WTF is going on at the FDA?

This is absolute garbage. One study shows zero benefit with the added bonus of 40% of participants getting brain swelling. Another study showed the same, but then Biogen went back and miraculously came up with slight statistical significance and plaque reduction a convenient “residual” study.

A statistical evaluation by FDA reviewers (page 247) thoroughly dismantled Biogen’s analysis, concluding that “there is no compelling substantial evidence of treatment effect or disease slowing” and that “another study is needed to confirm or deny the positive study and the negative study.”

Likewise, in November of 2020, an independent advisory committee for the FDA roundly rejected the drug and Biogen’s data. Ten of the 11 committee members voted “no” to the question of whether it was “reasonable” to consider the limited data Biogen collected as “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.”

The drug costs $56,000 per year and the company expects to bring in $5-$6 billion per year.

So who at the FDA is making this decision? Do they own stock in Biogen or have some kind of relationship with them? Because this is utter bullshit. 40% have brain swelling and very few participants had any kind of improvement. It literally does more harm than good.

There are several pathways by which drugs can be released to the public by the FDA. The usual approval route requires years of testing to demonstrate an actual benefit to patients. You may also be familiar with “Emergency Use Authorization”, in which lower standards are used for emergencies like COVID. Waiting years for formal approval of a COVID vaccine would be inappropriate for the clinical needs of the population. When drugs are released using a lower standard, the FDA makes much stricter demands regarding post-release surveillance and has a lower threshold for recalling the drug.

However, in the 1990s it became clear that for some clinical problems, neither a temporary measure (Emergency Use) nor a standard demonstration of clinical benefit was appropriate. The problem in question was HIV. As most people know, HIV can take a decade or more before it causes any clinical problems at all. That means that under the normal approval process, a new drug could require a decade of testing before it could even hope to show a clinical benefit. Especially if the drug was meant to act the earliest possible stage, when success is most likely.

It would be grossly inappropriate for the FDA to require any possible HIV therapy to be tested for 10+ years, given the lack of any other treatment for HIV. So they made a new category: Accelerated Approval. Unlike the standard approval, drugs could pass through Accelerated Approval even if they didn’t show a clinical benefit provided they showed benefit to “surrogate” markers. In the case of HIV, this meant CD4 counts, which constantly decline in patients with HIV until they finally come down with AIDS. If a drug could prevent CD4 counts from falling today, then maybe it could prevent AIDS ten years later. Like Emergency Use, this approval process is attached to stricter conditions regarding post-release surveillance. And so we finally turned the tide in the battle against HIV.

Well, Alzheimer’s today has some similarities to HIV in the 90s. First and most important, all current drugs are pretty ineffective. Next, patients have a gradual increase in certain biochemical markers, i.e. amyloid and tau. In addition, patients have few or no symptoms until amyloid has been building up for decades. At the point when patients finally report mild memory loss, amyloid has basically peaked and it’s quite likely that too much damage has already been done to alter the eventual course. That’s why current Alzheimer’s drugs are terrible, they are trying to patch up an amyloid-ravaged brain rather than preventing the damage to begin with.

As in HIV, new drugs aimed at preventing Alzheimer’s should probably target surrogate markers (amyloid, CD4 counts) rather than trying to fix the end-stage clinical problems (memory loss, opportunistic infections). And this particular drug apparently is effective at getting rid of amyloid (see page 49 on the pdf you linked). But under the normal approval process, it was required it to demonstrate improvement in memory. Since it is meant to act at an early stage and the study didn’t last a decade, it hasn’t yet showed much effect.

Under the Accelerated Approval pathway, it only has to show that it reduced amyloid. And the FDA agreed that under those conditions, it could be approved.

It’s a deeply disturbing situation and I, too, would like to know who at the FDA decided to overrule their own panel of experts on this. It’s going to severely undermine public faith in the FDA (which has already taken some bad hits under Trump) when this is inevitably withdrawn from the market as the lawsuits stack up.

The FDA did not overrule their experts. If you look at the transcript of their meeting (pp 296-302) you will see that most experts agreed that there was good evidence that aducanumab decreased amyloid, but not good evidence that it reduced symptoms. If the FDA believes its experts, then it is justified in denying regular approval but granting accelerated approval.

Keep in mind that the experts committee is not meant to give an opinion on whether a drug should be approved. They simply interpret the data to answer some factual questions for the FDA (i.e. “There is good evidence of X, there is not good evidence of Y”). The FDA then uses their answers (among other things) to make the decision.

