By Rachel Sachs
This morning, the FDA finally reached a decision in the closely watched case of Sarepta Therapeutics and its drug for the treatment of Duchenne Muscular Dystrophy (DMD). The FDA granted accelerated approval to Sarepta’s drug, Exondys, on the condition that Sarepta complete a new trial demonstrating the drug’s clinical effectiveness. As regular FDA observers already know, Exondys’ path to approval has been highly contentious. The key clinical trial used to support approval contained just twelve patients and no placebo, and the FDA Advisory Committee voted against both full approval of the drug and accelerated approval. The FDA’s 126-page Summary Review, released today with their approval letter, reveals the intense disagreements within the agency over Exondys’ approval. FDA staff scientists charged with reviewing the drug recommended against approval but were overruled by Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research. FDA Commissioner Califf deferred to her decision.
Sarepta presented the FDA with a series of bad options. DMD is a rare, heartbreaking, and ultimately fatal genetic disease with no other real treatments, and it is clear why patients and their families would fight for access to anything that might work. At the same time, the FDA has rarely if ever approved a drug on less evidence than that provided by Sarepta, and approving the drug might send a dangerous signal to both the public and other companies investigating rare disease drugs. The FDA has now made its choice. Where do we go from here? In my view, there are at least three key issues to watch going forward.
- What does Exondys’ approval mean for other companies developing rare disease drugs? I would expect other companies developing rare disease drugs to submit clinical trial data for approval that, until today, had seemed categorically insufficient in terms of demonstrated efficacy. I would also expect them to marshal the support of the rare disease group in question, as it seems that the FDA may have been influenced at least to some degree by the vociferous patient advocates at the Advisory Committee meeting and throughout this process. More problematically, I would also expect some drug companies to engage in less robust clinical trials going forward. In this case, the FDA took the highly unusual step of releasing a summary of its meetings with Sarepta, spelling out the kinds of information the FDA had asked for. Seemingly, the FDA was concerned that Sarepta had misrepresented what the FDA wanted and was continuing with poorly designed clinical trials the FDA had already deemed insufficient for approval. If companies know that failing to follow the FDA’s trial design recommendations will not disqualify them from approval, they may pursue cheaper and less robust clinical trials. A key decision for the FDA on this issue will be what to do about its approval of Exondys if Sarepta’s new trial fails to demonstrate a clinical benefit. Accelerated approval is a conditional status under which manufacturers must study the drug further and demonstrate its clinical benefit. If the post-market trial fails to show such benefit, the FDA may withdraw approval for the drug. But the FDA has rarely if ever exercised this power, and when they try, there is inevitably strong opposition.
- What does Exondys’ approval mean for public trust in the FDA and its approval process? In the past, the FDA has generally erred on the side of caution in approving new drugs. In general, the FDA would rather fail to approve a drug that actually is safe and effective than approve a drug that later turns out to be unsafe or ineffective. The FDA has been criticized for this precautionary stance and many have argued the FDA should recalibrate its balance of these errors. But one benefit of the FDA’s caution is that the public has great trust that drugs approved by the FDA are safe and effective for their intended use. If the FDA recalibrates its balance of errors going forward, it may lose some amount of that reputation and public trust. To be clear, the safety profile for Exondys isn’t worrisome. But if the FDA’s new default is to approve drugs that may or may not be effective, but at least won’t harm patients who take them, patients may begin to see the agency very differently.
- Will insurers cover Exondys, and if so, with what conditions? Hours after receiving FDA approval, Sarepta announced that Exondys would cost on average $300,000 per patient per year, in line with other rare disease drugs but lower than what some Wall Street analysts had estimated. That’s $300,000 a year for a drug whose label states that “[a] clinical benefit of Exondys 51 has not been established.” Professor Walid Gellad summed up this issue succinctly on Twitter: “a drug the FDA says has no clinical benefit will cost 4+ times as much as a drug that cures Hepatitis C.” Some payers may decline to cover Exondys, but others will be legally required to pay for it. Payers will presumably require genetic sequencing as a precondition for covering the drug, as it is only approved for a subset of patients with a particular genetic mutation. Will payers demand special deals from Sarepta, perhaps money-back guarantees if the drug fails to show efficacy in the new trial for its intended purpose? Will payers even have the leverage to do so, given coverage mandates and the lack of competition in this area? By approving Exondys, the FDA has not fully resolved the controversy. It has merely punted it to insurers.
Sarepta presented the FDA with a no-win situation. In many ways, this was a problem of Sarepta’s own making, as they declined to follow the FDA’s clinical trial recommendations. Sarepta has now “won.” But have patients? I’m concerned about the effects of this decision on the FDA going forward, and we should all be watching closely.