As the FDA unveils a parade of initiatives aimed at accelerating drug development for rare diseases, experts appeal for a consistent approval process that will support and further catalyze momentum.
Rare diseases should be enjoying a moment at Marty Makary’s FDA. The FDA commissioner, along with Center for Biologics Evaluation and Research director Vinay Prasad, has made numerous statements throughout the year apparently supportive of easing market access for new rare disease treatments and recently unveiled a plausible mechanism pathway for ultrarare conditions. But action on this front has been vague and some say arbitrary—as some drugs are given the benefit of the doubt while others are turned away.
This year, the FDA has greenlit treatments for Barth syndrome and glioma, while investigational drugs for advanced melanoma and for pyruvate dehydrogenase complex deficiency, an ultra-rare mitochondrial disease, were rejected. UniQure’s Huntington’s disease gene therapy, once seemingly market-bound, is now in limbo.
“I see the breakdown as we don’t have a consistent policy for relentlessly progressive diseases,” Steven Grossman, policy and regulatory consultant and author of the FDA Matters blog, said during a recent BioSpace webinar. “We need to have a consistent policy when to say, ‘Yes, unproven, but you can have it,’ and ‘No, unproven makes enough of a difference here.’”
Mark Veich, CEO of Advancium Health Network, a Deerfield Management and the Deerfield Foundation initiative advancing pediatric medical devices and drug therapies, agreed that a consistent approval process is required.
“I think, like anything, when there’s uncertainty, people tend to shy away from working in that space, investing in that space,” Veich told BioSpace in an interview last month. “If there could be some standardization in this kind of rare disease space, I think everybody wins.”
That could be easier said than done, however, John Stanford, founder & executive director of Incubate, told BioSpace. “It’s hard to balance, it’s hard to standardize” when rare disease captures such a “broad set of maladies.”
One Size Fits All?
While the nature of rare diseases means there’s unlikely to be one prescription for everybody, Veich said, the FDA could provide consistent guidelines in terms of clinical trial requirements. He suggested, for example, that if there was a standard number of patients required, possibly based on the prevalence of a disease, “that would be helpful.”
Other standards Veich would like to see implemented are those around the use of real-world data, natural history studies and artificial intelligence and machine learning in clinical trials. A debate over the value and applicability of natural history studies was at the heart of both uniQure’s regulatory issues with AMT-130 and the rejection of Biohaven’s spinocerebellar ataxia therapy troriluzole.
Using real-world evidence in rare disease trials as opposed to a placebo would accelerate patient recruitment because patients and parents currently fear being assigned to receive a placebo, Veich said.
This ethical quandary was also a subject of a debate during a panel hosted by BioSpace at BIO2025 in June. Many people will argue that there is “equipoise” in conducting randomized trials for investigational rare disease drugs because the drug has not yet been proven to work, Ultragenyx CEO Emil Kakkis said. “The problem is, in reality, most things that go into Phase III have had a Phase II study and have some evidence that maybe the drug might work. Otherwise, they wouldn’t invest in Phase III to begin with.”
For Stanford, there is also a broader ethical question that applies to the rare disease drug development space. He posed the question of whether a rare skin condition should “fall to the back of the line over a rare pediatric cancer.”
“I don’t think there’s consensus,” Stanford said. “I think a lot of it comes down to personal beliefs about what helps the most people, and almost a utilitarianism view that I think is very different depending on who you talk to in the ecosystem.”
The FDA has laid out where it stands on this issue—sort of. Implemented in 1992 in response to the HIV/AIDS crisis, the agency’s Accelerated Approval program is intended to “facilitate and expedite development and review of new drugs to address an unmet medical need in the treatment of a serious or life-threatening condition.”
While “life-threatening” is self-explanatory, the FDA isn’t as clear on how it defines “serious.” And even in the life-threatening category, some experts say prioritization is given to certain diseases over others.
“The system that’s being run now is kind of based on exceptionalism, and the rules are completely arbitrary,” Grossman said at the BioSpace event. “Why does DMD get a little extra consideration, but maybe not ALS?”
