Is that the primary goal, though? To do "Science"? Seems to me like it has a relatively large "cost-benefit analysis" role as well, which, as the voting citizens of the country that created the FDA, and who will bear both the costs and benefits of those analyses, I'm not sure it's the "man on the street" unjustly intruding on the FDA's "scientific" jurisdiction. It seems more like the FDA unjustly (and without the relevant expertise) intruding on citizens' implicit demand that their public health agencies serve their best (again, implicit in "best" is some kind of cost/benefit analysis) interests.
Thanks for linking to my piece. An interesting problem you bring up in the Axsome story is effectively a public goods provisioning problem: how do we incentivize good trials for generic drugs for repurposing?
Good trials for generic drugs provide the public good of accurate information on a clinical question, and then anyone can use that information.
Some ideas to make this better, ignoring novel drugs to simplify:
1. making clinical trials cheaper per patient. I don't know enough about this to have specific proposals, but it is something I'm eventually going to learn more about. Tentatively: something involving substantial reductions in the power of IRB's and using tech to make multi-site trials easier.
2. prizes for researchers who successfully discover a new use for a generic drug and prove it with a trial. This exists informally, in that a highly cited research trial paper will give you career capital and speaking invites.
3. Something involved prediction markets and clinical trial outcomes? Maybe people who are good predictors of successful drug repurposing should get $$ to choose more drug repurposing candidates?
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long
I doubt that when people support restrictions on drugs and stuff, they are thinking of *them* not being allowed to get something they want. They think of other irresponsible or stupid people. I can imagine supporting restrictions on an unsafe drug yet feeling it's an unfair privilege that someone specific gets to choose to circumvent them.
Even supposing Aducanumab doesn't treat Alzheimer's, if it truly is an anti-amyloid, it should have some beneficial effect. As you wrote earlier, doctors should be allowed to write prescriptions for it (since it seems safe), but insurance shouldn't have to pay for it for AD (since it doesn't seem effective against AD). Under our current system, a drug that might be useful against disease X will be banned forever if it's first tested against disease Y.
The $100 billion/year estimate from my blog post is a high end, and after writing that post, the FDA took a step back and restricted the indication to only early-stage patients. Still, it has the potential to be extremely costly.
Whenever you write about the FDA I can't help but think of the FAA. Drug companies have no incentive to sell dangerous drugs. Just like Boeing doesn't have an incentive to have planes suddenly plummet to the ground killing 100s. Boeing might not but individual Boeing employees certainly do. And not long after we started relaxing regulation those individual employees started to run amok. I don't see why we wouldn't' see the same issue with reduced regulation of Pfizer that we saw with Boeing.
I think the criticism raised by Charlie (and Kevin Drum, and others) just relies on... an unnatural reading of things? If you think a particular government agency should not exist -- if you think that the function it is supposed to perform is one that should not be performed, and therefore no agency should exist to perform it -- that would to my mind normally be described as you being "against" that government agency, and that is how I would normally someone interpret saying they are "against" a particular agency or that that agency is bad. I don't know why one would read it instead as a comment on the quality of the particular staff? I would normally think of government agencies primarily in terms of their function, not the particular people who happen to be executing that function...
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us.
I think there's an internally consistent position where the observer doesn't acknowledge that the drugs are being delayed too long, and just objects to the actor breaking the rules. Basically, in this framework whether the treatment works is moot, the objection is just about fairness and/or the morality of rule-following.
(Not supporting this position, in particular; just providing an observation for why most people don't think politicians are heroes when they cut the line, and also the criticism Biden is trying to pre-empt with his statement that he has to wait for FDA approval before taking his booster.)(
Andrew Gelman does a thing where he writes his content and puts them in a queue to post 6 months-ish later. Maybe that's an option foryour less time sensitive pieces.
The final example about bupropion-dextromethorphan highlights how misguided it is to solely fund clinical trials through the promise of patent-protection. Presumably the government could make a guess at how likely this would be to work, how valuable it would be if it did, and then the government could have people bid on the contract to run a clinical trial.
Does this happen? Does the government, or anyone, fund clinical trials with the condition that anyone can make the drug if it is approved? The Ketamine example fits here too it seems.
I'm kind of baffled how you can invoke the "normal knowledge that normal people use" as some kind of accessible source of information when nobody has the first clue how to gather or assess that. Normally among pundits it operationally reduces to "what me and the people I know/read/like think" but that leads straight to the Pauline Kael effect, and some of the unpleasant divisions between "expert opinion" and what vast swathes of regular folks think that we see today on any number of issues.
If nothing else, consider that the "knowledge of normal people" about which we have cared deeply for several centuries is "who should run the country?" and for this purpose we have this vast apparatus of elections, at various levels, terms of various sizes, representation or not, not to mention polling and focus groups and prognostication -- and yet we *still* are routinely surprised by the outcomes, and debate furiously just how genuinely representative they are.
What hope is there of actually discovering what the "knowledge of normal people" actually is on the question of whether Drug X should/should not have been approved, or whether the FDA should be "stricter" or "looser" in general, for various definitions of "strict" or "loose?"
I feel like all you're really saying that's 100% defensible here is that given time, a consensus will emerge, and using the clarity of hindsight we will all be able to say decision Z or T of the FDA was right/wrong or hasty/slow. But noting that hindsight is easier and more accurate than foresight is rather a truism and (barring the invention of time machines) gives no clue on how to improve the situation going forward.
""On March 19, 1972, the FDA reassigned Nestor to its Office of Compliance, as part of a reorganization in which Civil Service doctors were replaced as drug approvers by consultants who were often affiliated with commercial companies. Nestor began a grievance proceeding. A review panel determined that senior FDA officials gave "misleading" testimony against Nestor and concluded that Nestor was due an apology and appropriate duties.""
The final decision is made by a bunch of men-on-the-street: a jury. We decided that, even though justice system officials know a lot more about crime, it is too difficult to get rid of their inherent biases, so a group of men-on-the-street does better.
If we take this analogy even further, we could have juries for the FDA. The experts can make their arguments, but the decision would ultimately be decided by a group of men-on-the-street. Random people would get called to make decisions that effect the life and death of their fellow citizens.
While I think that this is interesting, I'm not convinced that it is a good idea. The FDA is often too slow to approve good drugs and the jury system is not exactly known for its speed.
I was also a bit disappointed in the post and subsequent discussions elsewhere, because the question on what influenced the Aducanumab decision is not really addressed. If the FDA is so risk averse, why authorize this drug and risk reputational damage if it turns out that it doesn't work? Scott kind of gestured at "some decisions will randomly stray from the decision mean in the other direction", but I find this terribly unconvincing, given that the FDA's scientific advisory committee was firm in its rejection. Plus, other bloggers have alleged regulatory capture by big companies, which seems more explanatory.
I feel like a model of how the institution works beside the short and imho simplistic "public perception incentivizes risk aversion" story should be required before condemning an institution so heavily.
> I don’t want to never write posts when I’m angry, because those tend to be the posts people like the most, and I think they get things done in terms of convincing people of important things.
This is a well known phenomenon. Outrage sells. But that doesn't make it good journalism.
