Wednesday, June 30, 2021

Aducanumab Approval, Part 2

So how did a drug with such dubious benefit get approved? At best, another clinical trial might be warranted, but certainly not approval. It's a result
  1. of a huge campaign by a company (Biogen) that would not accept the failure of its drug
  2. and
  3. of pressure from patient organizations like the Alzheimer's Association (which receives major money from pharma, including Biogen and its Japanese partner, Eisai).

The company campaign began in spring 2019, after its Phase 3 trials were stopped for futility after an interim review. A long, detailed, and excellent STATnews article published this week, drawing on insider sources, tells a fascinating but troubling story. The last-ditch effort to get approval was originally called "Operation Phoenix," but was re-titled "Operation Onyx." Biogen managed to get Billy Dunn, Director of the Office of Neuroscience at the FDA, on their side, to the point that he worked closely with them to provide a roadmap for approval, very inappropriately.

After the groundwork was laid for an approval of aducanumab despite the negative advisory committee recommendation, and prior to the announcing of a final decision, the patient organization campaign was carefully timed. In early May, the Alzheimer's Association launched a big campaign seeking to build grassroots support for drug approval. The "More TIme" campaign worked to pull at heartstrings with celebrity endorsements and poignant personal stories. Full-page ads were taken out in the Wall Street Journal and USA Today, and focused on what "more time" would mean to Alzheimer's patients and their families. There were google search ads, Facebook and Twitter and Instagram and LinkedIn posts. The campaign succeeded in getting over a million people to express support in petitions.

After the approval, the Alzheimer's Association spoke of victory:

As the first FDA-approved drug that delays decline due to Alzheimer’s disease, the approval of aducanumab (Aduhelm™) is a victory for people living with Alzheimer’s and their families.

Comments on articles including this one give the flavor of the passion with which some people want to try this unproven therapy.

Denying a medicine which might work is far more worse than approving one that might not work! Do you agree in the case of Alzheimer’s?
The negativity of these old fashion mentality is what has driven new discoveries to a halt. I don’t suffer from Alzheimer’s nor know anyone close to have been dx w it but we need to start somewhere. Prescribing the pharma will only help w research. Get in line MD.
Alzheimer’s is a horrible disease. If the medicine has a chance of success then prescribe it.

And public officials seem to be buffaloed. A Politico article said that not only are public officials mute about the approval, they are hesitant even about making a fuss about the pricing (about which more in another post):

[Politicians are] worried they’ll be seen as dashing desperate patients’ hope for an Alzheimer’s treatment — even one that may provide little or no benefit. The FDA’s controversial approval of Biogen’s drug, known as aducanumab or Aduhelm, has caught both political parties flat-footed ...Everyone is a bit terrified by Alzheimer’s, so the average person hears about the FDA approval of a treatment, and they don’t know about the controversy over whether it works or not,” said Craig Garthwaite, a health economist at Northwestern University’s Kellogg School of Management who lambasted FDA’s Aduhelm approval. “They hear there’s a new treatment and, that’s great, it’s a sign of hope. Do you want to be the politician who says, ‘I want to take that away from you?’”

Evidently, the public opinion campaign with its drumming up of support for this bogus drug has had its desired effect, creating cowardice to speak about the realities. Subsequent to the publication of the Politico article, two senators did speak out about pricing, but were careful to praise the drug:

Even as they criticize the price, however, Cassidy and Warren still stopped short of directly criticizing Biogen. They offered praise for the drug’s approval, too, calling it a “historic, watershed moment” in the history of the disease.

Public Citizen - who does not have to get elected - did not share this hesitancy. Their long public letter to HHS Secretary Xavier Becerra - which I recommend reading in full - begins as follows:

Public Citizen is writing to express its outrage over the Food and Drug Administration’s (FDA’s) indefensible decision to approve Biogen’s aducanumab (Aduhelm) for treatment of Alzheimer’s disease despite the lack of evidence that the drug provides any meaningful clinical benefit plus the fact that the drug has a well-documented risk of potentially serious brain injury. The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.

They go on to ask for resignation of key officials in approving aducanumab, including FDA acting head Janet Woodcock and Billy Dunn. They also ask that the Office of the Inspector General for HHS investigate the relationship and "close collaboration" between the FDA and Biogen prior to Aduhelm approval. In addition, they want rescission of the bogus approval:

You should direct the next Acting FDA Commissioner to consider whether the agency’s approval of Biogen’s BLA for aducanumab should be withdrawn.

Those who pushed for approval seem eager to foreclose any discussions of rescission. In an interview, there was this question and answer with Acting FDA Head Janet Woodcock:

Question: "There’s been some reaction that every time this criticism comes up, the FDA just dismisses it outright and doesn’t really meaningfully engage on it —doesn’t do soul-searching. … Should the FDA do some soul searching? Should you and the FDA be trying to respond more directly to these critics?" Woodcock's reply: "I think we will have some more public soul-searching type of discussions on accelerated approval itself, but the soul-searching when a decision is made goes on before the decision, and once we’ve made the decision, we’ve made the decision."

Similarly, the head of the Alzheimer's Association wants to end discussion of the approval:

Harry Johns is ready to stop talking about whether or not the Food and Drug Administration should have approved Aduhelm, the divisive new Alzheimer’s treatment that got the green light last week. “Dwelling on the approval at this point is not productive for those who can benefit from the treatment,” said Johns, the CEO of the Alzheimer’s Association. The “negative voices” focused on criticizing the decision, he said, are “not pro-patient.”

But, if the aducanamab approval is not rescinded, what will happen and what are the consequences? More on that in another post.

Tuesday, June 29, 2021

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 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.