Comment: Why is the FDA rushing a new and unproven ALS drug?

With the drug still in studies, the FDA seems content with pledges to pull the drug if it’s found ineffective.

By Lisa Jarvis / Bloomberg Opinion

A Food and Drug Administration advisory committee voted Wednesday to recommend approval for an ALS drug being developed by Amylyx Pharmaceuticals. The fate of this small company’s drug could matter well beyond ALS to influence how data are regarded for other medicines.

FDA and its advisers are skeptical the drug works as well as the company purports, and clear evidence of its efficacy won’t be available until 2024 at the earliest. Still, the agency is widely expected to formally approve the drug as soon as later this month. That sets up a bad precedent not only for future treatments for ALS, but for other diseases. And one analyst for a company developing other ALS drugs has already concluded that Wednesday’s decision signals a willingness to approve drugs based on data that is anything short of negative.

Wednesday’s vote reverses a negative decision in March by the committee. In this second-chance scenario, Amylyx didn’t provide any new data in the drug’s value in treating ALS, but rather new analyses of existing data; analyses that were heavily critiqued by the FDA’s own staff. But throughout the meeting, the agency took great pains to explain its ability to be flexible in its review of certain medicines, seemingly steering its advisers towards a positive vote.

The FDA’s decision may have far-reaching effects, something that was clear from the very start of yesterday’s unusual meeting. During his opening remarks, Billy Dunn, director of FDA’s office of neuroscience, stressed to the advisers that the agency has the power to remove a drug if a larger trial did not prove its effectiveness. He then called on Amylyx to voluntarily withdraw the study if a Phase 3 study, dubbed “PHOENIX,” failed. Results from that ongoing study are due by early 2024.

Minutes later, Amylyx co-chief executive officer Justin Klee responded, “If PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market.”

That stunning exchange loomed over the rest of the day-long meeting. It was repeatedly raised during committee members’ discussion. One adviser, National Institutes of Health neurologist Bryan Traynor, when explaining his “yes” vote, mentioned that he was “struck” by Klee’s vow to withdraw the drug.

But there’s a problem. The FDA can’t just pluck a drug off the market; in fact, it often doesn’t even try and instead relies on a manufacturer to do so. The law does grant it authority to repeal a drug’s approval, but the process takes a long time and, short of a serious safety issue, can be difficult to apply.

Take the case of Makena, a drug for preventing preterm births. In 2017, a large study showed that it did not work any better than older, much cheaper generic drugs. It took until 2020 for the agency to recommend that it be withdrawn from the market. The company disagreed, and a hearing finally will be held next month — two years after the FDA’s recommendation was made — to discuss the issue.

And although Amylyx’s Klee vowed to withdraw the drug if it turned out to not work, small biotech companies habitually go through management changes or are sold (Amag Pharmaceuticals, which developed Makena, was bought by Covid Pharma in late 2020). The next CEO might not feel as compelled to act.

Another very real possibility is that the ongoing Phase 3 study could take longer than anticipated to be completed, putting off the answer to the question of whether the drug works or not. That could leave a drug with questionable efficacy — and potentially a very high price — on the market for years while the company claims to be gathering additional data. “What is going to stop the manufacturer from lollygagging around? The incentive for them is not great,” says Reshma Ramachandran, co-director of Yale University’s Collaboration for Research Integrity and Transparency.

To be sure, the FDA and its advisers were in a difficult position with Amylyx’s drug. ALS is a devastating and universally fatal disease. During the public comment section of Wednesday’s meeting, one person with ALS described the daily experience of living with disease as like being buried alive. People with ALS, their families, and neurologists came out in droves to support the drug’s approval, making clear they were comfortable with the existing data on its value.

The FDA seemed determined to shepherd its advisers toward a positive outcome that would allow it to formally approve the drug without controversy. FDA stressed throughout the meeting that it has the authority to exercise flexibility in its consideration of the evidence for drugs. And while flexibility is certainly welcome for ALS, it would seem to be applying it rather broadly: Ramachandran and her colleagues found that 1 in 10 of all drugs approved by FDA in recent years had not hit the main goal in clinical trials.

That’s a worrisome pattern. Confidence in the neuroscience division has already been shaken after its decision, against the advice of its committee, to approve Biogen’s Alzheimer’s drug Aduhelm despite little evidence that it works. Leading that same committee down a disingenuous path, one that promises quick action on Amylyx’s drug if it doesn’t work, does nothing to restore that confidence.

Flexibility is welcome where the need is great, but the evidence is thin. But the FDA should be very selective about where it applies that flexibility and honest about how difficult it might be to dial back the decisions its gets wrong. Cherry-picking which drugs can skate by on scant evidence isn’t good regulatory science; and ultimately could be bad for patients.

Lisa Jarvis is a Bloomberg Opinion columnist covering biotech, health care and the pharmaceutical industry.

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