"Then someone finally realized that the jam was caused by a single citizen, one who commuted in the far left lane, driving exactly the speed limit for miles on end."
It distresses me that this was seen as improper behaviour. If the speed limit is too low, raise the speed limit - don't complain about people obeying the law.
From a consequentialist perspective, why is it better to let ten guilty men go free rather than convicting one innocent rather than having each kind of error be equally likely?
I've spent the last month and a half buried in the Alzheimer's Disease literature due to a likely case in a family member (and ironically, for this reason I must apologize in advance that I won't have time to engage in a detailed back and forth here). I think the evidence for both the amyloid cascade hypothesis and the efficacy of aducanumab is much stronger than is being characterized by most comments here.
It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β being the cause?" However, we have strong evidence that it's the cause.
In fact, in a subset of cases, we have smoking gun evidence that amyloid is the cause: certain mutations or duplications of the APP (amyloid precursor protein), PS1 & PS2 (presenilin 1 & presenilin 2, parts of the enzyme γ-secretase involved in cleaving APP to make amyloid-β) genes guarantee that one gets Alzheimer's, and typically quite early (between the age of 30 and 60 for the onset of clinical symptoms). We have mapped out the structure and function of the corresponding proteins extremely well, and we know how, functionally, those specific mutations affect the behavior of those proteins: either to increase total amyloid-β production, or to increase production of the specific peptide (amyloid-β 42) implicated in Alzheimer's Disease. [1] I am not aware of another plausible effect of those mutations besides this one, and the mutations guarantee you get Alzheimer's Disease.
Now, this represents approximately 1% of Alzheimer's cases, the so-called autosomal dominant variety, so it's a priori conceivable that the other cases have a different cause. In the remaining cases, we have evidence consistent with an impairment of amyloid clearance mechanisms, however that evidence is more circumstantial and in some cases compatible with other hypotheses. But the disease looks like exactly the same disease as the 1% of cases in which we have smoking gun evidence of amyloid being the cause: we still see the same progression of amyloid-β, followed by a progression of hyperphosphorylated tau, followed by neurodegeneration and cognitive decline, and with the same sequence of brain regions and cognitive symptoms.
Suppose there are two bank robberies. In the first, we have smoking gun evidence the culprit: a video camera showing a guy getting out of his car, with a clear image of his face and the license plate, and then of him walking into the bank, pointing a gun at the teller, the teller handing over a bag of cash, and him walking out with that bag of cash. In the second: we also have footage of the same guy and the same license plate at the scene of the crime, but an occlusion prevents clear footage of the exact moment of the robbery. However, the robbery occurred in the same town and on the same day, and eyewitness reports are that the robbery was conducted in basically the same manner. In that case, is there much question as to the identity of the robber?
***
As for the track record of amyloid-targeting therapy for Alzheimer's, I think it's fair to say that it's been less successful than hoped for but that also:
1) There has been a mixture of benefit and no effect; rather than the mixture of benefit, no effect, and harm which you'd expect to see if the drugs really were useless. For example:
A) The recent phase 2 trial of the similar drug donanemab showed success in its primary endpoint of reducing cognitive decline. [2]
B) With respect to aducanumab [3], the first phase 3 trial, EMERGE, passed its primary endpoint and all pre-designated secondary cognitive endpoints, with p-values for the high dose arm between 0.0006 and 0.0493 (0.0120 on the primary endpoint), and effect sizes ranging from an 18% slowdown to a 40% slowdown in cognitive decline (22% on the primary endpoint).
The second phase 3 trial, ENGAGE, did not show statistically significant benefits on any pre-designated endpoints, but the effect sizes still ranged from -3% to 18% (-2% on the primary endpoint). So given only pre-designated endpoints, we have two trials, one of which showed a clear benefit, and the other of which showed no effect, or very slight benefit if we give some weight to pre-designated secondary endpoints. From a Bayesian perspective, this has to be seen as weak evidence of benefit.
Furthermore, the post-hoc analysis, while always to be taken with a large serving of salt, was not done arbitrarily. Rather, they looked specifically at the subpopulations which received higher dosages, an a priori plausible sub-population within which to expect higher efficacy.
Lastly, both trials showed a substantial and significant (p < 0.001 in EMERGE, p < 0.01 in ENGAGE) reduction in phosphorylated tau, a neuropathology both regionally and chronologically highly correlated with volume loss and cognitive decline in Alzheimer's Disease.
2) The amyloid cascade hypothesis offers explanations for past failures of amyloid-targeting therapy, for example poor target specificity (some therapies such as semagacestat were not proven to engage amyloid in the first place, and were also known to produce other toxic effects unrelated to reduction in amyloid), deficient screening of participants (in some cases, patients were selected only for cognitive symptoms and not for the presence of amyloid, thereby reducing statistical power), and not intervening early enough (no one believes amyloid is the main proximate cause of neurodegeneration, so if you intervene late, it might be too late to prevent the cascade of problems it's believed to cause).
By contrast, I'm not aware of alternative hypotheses which even offer a story which can account for the known facts, such as the aforementioned evidence in the APP and PS1/PS2 genes.
***
For those interested in learning more, a good starting point for the current state of the science is [4]. A more up-to-date and comprehensive review paper is [5].
[1] Haass et al (2012). Trafficking and proteolytic processing of APP
[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease
[3] Cohen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease
[4] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years
[5] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
"The one part of this I want to ask about is the “aren’t really any [other] Alzheimers drugs”. There’s galantamine, rivastigmine, donepezil, and maybe some others I’m forgetting. These don’t work very well (or maybe at all). But aducanumab also doesn’t work very well or maybe at all, so why is everyone treating it as so unprecedented?"
Those are cholinesterase inhibitors (NMDA-receptor blockers like memantine are also used against Alzheimer's). The effect on cognition for cholinesterase inhibitors is not very good, NNT around 12, though still better than aducanumab, even if you take biogen's data at face value. However, cholinesterase inhibitors and NMDA-receptor blockers do not treat the underlying disease process of Alzheimer's disease. The hope with anti-amyloid drugs like aducanumab that they would actually be disease-modifying.
> That’s fair. I’ve seen some studies by economists saying that “defensive medicine” and fear of malpractice lawsuits doesn’t seem to raise costs too much in the US - but every doctor I know (including myself) feels like they do.
The studies I have seen were doing some intra-US comparison (e.g., VA vs. non-VA bc VA doctors cannot be as easily sued; or the impact of changes to the rules in Texas) and they do find some limited effects. However, none of these studies have a true counter-factual. VA doctors may themselves be more protected from lawsuits, but they are still in an environment where their colleagues from other institutions have instituted all sorts of "best practices," which they are still socially pressured into performing (I assume non-mormons end up drinking less than they would in New York if they move to Utah; which is still because of the LDS church).
So, the studies falsify the notion that the problem is doctors performing an explicit cost-risk legal analysis and then deciding "defensive medicine" is worth it. They do not falsify a fuzzier idea that medical norms are very heavily influenced by the legal environment, but in a way that responds slowly to changes of incentives and does not respect institutional boundaries. Of course, this hypothesis has the benefit of being hard to falsify, but "long-established legal norms lead to a cultural framework of behaviour that persists when those norms are removed" is a very common pattern in history.