Recent regulatory history in these two therapeutic areas gives weight to such a question. The FDA approved Sarepta’s exon-skipping Duchenne muscular dystrophy treatment Vyondys 53 in December 2019—four months after it rejected the drug due to safety concerns. In July of this year, the FDA again appeared to bow to DMD patient advocates and political pressure over safety risks when it lifted the voluntary hold on Sarepta’s Elevidys less than a week after the company conceded to the agency’s request to stop shipments of the gene therapy after the deaths of two teenage patients.
Conversely, BrainStorm Cell Therapeutics’ ALS candidate NurOwn remains stalled in a Phase IIIb trial after an advisory committee voted 17-1 in August 2023 against its approval, citing lack of efficacy. NurOwn missed the primary endpoint in its initial Phase III trial—a fate also experienced by several other drugs approved by the FDA between 2018 and 2021.
On the other hand, in September 2022, Amylyx’s ALS drug Relyvrio was granted a rare second adcomm after losing the first vote 4-6 in March of the same year. Relyvrio prevailed in September on new analyses and was ultimately approved later that month. The momentum spurred by the approval of this third-ever ALS treatment came crashing down in March 2024, however, when Relyvrio failed its confirmatory study and the company’s co-CEOs Josh Cohen and Justin Klee elected to pull it from the U.S. and Canadian markets, honoring a promise made to regulators.
Vyondys 53, as well as another exon-skipper from Sarepta called Amondys 45, could face a similar fate after both drugs failed to significantly improve motor function in a confirmatory trial last month. However, Sarepta has said it intends to move ahead with plans to file for traditional approval of the treatments based on “encouraging trends” in the ESSENCE study.
But when it comes to the perception of prioritization, Veich said it’s just that: perception. Diseases like ALS, DMD and spinal muscular atrophy are featured in the news more often than an orphan disease, which affects less than 200,000 people, he said. This creates a kind of catch-22 situation: because they’re written about more, they’re easier to understand. “But I don’t know that the FDA is giving them any favoritism,” he said. “The FDA first and foremost, in my view, is just making sure that patients are safe.”
Winners and Losers
Whether one therapeutic area is prioritized over another at the FDA is an open debate. But Stanford said one particular agency initiative, the Commissioner’s National Priority Voucher program, is providing some companies with a unique advantage. Launched in June, the CNPV intends to shorten the drug review timeline from 10–12 months to 1–2 months for certain drugs. Vouchers are granted to companies and products that are “aligned with U.S. national priorities,” such as those delivering more innovative cures or addressing a health crisis or an unmet public health need.
“We seem to be in a winners and losers moment,” Stanford said. “If you’re a winner, if you get one of the Commissioner’s sort of subjective review vouchers, great—then you love this idea that you’re going to get your stuff out of the FDA within a month.” But, “If we’re trying to build a business plan on whether or not we will be in the FDA Commissioner’s good graces, that is not something that a venture model is great at betting on.”
Richard Pazdur, who filed retirement papers last week after less than a month as director of the Center for Drug Evaluation and Research, has raised concerns about the legality of such programs, arguing that they could put patients at risk.
As for the business side, Stanford pointed to the FDA’s rejection of Replimune’s oncolytic immunotherapy RP1 for advanced melanoma as an example of what can happen when this certainty is lacking. “It definitely sent shudders through some of the ecosystem of, ‘Wow, things can go sideways pretty quickly beyond just the science.’” Replimune’s stock plummeted 75% following the complete response letter and has been on a rollercoaster ride ever since—a nauseating experience to which executives at uniQure and Capricor Therapeutics can likely relate.
“I think the folks who designed some of the accelerated approval pathways would like to hope that medicines that can do the most good for the most dire cases get through faster, all things being equal,” Stanford said. “That falls apart really fast when you actually get into CDER and CBER [where] there are finite resources at the agency to undertake reviews, and expediting a promising asset likely means deprioritizing others.”
Another important consideration, Stanford noted, is maintaining—or restoring—trust in the FDA. “What we also don’t want to do is move medicines that don’t work along too quickly and weaken confidence in the whole system,” he said. “I do think we’re going through a moment—whether it’s because of MAHA medicine skepticism, or some drugs that did make it through whose efficacy has been questioned by payers—where people are questioning the FDA more than they normally do, and that’s got to be something we’re really mindful of.”
