Whassup with the FDA approval of that Alzheimer’s drug? A “disgraceful decision” or a good idea?

Andrew Klaassen writes:

Any chance you’ll be weighing in on your blog on the apparently wobbly studies supporting the FDA’s approval of Aduhelm? I’m hearing angry things being said about it by the random people I know in medical research, but don’t know much beyond that.

Here’s the one link on the story [by Beth Mole] that I’ve read so far.

And Deborah Mayo points to this discussion by Geoff Stuart that is critical of the FDA’s reasoning.

Beyond all that, I talked with someone who works more on the policy side who said she thought the drug approval was a terrible idea and asked me how the FDA could ever have made this decision.

Here are my two thoughts.

First, I defer to the experts on this. If everybody thinks the FDA approval was a bad idea, it probably was. I base this conclusion not on the statistical details I’ve seen but rather on a more general impression of rules and fairness, that if other drugs with similar trial results wouldn’t get approved, that some better justification would be needed. Again, I say this not based on any analyses of mine, just based on my respect for all the people who expressed this view. Also the usual concerns about burdening the taxpayer (if this drug is approved for Medicare payments), diverting resources from other treatments, etc.

Second, I can see a rationale for approving a drug in this case even if there’s no evidence that it work. It goes like this. If you approve the drug, some people will try it. If some people will try it, we’ll get some data. Not randomized data—but it’s not clear that randomized data are really what we need. If the treatment is approved now, then we’ll get real-life data, and in 2022 we’ll have one year of real-life data, in 2026 we’ll have five years, etc. It seems likely that this treatment probably won’t do so much to help people right now, but some real-world longitudinal data could help understand what it does do, and that could be valuable in helping to develop future treatments.

If this argument is correct, then the rationale for approval is not about whether this particular drug does the job, but rather whether this line of research might ultimately be successful. Approve the first crude attempt now, and then this will put us on the escalator to developing the thing that really works. Don’t approve, and you delay this future development.

Again, I’m not saying I think the FDA made the right decision in approving the drug—I’ll defer to the experts who say otherwise—I’m just saying I can see a justification in general terms.

It is perhaps helpful to consider this future-looking justification when evaluating the arguments for and against approval. For example, the above-linked news article shared this post from the director of the FDA’s Center for Drug Evaluation and Research:

We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit… [T]reatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit.

From the other side is this statement from Mark Dallas, a neuroscientist at University of Reading:

This sets a dangerous precedent for future drugs in the fight to combat Alzheimer’s and other complex diseases. In many ways the clinical trials undertaken do not present a clear picture that this medicine will be of tangible benefit to individuals living with dementia.

And this from Robert Howard, a psychiatry professor at University College London:

As a dementia clinician and researcher with personal family experience of Alzheimer’s disease, I want to see effective dementia treatments as much as anyone. I consider the approval of aducanumab represents a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade.

This last quote is interesting because he offers a forward-looking argument in the No direction. If I’m interpreting his statement correctly, Howard is saying not just that the new drug has not been proven effective but also that he suspects this line of research is a dead end.

This to me connects to a general issue of statistics and policy analysis:

Decisions are made based on immediate questions that are (partially) resolvable by available data: Did this particular drug work on this particular group of people? But the best reasons for the decision are long-term: Will approving this drug take us in a useful direction going forward? It’s tricky because government decisions should be based on some principles, and once we move away from the hard numbers there is the risk of bad decisions and political interference.

But still. When considering, say, a construction project, the government will do some cost-benefit analysis and this will be forward-looking: some estimate, for example, of the number of people who in five years will be driving over this hypothetical bridge or riding this particular train or whatever. These projections will be based on assumptions, and these assumptions should be stated clearly, but at least the accepted framing is about the future. I am bothered that much of the discussion of drug approval is backward-looking, all about details of a particular study that’s already done. This seems related to the general problem of statistical studies being analyzed in isolation and a focus on noisy summaries such as statistical significance.

Just to be clear: I believe that the FDA and its critics are ultimately thinking about long-term benefits. I just feel that much of the available language for this discussion is focused on static analyses of a single study, so that the long-term questions are implicit and not foregrounded.

