If you're facing a serious illness, you better hope it's not rare.
After an often tortuous path to diagnosis, people with rare diseases are likely to discover that no good treatment options exist and none are on the horizon. Many of these diseases are not well understood and conducting studies in small patient populations may be virtually impossible. Most medications will not work, and those that do will have little demand and financial return, no matter how beneficial they are. Pharmaceutical companies often turn their attention elsewhere.
Recognizing these challenges, policymakers have worked since the 1980s to encourage the development of drugs for rare diseases. They have allocated federal funds for research, they have established programs at the Food and Drug Administration, expanded protection against competition to help ensure profits and provide lucrative incentives for medications for rare pediatric diseases. Still, 95% of rare diseases, which affect about 30 million Americans, lack any approved therapy.
Some Blame the FDA. They say the agency is too rigid, imposing impossible requirements and requiring unreasonable evidence of efficacy and safety for drugs for rare diseases. Some suggest that patients would be better off if the FDA simply went off the road — not only for treatments of rare diseases, but also more generally.
The current administration now seems determined to do just that, at least for products that fit the bill. “Make America Healthy Again” Agendasuch as stem cells and psychedelics (not to mention recent intrusions into doOVID vaccines and abortive drugs).
Large FDA expert groups have been DOGE or otherwise forced out of the agency. Commissioner Martin Makary has proposed approving medicines based solely on their scientific plausibilitywhile the agency's medical and scientific director fiance “take action at the first promising sign for rare diseases,” which could make treatments available much sooner, even though many drugs that seem promising at first turn out not to work.
Last month, the FDA announced approval of a medicine that, according to the commissioner, would help “hundreds of thousands of children”with autism, based not 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 comes from inside the house.
Criticisms of the agency's surveillance are certainly not newbut critics are especially vowel now. Relying on the expectations that the trump administration would break through perceived bureaucracy, they are calling on the White House and new FDA leadership to approve rare disease drugs with much less attention to safety and effectiveness that to keep companies financially interested in the development of treatments for rare diseases and their commercialization.
It may be reasonable to evaluate rare disease drugs differently, as the usual market-driven incentives often fail to generate 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 simply weren't any good?
The ideal would be to see the effectiveness of a drug replicated in at least two studies to have confidence in the results. For drugs approved to treat common diseases (other than cancer), such replication is typical. But only 13% of rare passed drugs for diseases (again outside of cancer) relied on more than one solid clinical trial to show that they work. Recent FDA policy has made it clear that this unique study approach will be the norm for drugs for rare diseases and potentially for other conditions forward.
Medicines for rare diseases are also increasingly granted “accelerated approval“, a pathway that allows drugs for serious diseases to be approved based on an expected benefit rather than a proven benefit. Companies must complete required studies after approval, but the FDA has allowed drugs to remain on the market even if these studies fail. This happened during a recent gene therapy for Duchenne muscular dystrophy, a therapy that was later linked to patient deaths.
Even outside of accelerated approval, the agency sometimes approves drugs that don't meet pre-chosen targets to show that the drug works. TO recent study found that this happens in 1 in 10 approvals, about half of which were for rare diseases.
Despite this flexibility, criticism continues. Rather than taking the 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 actions on elamipretide to barth syndromea very rare and life-threatening genetic disorder characterized by heart, muscle, and immune system abnormalities that affects approximately 300 patients globally.
Given the small patient population, Stealth BioTherapeutics, the company developing elamipretide, conducted a trial in just 12 people, which failed to show that the drug worked. Some patients continued on an extended version of the trial and appeared to do better on tests of walking distance and fatigue. However, the FDA was reasonably concerned that this could be because patients were aware that they were receiving the drug, causing a placebo effect.
After reviewing the evidence, the FDA issued a letter In May 2025, it refused to approve elamipretide. Recognizing the need for flexibilityHowever, 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, after important public criticism of patient advocates and members of CongressThe FDA granted the drug accelerated approval. Stealth will now have to complete another study to see if the treatment actually helps patients, but even if that study fails, the agency cannot withdraw approval.
Even if elamipretide doesn't work, one might wonder what harm there is in simply approving it. Maybe it can provide some hope to patients who have nothing else, while also encouraging companies not to abandon rare diseases.
The problem is this: Those who criticize the FDA for setting the bar too high ignore trial data that show no benefit, arguing that It does not mean that the medication is ineffective.. But it is very difficult to prove that a drug No work. If that were the standard, FDA reviewers should simply go out of business and leave a universal “approved” seal for any drug that appears not to kill patients.
When it works well, FDA approval tells patients (and their doctors and insurers) that “this drug has been shown to work,” or at least “this drug has been shown to be very likely to work.” If FDA approval means anything less, such as “this drug has not been shown to No to work”, does not serve patients and does not leave them in a better situation than if they were browsing unproven dietary supplements on Amazon. They might even be worse off if they were tricked into relying on FDA approval as a meaningful indicator of benefit.
Patients with rare diseases, like all patients, should receive medications that work. The burden of proving that their medicines are medicines should fall on companies. Changing 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 illnesses to try investigational drugs that are not yet approved. The federal government could also increase support for research needed to understand, diagnose and treat rare diseases, helping companies focus on the most promising targets and minimizing failures. Unfortunately, the Trump administration in progress execution of federal health agencies and research, instead, sets back the science of rare diseases.
Public trust in authorities like the FDA is already exhausted. Demanding that the agency greenlight more rare disease drugs, evidence be damned, will make this problem worse and probably leave rare disease patients no better off. Instead of blaming the FDA, policymakers, companies, and patient advocates should do everything they can to present better drugs to the agency's reviewers.
Holly Fernández Lynch is principal investigator of the Leonard Davis Institute for Health Economics at the University of Pennsylvania, where she is also an associate professor of law and medical ethics. 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.
