The Food and Drug Administration (FDA) on Thursday announced expanded approval for a gene therapy to treat Duchenne muscular dystrophy (DMD) — despite the fact that it failed a Phase III clinical trial last year and that the approval came after objections from three of them. The FDA’s own expert review teams and two of its directors.
In fact, the decision to expand approval of the therapy — called Elevidys (delandistrogene moxeparvovec-rokl) — appears to have been made almost entirely by Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research.
Elevidys initially won approval from the FDA last year, also over objections from staff. The therapy intravenously delivers a transgene that codes for selected parts of a protein called dystrophin into healthy muscle cells; the protein is mutated in DMD patients. The initial approval last year was done under an accelerated approval process and was for use only in DMD patients aged 4 and 5 years who are able to walk. In Thursday’s action, the FDA granted a traditional approval for the therapy and opened access to DMD patients of all ages, regardless of outpatient status.
“Today’s approval expands the spectrum of patients with Duchenne muscular dystrophy eligible for this therapy, helping to address the ongoing and urgent need for treatment for patients with this devastating and life-threatening disease,” Marks said in Thursday’s announcement. “We remain steadfast in our commitment to help advance safe and effective treatments for patients who desperately need them.”
Critics
The move, which follows a string of controversies in recent years when the FDA issued questionable approvals over assessments by its advisers and staff, has quickly drawn criticism from agency watchers.
In a blog post on Friday, well-known pharmaceutical industry expert and commentator Derek Lowe announced the approval. Lowe expressed concern that the agency appears to be leaning toward emotional rhetoric and the will of patient advocates over scientific and medical evidence.
“It seems all you need is a friend high up in the agency and your clinical failures just aren’t a problem anymore,” he wrote. “Review committees unconvinced? Statisticians not buying your arguments? Who cares! Peter Marks is here to deliver hot, steaming containers full of hope… And while I realize this can make me I sound like a heartless SOB, I think this is a big mistake that we will be paying for for a long time.”
In a comment to Stat News, former FDA chief scientist Luciana Borio echoed concerns about how such decisions will affect the agency in the longer term.
“I don’t know what to say. Peter Marks makes a mockery of the scientific reasoning and approval standards that have served patients for decades,” said Borio, who has also opposed previous controversial approvals. “This type of action also promotes growing distrust in scientific institutions like the FDA.”
Internal dissent
In a series of review documents and memos released by the FDA, the split between Marks and agency staff is stark. A review by FDA statisticians concluded that the collective clinical trial results “do not suggest that there is substantial evidence to support the effectiveness of [Elevidys] for the expanded indication for all DMD patients and do not support conversion from accelerated to traditional approval.”
A joint review by the agency’s Clinical and Clinical Pharmacology teams also concluded that “the totality of the data does not provide substantial evidence of the effectiveness of Elevidys for the treatment of ambulatory DMD patients of any age” and that the results “argue” for expanding the access.
In a memo, Lola Fashoyin-Aje, Director of the Office of Clinical Evaluation at the Office of Therapeutic Products (OTP) and Dr. Nicole Verdun, Director of the OTP Super Office, concluded that the clinical results “cast significant uncertainty about the benefits of treating DMD with Elevidys.” The two directors found that the primary clinical trial endpoint results were “not statistically significant” and smaller analyzes looking at secondary endpoints of patient-specific measures – such as the time it takes patients to get up from the floor or to walked 10 meters – were “inconclusive”. in some cases “conflicting” and generally illustrates “the unreliability of exploratory analyzes to support regulatory decision-making.”
In a memo, Marks agreed that the trial’s primary endpoint — based on scores on a standardized assessment of motor function in patients — did not show a statistically significant benefit. But he argued that the secondary endpoints were compelling enough for him. Marx wrote:
Specifically, while acknowledging that the applicant’s randomized study of Elevidys failed to meet its primary statistical endpoint … I find that the observations regarding the secondary endpoints and the exploratory endpoints are compelling and, combined with other data given in the efficacy supplement and the original [Biologics License Application]meet the essential evidence of effectiveness standard…
If Marks had not bypassed reviewers and agency directors, Fashoyin-Aje wrote that she would have recommended the therapy’s maker, Sarepta, conduct “an additional adequate and well-controlled study of Elevidys in patient subgroups for whom [Sarepta] believes the effects of Elevidys are most promising.” However, Marks’ decision to approve makes the possibility of such a trial “highly unlikely to be explored in a post-approval setting,” she wrote.