Total non-expert here - isn't there a case that amyloid plaques are a cause and/or symptom of aging, and so drugs that remove them could increase lifespan, even if they don't help with alzheimer's?
About politicians either being privileged by the ability of getting the drugs in advance or heroes for testing them, I think there is a way of making the distinction: how do they think about it themselves? I suspect none of them consider it taking a heroic risk, and therefore that should be our point of view too.
>But the cost-benefit analysis is still heavily in favor of the drug, as it is very safe, molecularly effective, and with no alternatives, in a very widespread and destructive disease. The only cost being some people paying money for a drug that won't help them
I think it's worth pointing out that it's an artifact of our local economic system (maybe not capitalism generally, but the specific model of capitalism plus regulations plus government payments plus etc that governs our health system) that creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
Because we only know how to value things through the process of supply and demand, we build the entire economy around the maintenance of artificial scarcity in cases where production is cheap and supply could easily be near-limitless, and grant the right to monopoly pricing to all kinds of actors in order to encourage them to keep acting.
I get that we've let the system fall into this situation for a reason - we want to encourage creators to create things, pharmaceuticals especially can be a huge and expensive gamble so you need a big payoff the one in X times it works, etc. But I think it's a deficiency of our system that we provide this incentive by using artificial scarcity to *deny medical treatments that are extremely cheap to administer* to tons of people through outsized pricing.
I think your last point requires a whole lot more evidence to be believable. Sure, everyone knew that Al Capone was a criminal, but also everyone knew that the Central Park Five were guilty, that Airborne was an effective thing to take when you get a cold, and that deoxygenated blood is blue. Everyone knows lots of things that are totally wrong. If you want to claim that everyday reasoning is better than institutional decisionmaking, you can’t just point to a single case where the common people got it right and the institution got it wrong, you need some evidence that that is consistently true over a large body of decisions.
Bupropion-dextromethorphan: I was curious so I bought some DXM from Dollar Tree (where it is 6x cheaper than at CVS) to see whether it does anything in addition to bupropion, but at least I didn't notice anything. (Apparently DXM has some abuse potential so the register makes an embarrassing loud beep when it is scanned.) Interestingly, it seems like the US is the only country where DXM is sold over-the-counter, so it might end up being slightly less trivial to get around Axsome in other countries.
> But that’s not what happened. Instead, the FDA sent Axsome a letter on July 30 saying that they found “deficiencies” that prevented them from moving forward with the approval. What are those deficiencies? Oh, the FDA doesn’t say. They don’t even give a hint. They just told them to hang tight until August 22.
> I remember the FDA rejected an EpiPen competitor for “certain major deficiencies” without giving more information (at least not to the public). EpiPen took advantage of this to quadruple their prices, although the FDA did eventually approve the competitor a few years later.
I really hope the SEC is taking a good hard look at the trades that happen around FDA members...
The thing that puzzles me about all this discussion is that the problem and solution seems clear and simple, yet Scott hasn't presented it in a clear and simple way.
Simply put, Scott isn't opposed to anyone at the FDA, he just wants some elements of the legal framework around the FDA to be changed. The obvious political slogan: "support FDA reform!"
Specifically, certification of safety needs to be separate from certification of efficacy, so that doctors can prescribe safe drugs even if they aren't proven to work.
The devil's in the details of course, so why not shift the conversation to those details? One issue that jumps to mind is that if a drug is shown to be safe in average healthy people, that doesn't mean it's safe in the sick population it's meant for, so even the safety certification may need to be scoped to a subpopulation.
Want an intern? My previous employers have commended my ability to intuit instructions and take initiative, so you don't need to be too concerned about communicating. I have a few years of experience in research, writing, and editing, mostly for student publications.
If you're interested, email me at t [dot ] amarchana640 [at] gmail [dot] com.
I presume someone else has done this, but I need the exercise; in the spirit of doing things with made-up statistics.
1. The cost of aducanumab to the US health-care system is potentially $100B/year (as per [this](https://denovo.substack.com/p/a-travesty-at-the-fda#footnote-1), because it costs $56k/year per patient, and on approval is mandatorily covered by Medicaid, with the assumption that 1.8 million patients would be treated).
2. According to [a 2008 study](https://pubmed.ncbi.nlm.nih.gov/18362813/) (the highest in [the first link](https://www.nytimes.com/2020/05/11/upshot/virus-price-human-life.html) I managed to find in a cursory googling), "Our base case analyses suggest that plausible lower and upper bounds for a cost-effectiveness decision rule are $183,000 per life-year and $264,000 per life-year, respectively." (incidentally,this means that aducanumab would be a steal at $56k/year if it worked)
In order to be worth it at the above exchange rate, aducanumab would need to save 378,787 lives ($100B/year divided by $264k/year (are years and QALYs fungible in this way? Do we discount actual years somehow, especially given that this medication is likely to be administered near end-of-life?)). If you're more pessimistic about the value of a QALY, it's more like 546,448 lives. If you're _extremely_ pessimistic about it, more like 2,000,000.
If you believe that aducanumab will actually save close to 0 lives, then the answer to
> "So how often do you have to save hundreds of thousands of lives before it’s worth the risk of occasionally also permitting a dud medication that “offers false hope”? _How is this even a question?_"
empirically is "once or twice" if you're an optimist, and "four or five times" if you're a pessimist. It's a question because of the way US medical insurance is structured; specifically the way Medicaid seems to be required to cover anything FDA approved. In this light, it's not implausible or inappropriate to at least ask the question of "are the FDA being to lax".
As I write this, [worldometers says there have been ~640k deaths in the US](https://www.worldometers.info/coronavirus/country/us/) from Coronavirus. Assuming they could _all_ have been prevented by having a maximally lax FDA, how many aducanumabs would have gotten through as a result? If you believe the numbers above, and are a QALY-value optimist, and you think a lax FDA would have let through even two more aducanumab-level drugs, you've just broken even. Under the same assumption, but more such drugs getting through, you've effectively killed more people than you've saved by pushing the FDA lever to "lax".
The more I look at these numbers, the less I agree with Scott's overall position. It really, _really_ seems to be unfair to summarize the situation as "the FDA is incompetent". The real problem is, regardless of the competence of the FDA, their decisions automatically force people to spend money on anything they find in favor. _That's_ the actual problem; take _that_ away and the FDA arguably does no damage. But forcing the FDA to be laxer in the absence of solving the larger problem seems like a _really_ bad idea under the circumstances.
I've forgotten a lot of the history of HMOs, but someone wanting to make an effort post could get a good start by looking up how HMOs reacted to high-dose chemotherapy.
> The HMO bean counters stubbornly refused to look beyond the black letter of their policy rules. The HMO wanted Dr. Billinsley, who was trained and experienced as a cardiac surgeon -- not a thoracic surgeon trained to perform a radical pleurectomy with interoperative chemotherapy or radiation. Obviously, the Stewarts did not need this kind of stress. Now, in addition to dealing with an "incurable" tumor, the Stewarts had to deal with an inflexible, cold and lethargic HMO bureaucracy.
