Is Eteplirsen an Exceptional Case for the FDA?

Prospective Duchenne muscular dystrophy (DMD) treatment eteplirsen faced an uphill battle at the April 25th FDA advisory panel (replay here). Earlier release of the briefing documents had underlined the FDA’s persistent concerns about the sponsor Sarepta’s data package, leaving most observers skeptical about the panel’s chance at a positive outcome. The advisory panel itself was a long affair marked by an open public hearing full of resolute and emotional statements made by young boys with DMD, parents of boys with DMD, medical doctors and researchers. 

At the end of the ~11 hour panel, those previously unconvinced of the drug’s efficacy were likely in agreement with the negative tallies that accrued for the voting questions. Nonetheless, those hopeful for the drug’s prospects perceived two significant lifelines cast out by medical doctors as well as by prominent FDA staff members.


The Doctors

Medical doctors who had treated boys with eteplirsen voiced a unanimous message: boys with DMD who had received eteplirsen performed unequivocally better than other boys in their practice history. Such comments understandably bolstered the confidence of advocates and families pushing for approval. Although encouraging, the anecdotal comments by the doctors are unlikely to trump the accrued clinical data, for a few reasons:

  1. Doctors should indeed be advocates for their individual patients and no one should want a doctor who isn't. In that regard, it is not unreasonable or out of place to see individual doctors lobby on behalf their patients, even if the drug in question provides an ambiguous outcome.
  2. Clinical trial history has shown anecdotal individual experience, either by a patient or a treating physician, to be no substitute for larger controlled trials. In this case, the statements by the doctors left no room to suggest any overlap between the performance of boys on eteplirsen versus previous boys in their practice. Unfortunately, the clinical data are not indicative of such a uniformly exceptional experience.

Shown below are figures from Sarepta’s briefing documents (Fig. 19) and the FDA’s (Fig. 2).

Perhaps some advocates can reconcile the uniformly exceptional performance cited by the testifying clinicians against the clear overlap of the eteplirsen and control data sets. However, to neutral observers, such graphs are unlikely to mesh with their mental image of an unequivocal effect. It’s understandable that the doctors who participated in the open hearing are advocating for their patients, but this advocacy has little scientific backing.



Ultimately, the decision of approval lies with the FDA. Adam Feuerstein’s recent article builds on this theme and assembles clues to buttress Sarepta’s case. Initially, he notes:

“If Woodcock [FDA Director, Center for Drug Evaluation and Research] agreed with all the bad things said about eteplirsen on Monday night, if she had no plans to overrule or cast aside the recommendations against approval, why did she go out of her way to meet with DMD boys and their families immediately after the meeting ended?
Could the answer be that Woodcock plans to approve eteplirsen?”

An observer could certainly sense positive vibes from this type of post-panel interaction, if they were so inclined. However, this meeting could just as easily be described as normal social behaviour. In fact, Monday’s panel was not the first time that Dr. Woodcock had met these families. In February of 2013, Drs. Woodcock and Robert Temple of the FDA met with the Jett Foundation, a group working to improve the lives of those with DMD. After that meeting, the group wrote:

“Our conversation with the FDA leaves us positive and optimistic. These high ranking FDA officials were extremely supportive, engaging, and receptive to our ideas about accelerated approval. It was our collective impression that the FDA seemed committed to working as expeditiously as possible to grant access to life saving treatments to those who will benefit. We were able to start the dialogue that will affect how Duchenne is viewed by the regulatory agency. We appreciate that the FDA is allowing patients, parents, and advocates to play an integral role in the regulatory process. We will continue our work with the FDA as more drugs begin to reach trial level. Our goal is that all Duchenne patients get treatment as quickly as possible.”

In that regard, Dr. Woodcock is simply being a normal, decent human being. She has met these families before and no doubt cares for their compelling cause. There is little reason to believe she would have ignored these parents even if the agency was on track to reject the application for marketing. To further buttress this interpretation, we can go back to 2013 once again. Despite the positive interaction the Jett Foundation had with Drs. Woodcock and Temple in February, November 2013 saw the FDA push back a potential filingby eteplirsen’s sponsor.


