Drug Development

Backlash: Harvard experts fret over the fallout from FDA’s OK for Sarepta’s controversial Duchenne drug

Two of Harvard’s top FDA policy experts, Aaron Kesselheim and Jerry Avorn, have expressed some deep concerns about the agency’s approval of eteplirsen, OK’d to be sold as Exondys 51 for $300,000-plus a year, and the implications for further showdowns in the near future as more developers look to test the boundaries on the agency’s standards.

Writing online in the Journal of the American Medical Association, the two reviewed the campaign used to back eteplirsen, winning an OK with scant evidence of success in producing dystrophin — contrary to what Sarepta had claimed — a problematic reliance on historical comparisons, and the unanimous opposition of the main reviewers, including senior officials who appealed Janet Woodcock’s lone insistence on an accelerated approval.

They didn’t see much merit in Sarepta’s case, and more of these confrontations are likely on the way now, they note. The two policy experts also concluded that the approval threatens patients and other companies that stuck with FDA guidelines requiring much more rigorous data. They wrote:

Speeding drugs to market based on such biomarker outcomes can actually lead to a worse outcome for patients, even those with life-threatening diseases, if a product confers no meaningful benefit and carries a risk of adverse effects and a high cost. Immediately after approval, the manufacturer announced a price of $300,000 per year for eteplirsen. This approach also unfairly penalizes manufacturers that pursue a more rigorous course of development using more clinically relevant end points, while rewarding competitors that submit trials that have less evidence supporting efficacy.

The experts also raised further concerns about a drug that relied on a vehement campaign by patient advocates and the way in which the regulator should approach the anecdotal support provided by patients and their families in tiny, uncontrolled studies.

Echoing remarks from NYU’s Art Caplan, who recently outlined his thoughts in an interview with me, Kesselheim and Avorn are also looking for a new approach that can provide a better framework for more such approvals, including programs that offer these drugs at cost, rather than with a big profit built in.

Patients with DMD need better treatments, and drugs like eteplirsen might one day fill that role. For now, though, the drug has provided a worrisome model for the next generation of molecularly targeted therapies: demonstrate a slight difference in a laboratory test, activate the patient community, win approval, and charge high prices, while relying on limited regulatory follow-up.

The FDA’s John Jenkins recently outlined just why the FDA needs to stick with rigorous development requirements, noting that Sarepta’s campaign was “NOT” a good model for others to follow. But what Kesselheim, Avorn and Caplan are saying is that the discussion about the fallout from the Sarepta decision is just beginning, no matter how much top regulators would like to put it behind the agency.


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RAPS Regulatory Convergence 2017