FDA approval of Alzheimer’s disease drug aducanumab – Inspector General may investigate

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Last week, the US Food and Drug Administration (FDA) approved the first new drug, Aduhelm (aducanumab), for Alzheimer’s disease in 18 years. The new drug is manufactured by Biogen, a US-based pharmaceutical company, and if you read the news reports and social media posts, you’d think the new drug is a miracle.

Given that Alzheimer’s disease afflicts over six million Americans each year, we wanted to celebrate aducanumab as a miracle. Except, there’s really nothing to celebrate here.

The FDA ignored the advice of its own expert advisory committee, which voted overwhelmingly (eight against approval, one for, and two abstained) to not recommend the drug because, according to the FDA’s own analyses, the drug failed to show that it can do anything to treat Alzheimer’s devastating cognitive decline. Plus aducanumab costs $56,000 per year (yes, $56,000) and comes with a relatively high risk for brain swelling and bleeding.

In response to the outcry, Acting FDA Commissioner Janet Woodcock wrote a letter to the acting inspector general of the Department of Health and Human Services, acknowledging that there has been “significant attention and controversy” surrounding the approval of Aduhelm. In particular, Woodcock said, concerns continue to be raised about the agency’s contacts with Biogen, including “some that may have occurred outside of the formal correspondence process.”

So we have to ask why would the FDA approve this new drug for Alzheimer’s disease, even though aducanumab is expensive, has serious side effects, and probably doesn’t do anything to improve the outcomes of Alzheimer’s patients? And because the drug is so expensive and everyone will demand the drug for the disease, this could add hundreds of billions of dollars to the cost of healthcare in the USA and across the world (don’t believe for a second that this possibly worthless drug is going to cost only $5.00 in Denmark, because it won’t).

The answers to these questions are complicated, and I’ll try to explain. But I think what happened here is disturbing and tragic. And it could have implications for any new drug approved by the FDA.

What is this miracle Alzheimer’s disease drug?

Aducanumab is a monoclonal antibody that targets aggregated forms of Amyloid beta (Aβ) which is found in the brains of people with Alzheimer’s disease.

In 1991, researchers proposed the amyloid hypothesis that postulated that extracellular Amyloid beta (Aβ) deposits are the fundamental cause of the disease. However, the evidence is circumstantial, and there is no scientific consensus that Aβ is a cause of the disease.

We don’t know what these amyloid plaques mean to Alzheimer’s disease. Do they cause it? Do they worsen it? Are they incidental? In fact, many researchers think they may be protective!

Aducanumab went through some tortured clinical trials to get to the point where the FDA finally decided to approve the drug:

  • A Phase Ib study was published in August 2016, based on one year of monthly IV infusions of aducanumab. Patient brain scans were used to measure Amyloid beta plaques. The study showed that it did reduce these plaques, but let’s remember that phase 1 clinical trials are not powered to actually tell us anything but safety.
  • The FDA did not require a Phase II study which is highly unusual, and the FDA received criticism for that decision.
  • Phase III clinical trials were canceled by Biogen in March 2019 after “an independent group’s analysis show[ed] that the trials were unlikely to ‘meet their primary endpoint.'”
  • In October 2019, Biogen decided to proceed with the FDA approval process by redoing its data analysis in an attempt to get the results it wanted. In the first “EMERGE” trial, an analysis split by dose indicated that high doses reduced the rate of decline by 23% versus placebo. A second identical trial “ENGAGE” failed to replicate this, with a non-significant 2% reduction in decline compared to placebo.
  • A subsequent analysis of both trials showed that neither trial provided evidence that the Alzheimer’s disease drug had any effect on cognitive decline.
  • Once again, the FDA’s own expert committee on the drug overwhelmingly voted against approval of the drug.

So that’s how we got to this point.

Alzheimer's disease drug
Photo by Robina Weermeijer on Unsplash

WTF happened?

Of course, the FDA’s approval has gotten a lot of people in the biomedical community really upset. Despite the claims that we are all Big Pharma shills, we mostly just care about the evidence supporting the use of any medical procedure, including pharmaceuticals, and for this Alzheimer’s disease drug, there is nothing.

I think we need to explain what clinical trials are supposed to do, which I know can be confusing. Clinical trials need to show one of two things, though it’s much better when both is done.

One, it should show a real-world outcome like preventing death. Vaccine clinical trials are good examples of this.

The second one is to show surrogate outcomes. For example, a vaccine may show increased antibody titers against an infectious disease, but we may not know if it prevents death from that disease.

