Did the FDA Just Make a Huge Mistake?

Normally, I’d be excited to explore and write about a breakthrough medical development that could vastly improve and extend the quality of life for more than 6 million people. But I am worried about that newly approved drug for Alzheimer’s disease—and not just about the drug itself.

Before the FDA’s approval of Biogen’s new monoclonal antibody (aducanumab—brand name Aduhelm), two compelling/competing narratives were emerging.

The first was that families and adherents were pushing hard for approval because there have been so many failed clinical trials, the suffering is great and growing, and We have to do something!

Statnews quoted a 57-year-old man named Jeff Borghoff, who’s had Alzheimer’s symptoms for six years and has been receiving the new drug on and off during clinical trials since 2018. He said the drug has helped his cognition and ability to focus and has been great for his family. He’s building memories with them now, he stated. “Ultimately, I’ll lose those memories, but they won’t.”

The other narrative is from many in the scientific community. They warned that the evidence for approval was shaky at best, and that giving this drug the green light would set a bad precedent by approving a new drug for widespread use based on such weak evidence.

The FDA ignored an independent panel of experts who found Biogen’s clinical trial data unconvincing and strongly advised the FDA not to approve it.

What’s more, the clinical trial was conducted with people who have early stage Alzheimer’s and evidence of amyloid plaques: clumps of a protein that is believed to destroy neurons; their presence in these patients’ brains was confirmed by PET scan.

But the FDA approval doesn’t specify which patients are best suited to receive the therapy.

“Many experts were left stunned by that decision,” reports another statnews article. “On a press call, FDA officials argued that because Aduhelm helped clear amyloid plaques, it could provide benefits for people in any stage of the disease — at the same time as they acknowledged that any benefit from Aduhelm, even for patients in the early stages of the disease, was still unclear.

“(Many experts also strongly push back against the claim that erasing amyloid plaques could help people in the late stages of the disease. Clinical trials of other amyloid-targeting therapies in moderate and severe Alzheimer’s have repeatedly failed to show a clinical benefit.)”

The drug didn’t show any improvements in cognition, but it did show destruction of beta-amyloid, the protein in question. An FDA spokesman stated that amyloid pathology is a marker of the disease across the severity spectrum. Apparently, that was the thinking behind leaving its use up to the clinician caring for the patient.

In attempting to thread the needle between the two communities, the FDA seems to have been reaching for a compromise. Let Biogen market the drug while doing a more extensive clinical trial intended to show that removing the plaques resulted in cognitive benefits. If the trial results are negative, the FDA can withdraw its approval.

Huh? This new med is no simple home pop-a-pill remedy. It requires monthly infusions (for which clinicians get paid more). The list price for a year’s treatment, according to Biogen, is $56,000. It had been expected to cost between $10,000 and $25,000 a year—already a high figure for a medication that will be marketed to primary care physicians.

The cost to patients will depend on their insurance. Medicare will cover it, but patients on traditional Medicare will have a 20% copayment. And Medicare hasn’t routinely covered the PET scans to detect the amyloid plaques, a necessary step prior to treatment. (The impact on Medicare could be substantial.)

It’s not surprising that we’re already hearing warnings about impending healthcare disparities, as wealthy people rush to pay for the treatment themselves, while it’s simply out of reach for many others.

There are also expectations that insurance companies generally will make access to the drug extremely difficult.

As for the side effects/safety, about 40% of the patients in the clinical trials developed brain swelling, which reportedly goes away in time and doesn’t cause symptoms, but the FDA website cites the prescribing information:

“…some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. Another warning for Aduhelm is for a risk of hypersensitivity reactions, including angioedema [swelling under the skin] and urticaria [itchy rashes].

“The most common side effects of Aduhelm were ARIA [amyloid-related imaging abnormalities], headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.”  

About 17%-18% had small bleeds in their brains.

Patients will be monitored for swelling prior to the infusions in weeks 7 and 12. If it’s severe, they’ll be able to continue treatment only after imaging and evaluation show their condition has stabilized.

Here’s what’s really strange: Biogen had tested this drug in two Phase 3 randomized placebo-controlled trials with the same designs. An interim analysis of the data in March, 2019, by independent monitors resulted in both trials being halted because they didn’t seem likely to be beneficial. Some called the results a “stunning failure.”

Biogen then stated in October, 2019, that it had evaluated data showing that one of the studies slowed cognitive decline to a statistically significant degree. The benefit: on an 18-point scale, the drug outperformed placebo by less than one point (!). And when Biogen did that analysis on the data from the other trial, it didn’t even show those small positive results.

One thing’s for sure: Biogen will do well—possibly $5 billion well.

It would be wonderful if the subsequent clinical trial results show that this drug is truly effective in enhancing cognition and delaying the dementia that makes Alzheimer’s such a dreadful disease.

But there seem to be so many questions about whether that’s a realistic expectation based on the trials to date.

