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The Underside of the Aducanumab Approval

I would like to recommend this piece at Stat about the details of the Biogen aducanumab approval. It’s behind the paywall, but it’s a deeply reported piece from Adam Feuerstein, Matthew Herper, and Damian Garde about how in 2019 Biogen launched an effort to get their apparently failed drug approved by the FDA anyway. They called it “Project Onyx”, renamed from the original “Project Phoenix” after Biogen’s lawyers objected to the implications of that one.

A key moment was a face-to-face meeting between Biogen’s Al Sandrock and Billy Dunn at the FDA’s Office of Neuroscience. This took place when the two were separately attending a neuroscience meeting in Philadelphia, and it was not in any way an official contact between the company and the regulatory agency. This appears to have been contrary to FDA policy, on the face of it, and is at the very least worth knowing about – a former Biogen employee told Stat that after the meeting, “It was clear that Billy Dunn was an ally, so the job for Biogen became figuring out how to support his efforts within the FDA“. A month after the meeting, the FDA proposed the idea of an accelerated approval designation for aducanumab to Biogen, a huge victory which seems to have taken even Biogen’s executives by surprise. And the FDA’s official statements about how they came to the accelerated approval idea say nothing about the Dunn/Sandrock meeting.

The Stat article has plenty of inside-baseball details on the strains inside Biogen over the last few years, as the company went from being flush with money and new drug approvals to finding itself depending on – of all things – getting an Alzheimer’s antibody approved. I often wondered what people in the company thought about that, and I kept imagining David Byrne’s voice saying “Well. . .how did I get here?” There’s also an excellent look at how the company charged ahead in 2019 with an interim of the aducanumab results, a decision that led to biostatistician Thomas Fleming resigning from the monitoring board. But the company was confident of a good readout, and at that point they really needed one. What they got instead was a “halted for futility” decision. If you trust that one, then the FDA approval never should have happened. If you trust the FDA approval, then the futility call was an idiotic and premature mistake. I don’t see much room for a third option.

It’s important to realize just how weird the agency’s actions were during the entire aducanumab business. That’s underscored by the people who have resigned in protest from the outside advisory committee after its hugely negative vote was completely ignored by the agency. From the outside, it really looks now as if the FDA made it its mission to get this drug on the market one way or another. I’m not saying that’s exactly the decision they made, but their actions would have been no different if that were the case. The article also has details about the first formal meeting between Biogen and the FDA in June of 2019 – that’s where the accelerated approval idea came up, and frankly the meeting reads like the agency reading Biogen’s most optimistic spin back to the company. No wonder the Biogen execs were a little disoriented.

Meanwhile, none of that was conveyed to the advisory committee. You’d think that the idea of accelerated approval versus outright rejection would be worth hearing about, along with the reasons for thinking that, but the committee appears to have been sandbagged. They held their meeting in a world that had already been superseded by one in which the FDA was pushing aducanumab for approval. In retrospect, that makes the severed-hemispheres nature of the briefing documents easier to understand. The earlier sections were from the Go Biogen! Go Aducanumab! part of the FDA, the decision-making part as it turned out, while the extremely unfavorable review from the FDA’s statisticians at the end was from the What Are These Numbers Really Telling Us part, which is where the advisory committee was as well.

Silly people! They should have taken off their Statistician and Clinician hats and put on their Drug Approver hats. I mean, it says right there in the agency’s charter that its mission is to Give People Hope One Way or Another, right? That its job is to Approve Drugs, which means that you can defer for years the question of whether they actually do any good? And that if a given drug candidate actually has stronger evidence that it does harm, that this can be cancelled out by the amount of Hope Delivered? Billy Dunn and Janet Woodcock can apparently tell you where those parts of the mission statement are, and the rest of us just need to Believe, to Hope, and to Trust. What a beautiful sight it all is.

58 comments on “The Underside of the Aducanumab Approval”

  1. Project Osprey says:

    Can they revert their decision now that it’s been made?

    Obviously that would be hard, and it would be contested – very strongly – but is it possible? Or are we stuck where we are?