For the case that broke the dam, look to "Overtreated" by Brownlee, starting around page 120:
Setting the stage with emotional appeals:
> "Bill [Peters] took the microphone and said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' Then he asked the seventy or so breast cancer patients who had accompanied him to the lunch to stand up." ... "'As you look at a woman across the table from you, ask yourself, is the price of this woman's life worth the price of a luxury car?' "
Didn't work:
> ... the publication of clinical trials that would show the treatment wasn't a cure for breast cancer. Even when the evidence was in and it was finally clear that high-dose chemotherapy was no better than standard treatment, some doctors continued to argue that it could benefit some women.
Insurance was forced to pay anyway:
> How is it that a dangerous, highly experimental treatment came to be given to thousands of women before it had been adequately tested? The story ... involves the courts, insurers, hospital administrators, and proselytizing doctors like Bill Peters, as well as the desperate women who were led to believe, by their doctors and the press, that going through the ordeal of a transplant would save them from cancer.
...
> By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley California in 1991, she had learned a thing or two about building a case against health insurers who refused to pay for medical treatments. ... Her new client's name was Ricki ... [who had] an advanced case of breast cancer. When Ricki was first diagnosed three years earlier, she underwent a double mastectomy and chemotherapy. Now the cancer was back, and Ricki was looking to high-dose chemotherapy and a bone marrow transplant as her only hope. But her insurer, a Blue Cross affiliate, did not want to pay for it.
> The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $150,000 and could hit $500,000 if the patient suffered complications. ... Privately, insurers worried that if they agreed to pay for one expensive, experimental procedure, there was no limit to the questionable therapies desperate patients might demand.
...
> [Philipson] bombarded the company with scientific papers and letters from cancer experts saying the procedure was standard practice. ... In the end, the company agreed to pay for Ricki's transplant. Her case was one of the first ever that successfully forced an insurer to pay for a bone marrow transplant for breast cancer. It would not be the last. As Philipson's name circulated among breast cancer support groups, more women came to her, hoping to get their transplants covered by their insurers. Over the next two years, she won three more cases. Then, in 1993, Philipson assisted in a landmark trial that threw open the legal floodgates and forced insurers to begin paying for increasing number of transplants across the country. That year ... Mark Hiepler suyed Health Net on behalf of his sister, Nelene Fox, who has died from her breast cancer while trying to persuade the insurance company to cover a transplant. ... He soon discovered the company doctor who made the decision got a bonus at the end of the year if Health Net saved money. "It sounded terrible" Philipson recalls. ... The [insurer's] defense attorney says 'It's no different from John Deere.' ... The jury comes back and says 'The hell it isn't different.'" ... The jury awarded the Fox family $89 million in damages.
> Ricki didn't live to see the end of the Health Net case. She had survived the transplant, and her cancer had stayed away ... [I]n 1993, it came back more aggressively than ever. She was dead in a matter of weeks. The cure had failed. Philipson was saddened ... but she was too busy with other breast cancer cases to focus on it. Within a year of the Health Net judgment, record numbers of women were filing suit against their insurers. The strategy was always the same. The plaintiffs argued that the insurer was refusing to pay for a treatment was accepted medical practice. Transplant doctors served as expert witnesses, testifying to that effect. Peters himself often served in that capacity, telling the courts, ... "[T]he regiment prescribed is neither experimental nor investigational, as all elements of the treatment as well established and the treatment was over the years proven itself to be an effective cancer therapy."
Much later:
> And the trouble was, high-dose chemotherapy wasn't a cure, even for breast cancer. Alice Philipson knew it by 1995. She had not thought to question the treatment when Ricki died. Medicine, she knew, was an art, and no cure worked every time. But then another former client died, and another. One day, Philipson realized that every woman she knew who had received a transplant was dead. "Nobody got cured," she says. ... "It was a cure that didn't work."
If this thread is still going, does the FDA have “tiers” of how likely a drug is to have some terrible, thalidomide or Vioxx drawback? It seems like monoclonal antibodies should be in “this is extremely likely to be safe” bin. We all make lots of antibodies, chances are, a new monoclonal antibody won’t cause birth defects. Seems speeding their approval would be a net plus.
Is there a word for drugs that are things you already produce, like steroid hormones or dimethyl tryptamine? Seems like these would have fairly predictable effects. Though evolutionary logic implies that they are optimized, they are optimized for people with very different lives. There could be low hanging fruit here. The harms are more or less predictable, and the FDA should approve easily, but not as as easily as yet another Amat.
Other drugs are variations on a theme of some existing drug with well understood pharmakinetics and downsides, THE #MeToo drugs, These seem less certain than the top two classes, though only a methyl group separates terrible methanol from wonderful ethanol.
Then there are things like “this is a variant of a drug with terrible side effects, but great function. We’ve tweaked it to try to make it safer. These are obviously riskier, and the FDA should be really cautious.
As a real example, this year’s flu vaccine antigens will not be put through a decade of testing. They are minor variants of things that have been extensively tested, interacting with well understood (lol, but kinda) physiology.
If the FDA can allow new flu antigens without a Brazilian dollars in testing, maybe there are other pharmaceuticals where this applies? They also have a readily-approved category for medical devices that are “substantially similar” or some such, I forget the wording, to things that are already approved.
Lastly, there are other first world and upper-tier developed-not-wealthy nations. Presumably they differ somewhat in what is approved and when. How does the FDA compare to Euro-FDA, Moscow-FDA, etc? Are drugs usually approved overseas first? How often? Of those that are approved somewhere else, but either approved here later or never, how often do the furriners have to pull the drug because of lack of efficacy or safety?
If other modern countries approve quickly, cheaply, and with few hiccups, that would be strong evidence that the FDA process is severely flawed. If other countries just follow America’s lead, then that does not help much.
"This is an interesting point. We sometimes see politicians “cutting in line” and managing to get advanced drugs that the FDA hasn’t yet made available to the general public. We usually interpret this as unfair privilege, and I think that’s a completely accurate interpretation. But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us."
This seemed pretty obvious to me. I'm surprised this idea didn't come more easily to some people. Perhaps they are more easily influenced by the news slant
This is why it was a good for politicians (Trump etc) to receive the good stuff. It might even speed the equivalent of FDA approval. We aren't yet at the stage where only politicians would benefit, though we are getting there
Some people are more capable, faster, intuitive, and natural with certain modes of thought, and, vice versa, others may have talent in other domains.
I'm glad you're making an effort to be fair and correct
Does the USA Health system have an equivalent of the UK's NICE ? If only for the government-funded parts of the system?
Dansuul says:
"a scientific organization (which the FDA is)"
Is that the primary goal, though? To do "Science"? Seems to me like it has a relatively large "cost-benefit analysis" role as well, which, as the voting citizens of the country that created the FDA, and who will bear both the costs and benefits of those analyses, I'm not sure it's the "man on the street" unjustly intruding on the FDA's "scientific" jurisdiction. It seems more like the FDA unjustly (and without the relevant expertise) intruding on citizens' implicit demand that their public health agencies serve their best (again, implicit in "best" is some kind of cost/benefit analysis) interests.
