7-Year Echo: Marks Overrode Reviewers on Duchenne Therapy
CBER director Peter Marks overrode his Center’s review team in granting the 6/22 accelerated approval of Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) gene therapy Elevidys, a move reminiscent of a review override (see story) almost seven years ago by then-CDER director Janet Woodcock on a Sarepta NDA for DMD drug Exondys 51 (eteplirsen). Both cases add up to top-level FDA responsiveness to activists for a U.S. patient population estimated at about 870,000, mostly males under 25 who die of the disease by about that age.
At the time, Woodcock’s interference sparked controversy and internal dissent when Office of Drug Evaluation 1 director Ellis Unger challenged Woodcock’s override and brought an appeal before the FDA Scientific Dispute Process Review Board chair and then-acting chief scientist Luciana Borio, who sided with Unger in his argument that the NDA’s data had not met the standard for accelerated approval. The board subsequently asked FDA commissioner Robert Califf, who was serving under his first term as the agency’s head, to review the scientific merits of the case, and he ruled in favor of Woodcock and the drug's approval.
Unger’s appeal noted he was particularly troubled that the approval could lower the standard for all rare disease drugs. He questioned whether any increase in a surrogate endpoint could be used to support approval for other drugs. “Perhaps granting accelerated approval to drugs that show a mere scintilla of an effect on a surrogate endpoint represents a stroke of brilliance — one that will stimulate investment in the development of drugs for these disorders,” he told Califf… “Your decision seems to say that the ‘reasonably likely’ standard for accelerated approval need have no quantitative component at all.” After 24 years at FDA, Unger left the agency in 2022 to join Hyman, Phelps & McNamara as a principal drug regulatory expert.
In siding with Woodcock, Califf contended that her approval decision is “clearly employing and interpreting the full range of appropriate information, comprising a ‘totality of evidence’ approach in determining that the clinical trials demonstrated an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.” He also said she “utilized the flexibility afforded under the relevant statutory provisions, including consideration of the life-threatening nature of the disease and the lack of alternative treatments.”
The rationale for approval then of Sarepta’s Exondys 51 is very similar to Marks’ override to allow the accelerated approval of the company’s gene therapy, according to a just-posted decisional memo. “Although I agree with the review team’s conclusions regarding product quality and safety, I disagree with certain interpretations of the efficacy data and come to a different conclusion regarding individuals ages four through five years,” the Marks memo says.
“The clinical efficacy outcome,” the memo continues, “using the North Star Ambulatory Assessment (NSAA) among four- and five-year-olds showed an average 4.3-point increase in the least square mean change from baseline in the SRP-9001 group compared to a 1.9-point increase in the placebo group and in the subset of these individuals for which data are available, this outcome correlated with the level of Elevidys micro-dystrophin protein expression. I therefore find that the data contained in BLA 125781, including from Study 102, provide substantial evidence of effectiveness of Elevidys by demonstrating an effect on the surrogate endpoint of expression of Elevidys micro-dystrophin protein that is reasonably likely to predict clinical benefit in the specific population of individuals ages four through five years.”
Marks’ memo appears to put most of the weight of his decision on one of three studies — Study 102, a randomized, double-blind, placebo-controlled crossover trial in individuals ages four to seven (n=41) using a version of the product not intended for commercialization. “Although I agree with the Statistical Review that it is not appropriate to note p-values for the outcomes of the NSAA in Study 102, the clinical efficacy outcome among four- and five-year-olds showed an average 4.3-point increase (standard error [SE] of 0.7) in the least square mean change from baseline in the SRP-9001 group compared to a 1.9-point increase (SE 0.7) in the placebo group,” he says. “While this may not be sufficient on its own to demonstrate clinical benefit because of the sample size, this outcome correlates with the proposed surrogate endpoint of Elevidys micro-dystrophin protein expression. Although the data for treated participants are limited (n=8), Elevidys micro-dystrophin protein expression in individuals ages four through five years shows this correlation with their outcome on NSAA.”
Marks further says that accounting for the totality of the available evidence, and because of the high unmet medical need, “I conclude that the data provided in Study 102 for individuals ages four through five years along with other supporting information meet the standard for accelerated approval because they show that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit in this population. After carefully considering the totality of the available data and information, I have determined that accelerated approval is appropriate.”