    1. Process Chemist says:

      I really hope the FDA is sued by a patient advocacy group over this decision. The insurance companies should be suing as well.

      1. Anonymus says:

        Is it possible that lobbying efforts on the part of some advocacy groups contributed to this problem? Recommend STAT’s Readout Loud podcast from June 10th on this topic.

    2. aairfccha says:

      There still are the Stage 4 (post-approval) trials, theoretically the FDA can pull the plug then.

      https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease

      1. I doubt that the FDA’s theoretical ability to pull the plug in 2030 will benefit many patients starting taking the drug this year.

  2. Michael L says:

    The story is bizarre in more ways than one. Everybody else follows rules and precedence and would never think of asking for conditional approval based on a surrogate endpoint, but it turns out all you need to bypass all that is to ask a FDA staffer nicely at a conference. Now that that’s done, does it mean FDA is now obliged to issue approvals for $50,000/year drugs on any surrogate endpoints that are likely to indicate clinical benefit but have yet been proven to do so?

    1. Derek Lowe says:

      That’s the problem with this decision. The only answer now would seem to be “Why the hell not?”

      1. Anonymous says:

        It’s an insane victory for the “We don’t need the gubment to tell us wut drugs to take! We is Murican!”” crowd. I guess it’s not poisonous (right? aducanumab isn’t going to outright kill anybody, right?) … so.

        If I was running my own insurance company, I’d be looking really hard at policies for reimbursement of drugs.

        1. Anonymous says:

          Well, no, it’s not. If you bothered to develop even a vague familiarity with any principles of free market economics, the fact that Medicare now needs (most likely, depending on how you interpret its mandate to cover drugs) to cover Aduhelm is precisely the opposite of a victory, since the decision is going to drive a massive increase in public spending for yet another thing that doesn’t work. If anything, this terrible decision highlights what an embarrassing system of governance we have in the US.

          1. Anonymous says:

            Sure it is. The FDA rolled over and basically said “sell what you want, we don’t care if it works. Let the buyer beware.”

          2. Anonymous says:

            Oh, sorry, I meant “victory” facetiously. But there are people who WANT this to be the way that drugs are administered.

          3. confused says:

            The problem is that FDA approval is an official statement that it works. It’s not just “this can be sold legally”. Even from the libertarian perspective, you don’t want the government to lie.

            I’m not a libertarian, though I have some leanings in that direction for issues that don’t involve “negative externalities” (IE, there need to be regulations to limit pollution, but I don’t care if you ride a motorcycle without a helmet).

            If the FDA could allow something to be sold legally *without* giving an official stamp of approval as working, that would be different. I wouldn’t necessarily be opposed to a system like that, but the Medicare issues would indeed need to be handled.

        2. aairfccha says:

          If only they would take that approach with recreational drugs. Contraction of the black market by maybe 90%, less black market associated violence, less impurities, less weird stuff and more reliable doses because much of the remaining black market should be supplied by diverted legal material, less international cartels, less enforcement costs, taxes…

  3. David says:

    The meetings between FDA and sponsors that I’ve attended are always large affairs, attended by multiple content specialists from both sides, with multiple people taking notes, and official minutes written up afterward. That’s the rules of the game, and it’s that way to ensure the discussion is on-target and appropriate. Who knows what was said at a one-on-one meeting? Who knows whether the discussion was confined to the scientific data behind aducanumab? This was grossly inappropriate. Billy Dunn should be fired, just for allowing a meeting of that kind.

    1. Lappan says:

      Indeed if the meeting took place in anything like the way described a brisk defenestration is called for, simply on the principle of Caesar’s wife (must be above suspicion, even if “known” to be innocent, also for the salutary effect & pour encourager les autres)

  4. In Vivo Veritas says:

    Congress has oversight over FDA, right?

    BTW, ~7 years back, I was in serious contention for a peachy job at Biogen. In the end, it went to the other candidate. This marks the 3rd time in those seven years I’ve seriously thanked the hiring manager for picking the other guy.