Is the FDA decision simply giving in to pressure from the understandably desperate Alzheimer’s community, and allowing an expensive, unproven drug with side effects that could be serious in an already vulnerable population?

Is it wise—even fair—to give people what they want when the preponderance of evidence suggests it’s not worth it? Is this simply a very expensive placebo?

And what does the FDA decision suggest about the agency’s decision-making for future drugs to alleviate terrible diseases and conditions that we all wish could be effectively slowed or, better still, eradicated?

I’d rather not be questioning the FDA at this point, when we’ve just emerged from such a sustained attack against the government institutions that we depend upon for good scientific judgment. It looks like they’re still organizing: there’s an Acting FDA Commissioner, Janet Woodcock, and the position of Principal Deputy Commissioner remains vacant.

However, plenty of highly trained career people work there, and I think we have a right and obligation to pursue what seems to many with far more knowledge than I possess to be a questionable decision with large ramifications.

It’s noteworthy that nearly all the clinical trials targeting amyloid-beta plaques until now have failed. In fact, researchers at the Salk Institute have offered another hypothesis. According to Science Daily, they published an article in April, 2021, suggesting that “dense core plaques play a protective role, so treatments to destroy them may do more harm than good.”

“IT’S A NEW DAY IN THE FIGHT AGAINST ALZHEIMER’S,” trumpeted a full-page ad placed by the Alzheimer’s Association in today’s New York Times. It called the FDA approval “a milestone in the treatment of Alzheimer’s” and urged readers to “Join us at alz.org/newday.”

I sure hope they’re right, and the folks at the Salk Institute and on the expert panel that opposed approval are wrong. UPDATE: See clarification below.

Annie

Photo by Steven HWG @rebelvisual. Found via unsplash.com.

Additional information derived from a statnews FAQ.

AN IMPORTANT CLARIFICATION:

I’m adding information from the Science Digest article to clarify the position stated by Greg Lemke, a professor in the Salk Institute’s Molecular Neurobiology Lab, which shows a more complex view of amyloid-beta than I believe I presented above.

“Lemke, who holds the Françoise Gilot-Salk Chair, believes that the current failure rate of most Alzheimer’s drug trials is about to end. ‘Some people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain,’ says Lemke. ‘But we argue that amyloid-beta is still clearly a bad thing; it’s just that you’ve got to ask whether dense-core plaques are a bad thing.’

“Lemke suggests that scientists looking for a cure for Alzheimer’s should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.”

38 thoughts on “Did the FDA Just Make a Huge Mistake?

    1. I hope so, Neil. Some advocates of this drug’s approval claim it will spur research on other drugs for Alzheimer’s. I’m concerned that it not be a setback—and that other drugs that so many experts think don’t merit approval will simply not receive approval.

      Liked by 1 person

  1. To my mind, there’s just too much that’s alarming in these results, not to mention the cost. I feel deeply for those who suffer, and for their families, but this feels rushed and poorly conceived. It’s especially alarming that the approach may be wrong in its entirety. I put my faith in more study.

    Liked by 3 people

    1. My sentiments as well, Denise.
      I happened to speak today with someone I know who was in the clinical trials that were stopped in 2019. He’s bewildered by the FDA’s decision.

      Like

  2. It seems odd that approval would result from such weak trial results. Particularly with a disease that is so poorly understood. I would prefer that the researchers work their way to more knowledge through clinical trials instead of through full approval (that sounds like an uncontrolled clinical trial). Particularly if the risk of harm is significant.

    Liked by 4 people

    1. I agree, JP. It’s all quite puzzling.
      It won’t be an uncontrolled trial, though. They’re calling it Phase 4. I just have so many questions about “unringing the bell” after time has elapsed if the data aren’t strong—and what kind of surveillance will be ongoing in this vulnerable population.

      Liked by 1 person

  3. Aducanumab? Sounds like a character from the Old Testament. Who concocts these names?

    This is a difficult question, and one I hesitate to comment on due to lack of adequate relevant knowledge. But the deciding factor in such cases should be the evidence provided by clinical trials, and based on what we see here, it doesn’t sound as if the approval was justified.

    I do know that there is a long history of promising Alzheimer’s treatments being abandoned because they led to brain swelling in clinical trials on humans — in some cases, resulting in death. So if that happened here, it wouldn’t be unusual.

    One thought that occurs to me is that, if the FDA approved aducanumab due to pressure from Biogen, it could be because there are still Trump-appointed people in critical posts whose inclination is to kowtow to a powerful corporation rather than to strictly follow the science. If that’s the case, any approvals they issue should be viewed as suspect until Biden has replaced any such leftover Trump appointees — or until the same drug is approved in another developed country. Based on a brief search, aducanumab has not been approved for use in Europe, Japan, or Israel, though it’s been under review in the EU since October.

    Liked by 3 people

    1. Let’s hope it isn’t as much of a havoc-wreaker as some of those Old Testament guys, Infidel. I thought of Queen Mab, the “fairies’ midwife” in Romeo and Juliet, but she was gentle.