Thanks for linking to my piece. An interesting problem you bring up in the Axsome story is effectively a public goods provisioning problem: how do we incentivize good trials for generic drugs for repurposing?
Good trials for generic drugs provide the public good of accurate information on a clinical question, and then anyone can use that information.
Some ideas to make this better, ignoring novel drugs to simplify:
1. making clinical trials cheaper per patient. I don't know enough about this to have specific proposals, but it is something I'm eventually going to learn more about. Tentatively: something involving substantial reductions in the power of IRB's and using tech to make multi-site trials easier.
2. prizes for researchers who successfully discover a new use for a generic drug and prove it with a trial. This exists informally, in that a highly cited research trial paper will give you career capital and speaking invites.
3. Something involved prediction markets and clinical trial outcomes? Maybe people who are good predictors of successful drug repurposing should get $$ to choose more drug repurposing candidates?
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long
I doubt that when people support restrictions on drugs and stuff, they are thinking of *them* not being allowed to get something they want. They think of other irresponsible or stupid people. I can imagine supporting restrictions on an unsafe drug yet feeling it's an unfair privilege that someone specific gets to choose to circumvent them.
Even supposing Aducanumab doesn't treat Alzheimer's, if it truly is an anti-amyloid, it should have some beneficial effect. As you wrote earlier, doctors should be allowed to write prescriptions for it (since it seems safe), but insurance shouldn't have to pay for it for AD (since it doesn't seem effective against AD). Under our current system, a drug that might be useful against disease X will be banned forever if it's first tested against disease Y.
The $100 billion/year estimate from my blog post is a high end, and after writing that post, the FDA took a step back and restricted the indication to only early-stage patients. Still, it has the potential to be extremely costly.
Whenever you write about the FDA I can't help but think of the FAA. Drug companies have no incentive to sell dangerous drugs. Just like Boeing doesn't have an incentive to have planes suddenly plummet to the ground killing 100s. Boeing might not but individual Boeing employees certainly do. And not long after we started relaxing regulation those individual employees started to run amok. I don't see why we wouldn't' see the same issue with reduced regulation of Pfizer that we saw with Boeing.
I think the criticism raised by Charlie (and Kevin Drum, and others) just relies on... an unnatural reading of things? If you think a particular government agency should not exist -- if you think that the function it is supposed to perform is one that should not be performed, and therefore no agency should exist to perform it -- that would to my mind normally be described as you being "against" that government agency, and that is how I would normally someone interpret saying they are "against" a particular agency or that that agency is bad. I don't know why one would read it instead as a comment on the quality of the particular staff? I would normally think of government agencies primarily in terms of their function, not the particular people who happen to be executing that function...
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us.
I think there's an internally consistent position where the observer doesn't acknowledge that the drugs are being delayed too long, and just objects to the actor breaking the rules. Basically, in this framework whether the treatment works is moot, the objection is just about fairness and/or the morality of rule-following.
(Not supporting this position, in particular; just providing an observation for why most people don't think politicians are heroes when they cut the line, and also the criticism Biden is trying to pre-empt with his statement that he has to wait for FDA approval before taking his booster.)(
Andrew Gelman does a thing where he writes his content and puts them in a queue to post 6 months-ish later. Maybe that's an option foryour less time sensitive pieces.
> "I probably shouldn’t choose an acronym that nobody will understand until I explain it to them"
Is there any other kind?
The final example about bupropion-dextromethorphan highlights how misguided it is to solely fund clinical trials through the promise of patent-protection. Presumably the government could make a guess at how likely this would be to work, how valuable it would be if it did, and then the government could have people bid on the contract to run a clinical trial.
Does this happen? Does the government, or anyone, fund clinical trials with the condition that anyone can make the drug if it is approved? The Ketamine example fits here too it seems.
> a YIMBY analogy by dubbing my position YIMCS (“Yes In My Circulatory System”)
Call it YIMBI: Yes In My Body Innards!
I'm kind of baffled how you can invoke the "normal knowledge that normal people use" as some kind of accessible source of information when nobody has the first clue how to gather or assess that. Normally among pundits it operationally reduces to "what me and the people I know/read/like think" but that leads straight to the Pauline Kael effect, and some of the unpleasant divisions between "expert opinion" and what vast swathes of regular folks think that we see today on any number of issues.
If nothing else, consider that the "knowledge of normal people" about which we have cared deeply for several centuries is "who should run the country?" and for this purpose we have this vast apparatus of elections, at various levels, terms of various sizes, representation or not, not to mention polling and focus groups and prognostication -- and yet we *still* are routinely surprised by the outcomes, and debate furiously just how genuinely representative they are.
What hope is there of actually discovering what the "knowledge of normal people" actually is on the question of whether Drug X should/should not have been approved, or whether the FDA should be "stricter" or "looser" in general, for various definitions of "strict" or "loose?"
I feel like all you're really saying that's 100% defensible here is that given time, a consensus will emerge, and using the clarity of hindsight we will all be able to say decision Z or T of the FDA was right/wrong or hasty/slow. But noting that hindsight is easier and more accurate than foresight is rather a truism and (barring the invention of time machines) gives no clue on how to improve the situation going forward.
I find a rather different interpretation of Nestor's shuffle about the FDA on (the ever inerrant) Wikipedia: https://en.wikipedia.org/wiki/John_Nestor ::
""On March 19, 1972, the FDA reassigned Nestor to its Office of Compliance, as part of a reorganization in which Civil Service doctors were replaced as drug approvers by consultants who were often affiliated with commercial companies. Nestor began a grievance proceeding. A review panel determined that senior FDA officials gave "misleading" testimony against Nestor and concluded that Nestor was due an apology and appropriate duties.""
By analogy, consider criminal trials.
The final decision is made by a bunch of men-on-the-street: a jury. We decided that, even though justice system officials know a lot more about crime, it is too difficult to get rid of their inherent biases, so a group of men-on-the-street does better.
If we take this analogy even further, we could have juries for the FDA. The experts can make their arguments, but the decision would ultimately be decided by a group of men-on-the-street. Random people would get called to make decisions that effect the life and death of their fellow citizens.
While I think that this is interesting, I'm not convinced that it is a good idea. The FDA is often too slow to approve good drugs and the jury system is not exactly known for its speed.
I was also a bit disappointed in the post and subsequent discussions elsewhere, because the question on what influenced the Aducanumab decision is not really addressed. If the FDA is so risk averse, why authorize this drug and risk reputational damage if it turns out that it doesn't work? Scott kind of gestured at "some decisions will randomly stray from the decision mean in the other direction", but I find this terribly unconvincing, given that the FDA's scientific advisory committee was firm in its rejection. Plus, other bloggers have alleged regulatory capture by big companies, which seems more explanatory.
I feel like a model of how the institution works beside the short and imho simplistic "public perception incentivizes risk aversion" story should be required before condemning an institution so heavily.
> I don’t want to never write posts when I’m angry, because those tend to be the posts people like the most, and I think they get things done in terms of convincing people of important things.
This is a well known phenomenon. Outrage sells. But that doesn't make it good journalism.
