to patients under such a pathway “is a fairly significant assumption.”

One issue is that there could also be liability issues for companies, Kracov noted. “Is a conditional approval preemptive of state [law]suits [based on] failure to warn about something you haven’t studied yet, fully? That’s a big unknown at this point.”

Emil Kakkis, president and CEO of Ultragenyx, said that companies could operate under a conditional approval pathway for some of the rarest conditions, but agreed with Kracov that issues could arise on the reimbursement front “since this has been raised recently by payors.”

For Kakkis, a whole new regulatory pathway may not be necessary in most cases. “For many rare diseases in which reasonable clinical trials are possible, I would expect that the current accelerated approval pathway using biomarker or intermediate clinical endpoints should be utilized as [a] very viable pathway and one that does not require new legislation,” he told BioSpace in an email.

However, he added, “I am encouraged that Makary is being open-minded about how to manage rare disease situations where unmet needs are high and the feasibility of conducting randomized clinical trials is low.”

The possibility also exists that not all HHS leaders would be on board. While Makary has expressed enthusiasm for a conditional approval pathway for ultrarare diseases, past comments and publications indicate that newly appointed CBER head Vinay Prasad may take a different approach.

In a 2015 JAMA article, the prolific oncologist and hematologist and his coauthor Chul Kim of the National Cancer Institute pointed to a 2009 Government Accountability Office report that criticized the FDA for failing to enforce postmarketing study commitments for such medicines. And last August, Prasad penned a letter with his University of California, San Francisco, lab member Timothée Olivier, questioning the FDA’s approval of Elevidys. “Despite its high cost and potential toxicity, the clinical benefits of Elevidys remain uncertain,” the pair wrote.

Following Prasad’s appointment, William Blair wrote in a note to investors: “We are surprised by the announcement, because it seems to be in stark contrast to themes and initiatives that have been laid out by Dr. Makary.”

BioSpace reached out to HHS regarding this matter and received the following response from a spokesperson: “Commissioner Makary and Dr. Prasad are both committed to ensuring patient safety through the Gold Standard of Science.”

Certainly, a difference of opinion doesn’t have to be a negative. “It’s more likely there will be a healthy and necessary tension rather than a conflict,” Etherington said. He added that while Prasad has voiced concerns about overreliance on unvalidated biomarkers, his emphasis has consistently been on ensuring that accelerated approvals are ultimately grounded in meaningful clinical outcomes.

“If a treatment demonstrates strong safety, shows biomarker-driven promise and is backed by confirmatory Phase III trials, there appears to be ample common ground between Dr. Makary’s call for regulatory agility and Dr. Prasad’s call for evidentiary integrity.”