Except they had one full study that showed it didn’t, and then a second study that showed it didn’t either. And then they had this higher dose “residual” study that showed it did some reduction in some people (barely topped the statistical significance threshold). And here’s the problem. Do you honestly think there was no p-stat jiggering to get it to that point? I don’t.

What all these studies do show, unequivocally, is that it causes brain inflammation in 40% of the recipients which is a much higher percentage than those that had amyloid reductions.

And with increased brain inflammation, they may actually hasten an individual’s death due to disease. But since every case of Alzheimer’s is different, quantifying accelerated death rates is nearly impossible.

If this drug is really the windfall, and as great as Biogen claims, then they need to make it free for recipients, not charging individuals, nor insurance, nor the government $56,000 per year.

I think you are confusing the results. They had one study that possibly showed clinical improvement, and another that didn’t. Those figures refer to “CDR-SB”, which is basically a memory test.

However, the studies clearly showed reduction in amyloid, which is not the same as memory improvement. The p-value was <0.001, which is highly significant, not marginal. Most of the experts said that amyloid is clearly reduced, just read the transcript. Or just look at the data:

The question is whether a drug should be approved if it reduces amyloid over a year or so without improving memory. Based on the decade-long disease course of Alzheimers, I think there is a good argument in favor of doing so.

Incidentally, “brain swelling” was also a surrogate marker, ie it was seen on MRI but was not actually associated with symptoms. So if you think that amyloid reduction should be ignored in the absence of other clinical benefit, then you should also ignore brain swelling in the absence of clinical symptoms. And in that case, don’t expect to see any treatment for Alzheimers for at least a decade.

Thanks, @Magnet for the detailed explanation. That honestly seems like a fairly reasonable decision was made.

Glad it helped! There is one more wrinkle in this debate: scientists are still sharply divided about the role of amyloid. Traditionally, amyloid was considered a cause of Alzheimers but today there are many who argue that amyloid is merely a side effect of Alzheimers (even though amyloid accumulation definitely precedes memory loss).

I don’t know which side is right, but this drug is premised on the traditional idea that amyloid causes Alzheimers. Thus, it’s easy to understand why scientists in the latter group are railing against the FDA.

I think Derek Lowe is absolutely right that this is setting a horrible precedent. The drug was in a phase III trial which was stopped for futility for crying out loud.

No, that precedent was set in 1992. That’s when the FDA approved Zalcitabine for the treatment of HIV. It was based on data that it improved CD4 counts, before any clinical efficacy could yet be shown.

I’m not aware that a Zalcitabine clinical trial was stopped for futility. That’s the precedent I mentioned.

I also think our understanding of HIV pathophysiology was a lot stronger in 1992 than our understanding of what causes Alzheimer’s today in 2021. Which means making a stretch a bit more defensible.

I don’t see anything like that here. I haven’t seen anyone really defend the amyloid hypothesis as originally constructed (other than Biogen and other manufacturers of failed drug candidates) for a long time. Don’t get me wrong, amyloid has something to do with the disease but we’re clearly missing a huge piece of the puzzle otherwise we’d have some type of progress.

And I’m not critical of failed drug candidates – it’s expected part of the business. But a failure needs to be called a failure otherwise we’ll just throw even more money down the rathole. This looks way too much like post hoc rationalization and we’re going to throw away billions of dollars for mostly political reasons.

Hmmm, maybe we should be listening to a doctor who worked with Biogen and said under no circumstances should this drug be approved.

The nervous system advisory committee voted in November that the FDA shouldn’t approve the drug. Knopman wasn’t a part of that meeting because he works with the the drug’s manufacturer Biogen as a clinical trial investigator. He has publicly spoken out against approving the drug over the last eight months.

On the contrary, the committee did not make a formal recommendation of approval vs disapproval. Neither did Knopman, who explicitly stated this in the article you cited:

Similarly, although approval would have a massive impact on health-care economics and the feasibility of conducting future clinical trials if ADU infusions become standard-of-care, we will not consider these important issues here. We will focus, simply, on the case for efficacy of ADU based on the clinical trial data that Biogen has made publicly available.

Like the committee and (probably) the FDA, he concluded that this drug does decrease amyloid but has not yet been shown to improve memory. Which leaves open the possibility of approval under an alternate pathway.

It’s easy to find experts on either side of the debate and declare that maybe we should listen only to them. Look, here is The Lancet suggesting a few months ago that we should approve this drug based solely on its ability to reduce amyloid, but insist on strong post-release surveillance. Maybe the FDA listened to them:

For aducanumab and other treatments, regulators must find a way to allow access to potentially life-extending therapies while both scientific rigour and the safety of patients are maintained. Close post-approval monitoring of safety and effectiveness could help achieve this.

