Jenkins Slams Sarepta’s Development of Duchenne Drug
Is something amiss at CDER in the wake of last month’s controversial approval of Sarepta Therapeutics’ Duchenne muscular dystrophy drug Exondys 51 (eteplirsen)? One may suspect this after CDER Office of New Drugs director John Jenkins took an unprecedented opportunity to criticize (see presentation) the drug’s development and approval during a presentation at a National Organization for Rare Diseases summit this week in Arlington, VA. Jenkins was one of the Center’s senior officials who questioned director Janet Woodcock’s decision to approve the product. He and lower-level reviewers concluded that Sarepta had not provided evidence that the drug was effective at the dose studied.
During his NORD presentation, Jenkins said “flexibility in FDA regulations does not mean marketing approval prior to demonstration of substantial evidence of effectiveness.” He took issue with Sarepta’s development plan, saying their path taken was “not a good model for other development programs... A poorly planned and executed development program for a rare disease misuses valuable patient resources and serves to delay obtaining the knowledge required to understand the benefits and risks of a drug to support regulatory review and approval.” He also criticized the company for not following the agency’s advice and guidance offered during development meetings.
A lesson learned from Sarepta’s mistakes, Jenkins said, is that assays for biomarkers should be well validated before use to avoid obtaining misleading information and wasting clinical specimens. This is “particularly true when invasive procedure required to collect tissue in children,” he said. Also, rigorous blinding and control procedures should be in place to minimize bias in assay interpretation, and the “protocol should specify blinding procedures, adjudication methods, and independence of readers,” he said.
As documented by numerous CDER officials in an earlier eteplirsen review summary, Jenkins reiterated that the use of the accelerated approval pathway should be prospectively planned, and not as a “rescue” for a failed program. The sponsor and FDA should agree on the surrogate and drug effect considered “reasonably likely” to predict clinical benefit before unblinding data, he said, adding that “any effect of a drug on a biomarker is not a basis for accelerated approval. Ideally, the confirmatory trial to further define clinical benefit should be started before (accelerated approval) is granted to ensure the trial will be completed in a timely manner.”
And addressing the ramifications caused by public criticism directed at CDER reviewers involved in the eteplirsen review, Jenkins said such personal attacks “creates an atmosphere of distrust and isolation rather than collaboration... Upholding statutory standards for approval in face of hopes and desires of patients, families, sponsors, and investors is a very difficult job.” He noted that recruitment and retention of qualified review staff is very challenging in such an environment.