Executive Summary

US FDA commissioner and others say they have put disagreements from controversial decision to approve Sarepta’s Duchenne muscular dystrophy drug behind them.

FDA entrance sign 2016

FDA’s controversial approval of Sarepta Therapeutics Inc.’s Duchenne muscular dystrophy drug Exondys 51 elicited emotional disagreements among FDA staff, but officials maintain that they have largely been put aside.

The decision’s effect on FDA morale has been a frequent question, given the internal conflict that ensued during the review. Multiple senior leaders at the agency said they did not believe the disagreements had long-term effects on the staff.

Commissioner Robert Califf said “we’ve had very direct discussions of feelings” with staff since the final decision was made. He reiterated that disagreements are allowed, but that the hierarchy at FDA is in place for a reason.

“These people are still working together,” Califf said Nov. 4 during the BioPharma Congress, sponsored by Prevision Policy and the Friends of Cancer Research. “They’re not adversaries.”

FDA reviewers and managers within the Office of New Drugs raised several concerns about whether Exondys 51 (eteplirsen) had shown enough efficacy in clinical trials. Many argued an approval was not appropriate. (Also see “Exondys 51’s Development: Was Placebo-Controlled Trial Possible?” – Pink Sheet, 16 Nov, 2016.)

But Center for Drug Evaluation and Research Director Janet Woodcock overruled them and decided to grant the product accelerated approval for use in Duchenne patients amenable to exon 51 skipping.

Following Woodcock’s decision, the staff appealed it to Califf, who ultimately sided with Woodcock, in part because he did not want a political appointee interfering in the drug approval process and because he was not qualified to make the decision. (Also see “Political Appointees Shouldn’t Influence Approval Decisions, Califf Says” – Pink Sheet, 20 Oct, 2016.)

The internal strife was evident based on the memos and other documents released when the approval was announced. (Also see “Sarepta’s Eteplirsen Approved After Contentious Internal Debate” – Pink Sheet, 19 Sep, 2016.)

A number of officials questioned Woodcock’s reasoning for overruling the review divisions. (Also see “Woodcock’s Consideration of Sarepta Financial Issues Raises Eyebrows” – Pink Sheet, 19 Sep, 2016.)

There also has been close scrutiny and speculation about whether a key reviewer’s departure from OND’s neurology division was related to the Exondys 51 approval. (Also see “FDA Neurology Clinical Team Leader Departure May Be Mountain Disguised As Molehill” – Pink Sheet, 15 Sep, 2016.)

Staff Refocused After Controversial Decisions, Jenkins Says

OND Director John Jenkins, who was among those against approving the product, said there was a lot of “passion” about the Exondys 51 science and data. But he also said that he has accepted Woodcock’s decision to approve the product.

“Janet and I continue to work together,” he said after a presentation at the conference. “We’ve moved on. That’s the way an organization has to work to get the job done. The good news is most decisions are not this controversial.”

Jenkins also said that reviewers take their jobs very seriously and that after controversial decisions staff “refocus themselves on why they’re there, what the mission is of the agency.”

Whether the internal aftermath of the Exondys 51 decision is in fact similar to other controversial decisions like HHS’ overrule of FDA’s decision to make Teva Pharmaceutical Industries Ltd.’s Plan B One-Step emergency contraceptive available over the counter will be interesting to watch. (Also see “HHS Overrules FDA On Plan B OTC, Sends Teva Back To Drawing Board” – Pink Sheet, 7 Dec, 2011.)

FDA has indicated that the patient advocacy campaign in favor of Exondys 51’s approval at times included unseemly behavior toward agency staff. It is feared that the discourse may drive staff out of the agency as well as make recruiting more difficult. (Also see “No More Sarepta-Like Development, FDA Officials Say” – Pink Sheet, 20 Oct, 2016.)

Indeed, CDER has hundreds of positions that need to be filled on the executive and rank-and-file levels. (Also see “Merck R&D Exec Jumps To US FDA As Office Of New Drugs Deputy Director” – Pink Sheet, 8 Nov, 2016.)

Focus On Hearing All Opinions

That may be part of the reason why FDA officials, in describing how it handled the decision internally, focused on agency processes for handling scientific disagreement.

“We want people to speak up when they disagree because you know they could be right,” Jenkins said. “When I’m making a decision, I want to hear the perspectives of all the staff because the lonely voice who speaks up very timidly from the back of the room may be right and the thundering herd is wrong.”

Richard Pazdur, acting director of FDA’s Oncology Center of Excellence, said during the conference that early involvement by senior leadership is important in resolving differences.

“Ultimately I cannot sign off on an application and approve or not approve an application based on something that I don’t believe in,” he said. “At the end of the day ultimately we as an agency have to sit down and say the following: is the American public ultimately better with this drug or without it?”

Pazdur said he wants his staff to “take a look at the entire field.”

“I think the key is communication and sitting down with the review staff and saying what can we do?” he said. “What are your issues versus what is the existing facts at the present time.”

https://pink.pharmamedtechbi.com/PS119518/Sareptas-Aftermath-FDA-Staff-…