Keep in mind that surveillance requires lots of data, which requires lots of patients. Given the predictable objections from insurance companies and doctors, I suspect Biogen will be forced to charge a lot less for the drug in order to collect all the data that they now need.

How many anti-amyloid drug candidates were used for more than one or two years before being declared failures? I honestly don’t know. But is it possible that the missing piece is that amyloid needs to be treated relatively early to have any hope of effect?

In contrast, antihypertensive meds are approved if they simply lower blood pressure. If we demanded that those drugs demonstrated an effect on clinical endpoints (stroke, renal failure) in the space of a year-long clinical trial, I wonder how many would have been approved.

Trying to make sure I’m following accurately (not being a doctor or pharmacologist or anything along those lines, but being very curious). Your read of the situation is that approval of this drug is either predicated on the causal relationship being there and/or is considered part of gathering long term data to determine that relationship. Thus the debate is both about whether that relationship is actually there and whether it’s appropriate to approve the drug as part of that data gathering process. Is that an accurate re-statement of what you’re getting at? If so you (or others) have a sense of which aspects of that are predominant in the discussions?

I think you have the gist of it. I would note that as far as the FDA is concerned, it’s definitely appropriate to approve a drug based on the causal relationship you describe, provided it fills an important unmet need. They established an entire regulatory mechanism to deal with these situations.

So as I see it, the open question is whether a sufficient causal relationship actually exists between amyloid clearance and cognitive function. If the relationship were well established, I doubt we would be seeing quite as much consternation.

But as you suggest, it’s possible that the FDA recognizes that its approval process has gotten in the way of the research needed to answer that general question. Though I don’t think they would acknowledge that, they do acknowledge that this specific drug needs more research after approval.

Hypertension is a known cause of morbidity and mortality through known mechanisms including renal disease etc. Amyloid is not a known cause of dementia, but has a correlation. Apples and oranges, sorry to say.

Yes, but we proved that hypertension is a cause by giving patients antihypertensives and observing the long term outcome.

So it’s a bit of a chicken and egg problem. There are some established biomarkers, like blood pressure, blood glucose, and cholesterol. A new drug can target those and be approved if it shows an immediate reduction in those biomarkers, without a long term study.

Then there are uncertain biomarkers, like amyloid. There are no approved drugs to lower them, so we don’t know whether lowering them is effective in the long term. But it’s almost impossible to approve a drug that lowers them, because showing an immediate effect on amyloid is not enough and nobody wants to pay for a ten year study.

The result is that drug companies churn out countless redundant drugs aimed at blood pressure and cholesterol. Or drugs expected to have an immediate effect, like Viagra.

Meanwhile, no really effective drugs are approved for Alzheimers, ALS, and similar long term problems. Is it because the drugs don’t exist, or because it is too difficult to show they are effective?

There are 3 more anti-amyloid drugs that failed which are now eligible for the same thing.

My problem with this entire situation, is if this drug is going to help the majority of people taking it, and make their life significantly better, that’s absolutely wonderful. But Biogen should be footing the bill to finish proving it, not us. And if this barely helps just some people, we’re looking at a crippling level of expense for that kind of result. What kind of crippling expense?

  • 5.5 million people with Alzheimer’s in the USA.
  • Drug cost of $56,000 per year.
  • IV infusion cost of $12,000 per year.
  • Added MRI cost of $5,000 per year.

5.5 million x $73,000 = $401,500,000,000

Let’s say in 9 years over the lifetime of the FDA edict, we find it didn’t markedly help people improve their quality of life. We’ve wasted $3.6 trillion dollars at the highest end of the scale.

Obviously all 5.5 million with Alzheimer’s will not be using this treatment, but when you look at the amount of money involved in a single drug that shows minimal efficacy, it becomes extremely worrisome how that will impact health insurance across this country.

I just don’t see the harm is doing smaller scale, higher dose studies to qualify the preceding results before moving to this stage.

As I suggested earlier, this was the price tag of the drug before the FDA slapped it with a metaphorical asterisk.

Now Biogen has a limited time to prove the drug is efficacious, even though many doctors will refuse to prescribe it and insurance companies will balk at paying for it. Biogen is between a rock and a hard place, and I think the sticker price will reflect that soon enough.

They have a massive lobbying arm, and cultivated a block of support groups that have been barraging the FDA non-stop. I expect a thousand commercials “talk to you doctor” ie “tell your doctor how to do his job and demand our drug”.

Do not underestimate the power of various platforms to influence these matters outside of the real science and statistical significance.