    1. CMCguy says:

      IVV please do not think Congress will do anything helpful in this situation? Over many years in Drug Development I have seen occasional direct meddling and the general continuing lack of adequate support create more problems at the FDA, typically expanding the already difficult mission to focus elsewhere or restricting how they can do things while failing to appreciate the issues involved (because never fits into a 5-10 second sound bite).

    2. confused says:

      Congress ultimately writes the laws that authorize/give power to these agencies, yes.

      However, more voters will see “now we have a drug for Alzheimer’s!” as a positive than will be concerned about messing up the FDA’s approval processes. So why would Congress act?

      Also, Federal agencies’ basic authorizing laws don’t get updated very frequently, even when they clearly need to be (the Clean Air Act was last updated in 1990, when no one in politics cared about greenhouse gases, which has created complex court battles re: EPA’s authority there).

  5. Lane Simonian says:

    The collaboration between FDA officials and Biogen executives was inappropriate. How inappropriate it was remains to be seen.

    The FDA approved aducanumab/Aduhelm without restrictions, even though it had the data to know that at the very best the drug was effective for a subgroup of the Alzheimer’s population and then only at its very earliest stages. The drug has no effect on non-ApoE4 carriers.

    “Did only ApoE4s Benefit? On the clinical measures CDR-SB, MMSE, ADAS-Cog 13, and ADSC-ADL, ApoE4 carriers fared better, while non-carriers did no better than the placebo group.”

    https://www.alzforum.org/news/research-news/aducanumab-still-needs-prove-itself-researchers-say

    In granting accelerated approval for the drug, the FDA repeatedly stated that the removal of amyloid plaques is expected to lead to a reduction in clinical decline, but this assertion was refuted by an FDA statistician who found at the highest dose there was no correlation between the removal of plaques and less decline in cognition.

    https://www.fda.gov/media/143504/download (p. 66 in overall document, p. 20 in statistician’s report).

    All of this is in line with reviews of results from other anti-amyloid trials.

    Lastly, one should not be able to approve the use of a drug for stages of Alzheimer’s disease (moderate to severe) for which no trial was done to establish either efficacy or safety.

    The first step is Congressional investigations and perhaps an Inspector General investigation, the next step may be to remove the FDA officials who collaborated with Biogen, the third step is for Medicare to restrict payments for Aduhelm to ApoE4 carriers with two copies of the gene (the only group which may clinically benefit from the drug) during the very early stages of the disease (and with careful monitoring to detect potentially severe side effects).

    Much damage was done by the FDA approval of Aduhelm, but some of it can potentially be repaired.

  6. a says:

    what possible mechanisms exist to un f**k this, – no matter how drastic.

    I’m serious.

  7. Eugene says:

    Billy Dunn won’t be fired, he will leave the FDA to “pursue other interests”. Expect him to setup his own drug approval consulting company whose first client will be Biogen, for a healthy fee of course. Purely coincidental!

    1. Benw123 says:

      The company name will be: BioYES!

      1. Druid says:

        or Buy-O-Yes!

  8. SP123 says:

    Dunn better hope he doesn’t have any relatives out to third cousins who made any profit on the approval, or he’s… done.

  9. Carl Rogerson says:

    I like how you slipped in a Talking Heads lyric.

  10. Adrian says:

    It is quite surprising that the price for the most irresponsible drug approval in the first half of 2021 does not go to anything COVID-19 related.

    1. Dr. Manhattan says:

      Actually, although both Pfizer and Moderna have filed for full FDA approval of the mRNA vaccines, they are at this point still operating under an EUA. Considering the enormous number of individuals vaccinated (well over 100 million for each vaccine) and the established efficacy and safety, one wonders why they haven’t received full authorization. Clear efficacy and safety in both these cases. It might help to have full approval in convincing at least some of the people who are vaccination holdouts.

      1. confused says:

        I had the same thought.

        I don’t know that it would make *that* much difference – I think most people who are actually worried about the vaccine don’t trust the FDA in the first place — but it would probably help *some*, at least by combating “it’s not *really* approved” doubt-sowing.