Later on during the panel, a theme emerged regarding the interpretation of the presented data and testimony: are we to believe the graphs and the underlying statistics, or should we give strong weight to the doctor and DMD community testimonies?

Dr. Woodcock explains:

“The standard is adequate and well controlled trials, OK, that's what is in this statute, but we are instructed to have flexibility on how we interpret that based on medical need.”
“We are instructed, as people said, to take the views of the patient community into account, more on the benefit and the risk. So, the statutory standard is more or less as described there but there is flexibility and that's where we should take the views of the community into account.”

As Feuerstein notes, the FDA’s Ellis Unger added this clarification:

“I think with the majority of the [eteplirsen] patients here, we have an incredible advantage in my time at the FDA that is unprecedented. To have all the patients here so that is an important advantage we have. One thing you can try to do is reconcile what you heard from the patients with the data that you've seen presented by the company. We're hearing patients are improving, doing things next year that they didn't do last year, and you have to figure out if you can reconcile that with the actual hard data you've been analyzing today.”

The suggestion is the above two comments tip the FDA’s position towards listening to the patients. Perhaps. But Dr. Unger is very clear the testimony and the actual data are at conflict, and his comments could simply be interpreted as a neutral acceptance the conflict is there and requires resolving by panel members. Woodcock’s comment regarding flexibility is true, but could also neutrally be viewed as a simple recitation of the standard under which the FDA operates.

Subsequently, Feuerstein outlines the following exchange between panel member Dr. Chiadi Onyike and the FDA’s Robert Temple:

Dr. Onyike: The question twice mentions 'well controlled,' and as you've heard repeatedly, some people have said they have trouble with the controls. So, this 'well controlled' phrase in a sense tips or constrains the question.
Dr. Temple: I understand a lot of people don't like historically controlled trials. They're not sure they believe they're well controlled. Our regulations since 1970 have said that a historical controlled trial can be adequately and well controlled study. The question here goes: Under the circumstances do you think it was? Do you think the way they selected patients, the way they analyzed them, was good enough to make it an adequate and well-controlled study? That's the question. Historically, historical-controlled trials have been the basis for approval -- sometimes in sort of obvious cases and sometimes in cases that quite aren't so obvious.

This is interpreted as the FDA “saying that comparing data collected from a single arm study against a historical control -- like what Sarepta did -- is definitely okay.” Absolutely. But this is again a recitation of FDA guidelines. Dr. Temple provides no hint the FDA believes Sarepta’s historically-controlled study is adequate; rather, he simply states the FDA would accept one, provided the sponsor conducted an adequate one, and that panel members should not see the use of a historical control arm to be disqualifying.

In sum, although many of the actions and statements at the panel can be weaved into a thesis for approval of eteplirsen, their simplest explanation supports a view of the FDA as fastidious and thorough in its duties. They asked panel members to reconcile data and testimony, clarified the prevailing statutes, and provided a forum for the DMD community to express their views.


Perhaps the Sarepta story is best summed up by Mr. Benjamin Dupree, a 23 year old with DMD who served as a patient representative on Monday’s panel. Mr. Dupree voted Yes in Vote 7, wherein panelists were asked:

“Do the clinical results of the single historically-controlled study (201/202) provide substantial evidence (ie, evidence from adequate and well-controlled studies or evidence from a single highly persuasive adequate and well-controlled study that is accompanied by independent findings that substantiate efficacy) that eteplirsen is effective for the treatment of DMD?”

When given a chance to comment on his vote, Mr. Dupree was overcome with emotion while saying the following:

“I voted yes. I can’t really reconcile the difference between the testimony that was given suggesting that boys are recovering abilities. I don’t… living with Duchenne I don’t understand how that’s even possible but at the same time the study doesn’t prove from a scientific… it doesn’t provide what i think is adequate evidence to support all this testimony that I am seeing in here.”

It’s not useful or fair to question how Mr. Dupree reconciled his Yes vote with his admitted difficulty in seeing adequate scientific evidence. That he was so emotionally overcome hints, at the least, to a part of Mr. Dupree that wishes the scientific data behind eteplirsen were as strong as the efforts of the DMD community.