P.S. Further discussion here by Gary Schwitzer who quotes some hypey headlines (“Aducanumab offers Alzheimer’s patients a new lease on life,” “A breakthrough drug, Aducanumab,” “Game-changing new dementia drug”) and writes, “The proposed cost for this low-evidence drug could bankrupt Medicare.” This is a good point. I guess that approval is a separate decision from whether Medicare would cover it, but there must be some connection.

41 thoughts on “Whassup with the FDA approval of that Alzheimer’s drug? A “disgraceful decision” or a good idea?

  1. Andrew wrote
    “I can see a rationale for approving a drug in this case even if there’s no evidence that it work.”

    There is a lot of “supposing” and rationalizing going on concerning this treatment so one more can’t hurt. Suppose Biogen, which has already set the list price for a year’s worth of Aduhelm at the unaffordible $56,000, as an expression of confidence and desire to benefit humankind, temporarily resets the list price to something close to zero dollars. Then what?

      • One difference, of course, being that Phase II/III trials showed that the vaccines work. That’s an important distinction.

        And analysis of field data has backed that up, in spades.

  2. I did not read any reports, although I read various news articles and blog posts. Through all of what I read, one issue did not seem to be fully addressed, which was a possible justification for relying on “intermediate end points” (plaque). The problem is the “cognitive tests”. I don’t know what they were. But such tests are often limited in their validity and reliability. The ones used by neurologists are meant to detect major issues such as effects of strokes that show up on imaging. Even those measures used in psychology often have limited test-retest reliability because they are affected by factors that vary over time. Moreover, even a battery of tests with several different subtests may include few measures that are particularly sensitive to cognitive decline in early Alzheimer’s. In research I did (with Myrna Schwartz) many years ago, for example, we found that one of the earliest reported symptoms (in a long list we provided) was difficulty making change. If this result is indicative, it suggests that other measures of “fluid intelligence”, such as backward digit-span, would be especially useful but others would not.

    The hint of an answer to this concern is that the trial was able to detect cognitive decline with the same tests. I would like to know how much statistical power was left for measuring the magnitude of that decline over the short period examined, even putting aside the fact that the analysis was post hoc.

    • “relying on “intermediate end points” (plaque)”

      That struck me as well. At one time I took a look at the sciency parts of the naturopathic literature, most of which was European at the time. The vast majority of the papers took the form of “pathological condition x is associated with elevated blood chemistry measurement y. Naturopathic remedy z is shown in our paper to reduce y.”

      Maybe this is not the worst approach to scientific discovery discussed on this blog, but it sure ain’t the best. I’m hoping that the FDA recognizes the potential for a slippery slope here.

  3. “Second, I can see a rationale for approving a drug in this case even if there’s no evidence that it work. It goes like this. If you approve the drug, some people will try it. If some people will try it, we’ll get some data. Not randomized data—but it’s not clear that randomized data are really what we need. If the treatment is approved now, then we’ll get real-life data, and in 2022 we’ll have one year of real-life data, in 2026 we’ll have five years, etc. It seems likely that this treatment probably won’t do so much to help people right now, but some real-world longitudinal data could help understand what it does do, and that could be valuable in helping to develop future treatments.”

    As a physician, I have trouble understanding what type of “real-life” data you’re referring to here. To illustrate the problem with taking an anecdotal or observational approach to assessing efficacy of treatments for Alzheimer disease, consider the daily conundrum doctors already face with other approved Alzheimer medications-cholinesterase inhibitors. Cholinesterase inhibitors have been shown to have marginal benefit, if at all, in trials. Nonetheless, patients are routinely started on them because they’re the only existing treatment option. Commonly (?usually), even after a patient has been on one these drugs for many months, families are uncertain whether it has helped at all.