      All Monoclonal AntiBodies end in “mab.”

      The brain swelling does sound alarming.

      There was clearly pressure involved in the FDA’s decision, and plenty from the “user” community. It’s conceivable that remnants of Trump administration appointees exerted influence in behalf of Biogen as well—and that info may emerge.

      Unfortunately, politicization of the FDA dates back to the Reagan years. It seems especially important now that the Biden administration work to fill those two top positions with demonstrably apolitical and highly qualified people.

      Interesting that US is the sole source of approval. My guess is that situation won’t change. Thanks for looking into that issue.

      Liked by 2 people

  4. I share your concerns Annie and was surprised too. The brain swelling side effect is particularly worrying. A pharmacy article I read this morning said they hope to complete further trials by 2030!!! Well that gives them nine years to make a nice healthy profit. The money is in biologicals these days it seems.

    Liked by 3 people

    1. Yes, the money sure seems to be in biologicals.
      2030 means an awful lot of people may be receiving this drug before we know whether it helps at all! Thanks for that info, Joni, troubling though it seems to be.

      Liked by 1 person

    1. Not good at all. This guy is a professor of medicine at Harvard — we can assume he knows what he’s talking about. As Annie says above, Biden needs to fill the top posts at the FDA with non-political people with a solid scientific and medical background, quickly. We’ve got to be able to trust the FDA.

      Liked by 1 person

      1. Thanks, Infidel. Of course one big stumbling block is the Senate opposition, who want to politicize everything.
        Note: I added a clarification to my post because I didn’t clearly explain the Salk Institute’s position on amyloid plaques.

        Liked by 1 person

  5. Man, the risk/reward as well as the cost/reward for this drug seems completely questionable. I would hate to be in a position of having to decide whether or not to use it. If I had a living parent with Alzheimer’s, I’d probably advise against it and only endorse its use if my parent and their doctor was pushing hard to try it.

    Since when does the FDA approve drugs with no proven efficacy under the proviso that their approval can be revoked if conclusive trials show it to be a dud? Here’s an idea: while trials continue and before the drug is known to work, the profit margin must be held at zero. In other words, you can’t have been making money hand over fist if it turns out you’ve been selling snake oil.

    I’m glad you’re following this story Annie. Seems like very dubious practices are underway that should be closely monitored.

    Liked by 1 person

    1. Thanks, Carol. Your idea sounds fair to me; unfortunately, I can’t see it becoming reality.

      I am certainly sympathetic to the desperation felt by individuals and families affected by Alzheimer’s. I received two offline comments from friends. One said he’d take the drug anyway; if he died from a side effect, that would shorten the time for his family to contend with. He wondered if any of my commenters had family members with the disease. The other, whose father did have Alzheimer’s, told me he himself had been in the clinical trials that were stopped in 2019 (I think because he’s considered high risk). He strongly opposes the FDA decision.

      Liked by 1 person

      1. I absolutely am with you Annie. I don’t judge any person or family having to make such a choice and I deeply feel for their predicament.

        In general, I’m not comfortable with shareholders of drug companies making outsized profits and paying fewer taxes on their earnings as a result. But in this case, the profiteering is even more distasteful.

        Your post and the NPR report that Shira pointed to don’t mention ill side effects other than brain swelling which does indeed sound serious. I suspect that there are many others as well. I’m not very educated on the matter but the little I do know about biological injectable medications gives me significant pause. I’ve looked into a couple of them for one of my loved ones and decided in their case, that the negative side effects were worse than treating the disease with a “less effective” but safer drug.

        Like

  6. Thank you so much for sharing this information with your followers. Up until now, I was completely unaware of the situation. It is indeed bizarre and dangerous that they would greenlight something like this without sufficient testing – luckily, there are people like you who are warning people about it. Thank you for such a clear, succint, and scientific article.

    Liked by 1 person

  7. Carol, I reference side effects, quoting from the FDA website’s description of prescribing information. Some of them seem particularly concerning because of the vulnerable population involved: falls, delirium, brain bleeds, etc.

    I wouldn’t condemn biologicals per se; some have had remarkable lifesaving results. But caution and information and guidance from knowledgeable professionals are always warranted in patients’ decision-making.

    Yes, the pharmaceutical industry needs greater regulation, and Medicare’s ability to bargain over pricing seems a no-brainer to me.

    Like

  8. Started this article couple of days ago whilst at work, but bookmarked it so as to give it my proper attention later. I thought this was a very well balanced piece, Annie. So much pressure for speed, and at times (Covid) that can perhaps be justified. I am very glad it’s not me making the decision to license or no.

    Liked by 1 person

    1. Thank you, Matthew. It’s a troubling scenario because of the previous politicization of a government health entity. I hope getting very accomplished and apolitical professionals in the top two positions is on the Biden administration’s radar; they have so much going on and still haven’t been able to get as many people in place due to the lag time caused by “the former guy’s” unwillingness to cooperate–and the Senate opposition.

      Liked by 1 person

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