"Then someone finally realized that the jam was caused by a single citizen, one who commuted in the far left lane, driving exactly the speed limit for miles on end."
It distresses me that this was seen as improper behaviour. If the speed limit is too low, raise the speed limit - don't complain about people obeying the law.
The Alzheimers drug you're forgetting is memantine, a drug I'm taking right now for my ADHD with great success!
From a consequentialist perspective, why is it better to let ten guilty men go free rather than convicting one innocent rather than having each kind of error be equally likely?
I've spent the last month and a half buried in the Alzheimer's Disease literature due to a likely case in a family member (and ironically, for this reason I must apologize in advance that I won't have time to engage in a detailed back and forth here). I think the evidence for both the amyloid cascade hypothesis and the efficacy of aducanumab is much stronger than is being characterized by most comments here.
It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β being the cause?" However, we have strong evidence that it's the cause.
In fact, in a subset of cases, we have smoking gun evidence that amyloid is the cause: certain mutations or duplications of the APP (amyloid precursor protein), PS1 & PS2 (presenilin 1 & presenilin 2, parts of the enzyme γ-secretase involved in cleaving APP to make amyloid-β) genes guarantee that one gets Alzheimer's, and typically quite early (between the age of 30 and 60 for the onset of clinical symptoms). We have mapped out the structure and function of the corresponding proteins extremely well, and we know how, functionally, those specific mutations affect the behavior of those proteins: either to increase total amyloid-β production, or to increase production of the specific peptide (amyloid-β 42) implicated in Alzheimer's Disease. [1] I am not aware of another plausible effect of those mutations besides this one, and the mutations guarantee you get Alzheimer's Disease.
Now, this represents approximately 1% of Alzheimer's cases, the so-called autosomal dominant variety, so it's a priori conceivable that the other cases have a different cause. In the remaining cases, we have evidence consistent with an impairment of amyloid clearance mechanisms, however that evidence is more circumstantial and in some cases compatible with other hypotheses. But the disease looks like exactly the same disease as the 1% of cases in which we have smoking gun evidence of amyloid being the cause: we still see the same progression of amyloid-β, followed by a progression of hyperphosphorylated tau, followed by neurodegeneration and cognitive decline, and with the same sequence of brain regions and cognitive symptoms.
Suppose there are two bank robberies. In the first, we have smoking gun evidence the culprit: a video camera showing a guy getting out of his car, with a clear image of his face and the license plate, and then of him walking into the bank, pointing a gun at the teller, the teller handing over a bag of cash, and him walking out with that bag of cash. In the second: we also have footage of the same guy and the same license plate at the scene of the crime, but an occlusion prevents clear footage of the exact moment of the robbery. However, the robbery occurred in the same town and on the same day, and eyewitness reports are that the robbery was conducted in basically the same manner. In that case, is there much question as to the identity of the robber?
***
As for the track record of amyloid-targeting therapy for Alzheimer's, I think it's fair to say that it's been less successful than hoped for but that also:
1) There has been a mixture of benefit and no effect; rather than the mixture of benefit, no effect, and harm which you'd expect to see if the drugs really were useless. For example:
A) The recent phase 2 trial of the similar drug donanemab showed success in its primary endpoint of reducing cognitive decline. [2]
B) With respect to aducanumab [3], the first phase 3 trial, EMERGE, passed its primary endpoint and all pre-designated secondary cognitive endpoints, with p-values for the high dose arm between 0.0006 and 0.0493 (0.0120 on the primary endpoint), and effect sizes ranging from an 18% slowdown to a 40% slowdown in cognitive decline (22% on the primary endpoint).
The second phase 3 trial, ENGAGE, did not show statistically significant benefits on any pre-designated endpoints, but the effect sizes still ranged from -3% to 18% (-2% on the primary endpoint). So given only pre-designated endpoints, we have two trials, one of which showed a clear benefit, and the other of which showed no effect, or very slight benefit if we give some weight to pre-designated secondary endpoints. From a Bayesian perspective, this has to be seen as weak evidence of benefit.
Furthermore, the post-hoc analysis, while always to be taken with a large serving of salt, was not done arbitrarily. Rather, they looked specifically at the subpopulations which received higher dosages, an a priori plausible sub-population within which to expect higher efficacy.
Lastly, both trials showed a substantial and significant (p < 0.001 in EMERGE, p < 0.01 in ENGAGE) reduction in phosphorylated tau, a neuropathology both regionally and chronologically highly correlated with volume loss and cognitive decline in Alzheimer's Disease.
2) The amyloid cascade hypothesis offers explanations for past failures of amyloid-targeting therapy, for example poor target specificity (some therapies such as semagacestat were not proven to engage amyloid in the first place, and were also known to produce other toxic effects unrelated to reduction in amyloid), deficient screening of participants (in some cases, patients were selected only for cognitive symptoms and not for the presence of amyloid, thereby reducing statistical power), and not intervening early enough (no one believes amyloid is the main proximate cause of neurodegeneration, so if you intervene late, it might be too late to prevent the cascade of problems it's believed to cause).
By contrast, I'm not aware of alternative hypotheses which even offer a story which can account for the known facts, such as the aforementioned evidence in the APP and PS1/PS2 genes.
***
For those interested in learning more, a good starting point for the current state of the science is [4]. A more up-to-date and comprehensive review paper is [5].
[1] Haass et al (2012). Trafficking and proteolytic processing of APP
[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease
[3] Cohen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease
[4] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years
[5] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
"The one part of this I want to ask about is the “aren’t really any [other] Alzheimers drugs”. There’s galantamine, rivastigmine, donepezil, and maybe some others I’m forgetting. These don’t work very well (or maybe at all). But aducanumab also doesn’t work very well or maybe at all, so why is everyone treating it as so unprecedented?"
Those are cholinesterase inhibitors (NMDA-receptor blockers like memantine are also used against Alzheimer's). The effect on cognition for cholinesterase inhibitors is not very good, NNT around 12, though still better than aducanumab, even if you take biogen's data at face value. However, cholinesterase inhibitors and NMDA-receptor blockers do not treat the underlying disease process of Alzheimer's disease. The hope with anti-amyloid drugs like aducanumab that they would actually be disease-modifying.
> That’s fair. I’ve seen some studies by economists saying that “defensive medicine” and fear of malpractice lawsuits doesn’t seem to raise costs too much in the US - but every doctor I know (including myself) feels like they do.
The studies I have seen were doing some intra-US comparison (e.g., VA vs. non-VA bc VA doctors cannot be as easily sued; or the impact of changes to the rules in Texas) and they do find some limited effects. However, none of these studies have a true counter-factual. VA doctors may themselves be more protected from lawsuits, but they are still in an environment where their colleagues from other institutions have instituted all sorts of "best practices," which they are still socially pressured into performing (I assume non-mormons end up drinking less than they would in New York if they move to Utah; which is still because of the LDS church).