        1. MetroGnome says:

          Survey data can be maddeningly soft and unreliable, but there is evidence that full FDA approval could improve uptake among erstwhile doubters to a significant extent. And at least as important, as former Surgeon General Jerome Adams has pointed out, “[voluntary] organizational vaccine mandates” could be a vital component of any coordinated nationwide COVID initiative, but “lack of FDA licensure leaves schools, colleges, businesses in a legal quandary” concerning the feasibility of such mandates.

          Here’s the article . . .
          https://www.forbes.com/sites/jackbrewster/2021/07/06/ex-surgeon-general-people-are-dying-because-fda-hasnt-fully-approved-a-covid-19-vaccine/?sh=318aa011a4bd

      2. Manabi says:

        It’s unlikely to get many of those people to get vaccinated. Most of that group are solidly anti-COVID-19-vaccine, but don’t want to admit it openly. Once the vaccines have full approval, they’ll move on to some other excuse.

        It’s really sad society has reached this point.

        1. MetroGnome says:

          It may be a moot point by then. If current trends continue, we’ll probably be back on full lockdown by the time approval is given. And if new, vaccine-resistant strains evolve among those anti-vaxxers who keep getting sick, we’ll be plunged right back into the middle of 2020 hell, with no exit in sight.

          Somehow, the fact that nationwide, over 98% (usually over 99%) of reported new cases, hospitalizations, and deaths are among the unvaccinated seems insufficient to convince people. Even allowing for margins of error and the probability that “breakthrough” cases are underreported because most are either mildly symptomatic or asymptomatic (i.e., the vaccines are doing their job), in an even semi-rational world those data would be enough to motivate at least most of the “resistant” to roll up their sleeves.

  11. Rodrigo says:

    Don’t forget that Biogen is also fighting in court because of their dimethyl fumarate drug for multiple sclerosis….

    1. Manabi says:

      Which they charge $54,000 a year for. They seem to like prices in the mid $50k range for their drugs.

  12. John Thacker says:

    It seems bad, but nowhere near the cost in lives lost from the FDA not approving (aka removing their ban) on COVID-19 vaccines, COVID-19 rapid testing, etc. It absolutely is the case that the Pfizer vaccine should have been approved several months before it was, and that would have saved plenty of lives. There’s a lot of learning by doing (from manufacturing to administering) but even shifting existing vaccinations somewhat earlier would have helped a lot. And FDA approval of AstraZenaca would reduce vaccine hesitancy across the globe in countries that currently have it but not others. (E.g., Australia.) Combine that with a wide variety of other things banned by the FDA (including more effective sunscreens), and the outrage should clearly be on the side of everything that the FDA bans, not what it allows doctors to prescribe.

    In a perfect world you’d like to avoid both errors of commission and errors of omission, but one side of the ledger is far worse. Pointing to the number of people who waste money taking excess Vitamin D or C will never stack up in my mind to the FDA’s COVID-19 bodycount.

    1. Trial data says:

      “It absolutely is the case that the Pfizer vaccine should have been approved several months before it was….”

      Really? When were the interim results even seen?

  13. Ammar Hasan says:

    This blunder in the middle of a time when trust in the FDA and medical authorities is needed terrifies me. More COVID-19 vaccinations are needed and they are need fast, when the FDA does things like this what kind of message does this send?

  14. SAS says:

    It definitely hurts to be a scientist and watch an agency, supposed to be our most critical medical science watchdog, make such an absurd dismissal of our scientific principles.

  15. Tom A says:

    News about the call for an investigation by former FDA Comm’s and watchdog groups is here. No paywall. The Stat article fired things up.

    https://www.statnews.com/2021/06/30/calls-investigation-fda-approval-biogen-alzheimers-drug/

  16. JasonP says:

    >>>>But the company was confident of a good readout, and at that point they really needed one. What they got instead was a “halted for futility” decision. If you trust that one, then the FDA approval never should have happened. If you trust the FDA approval, then the futility call was an idiotic and premature mistake. I don’t see much room for a third option. <<<<

    Along the lines of a third option…..

