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The FDA’s approval of Aduhelm to treat Alzheimer’s disease has unleashed criticism about the decision and calls for reform within the agency. As advocates for people living with Barth syndrome — an ultra-rare, life-threatening genetic condition affecting just 130 children and young adults in the U.S. — we fear the pushback will discourage the FDA from consistently exercising appropriate flexibility in its approval standards and stall progress being made in employing new regulatory strategies to improve access to safe and effective therapies.

Any moves that erect additional barriers to approvals will likely directly result in intensified reluctance to invest in future biomedical innovation, especially for ultra-rare diseases, and pose dire consequences for people living with the vast majority of the estimated 7,000 rare diseases for which there are currently no approved treatments. Taken together, these disorders affect as many as 30 million Americans, so this problem must not be overlooked.


In the past, the FDA has demonstrated considerable and appropriate decision-making flexibility. In March 2015, for example, it approved cholic acid (Cholbam) for certain ultra-rare disorders caused by single-enzyme genetic defects. Data supporting the drug’s safety and effectiveness were generated from a series of case reports of patients who had been treated with the drug via expanded access, also known as compassionate use, at a single academic center without a control group or pre-specified analyses. In November 2017, FDA approved vestronidase alfa-vjbk (Mepsevii) for treating another ultra-rare disease known as mucopolysaccharidosis VII, also called Sly syndrome. Readouts of the primary endpoint — the six-minute walk test — were not statistically significant, although trial participants experienced meaningful functional improvements.

For both Cholbam and Mepsevii, regulators appropriately considered the inherent challenges of designing trials and recruiting patients for ultra-rare diseases, defined as affecting fewer than 1 in 100,000 people. It can be literally impossible to recruit enough patients with these diseases to achieve statistically significant results. Alternative study designs, such as the one used for Cholbam, offer new approaches for clinical testing. Furthermore, by incorporating patients’ voices for Mepsevii, regulators exhibited appropriate flexibility and opened doors to advance therapies to consumers.

Unfortunately, the FDA has struggled to consistently apply the flexible decision-making standards it exhibited in the approvals of Cholbam and Mepsevii. Variability in the FDA’s regulatory approaches is jeopardizing approval of a promising investigational treatment called elamipretide, sponsored by Stealth BioTherapeutics, for Barth syndrome.


Unlike what the FDA did with Cholbam and Mepsevii, it has requested that Stealth BioTherapeutics consider new clinical trial designs with greater numbers of participants to augment statistical analyses supporting the drug’s effectiveness even though, given the ultra-rare nature of Barth syndrome, the agency has acknowledged it would be virtually impossible to do so.

While there may be some differences between the Cholbam and Mepsevii approvals, the FDA’s position on elamipretide, a drug that has been demonstrated to be safe, is arbitrarily inconsistent with practices observed in the FDA’s previous approaches. If perpetuated, the FDA’s inflexibility will be detrimental to Barth syndrome patients and could potentially strip them of the opportunity to access a treatment that may lead to meaningful improvements in their lives.

In line with these two case studies, patients more recently emerged as partners in the drug development and regulatory review process for Aduhelm. Signed into law in 2016, the 21st Century Cures Act cemented the framework to designate patients as integral to decision-making about their care, and the FDA incorporated patients’ perspectives into the approval process for Aduhelm.

Peter Stein, who directs the FDA’s Office of New Drugs, told Bloomberg News, “We’ve heard very clearly from [Alzheimer’s] patients that they’re willing to accept some uncertainty to have access to a drug that can provide meaningful benefit in preventing progression of this disease as we all know can have devastating consequences.” Stein’s comments strongly echo the insights voiced by Barth syndrome patients and their caregivers in a March 2021 meeting with the FDA.

Given the safety of elamipretide and the difficult present and bleak future Barth syndrome patients face, many made it clear that they are more than willing to accept a high degree of uncertainty about clinical benefit in exchange for access to a potentially effective drug. If a drug has been shown to help at least some patients with Barth syndrome, by and large the community strongly desires a chance to try it.

This perspective of Barth syndrome patients, though, has to date not been actively considered by regulators. Inconsistencies in the FDA’s approach to operationalizing the 21st Century Cures Act stand to treat individuals with Barth syndrome qualitatively differently from those with other diseases, such as Alzheimer’s, and points to a critical need for consistent application of patient perspectives in the review process across agency divisions and regulators.

Looking to the future, acting FDA commissioner Janet Woodcock said in a recent speech about ultra-rare disease drug development that this is “a place where mechanistic reasoning may play a major role” and “we have to stop just thinking that empirical evaluation is the only way of determining truth.”

That’s exactly how the Barth Syndrome Foundation, which we represent, approached the development of elamipretide. In this syndrome, defective mitochondria — the powerhouses of the cell — lead to Barth syndrome’s cardinal symptoms: a weakened heart, vulnerability to infection, debilitating fatigue, and gastrointestinal issues. Recognizing potential synergies between a commercial entity and academic preclinical work on a small-molecule compound, researchers affiliated with foundation approached Stealth BioTherapeutics to test the drug’s potential application in Barth syndrome.

The company’s drug, elamipretide, had shown an ability to normalize the synthesis of cardiolipin, a substance mitochondria need to operate correctly and generate energy for the body, thus directly addressing the underlying pathophysiology in this disease. The value of restoring normal cardiolipin production has since been demonstrated by its positive effects on cardiac structure among people with Barth syndrome and functional improvements, denoting meaningful, positive changes for patients.

Critics of Aduhelm’s approval are suggesting that regulators ignore Woodcock’s proposal to consider biological changes as indicators of a drug’s effectiveness. Rather, they are pushing the FDA to continue to uphold traditional endpoints based on morbidity or mortality as the gold standard. This methodology simply does not work for ultra-rare diseases. With so few patients available for clinical trials and responses to experimental therapies commonly varying across patients, analyzing data strictly for statistical significance constitutes a step in the wrong direction for ultra-rare diseases.

We support Woodcock’s position that observed biological improvements should actively be considered during regulatory evaluations as well as including patients’ voices in new drug evaluations.

We urge the FDA to continue applying the regulatory framework it has been evolving and incorporating in select drug approvals over the last decade, offering appropriate pathways for new drug development programs for ultra-rare conditions. This approach requires regulators to systematically operationalize the drug review process in different ways, extending beyond traditional statistical analyses, to counter a scenario whereby the agency, out of an abundance of caution, rejects a drug that provides therapeutic benefit that is meaningful to patients.

We commend the FDA for having exercised regulatory flexibility on occasion, especially when reviewing applications for rare and ultra-rare diseases. It needs to continue on that path, not take a step backward to regulatory rigidity.

Emily Milligan is the executive director of the Barth Syndrome Foundation. Katherine R. McCurdy, whose son died of Barth syndrome, is chair of the foundation’s board.

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