BioPharm Executive: Did the FDA Just Destroy Its Credibility?

Published: Oct 03, 2016

Did FDA Just Destroy Its Credibility?
September 28, 2016
By Karl Thiel for

One of the most interesting biotech stories of the last several years reached a climax this past week, and the outcome could ripple through the sector for a long time to come. Sarepta 's Exondys 51 (eteplirsen), the controversial exon-skipping therapy for Duchenne muscular dystrophy, got accelerated approval on September 19, marking the first and only treatment for this fatal disease and one of very few approvals for any kind of antisense therapy.

This story has spun out in so many directions that's it's hard to know how to draw it altogether. There is the investment angle—Sarepta shares shot up 74 percent on news of the approval and now trade over $60, after having been as low as $8 in the past year. Then there's controversial former CEO Chris Garabedian, who feuded with his own staff, antagonized the FDA and was eventually ousted from the company...while winning the dedication of many parents of kids with DMD. But mostly, there's the human angle, the political angle and the very large intersection of the two.

The FDA's Civil War

As has been widely reported, CDER Director Janet Woodcock—backed by FDA Commissioner Robert Califf—decided to approve Exondys 51 over the vocal objections of reviewers and staff scientists, also going against the (narrowly) negative vote of its own advisory committee. Ellis Unger, a CDER director, even filed a formal dispute (you can read it and more in the FDA's 126-page summary review). Robert Farkas, the reviewer in charge of the Exondys 51 application, has left the agency since the dispute (see Career Track), while many notable outside observers, including renowned cardiologist Eric Topol, have criticized the FDA for putting politics over science and approving a drug that, they say, very likely doesn't work.

There's no question that the critics raise some legitimate points, discussed (among other places) in Matthew Herper's recent Forbes article. Certainly the scientific case in favor of Exondys 51 is, at best, weak. While the drug spurs production of dystrophin—a protein normally missing in boys with DMD—it still seems to produce only a tiny fraction of normal quantities, and there's little evidence that this will result in a meaningful change to disease outcomes. Sarepta ran a fairly shoddy clinical program (only partly due to being cash-strapped), yet it is going to be rewarded with hundreds of millions of dollars in revenue over the next three years—money that will, to some degree, come from all of us. It's really not hard to see why a scientist would object to the approval.

But the FDA is not purely a scientific organization, and Woodcock and Califf made a canny political and morally defensible move by approving the drug. Critical is the fact that Exondys 51 has proven to be safe so far in clinical studies, limiting the likelihood that patients will be physically harmed by the treatment, even if it proves ineffective. (Of course, "safe so far" is a far cry from completely safe, so this can't be ruled out). Also critical—and something missing in the FDA's controversial decision to approve the female libido drug Addyi—is that this disease is progressive, fatal and has no alternative options.

Why The FDA Was Right This Time

Over at The Street, Adam Feuerstein has taken the "no harm, no foul" viewpoint, arguing that the fallout from Exondys 51 not being approved but later turning out to be at least somewhat effective (after kids have died or become wheelchair-bound) would be devastating, while the fallout from it being approved and later withdrawn for lack of efficacy is minimal. In terms of the near-term politics, he's probably right. But that doesn't mean that the FDA hasn't potentially opened a Pandora's box with longer-term implications. The Bill of Health blog over at Harvard Law School outlines three new fault lines. Paraphrasing:

1) The FDA's relaxed standards will cause other companies developing rare disease drugs to try to get away with less data and rely more on patient lobbying.

2) The FDA has lowered the public's trust.

3) Insurers won't be happy about the lack of proven efficacy and could demand special concessions.

Let's dispense with the second two points quickly. If Exondys 51 turns out to have some horrible, heretofore-unseen side effect that is worse than DMD itself, that may indeed damage public trust. Otherwise, this is a slippery slope argument that I doubt has much bearing on reality. The FDA doesn't have a "new approve drugs that may or may not be effective, but at least won’t harm patients," nor will it be regarded that way, even if—perhaps especially if—Exondys 51 is later withdrawn.

In terms of insurers demanding concessions, this is indeed a controversy that "the FDA has not fully resolved [but] merely insurers." The FDA isn't supposed to solve that sort of controversy, and a pay-for-performance deal actually may be a good idea; it's hardly an argument against the FDA's decision.

But the first point gets to what is making many scientists unhappy. I get it. Nevertheless, I'll argue that this isn't necessarily a bad thing. If you're old enough to remember the early days of the AIDS epidemic, you may remember that activist pressure—not so different from what is today being called "patient lobbying"—caused the FDA to rethink some of its clinical trial standards. Some of the things we take for granted today—Treatment INDs, surrogate endpoints and accelerated approval itsel—only came into existence after the mid-1980s (accelerated approval started in 1995).

These shortcuts have occasionally led to the approval of drugs that are later withdrawn for lack of efficacy or due to safety concerns. Far more often, subsequent research proves the initial decision correct. Exondys 51 may be more likely than most accelerated approvals to be subsequently withdrawn, but that alone shouldn't destroy the FDA's scientific credibility or ruin public trust.

Finally, it's worth noting that Janet Woodcock reportedly took Sarepta's financial condition into account. Specifically, she was concerned that the company would go under if Exondys 51 wasn't approved, killing off any further research on a treatment that could, in the end, prove valuable. No, the FDA isn't supposed to take that sort of thing into consideration, but the agency has a long history of stepping beyond its strict boundaries to do what it thinks is in the best interest of public health. Often, it overreaches. This time, it made sense.

-Karl Thiel

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