    What I don't understand and hope someone will explain is this –

    When Biogen got "half way" through the studies and decided to up the dosage – did they at that point make changes to the criteria for the futility study? Can you make changes to futility study criteria 'mid-stream?' Is it possible if those criteria were changed ( assuming they weren't) that the futility study result would have been different?

  17. Carl says:

    There’s on potential upside to this mess, (it shouldn’t need this mess to happen so it’s a not very nice upside, but an upside nonetheless), presumably there will be a lot more patients donating their bodies to science in the US who have significantly reduced or all but absent amaloyid levels. Thats going to force researchers using them to look at other factors, and that might finally break the logjam.

    As an aside i saw something interesting recently, no idea as a joe blogs how reliable the supposed publishing medium is but apparently at least one group of scientists has discovered some new method of signalling in the brain thats completely seperate from the existing ones. Makes me wonder how many others where missing and if a breakdown in one of those might not be the real cause here.

  18. Prigogine says:

    I went to a dinner for healthcare companies and investors and ‘thought leaders’ in Boston in 2018. At one of the tables was a senior person from Biogen (I can’t remember his exact title), and he explained to me (and anyone who wanted to listen) that he was very, very hopeful about the Alzheimer’s trial read outs. He was so confident that I worried for a while that I’d (and the rest of the dinner) had been made privy to insider information, but I wouldn’t have touched their stock even with a barge pole.

  19. Art says:

    The tricky part of an “caught in the act” happening like this, is the instant assumption that it must be happening more often, without public ever getting to hear about it.

    If they play it down as a normality to be approved upon, without consequences to the individuals, then it will just undermine the apparent reality of how agenda-grand-interest-dependend science/research has become…

    An ever repeated Tesla vs. Edison showdown, till we get it right.

  20. David Edwards says:

    Quite simply, any pharma/biotech company that plays fast and loose with the regulatory apparatus in this manner, should immediately be the subject of sufficient suspicion to warrant a formal investigation into its conduct.

    The very reason we have regulations in place covering medicines, is to stop duplicitous individuals or organisations engaging in activities that could potentially – or actually – kill people.

    Everyone who is participating in the management of pharma/biotech companies, should be made to sit down in a room, while they learn about the Elixir Sulphanilamide episode. Followed by a stern warning to the effect that trying to skirt around the regulations in order to line one’s pockets, invites a prison sentence – a long one if people end up damaged or dead as a result.

    It’s not as if we lack precedents for the injury count or body count that arises, when corporate execs in this field are more concerned about their Mercedes collection than the lives of patients. Thalidomide, Eraldin and Opren spring to mind. Furthermore, on probing for other examples, I found this list, which makes for sobering reading.

    Derek himself has posted at least one article informing us of the sort of mess that arises when spreadsheet concerns override public safety. Which, quite simply, should never happen in an industry whose products could have a a serious impact upon human lives.

    1. eyesoars says:

      “Everyone who is participating in the management of pharma/biotech companies, should be made to sit down in a room, while they learn about the Elixir Sulphanilamide episode. Followed by a stern warning to the effect that trying to skirt around the regulations in order to line one’s pockets, invites a prison sentence – a long one if people end up damaged or dead as a result.”

      Sadly, the Elixir Sulfananilamide episode would teach the opposite: the primary chemist involved suffered personally, but the company, Massengill, is still in business, having been deeply wounded (not) by fines, most notably for ‘fraud’ because it was sold as ‘elixir’ but contained no alcohol. It also result in the creation of the FDA, and fines for Massengill’s chief executive by some states. All this for causing over 100 deaths, mostly in children.

      1. Robert R. Fenichel says:

        The sulphanilamide scandal triggered the triggered the passage of the 1938 FD&C Act, but the FDA had been created in 1906. Simplistically,
        o The 1906 Act required that products’ contents be identified;
        o The 1938 Act required that products be safe (although how safety could be defined without reference to efficacy was undefined); and
        o The 1962 Act required that products be efficacious.

    2. Vader says:

      I’m going to quibble slightly.

