WASHINGTON -- The FDA approved the first-ever drug for Duchenne muscular dystrophy (DMD), despite internal disagreements over the drug's efficacy.
Eteplirsen (Exondys 51), a product of Sarepta Therapeutics of Cambridge, Mass., won approval from the agency -- despite a split vote from its own advisory committee -- to treat DMD patients who have a "confirmed mutation of the dystrophin gene amenable to exon 51 skipping" on Monday.
The FDA said it granted accelerated approval of the drug based on the surrogate endpoint of an increase in dystrophin production. However, its press statement failed to acknowledge the breadth of internal discord over this very point.
Following a conference call with investors Monday, Sarepta said that it anticipates charging $300,000 per patient per year for the new drug, according to .
'The Principal Question'
The agency's summary review chronicles a months-long dispute among senior staff and director of the Center for Drug Evaluation and Research (CDER) over what dubbed the "principal question -- whether the quantity of dystrophin produced by eteplirsen is an effect that is reasonably likely to predict clinical benefit," as required by FDA statute and regulation.
Woodcock said she believes that clinical benefit is predicted, but , office director of the CDER's Office of New Drugs (OND) disagreed. Back in April, seven of 13 members of the Peripheral and Central Nervous System Drugs Advisory Committee also said they felt eteplirsen failed to meet the minimum standards for accelerated approval.
In a to the Office of Scientific Integrity, Unger noted that members of the review team for Division of Neurology Products unanimously concluded that the new drug application should receive a "complete response action" (i.e. a rejection) and that OND director , also verbally supported that decision (Ronald Farkas, MD, PhD, a lead reviewer in the neurology products division who was highly critical of eteplirsen data has already left the agency, according to ).
In his appeal letter, Unger argued that the small increase in dystrophin shown in the trials was not "reasonably likely" to predict clinical benefit, and that the effect size of dystrophin levels was "inadequate on its face."
He noted that methods for quantifying dystrophin in the field are not standardized. Nevertheless, it was not valid to compare an increase in"Becker-type dystrophin" with dystrophin levels cited in other mutation or patient populations measured at other laboratories. Becker muscular dystrophy is a milder form of muscular dystrophy in which a truncated version of dystrophin is produced by muscle cells.
That said, if such a comparison were possible, Unger continued, "the largest change reliably demonstrated in Study 301 [a study comparing pre and post-treatment values of dystrophin after 48 weeks] of 1.3% is an order of magnitude less that the minimum dystrophin levels cited to be important in affecting the course of patients with Becker muscular dystrophy (at least 10%)."
Califf Defers
After Unger's appeal, Califf was called on by the Scientific Dispute Process Review board to either conduct his own scientific review of the data, or to direct a panel of experts to make a recommendation on the current data, and if it meets the standard for accelerated approval.
Califf chose to conduct his own review and ultimately deferred to Woodcock's "judgment and authority."
"Given that I do not have technical expertise beyond those already involved in this decision and the record contains adequate evidence to support her conclusion, I defer to the judgment of the Center Director to approve eteplirsen under accelerated approval," he stated in a letter.
He also responded to a series of concerns over Woodcock's actions, with regard to the drug:
- Her "intense involvement"at the early stages of the review process for the drug
- Her "extensive involvement" in planning and engaging in the April 25, 2016 advisory committee meeting
- Her "initial decision" to approval eteplirsen on May 4, 2016, before the reviewers had even established a decision-making process
- Her completion of a final decisional memorandum before Unger completed his own
At the core of such complaints was an underlying assumption of bias towards Sarepta, and the patient community, which Califf said he acknowledged.
"Overall, while I recognize the strain created by political and public pressures, given Dr. Woodcock's well documented history of not bowing to such influences and a record in this case showing her close consideration of all relevant scientific evidence, I do not find that this deviated from her responsibility as Center Director, nor do I find that she succumbed to pressure from the patient community, the public, the press, or others."
Califf defended Woodcock saying her "hands-on" management style has been a characteristic of her career thus far, and was not related to eteplirsen specifically. He said he acknowledged that her "general pattern of discourse and involvement" was not "typical," but affirmed that he did not "find that her conduct was in conflict with the job requirements for Center Directors at the FDA."
A Complex Process
51˶ spoke with two members of the advisory committee about the FDA's final decision, which went against their recommendation.
The process of approving a drug is very complex, said of Brigham and Women's Hospital in Boston, and a temporary advisory committee member who voted against approving eteplirsen. "As an advisory committee member, you are only involved in one small slice of the decision-making process."
Kesselheim said that he could not say whether the FDA's ultimate decision was a surprise. He added that he knew that the agency received additional data on eteplirsen prior to its decision, but that he had not been able to review that data in depth.
"I'm hopeful that the effectiveness of the drug ends up being validated in additional trials," he said, referring to the agency's approval requirement of post-market research. "It's a terrible disease, and the current treatment options, there aren't a lot of them. So if this drug does turn out to work in helping extend people's lives and making them better, that would be a great thing."
of the Sanders-Brown Center on Aging at the University of Kentucky in Lexington also voted against recommending the accelerated approval of eteplirsen. He called the data presented at the April review as only "borderline."
However, he pointed out that "this is a rare disease, and the more we learn about the therapy that's being suggested here, I think the better off we'll be." He noted that the FDA has asked Sarepta for additional data, including dose-response data, as a stipulation of approval.
Kryscio said he encourages parents in DMD activist groups to stay involved in the postmarketing research by getting patients to enroll in postapproval studies, "so we can get the kinds of data that we need."