If you’re faced with a serious disease, you better hope it’s not a rare one.
After an often tortuous path to diagnosis, people with rare diseases are likely to find that good treatment options don’t exist and none is on the horizon. Many of these conditions are poorly understood, and conducting studies in tiny patient populations can be practically impossible. Most drugs won’t pan out, and those that do will have little demand and financial payoff, no matter how beneficial they are. Drug companies usually direct their attention elsewhere.
Recognizing these challenges, policymakers have worked since the 1980s to encourage rare-disease drug development. They’ve earmarked federal research funding, established dedicated programs at the Food and Drug Administration, extended protection against competition to help secure profits, and awarded lucrative incentives for rare pediatric disease drugs. Still, 95% of rare diseases, which affect an estimated 30 million Americans, lack any approved therapy.
Some blame the FDA. They say the agency is too rigid, imposing impossible requirements and demanding unreasonable proof of effectiveness and safety for rare disease drugs. Some suggest patients would be better off if the FDA just got out of the way — not only for rare disease treatments, but also more broadly.
The current administration now seems determined to do just that, at least for products that fit the “Make America Healthy Again” agenda, like stem cells and psychedelics (never mind recent intrusions on COVID vaccines and abortion drugs).
Large swaths of FDA experts have been DOGE’d or otherwise forced out of the agency. Commissioner Martin Makary has proposed approving drugs based just on their scientific plausibility, while the agency’s chief medical and scientific officer pledged to “take action at the first sign of promise for rare diseases” — potentially making treatments available far sooner, even though many drugs that look promising at the start turn out not to work.
Just last month, the FDA announced approval of a drug the commissioner claimed would help “hundreds of thousands of kids” with autism, not based on a clinical trial but on published case reports of 40 patients with a potentially related condition — alarmingly and unprecedentedly accepting anecdotes as evidence of efficacy.
The call to disarm the FDA is coming from inside the house.
Criticism of the agency’s gatekeeping is certainly not new, but critics are especially vocal now. Banking on expectations that the Trump administration would break through perceived red tape, they are calling on the White House and new FDA leadership to approve rare disease drugs with far less attention to safety and effectiveness than to keeping companies financially interested in developing rare disease treatments and bringing them to market.
It can be reasonable to assess rare disease drugs differently as usual market-driven incentives often fail to yield treatment options. That’s why the FDA has been remarkably flexible about these approvals for decades. Sure, the FDA sometimes says no — but what if the drugs it rejects just weren’t any good?
Ideally, you want to see a drug’s effectiveness replicated in at least two studies to be confident in the results. For drugs approved to treat common diseases (outside of cancer), that replication is typical. But only 13% of approved rare disease drugs (again outside of cancer) relied on more than one robust clinical trial to show they work. Recent FDA policy has made clear that this single-study approach will be the rule for rare disease drugs and potentially for other conditions going forward.
Rare disease drugs are also increasingly granted “accelerated approval,” a pathway that allows drugs for serious diseases to be approved based on predicted rather than proven benefit. Companies must complete required studies after approval, but the FDA has allowed drugs to stay on the market even if these studies fail. This happened for a recent gene therapy for Duchenne muscular dystrophy, a therapy that was later linked to patient deaths.
Even outside accelerated approval, the agency sometimes approves drugs that miss the targets chosen in advance to prove the drug works. A recent study found this happens in 1 of 10 approvals, about half of which were for rare disease.
Despite this flexibility, criticism continues. Rather than taking FDA’s refusal to approve a drug as a critical warning sign, these decisions are often met with the assumption that the FDA must be wrong.
Take the agency’s recent action on elamipretide for Barth syndrome, an ultra-rare, life-threatening genetic disorder characterized by heart, muscle and immune system abnormalities that affects about 300 patients globally.
Given the tiny patient population, Stealth BioTherapeutics, the company developing elamipretide, conducted a trial in just 12 people, which failed to show the drug worked. Some patients continued in an extended version of the trial and appeared to perform better on tests of walking distance and fatigue. However, the FDA reasonably worried this might be because of patients’ awareness that they were receiving the drug, leading to a placebo effect.
After reviewing the evidence, the FDA issued a letter in May 2025 refusing to approve elamipretide. Recognizing the need for flexibility, however, the agency left the door open to approval based on a new, unverified measure of patient benefit: improved muscle strength in the knee. In September, following substantial public criticism from patient advocates and members of Congress, the FDA granted the drug accelerated approval. Stealth will now have to complete another study to see whether the treatment really helps patients — but even if that study fails, the agency may not withdraw approval.
Even if elamipretide fails to pan out, one might wonder what harm lies in just approving it. Maybe it can provide some hope to patients who have nothing else, while encouraging companies not to abandon rare diseases.
The problem is this: Those who criticize the FDA for setting the bar too high shrug off trial data that fail to show benefit, arguing that it doesn’t mean the drug is ineffective. But it is very hard to prove that a drug doesn’t work. If that were the standard, FDA reviewers should just close up shop, leaving a universal “approved” stamp for any drug that appears not to kill patients.
When it’s working well, FDA approval signals to patients (and their doctors and insurers) “this drug has been shown to work” — or at least “this drug has been shown very likely to work.” If FDA approval means anything less, such as “this drug has not been shown not to work,” it fails to serve patients, leaving them no better off than if they were browsing unproven dietary supplements on Amazon. They might even be worse off, if duped into relying on FDA approval as a meaningful indicator of benefit.
Rare disease patients, like all patients, should have drugs that work. The burden must be on companies to prove that their drugs do. Shifting or altering that burden by changing FDA approval standards won’t help, but other changes might. For example, policymakers could improve existing legal approaches that allow patients with serious diseases to try investigational drugs that aren’t yet approved. The federal government could also increase support for the research needed to understand, diagnose and treat rare disease, helping companies focus on the most promising targets and minimizing failures. Unfortunately, the Trump administration’s ongoing decimation of federal health agencies and research instead sets back rare disease science.
Public trust in authorities like the FDA is already depleted. Demanding that the agency greenlight more rare disease drugs, evidence be damned, will make this problem worse — and likely won’t leave rare disease patients better off. Rather than blaming the FDA, the policymakers, companies and patient advocates should be doing all they can to get better drugs in front of the agency’s reviewers.
Holly Fernandez Lynch is a senior fellow at the Leonard Davis Institute of Health Economics at the University of Pennsylvania, where she is also an associate professor of medical ethics and law. Reshma Ramachandran is a family medicine physician and assistant professor at Yale School of Medicine, where she co-directs the Yale Collaboration for Regulatory Rigor, Integrity and Transparency.
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