Ideally, we should have both – a surrogate outcome and a real-life outcome.

For aducanumab, Biogen was able to show that it had positive surrogate outcomes, that is, the reduction in Amyloid beta plaques. There are two issues with that outcome:

  1. There is not strong evidence that Amyloid beta plaques causes Alzheimer’s disease, even if aducanumab showed a reduction in those plaques.
  2. Aducanumab did not show any real-life outcomes like improvement in cognitive outcomes or reduction in mortality.

Aducanumab does not seem to show much benefit to patients according to a clinical dementia rating scale (a real-world outcome, approximately—some researchers say it’s not quite as firm as an outcome like “death”). The surrogate outcome allowed the drug to not enter the long list of failed Alzheimer’s treatments – but that seems to be on a technical point rather than clinical usefulness.

One more thing you need to know – clinical trials for surrogate outcomes are much cheaper and faster for approval than the real world outcomes. For example, if the clinical trial was designed to show a reduction in mortality, that could take a decade or more. And the cost to follow thousands of patients over that time is immense.

The FDA created an “Accelerated Approval” program to fast-track urgently needed drugs based on surrogate outcomes alone. However, the drug companies had to continue post-marketing studies that would assess real-world outcomes, like cognitive decline and mortality – depending on those results, the FDA can withdraw its approval of the drug.

Now, I do not think that all surrogate outcome clinical trials are bad. They aren’t, especially if we have strong evidence that the surrogate outcome will probably influence the real-world outcome. For example, the Accelerated Approval of HIV drugs in the early 1990s was based on improved white cell counts – scientists were fairly certain of the link between those white cell counts and real-world outcomes.

However, HIV drugs are just about the only class of drugs where the Accelerated Approval ended up being supported by future evidence.

And there have been approvals based on surrogate outcomes that turned out to be disasters. For example, there were two class Ic anti-arrhythmic drugs that were approved based on surrogate outcomes – they suppressed abnormal heartbeats. But there were no clinical studies, at the time of approval, that provided evidence that the drugs actually prevented death.

A few years later, that clinical study was done, and guess what was found – the study had to be stopped because the drugs actually increased the risk of death. Using the surrogate outcome clinical studies for approval may have led to an unknown number of additional deaths in patients who took those drugs.

Like I said previously, we do not have any strong evidence of causality between Amyloid beta and Alzheimer’s disease. This new drug may or may not have any real-world effect.

There have been other drugs targeting amyloid plaques that have been developed and subsequently failed during clinical trials because not a single drug had any effect on Alzheimer’s disease or dementia. Unfortunately, the FDA approval of aducanumab relied almost entirely on the scientifically unsettled amyloid hypothesis.

If you throw in the exorbitant price for the drug and the substantial adverse effects observed in the trial. According to Biogen itself, about 30-40% of study participants showed either brain swelling or bleeding.

It’s hard to support what the FDA has done here. Especially since Biogen actually did submit real-world outcomes data. One study showed no effect and another showed such a small effect the it has little or no clinical relevance.

According to Chiadi Onyike, professor of psychiatry and behavioral sciences at Johns Hopkins:

The effect sizes are trivial from a clinical point of view. They are meaningless—no different from the ebb and flow a patient might show from week to week.

Basically, the FDA approved the drug totally on surrogate outcomes while ignoring the actual data for real-world outcomes.

Update – request for Inspector General investigation

As I mentioned above, Acting FDA Commissioner Woodcock formally requested that the Inspector General of HHS examine whether the FDA acted properly with respect to the approval of this potentially useless drug.

In general, this is a good thing, and Woodcock should get some plaudits for doing this.

And in response to the criticism, the FDA changed the prescribing instructions for the drug to limit it to patients with early-stage Alzheimer’s disease. This change was in direct response to a large outcry that the drug, which again has not shown to do anything, will be used widely in all Alzheimer’s patients. This seems like the FDA threw a bone to the critics, while Biogen still will make mountains of money.

However, there’s a lot of troubles issues at the FDA that have been uncovered which may have led to this ridiculous approval.

Stat, a website covering medical and science news (and behind a paywall), reported in June 2021 that Biogen battled, in something called “Project Onyx,” to secure FDA approval for the drug after it performed badly in clinical trials. Stat reported that there was an informal meeting in May 2019 between Alfred Sandrock Jr., a top Biogen official, and Billy Dunn, the head of the FDA’s neuroscience office, at a conference in Philadelphia.