    In general, the “N of 1” approach is not a particularly reliable one for assessing therapeutic efficacy in conditions with a natural history like that of Alzheimer disease. Alzheimer disease involves slow, progressive deterioration, often with intermittent waxing and waning of symptoms for unclear reasons, generally over a 10 year period (from diagnosis to death). Clinically, it’s very difficult to identify a benefit of existing drugs in individual patients. If a patient has not been able to feed himself for the past 3 years and suddenly regains the ability to do so after starting medication, then this is an obvious signal of benefit. But in my (granted limited) experience with my own patients, these types of clear-cut improvements with existing drugs are not common. If there are benefits (in the form of improved daily functioning), they are often so subtle that the family does not perceive them. At that point, the question is always whether to continue the medication or not. If the family does not perceive a benefit and the medication has potential side effects (e.g., bradycardia, nausea), should it be continued or stopped? Nearly universally, specialists seem reluctant to stop these medications for fear of “making things worse.” As a result, Alzheimer patients often end up on multiple medications in the long term and nobody can tell if they’re doing anything at all. Doctors who work with Alzheimer patients see the same future for aducanumab. Alzheimer disease therapies *must* be studied in RCTs. If aducanumab were a “miracle drug” amenable to reliable efficacy assessment through N of 1 trials (like L-dopa for Parkinson disease), we’d know by now.

    Alzheimer trials will likely need to follow large numbers of patients over many years, using objective measures of daily functioning to identify intrinsic efficacy. If FDA feels strongly that this line of research is promising (I’m not qualified to assess whether this is a reasonable bet to make), yet doesn’t feel that drug sponsors should have to shoulder the financial burden of conducting the large, long-term clinical trials needed to prove efficacy for clinically important outcomes, then government should fund the trials. Bankrupting desperate, distressed families who will feel guilty for not “trying everything” for their loved ones is ethically abhorrent.

    • “If the family does not perceive a benefit and the medication has potential side effects (e.g., bradycardia, nausea), should it be continued or stopped?”

      But isn’t that exactly the sort of descision that we he physician for and not some automated algorithm?

      This sort of benefit vs side effect tradeoff is going to be so heterogeneous across a population that I struggle to see how a RCT or regulator should bear the burden of this.

    • Chiming in to agree with Erin Smith, the putative “real-life data” on offer here reminds me of the infamous “trying to use a bathroom scale to weigh a feather—and the feather is resting loosely in the pouch of a kangaroo that is vigorously jumping up and down.”

  4. I think the criticisms are forward looking for a number of reasons. For one thing, it will encourage the next drug appraisal based on similar post hoc selection to argue that its evidence is every bit as strong as was that for Aduhelm. Further, I think people will be less willing to give their frank advice on FDA advisory committees, after feeling they were ignored on this on2 (as several said–2 quit). I’m not up on the latest status of the amyloid plaque theory, but I do know that other drugs have achieved a reduction of amyloid in the brain, without improved cognitive function. Had this drug been turned down, it might have been taken as falsifying the amyloid theory altogether, and given the impetus to several other promising pathways which might not be pursued now. Waiting for another year or so of data could have decided the matter without tending to derail other approaches. The consequences for future health economics of a drug that will cost upward of $50,000 a year, with an aging population, is also of great concern.

    • Mayo – surprising argument, I would have expected to hear from you about the level of severe testing of the experimental outcomes used by the FDA to support their decisions. The counterfactual you use is of secondary value. Can you indicate the level of severe testing of this pre-registered trial??

  5. How does approval of one drug delay the discovery of other meaningful dementia drugs for a decade?

    I don’t get that line of argument. Isn’t it self defeating.

    • Many people that would have participated in clinical trials for other treatments will now take instead this drug that was approved against the recommendation of the advisory panel.

      • But if it’s so obvious that this is a bad drug ( for arguments sake) then won’t doctors / patients refuse to take / prescribe it?

        I think we generally overestimate our ability to judge efficacy in a watertight way via clinical trials especially of the sort of drugs where effect sizes may be small and heterogeneous over populations.

        So long as FDA is satisfied about safety we should encourage it to be a bit liberal about efficacy. Let post approval data was doctors to their own conclusions gradually.

        • > But if it’s so obvious that this is a bad drug ( for arguments sake) then won’t doctors / patients refuse to take / prescribe it?

          Someone with actual clinical experience should weigh in but my guess would be that for the (vast?) majority of doctors/patients, the stamp of approval from the FDA is enough to prescribe/take it. This guess is largely derived from the reaction to the pandemic but I admit the scenarios are not quite the same.

        • My suspicion is that the backlash against this drug since its controversial approval has now doomed it-hopefully. Only time will tell.