      People and companies are _always_ going to try to get the government to see things their way. In fact, it’s a constitutional right, and I see no safe way to restrict that right.

      Don’t misunderstand me. If Biogen actually withheld important data, or provided fraudulent data, or actually bribed someone, sure. Lower them by inches into boiling boil.

      But I’ve not seen anyone suggest that that took place. What I’ve seen is the FDA making a very suspect decision on the basis of the actual data provided.

      Which means it should be some folks at FDA who should be lowered by inches into boiling oil.

      But then, my politics are idiosyncratic, to the point where I consider the Civil Service Act unconstitutional.

  21. dearieme says:

    When, as sometimes happens, a judge in an English civil court returns a decision that makes no sense at all I tend to enquire whose job it is to check judges’ bank accounts.

  22. Joe Psycho says:

    I think that this boils down to the fact that doctors have the final say in every case and their interests often align with corrupt pharmaceutical executives and not practicality or the patient’s individual needs. I know that there are plenty of good doctors that actually care about the patients but there just as many doctors that put profits before people and do not listen to their patients or care about their individual needs and choices, and leave patients for dead if they want a different but still acceptable treatment that they cannot profit from

    1. Wallace Grommet says:

      Did you even read and comprehend the post? Doctors never had any final say in the approval process. Having an MD after your name while being in an executive role makes the person upper management, not a medical practitioner. This process was a power play/ back room deal between a Pharma top brass player and an FDA ally.

      1. Erik Beall says:

        Actually, doctors do hold an incredible amount of power, they ultimately can overrule bullshit like this, but they’ve squandered their effective final say for so many years, keeping their heads down while also justifying business as usual including allowing their practice to align perfectly with the hospitals, insurers and pharma/device industries “because otherwise the system would collapse and us need doctors must do our duty to keep it running!” … without sparing a moments thought to actions they can take to right this damn ship.

  23. N says:

    One sad consequence of this might be that many pharma companies now ask themselves whether they need all these expensive scientists, doctors and statisticians if all they need are a bunch of lobbyist that can open the right back channel and get almost anything approved without too much of a real signal.

    Now might be a good idea to get homeopathic drugs approved.

  24. TSC says:

    No need to wait 9 years to see if Aduhelm works in phase 4.There was a report few years ago tracking patients who were vaccinated with AN 1792,an anti beta amyloid vaccine for 14 years and found that while the beta amyloids were gone, there was absolutely no benefit.All the patients still died of severe AD, with no statistical significance in life extension.FDA just ignores such scientific report .

    1. Mike Williams says:

      Do you have the reference?

    2. sgcox says:

      There is a good summary in Nat. Rev. Neurol.,
      https://www.nature.com/articles/s41582-019-0239-4
      Probably under paywall. The situation is a bit more complicated as I can tell.
      There was indeed a dramatic reduction in Ab plagues and none have progressed to Braak VI BUT all patients had severe dementia at the moment of death. There are speculations it was due to increased vascular dementia due to immune system activation.

  25. Lane Simonian says:

    The first step in the FDA “redemption” process:

    “Aduhelm, also known as aducanumab, was studied in patients with early disease who tested positive for a component of amyloid brain plaques, but the FDA approval last month did not restrict its use to a specific group of patients.

    Treatment with the drug should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, according to the updated product information on the drug.

    The updated label, which was approved by the FDA after the company submitted it, also said there was no safety or effectiveness data on initiating treatment at earlier or later stages of the disease.”

    https://www.nasdaq.com/articles/u.s.-fda-narrows-label-for-biogens-alzheimers-drug-2021-07-08

  26. Siddharth Dasgupta says:

    Interesting perspective in JAMA along with defense from FDA, and criticism from outside!
    https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2782122

  27. An Old Chemist says:

    The Wall Street Journal. (July 15, 21)
    Two Large Hospitals Won’t Give New Alzheimer’s Drug

    https://www.msn.com/en-us/health/medical/two-large-hospitals-won-t-give-new-alzheimer-s-drug/ar-AAMcg3U?ocid=msedgntp

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