So, the studies falsify the notion that the problem is doctors performing an explicit cost-risk legal analysis and then deciding "defensive medicine" is worth it. They do not falsify a fuzzier idea that medical norms are very heavily influenced by the legal environment, but in a way that responds slowly to changes of incentives and does not respect institutional boundaries. Of course, this hypothesis has the benefit of being hard to falsify, but "long-established legal norms lead to a cultural framework of behaviour that persists when those norms are removed" is a very common pattern in history.
Total non-expert here - isn't there a case that amyloid plaques are a cause and/or symptom of aging, and so drugs that remove them could increase lifespan, even if they don't help with alzheimer's?
About politicians either being privileged by the ability of getting the drugs in advance or heroes for testing them, I think there is a way of making the distinction: how do they think about it themselves? I suspect none of them consider it taking a heroic risk, and therefore that should be our point of view too.
>But the cost-benefit analysis is still heavily in favor of the drug, as it is very safe, molecularly effective, and with no alternatives, in a very widespread and destructive disease. The only cost being some people paying money for a drug that won't help them
I think it's worth pointing out that it's an artifact of our local economic system (maybe not capitalism generally, but the specific model of capitalism plus regulations plus government payments plus etc that governs our health system) that creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
Because we only know how to value things through the process of supply and demand, we build the entire economy around the maintenance of artificial scarcity in cases where production is cheap and supply could easily be near-limitless, and grant the right to monopoly pricing to all kinds of actors in order to encourage them to keep acting.
I get that we've let the system fall into this situation for a reason - we want to encourage creators to create things, pharmaceuticals especially can be a huge and expensive gamble so you need a big payoff the one in X times it works, etc. But I think it's a deficiency of our system that we provide this incentive by using artificial scarcity to *deny medical treatments that are extremely cheap to administer* to tons of people through outsized pricing.
I think your last point requires a whole lot more evidence to be believable. Sure, everyone knew that Al Capone was a criminal, but also everyone knew that the Central Park Five were guilty, that Airborne was an effective thing to take when you get a cold, and that deoxygenated blood is blue. Everyone knows lots of things that are totally wrong. If you want to claim that everyday reasoning is better than institutional decisionmaking, you can’t just point to a single case where the common people got it right and the institution got it wrong, you need some evidence that that is consistently true over a large body of decisions.
Bupropion-dextromethorphan: I was curious so I bought some DXM from Dollar Tree (where it is 6x cheaper than at CVS) to see whether it does anything in addition to bupropion, but at least I didn't notice anything. (Apparently DXM has some abuse potential so the register makes an embarrassing loud beep when it is scanned.) Interestingly, it seems like the US is the only country where DXM is sold over-the-counter, so it might end up being slightly less trivial to get around Axsome in other countries.
> But that’s not what happened. Instead, the FDA sent Axsome a letter on July 30 saying that they found “deficiencies” that prevented them from moving forward with the approval. What are those deficiencies? Oh, the FDA doesn’t say. They don’t even give a hint. They just told them to hang tight until August 22.
> I remember the FDA rejected an EpiPen competitor for “certain major deficiencies” without giving more information (at least not to the public). EpiPen took advantage of this to quadruple their prices, although the FDA did eventually approve the competitor a few years later.
I really hope the SEC is taking a good hard look at the trades that happen around FDA members...
The thing that puzzles me about all this discussion is that the problem and solution seems clear and simple, yet Scott hasn't presented it in a clear and simple way.
Simply put, Scott isn't opposed to anyone at the FDA, he just wants some elements of the legal framework around the FDA to be changed. The obvious political slogan: "support FDA reform!"
Specifically, certification of safety needs to be separate from certification of efficacy, so that doctors can prescribe safe drugs even if they aren't proven to work.
The devil's in the details of course, so why not shift the conversation to those details? One issue that jumps to mind is that if a drug is shown to be safe in average healthy people, that doesn't mean it's safe in the sick population it's meant for, so even the safety certification may need to be scoped to a subpopulation.
Scott,
Want an intern? My previous employers have commended my ability to intuit instructions and take initiative, so you don't need to be too concerned about communicating. I have a few years of experience in research, writing, and editing, mostly for student publications.
If you're interested, email me at t [dot ] amarchana640 [at] gmail [dot] com.
I presume someone else has done this, but I need the exercise; in the spirit of doing things with made-up statistics.
1. The cost of aducanumab to the US health-care system is potentially $100B/year (as per [this](https://denovo.substack.com/p/a-travesty-at-the-fda#footnote-1), because it costs $56k/year per patient, and on approval is mandatorily covered by Medicaid, with the assumption that 1.8 million patients would be treated).
2. According to [a 2008 study](https://pubmed.ncbi.nlm.nih.gov/18362813/) (the highest in [the first link](https://www.nytimes.com/2020/05/11/upshot/virus-price-human-life.html) I managed to find in a cursory googling), "Our base case analyses suggest that plausible lower and upper bounds for a cost-effectiveness decision rule are $183,000 per life-year and $264,000 per life-year, respectively." (incidentally,this means that aducanumab would be a steal at $56k/year if it worked)
In order to be worth it at the above exchange rate, aducanumab would need to save 378,787 lives ($100B/year divided by $264k/year (are years and QALYs fungible in this way? Do we discount actual years somehow, especially given that this medication is likely to be administered near end-of-life?)). If you're more pessimistic about the value of a QALY, it's more like 546,448 lives. If you're _extremely_ pessimistic about it, more like 2,000,000.
If you believe that aducanumab will actually save close to 0 lives, then the answer to
> "So how often do you have to save hundreds of thousands of lives before it’s worth the risk of occasionally also permitting a dud medication that “offers false hope”? _How is this even a question?_"
> - [Scott A.](https://astralcodexten.substack.com/p/adumbrations-of-aducanumab)
empirically is "once or twice" if you're an optimist, and "four or five times" if you're a pessimist. It's a question because of the way US medical insurance is structured; specifically the way Medicaid seems to be required to cover anything FDA approved. In this light, it's not implausible or inappropriate to at least ask the question of "are the FDA being to lax".
As I write this, [worldometers says there have been ~640k deaths in the US](https://www.worldometers.info/coronavirus/country/us/) from Coronavirus. Assuming they could _all_ have been prevented by having a maximally lax FDA, how many aducanumabs would have gotten through as a result? If you believe the numbers above, and are a QALY-value optimist, and you think a lax FDA would have let through even two more aducanumab-level drugs, you've just broken even. Under the same assumption, but more such drugs getting through, you've effectively killed more people than you've saved by pushing the FDA lever to "lax".
The more I look at these numbers, the less I agree with Scott's overall position. It really, _really_ seems to be unfair to summarize the situation as "the FDA is incompetent". The real problem is, regardless of the competence of the FDA, their decisions automatically force people to spend money on anything they find in favor. _That's_ the actual problem; take _that_ away and the FDA arguably does no damage. But forcing the FDA to be laxer in the absence of solving the larger problem seems like a _really_ bad idea under the circumstances.
I've forgotten a lot of the history of HMOs, but someone wanting to make an effort post could get a good start by looking up how HMOs reacted to high-dose chemotherapy.
