FDA Approval of Aducanumab

Almost twenty years ago, I was a volunteer nursing-home ombudsman. The doctor at the nursing home I visited was a huge proponent of preventive therapies, and prescribed as many preventive drugs as possible for residents (while frequently ignoring complaints about current medical problems that were bothering them). Among the drugs he very freely prescribed were cholinesterase inhibitors for Alzheimer's disease, then fairly new. I was stunned when I learned he prescribed one to a resident whom I knew well and who seemed fully oriented to me, but that was the case. From what I've learned since, these drugs don't have any really noticeable clinical benefits anyhow, so they are unimpressive.

But if prescribing those drugs so freely seemed like a dubious course of action to me then, they look almost good now by comparison to the latest drug approved by the FDA for Alzheimer's disease, aducanumab (Aduhelm). This drug doesn't have any convincing evidence that it benefits patients, AND it comes with potentially serious side effects that require a lot of monitoring.

The quality of life implications of this are troubling. As one doctor notes:

"This is a drug that medicalizes someone’s life,” said Mantyh. Besides the hourlong, once-monthly infusions, an Aduhelm prescription comes with frequent lab tests and brain scans to monitor for signs of swelling or bleeding. In two of Biogen’s clinical trials, more than one-third of participants who received Aduhelm developed painful brain swelling; about 17% to 19% had small bleeds in their brains. Headaches, dizziness, nausea — all might trigger more time spent in the hospital. Such constraints could make it difficult to travel internationally or spend time with family members in other states.

The article also notes that, except in the case of adverse side effects, it is hard to decide when to discontinue a drug when it's likely to be quite unclear whether it's benefitting the patient or not.

How did the FDA come to approve this drug without stronger evidence that it is actually beneficial? It used an "accelerated approval" pathway and based the approval on the fact that the drug diminishes the size of amyloid plaques. This was despite the fact that in multiple trials. reducing amyloid plaques has not been shown to improve things clinically for patients. As Derek Lowe wrote (and his whole post is well worth reading):

So the FDA has, for expediency’s sake, bought into the amyloid hypothesis although every single attempt to translate that into a beneficial clinical effect has failed. I really, really don’t like the precedent that this sets: what doesn’t get approved, now? I suppose only things that definitely cause harm, because otherwise why not just ask for the same deal that Biogen got, and go out and prove efficacy while you turn a profit?

A commenter on the Lowe blog ("Radioactive Man") wryly noted:

All the other companies that successfully developed anti-amyloid drugs then discontinued them for lack of efficacy must be kicking themselves to realise they were approvable all along. It makes me wonder, could they just simply dust off their old phase 3 results and go straight to applying for approval without even doing any more clinical studies? If those results are comparable to aducanumab, why not?

Elsehere too, there was speculation on whether other companies could go back and now seek approval of similar drugs that cleared plaque without showing clinical improvement.

[Could] a slew of amyloid-reducing agents from the past...now be re-evaluated under the accelerated approval pathway?...In a public defense of her agency’s decision on June 22, Woodcock said future approvals under this pathway would be possible if the magnitude of plaque reduction was great enough.

Not one of the FDA advisory committee members voted to recommend approving aducanumab. Ten voted against, and one voted "uncertain." Three have since resigned in protest. In his resignation letter, one stated this is "was probably the worst drug approval decision in recent FDA history."

A professor who has served on many FDA committees commented:

“This isn’t the first time when I was on a committee where the committee voted one way and the FDA decided another,” said biostatistician Scott Emerson....“This was the first time that nobody voted for approval of this drug — nobody — and they went against that.”

Despite the protests, proponents of the drug were breezy, lauding it as a great "breakthrough." The acting commissioner of the FDA, Janet Woodcock, said that she is “not that concerned” about criticisms of the approval. And meanwhile, the first patient got his first infused dose of aducanumab. Dr. Stephen Salloway, director of the memory and aging program at the Rhode Island hospital giving the infusion, stated at a press conference: "It's transforming how we treat Alzheimer's." He snottily added, "For those of you who don't know, it's a devastating disease."

Salloway's remarks make me really furious. A supposed medicine has to be judged by its results, not by the urgency or seriousness of the condition it is alleged to treat. And the "evidence" was totally cherry-picked post hoc after the failure of their Phase 3 trials, following the bad rule: "If you don't succeed, change the definition of success."

There's more to be said about the aducanumab approval, but this post is long enough. More in the next post.