          And I’m also starting to suspect that FDA anticipated that this would happen- they’re not stupid. Plausibly, FDA has decided to adopt a new (but IMO dangerous and profoundly cynical) approach to drug regulation. Lobbying groups have become increasingly powerful over the years, employing vocal patient advocates to harangue FDA into doing their bidding. These groups know that there’s huge money to be made from exploiting the desperation of families whose loved ones are slowly slipping away from them.

          FDA knows that if they resist powerful lobbyists, they’ll be criticized for quashing the hopes of patients and their families. On the other hand, if they approve the drugs that lobbyists are asking for but which lack solid evidence of efficacy, the other side protests that they’re caving in. So maybe they’ve settled on a new approach to drug regulation that essentially “lets the market decide” which drugs are worth using. Specifically, if they approve a marginal drug, but do so in the context of highly publicized overwhelming advisory committee rejection, then they can be assured that negative media coverage/”word of mouth” about the drug will likely sink it in the long run. So basically, FDA seems to be betting that although they’ve approved a useless drug, doctors and the public/payers won’t end up playing along, so the drug will end up bombing.

          The problem with the above approach is that FDA is treating desperate patients and families like puppets. When it’s your mother or father who’s not going to recognize you in a couple of years, you’ll cling to any faint hope of improvement, however poorly supported. And seeing that FDA “seal of approval” will likely be enough to prompt many families to spend their life savings on a useless drug, when they could have spent their money in far more valuable ways (e.g., increased nursing care/respite care).

          At the end of the day, nobody should be paying for this drug outside the context of an ongoing clinical trial. And FDA should have grown a pair and said so, in no uncertain terms.

        • And this is exactly the sort of cost benefit analysis that the FDA should not be doing at an aggregate level. This is much better left to the individual treating physicians or even the patient families themselves.

          If I have a million dollars in the bank my view is going to be different about taking an small chance to extend life ot improve quality of life.

        • This is exactly why FDA’s decision is so slimy. At some point, someone needs to put their foot down and set a low bar for efficacy, below which approval won’t be granted. But nobody wants to do this because of the money involved.

          One view (uniquely American), is that the rich should be able to purchase whatever they want, including false hope. But this approach leaves the remaining 99.9% of families (equally desperate) feeling guilty that they couldn’t afford “the best” care for their loved one. In the end, I’ll be very surprised if this drug gets approved in any other country.

        • The FDA does usually set a (sometimes low) bar for efficacy and it denies approvals all the time despite of the money involved.

          They didn’t need to grow a pair of anything to say “no” in this case. That was the expected answer. The report from the internal reviewers was not favorable, the external panel was not better.

          It was surprising that the FDA granted the approval but it may be even more surprising if the CMS denies now Medicare coverage. Both are government agencies and it’s hard to imagine that the FDA decided to approve the drug against all expectations without considering the consequences.

        • “One view (uniquely American), is that the rich should be able to purchase whatever they want…”

          It’s called a price-coordinated economy, and because of it the united states has an abundance of choices found nowhere else on earth. It’s one reason that the US has the highest GDP per capita among countries with more than 10M people.

          I’m not sure what I think about FDA approval of this drug. However, I’m damned sure it makes much more sense to let the rich pay for a useless drug (if they want it) than to have the 90% pay for it through their medical premiums or taxes. And however this all shakes out I sure as hell don’t want to pay it.

        • Part of the problem here is convoluting the drug regulators descision making with the budgetary impact on an insurer.

          CMS ( and other insurers) should have the ability (or balls) of saying no to a drug even though the FDA has approved it.

          Just because not everyone can afford a drug seems a silly reason to keep those who can afford it out.

    • I think it could also be that if Biogen already has an Alzheimer’s drug on the market they might reduce their investment in future research in this area? Or maybe the effect goes the other way, I’m not sure.

        • Except for the “good” part, at least according to the experts in the advisory committee who voted 0 yes, 10 no and 1 uncertain on the question, “In light of the understanding provided by the exploratory analyses of Study 301 and Study 302, along with the results of Study 103 and evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology, it is reasonable to consider Study 302 as primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease?”. Three of them have resigned this week.