At the time of that meeting, Biogen had halted trials of the drug but they were re-analyzing additional data. Based on this unscientific method of reworking the data, Biogen had convinced themselves that the drug may work, despite the failure of one clinical trial and nearly useless results from another. I won’t say that Biogen saw the tons of money they would be able to print because of desperate families of Alzheimer’s patients, but my cynicism towards Big Pharma has no bounds.

But there’s more. Stat also reported that the FDA early in the approval process mentioned several possible paths to clearance, including one called accelerated approval (which was used) — even though officials told an outside advisory committee later that the option was not under consideration.

Again, I don’t want to be overly cynical, but this is not how a transparent FDA should work. It should hold Big Pharma at an arm’s length distance and decide if a drug works or doesn’t based on science. Not Biogen’s stock price.

But there’s more. Public Citizen, a watchdog group that frequently criticizes FDA, had called for an inspector general investigation several months before the approval, stating the FDA and Biogen worked together to save the drug from the pharmaceutical waste dump, and “jointly relied on dubious analyses” that used suspect statistics in an attempt to show some benefit.

Worse yet, Public Citizen accused the FDA and Biogen of co-authoring a joint briefing document for the advisory committee meeting. Even that didn’t work, as the advisory committee voted against approval for the drug.

Photo by Cristian Newman on Unsplash

My thoughts

From my personal point of view, I think that the FDA has decided to forsake its responsibility to provide safe and effective drugs and plant its regulatory flag on the side of the “right to try” territory based on surrogate outcomes. Alzheimer’s advocates have been pushing for this drug not out of scientific evidence for its effectiveness but because of desperation.

This is about cold hard cash for Biogen – in an article in The Atlantic, Nicholas Bagley, JD, and Rachel Sacks, JD, MPH, estimate that if the drug is prescribed to just one-third of eligible Alzheimer’s disease patients in the USA, it would cost Medicare $112 billion a year. That would far more than any other drug in that system.

And Biogen apparently did everything it could to save its drug including lobbying FDA scientists (admittedly under the Donald Trump anti-science, pro-business regime) to help get the drug approved.

And don’t believe the myth that the FDA will withdraw it’s approval of the drug based on real-world outcomes. They won’t.

According to an article in Slate:

Ross, the Yale FDA regulatory expert, looked at FDA approvals from 2005–12, and found that post-market confirmatory studies—ones that truly verified the clinical value of a surrogate outcome—only took place about 10 percent of the time. Despite this dismal compliance rate, according to Ross, the FDA has never fined a company for failing to do a confirmatory study and rarely uses its power to withdraw a drug later shown to be clinically ineffective. In an email to Slate, the FDA did not offer comment on whether it would use its power to withdraw Aduhelm should the drug ultimately prove clinically ineffective but “will carefully monitor trial progress and support efforts to complete this trial in the shortest possible timeline.”

My vision of the FDA is that it should protect citizens, especially if they are desperate and vulnerable, from making choices that may not be in their best interest. We should demand that drugs be both safe and effective, not from surrogate data, but from real-world data.

We complain about snake oil salesmen who push useless supplements for COVID-19, because they sell their quackery without clinical evidence. I’m going to hold Biogen to that same standard, but the FDA seems “trust” Biogen more than Joe Mercola.

The FDA often approves drugs without robust evidence they are effective – such as in the case of aducanumab. Then, it is reluctant to withdraw the products or specific indications even when trials fail to confirm any beneficial real-world outcomes.

Right wingers want the FDA to not exist – they think that “market forces” will push ineffective and unsafe drugs off the market. Except, people might die and billions of dollars will be spent.

Today, we seem to have an FDA that is doing what libertarians want – approve expensive drugs as long as the surrogate outcomes show it works. Even if it doesn’t.

I find this whole story detestable. I find Biogen’s actions suspect at best and unethical at worst. I find the FDA’s obligation to citizens of the USA to be nonexistent with this drug. And Alzheimer’s advocates, much like the “Chronic Lyme Disease” activists, are probably influenced by quacks (some of whom are in Big Pharma apparently) rather than good science.

Notes

One last thing – in case an anti-vaxxer shows up to this article and points their gnarled fingers at me, saying “see, how can we trust vaccines, because blah blah blah Big Pharma” don’t bother. Vaccines almost always rely upon real-world data, like preventing death and hospitalization, before receiving approval by the FDA. And it would take 10 years of sales of every vaccine across the world to come even close to one year of sales of aducanumab.

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The Original Skeptical Raptor
Chief Executive Officer at SkepticalRaptor
Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!