By luck, a web search found exactly what I wanted: someone angry (looks like a lawyer) that the HMO *refused* to cover chemotherapy. https://www.worthingtoncaron.com/Patient-Stories/HMO-Thwarts-Treatment-Plan.aspx
> The HMO bean counters stubbornly refused to look beyond the black letter of their policy rules. The HMO wanted Dr. Billinsley, who was trained and experienced as a cardiac surgeon -- not a thoracic surgeon trained to perform a radical pleurectomy with interoperative chemotherapy or radiation. Obviously, the Stewarts did not need this kind of stress. Now, in addition to dealing with an "incurable" tumor, the Stewarts had to deal with an inflexible, cold and lethargic HMO bureaucracy.
Today, the track record of high-dose chemotherapy is probably overall negative. https://blogs.scientificamerican.com/cross-check/cancer-medicine-is-failing-us/
For the case that broke the dam, look to "Overtreated" by Brownlee, starting around page 120:
Setting the stage with emotional appeals:
> "Bill [Peters] took the microphone and said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' Then he asked the seventy or so breast cancer patients who had accompanied him to the lunch to stand up." ... "'As you look at a woman across the table from you, ask yourself, is the price of this woman's life worth the price of a luxury car?' "
Didn't work:
> ... the publication of clinical trials that would show the treatment wasn't a cure for breast cancer. Even when the evidence was in and it was finally clear that high-dose chemotherapy was no better than standard treatment, some doctors continued to argue that it could benefit some women.
Insurance was forced to pay anyway:
> How is it that a dangerous, highly experimental treatment came to be given to thousands of women before it had been adequately tested? The story ... involves the courts, insurers, hospital administrators, and proselytizing doctors like Bill Peters, as well as the desperate women who were led to believe, by their doctors and the press, that going through the ordeal of a transplant would save them from cancer.
...
> By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley California in 1991, she had learned a thing or two about building a case against health insurers who refused to pay for medical treatments. ... Her new client's name was Ricki ... [who had] an advanced case of breast cancer. When Ricki was first diagnosed three years earlier, she underwent a double mastectomy and chemotherapy. Now the cancer was back, and Ricki was looking to high-dose chemotherapy and a bone marrow transplant as her only hope. But her insurer, a Blue Cross affiliate, did not want to pay for it.
> The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $150,000 and could hit $500,000 if the patient suffered complications. ... Privately, insurers worried that if they agreed to pay for one expensive, experimental procedure, there was no limit to the questionable therapies desperate patients might demand.
...
> [Philipson] bombarded the company with scientific papers and letters from cancer experts saying the procedure was standard practice. ... In the end, the company agreed to pay for Ricki's transplant. Her case was one of the first ever that successfully forced an insurer to pay for a bone marrow transplant for breast cancer. It would not be the last. As Philipson's name circulated among breast cancer support groups, more women came to her, hoping to get their transplants covered by their insurers. Over the next two years, she won three more cases. Then, in 1993, Philipson assisted in a landmark trial that threw open the legal floodgates and forced insurers to begin paying for increasing number of transplants across the country. That year ... Mark Hiepler suyed Health Net on behalf of his sister, Nelene Fox, who has died from her breast cancer while trying to persuade the insurance company to cover a transplant. ... He soon discovered the company doctor who made the decision got a bonus at the end of the year if Health Net saved money. "It sounded terrible" Philipson recalls. ... The [insurer's] defense attorney says 'It's no different from John Deere.' ... The jury comes back and says 'The hell it isn't different.'" ... The jury awarded the Fox family $89 million in damages.
> Ricki didn't live to see the end of the Health Net case. She had survived the transplant, and her cancer had stayed away ... [I]n 1993, it came back more aggressively than ever. She was dead in a matter of weeks. The cure had failed. Philipson was saddened ... but she was too busy with other breast cancer cases to focus on it. Within a year of the Health Net judgment, record numbers of women were filing suit against their insurers. The strategy was always the same. The plaintiffs argued that the insurer was refusing to pay for a treatment was accepted medical practice. Transplant doctors served as expert witnesses, testifying to that effect. Peters himself often served in that capacity, telling the courts, ... "[T]he regiment prescribed is neither experimental nor investigational, as all elements of the treatment as well established and the treatment was over the years proven itself to be an effective cancer therapy."
Much later:
> And the trouble was, high-dose chemotherapy wasn't a cure, even for breast cancer. Alice Philipson knew it by 1995. She had not thought to question the treatment when Ricki died. Medicine, she knew, was an art, and no cure worked every time. But then another former client died, and another. One day, Philipson realized that every woman she knew who had received a transplant was dead. "Nobody got cured," she says. ... "It was a cure that didn't work."
If this thread is still going, does the FDA have “tiers” of how likely a drug is to have some terrible, thalidomide or Vioxx drawback? It seems like monoclonal antibodies should be in “this is extremely likely to be safe” bin. We all make lots of antibodies, chances are, a new monoclonal antibody won’t cause birth defects. Seems speeding their approval would be a net plus.
Is there a word for drugs that are things you already produce, like steroid hormones or dimethyl tryptamine? Seems like these would have fairly predictable effects. Though evolutionary logic implies that they are optimized, they are optimized for people with very different lives. There could be low hanging fruit here. The harms are more or less predictable, and the FDA should approve easily, but not as as easily as yet another Amat.
Other drugs are variations on a theme of some existing drug with well understood pharmakinetics and downsides, THE #MeToo drugs, These seem less certain than the top two classes, though only a methyl group separates terrible methanol from wonderful ethanol.
Then there are things like “this is a variant of a drug with terrible side effects, but great function. We’ve tweaked it to try to make it safer. These are obviously riskier, and the FDA should be really cautious.
As a real example, this year’s flu vaccine antigens will not be put through a decade of testing. They are minor variants of things that have been extensively tested, interacting with well understood (lol, but kinda) physiology.
If the FDA can allow new flu antigens without a Brazilian dollars in testing, maybe there are other pharmaceuticals where this applies? They also have a readily-approved category for medical devices that are “substantially similar” or some such, I forget the wording, to things that are already approved.
Lastly, there are other first world and upper-tier developed-not-wealthy nations. Presumably they differ somewhat in what is approved and when. How does the FDA compare to Euro-FDA, Moscow-FDA, etc? Are drugs usually approved overseas first? How often? Of those that are approved somewhere else, but either approved here later or never, how often do the furriners have to pull the drug because of lack of efficacy or safety?
If other modern countries approve quickly, cheaply, and with few hiccups, that would be strong evidence that the FDA process is severely flawed. If other countries just follow America’s lead, then that does not help much.
"This is an interesting point. We sometimes see politicians “cutting in line” and managing to get advanced drugs that the FDA hasn’t yet made available to the general public. We usually interpret this as unfair privilege, and I think that’s a completely accurate interpretation. But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us."
This seemed pretty obvious to me. I'm surprised this idea didn't come more easily to some people. Perhaps they are more easily influenced by the news slant
This is why it was a good for politicians (Trump etc) to receive the good stuff. It might even speed the equivalent of FDA approval. We aren't yet at the stage where only politicians would benefit, though we are getting there
Some people are more capable, faster, intuitive, and natural with certain modes of thought, and, vice versa, others may have talent in other domains.
I'm glad you're making an effort to be fair and correct