  6. Derek Lowe’s thoughts on this drug impressed me: https://blogs.sciencemag.org/pipeline/archives/2021/06/08/the-aducanumab-approval
    Also, I think that it useful to point out that there is some reasonable evidence for blunting dementia with simple hygienic measures like exercise, a prudent diet, proper sleep, and moderation of alcohol intake. I plan to ride my bicycle today, have salad nicoise for dinner, and get to bed by 10. My glass of pinot noir is a little bigger than recommended, but I’m sure that I have a better than average alcohol metabolism. Also, https://www.americangeriatrics.org/sites/default/files/inline-files/American%20Geriatrics%20Society_Letter%20to%20FDA%20Biogen%20Drug%20for%20Alzheimer%27s%20%28June%202021%29%20FINAL%20%281%29.pdf
    Might be good for the FDA to say something about the Covid vaccines now that 307 million Americans have had one dose.

    • Lowe in another post provides a link to an FDA report https://www.fda.gov/media/143502/download.

      I have not read the clinical report section but the statistical report, starting on pg.247, is what I would consider to be “less than positive”. Perhaps, “damning” is the term I am looking for.

      At the moment this looks like a drug that has met the same standards as a homeopathic concoction.

    • Hi Oncodoc,

      Good advice. The results that several of these Lifestyle and Functional Medicine physicians have yielded through clinical trials of dietary and exercise regimes are not short of remarkable. All endorse a plant based diet: meaning no dairy or meat [chicken, beef, or fish], which they claim contains hormones and toxins that produce or exacerbate diseases.

      In particular, Dean Ornish has shown considerable reductions and reversals in heart disease markers like arterial plaques, high blood pressure, and diabetes 2. Other physicians in this effort are Caldwell Esselstyn, Michael Greger, John McDougall, and of course Neal Barnard. They are featured, these days, on some of the Youtube podcasts moderated by younger health experts. I watch their interviews regularly. Plus, I favor a plant based diet, with salmon or sardines for the Omega 3 fats, two or three times a week

      Now with dementia, there is a controversy between physician David Perlmutter a keto diet advocate and the plant based physicians over diet. Permutter strongly endorses a keto, gluten free diet. He also claims that cholesterol is needed for the brain. Moreover, Perlmutter has focused on brain disorders and health. He has noted that Alzheimer’s disease runs in his family.

      All of the physicians endorse an exercise regime of at least 3 times a week.

  7. This drug, even if effective, its effect must have low SNR. Data to be collected from clinical use will be a lot noisier than RCT data. They had over 3000 patients in their RCT. Suppose collecting live use data from 30000 patients for 5 years would provide some more definitive insight, it will cost over 8 billion dollars given the price tag. It seems an inefficient use of resource based on this very rough guestimate.

    There are 6M Alzheimer’s patients in the US alone. If this drug becomes Medicare eligible, it will take up a huge portion of the resource even with a large discount. On the other hand, if it does provide clear benefit, it will have huge impact.

  8. For lack of enough data, the estimation for long term benefits and costs is almost always an extrapolation from subjective priors and oversimplified models, as akin to a career choice at a young age. Making a point decision with a weak evidence is hard: Despite the most radial tension in between, the FDA and its critics sit only two epsilon apart, but on the opposite side of Bernoulli(.5).

  9. This is an awful decision just in the short term.
    One trial completely failed
    They used a signal on a second trial claiming that more had the higher dose of the drug but this effect was considered small
    There is higher risk of brain hemorrhage and edema in the higher dose group as well! So it’s entirely unclear if this drug is actually not more harmful than just neutral.
    The FDA went full bore on a surrogate marker impact with amyloid but this hypothesis is actually failing. Reducing amyloid in multiple other clinical trials did not result in clinical improvement and the field has a whole is wondering whether amyloid is a necessary factor but other proteins such as tau are more causative in terms of neurodegeneration.
    They approved it for ALL AD even though the trial only included a specific subset of patients with mild AD

    All this does is shift clinical research onto the backs of taxpayers and employers while decreasing the quality of said research: the drug company gets huge profits win or lose now. https://www.theatlantic.com/ideas/archive/2021/06/aduhelm-drug-alzheimers-cost-medicare/619169/

    • “All this does is shift clinical research onto the backs of taxpayers and employers”

      I agree. It’s basically opening the treasury to pay for a drug that does nothing.

