Outrage of the Month: Expanded FDA Approval of a Gene Therapy for Muscular Dystrophy
Health Letter, October 2024
By Robert Steinbrook, M.D.
Director, Public Citizen's Health Research Group
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you’re not paying attention!
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(A version of this article appeared in the October 2024 issue of Public Citizen’s Worst Pills, Best Pills News.)
In June 2024 the Food and Drug Administration (FDA) expanded its earlier approval of delandistrogene moxeparvovec-rokl (ELEVIDYS), a gene therapy for patients with Duchenne muscular dystrophy.[1] Basing his unilateral decision on convoluted reasoning rather than convincing scientific evidence, a senior FDA official cast aside the misgivings of other agency officials and review teams, and green-lighted the approval.[2] The decision was even more astounding because a large randomized clinical trial designed to confirm the clinical benefit of the gene therapy did not meet its primary endpoint of improvement compared with a placebo on a scale commonly used to assess the motor function of males with Duchenne muscular dystrophy who are capable of walking.[3]
Duchenne muscular dystrophy is a rare but devastating genetic condition that mainly affects males (incidence of about 1 in 5,000 live male births); the disease leads to weakness and wasting away of the body’s muscles so that affected children typically have gait disturbances by the age of five years and become wheelchair dependent by an average of 13 years of age.[4]
The FDA granted accelerated approval for delandistrogene moxeparvovec-rokl in June 2023 for children who are four or five years of age and ambulatory (able to walk) in another controversial decision by the same agency official and also based on scant evidence. The agency subsequently expanded the approval to include traditional approval in ambulatory individuals four years of age and older with the disease and a confirmed mutation in the Duchenne muscular dystrophy gene; the agency also added accelerated approval for wheelchair-dependent individuals four years of age and older.[5]
This adeno-associated virus vector-based gene therapy is one of the most expensive drugs in the world, costing $3.2 million for a one-time, single-dose intravenous infusion.[6] Moreover, patients who receive the therapy may be unable to receive better treatments in the future because they will have developed antibodies to the adeno-associated virus vector used to deliver the treatment.[7] A vector is a vehicle that delivers the therapeutic genetic material directly into a cell.
Gene therapy holds promise for Duchenne muscular dystrophy and other rare diseases. The expanded approval of delandistrogene moxeparvovec-rokl, however, sets a disturbing precedent for the FDA, which should invariably ground its decisions about drugs on convincing scientific and clinical evidence that they are safe and effective, not wishful thinking.
The FDA should promptly review its internal procedures for approval decisions and establish guardrails that protect the integrity of the process. Every time the FDA approves a drug without convincing scientific and clinical evidence that it is safe and effective, it becomes more difficult to uphold the agency’s standards for other drugs or to require pharmaceutical companies to conduct further clinical trials of the approved drug (offering patients a placebo in a trial of a drug that has already been approved could be considered unethical).[8]
A more sensible approach, as recommended by other FDA officials who were overruled, would have been for the agency to continue the accelerated approval of the gene therapy without expanding it and to require the manufacturer to conduct additional placebo-controlled trials in specific groups of patients for whom there was promising but inconclusive evidence of potential benefit.[9]
The FDA should not have granted delandistrogene moxeparvovec-rokl accelerated approval in 2023, nor should it have granted it full approval in 2024.
References
[1] Food and Drug Administration. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. FDA news release. June 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy. Accessed August 5, 2024.
[2] Marks P. Center director decisional memo. BLA 1255781/Amendment 34. https://www.fda.gov/media/179485/download. Accessed August 5, 2024.
[3] Food and Drug Administration. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. FDA news release. June 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy. Accessed August 5, 2024.URL
[4] Kariyawasam, D, D’Silva A, Mowat D, et al. Incidence of Duchenne muscular dystrophy in the modern era; an Australian study. European Journal of Human Genetics. 2022;30:1398-1404. Accessed August 4, 2024.
[5] Food and Drug Administration. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. FDA news release. June 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy. Accessed August 5, 2024.
[6] Rind DM. The FDA and gene therapy for Duchene muscular dystrophy. JAMA. 2024;331(20):1705-1706. Doi:10.1002/jama.2024.5613
[7] Public Citizen. Letter to the FDA opposing accelerated approval of the gene therapy SRP-9001as a treatment for Duchenne muscular dystrophy. Public Citizen’s Health Research Group Publication #2660. June 15, 2023. https://www.citizen.org/article/letter-to-the-fda-opposing-accelerated-approval-of-the-gene-therapy-srp-9001-as-a-treatment-for-ambulatory-duchenne-muscular-dystrophy-dmd/. Accessed August 5, 2024.
[8] Ibid.
[9] Bendicksen L, Cliff E, Kesselheim AS. This gene therapy may not work. So why did the FDA fully approve it. Washington Post. July 22, 2024. https://www.washingtonpost.com/opinions/2024/07/22/fda-gene-therapy-elevidys/. Accessed August 5, 2024.