  10. “Second, I can see a rationale for approving a drug in this case even if there’s no evidence that it work. It goes like this. If you approve the drug, some people will try it. If some people will try it, we’ll get some data.”

    These three sentences really struck me as an abandonment of morality. In particular the morality we apply to studied populations. These unwitting study participants will have been lead to believe that the drug is effective. After all, scientists developed it and it was approved by the FDA. And you (apparently) are happy to treat them with a drug that may do no more than bankrupt them.

    Tell me how is this morally better than leaving poor black people untreated for syphilis in order to study its effects and improve future treatments? They too were sacrificed without due consent at the alter of “We’ll get some data.”

    I guess the ends justify the means?

    • Ian:

      First off, as I wrote above, I don’t think the approval was a good decision. The fact that I think there could be a good reason to approve the drug doesn’t mean that I recommend approval. Complicated decisions can have lots of arguments pro and con.

      Second, more generally, lots of treatments don’t work on a lot of people. If a treatment is expensive, then, yes, it “may do no more than bankrupt them.” That’s unavoidable for any expensive treatment. It’s either paid for by the taxpayers or it can bankrupt people. That would be the case even if the data showed an unambiguously positive effect in the population. So the bankrupting thing seems like a separate issue to me.

      Third, the difference between this case and the famous syphilis experiment is that in that historical example the truth was hidden from people. Here it’s all out in the open. Nobody’s being sacrificed; rather, there are people who already have a horrible disease who are being told that a drug is available with unclear possible benefits. In answer to your question, I think it’s morally much better to provide people with information and to make the uncertainty clear than to know that someone has a serious disease and not tell them!

      • I was a little overly harsh. A few points though:

        1. I don’t view it as a treatment yet. Until clinical benefit is shown, it is an experimental drug.

        2. Bankrupting people is a negative side effect, which is especially pernicious if the medication only provides false hope.

        3. The drug has the FDA stamp of approval. The FDA has stated the position that patients should be expected to benefit clinically from the drug [1]. Patients are desperate for a glimmer of possible hope and will grab onto any that is given. I worry that patients are being misinformed by trusted authorities. Misinforming in the name of data collection brings to mind the worst abuses in medical research.

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

  11. One thing that seems to be missing so far in this discussion:

    In many cases patient advocacy groups push the FDA to approve marginal or incompletely tested drugs because the patients have no other choice. Whether or not that’s the case here I don’t know, but this approval could be in part a response to that pressure.

  12. Hi Andrew:

    Actually, Medicare will not necessarily pay for it. They make their own evaluation of what they will and will not pay for. And I’m hopeful that this will not be chosen until it is proven to work.

    Rodney

  13. It’s not just one failed trial. The reason this approval seems so arbitrary is because more than a dozen trials of drugs with the same mechanism of action have failed over the years. The worry now is that pharma will jump on making me toos since the market is so large and lucrative, will underinvest in new pathophysioloic hypothesis instead of the failed amyloid hypothesis. Like tau protein. Amyloid (target of the biogen drug and countless others, failed) appears to be correlated to an underlying pathophyiologic mechanism of Alzheimer’s rather than causative.

  14. https://www.statnews.com/2021/06/15/6-ways-fda-approval-aduhelm-does-more-harm-than-good/

    “Elbowing aside existing treatments. The harm posed by Aduhelm’s approval to the detriment of more promising drugs is not merely theoretical. This is already happening with galantamine — an inexpensive oral drug approved to treat Alzheimer’s two decades ago — that operates on a different principle than Aduhelm. […] The performance of galantamine over decades is far superior to the uninterpretable data package upon which the FDA relied in approving Aduhelm.

    “The FDA’s baseless decision has served to focus patients, families, and clinicians on how to operationalize the approval of a costly, unreimbursed, intravenous infusion drug as patients by the hundreds or thousands reach out to their doctors asking when and how can they begin receiving it. At almost the same moment, far superior data pointing to a safe, affordable, orally active, immediately available medication are almost totally ignored.”

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