Nearly 400 medical devices, procedures and practices found ineffective in study
sciencealert.com
sciencealert.com
Article: Efficacy of infant simulator programmes to prevent teenage pregnancy: a school-based cluster randomised controlled trial in Western Australia
Summary: The infant simulator is an example of persuasion technology or captology, where the use is intended to prevent teenage pregnancy.26 Their use is widespread in developed countries27 and is expanding into low-income and middle-income countries.28 However, in this study done in Australia, the infant simulator-based VIP program did not reduce teenage pregnancy. In fact, girls in the intervention group (n=1,267) were more likely to experience a birth (8% vs. 4%; HR=1.35; 95% CI=1.06-1.73; p=0.016) or an induced abortion (9% vs. 6%; HR=1.33 (1.00-1.78; p=0.049) than those in the control group (n=1,567) before they reached 20 years of age. This is a reversal of the practice of infant simulator programs to prevent teenage pregnancy.
A school district I contract with purchased some of these "infant simulators" a few years ago. I shared spooky photos of them entombed in foam in their storage cases (evoking visions of racks of "hibernating" astronauts from sci-fi) with my wife. She made a general observation that she thought some fraction of teenage girls would feel encouraged to have a baby after time w/ the infant simulator. Guess there was some truth to that intuition after all.
- child gets pregnant
Then
- parents find out, recommend terminating pregnancy
- friends find out, recommend terminating pregnancy
- doctor finds out, recommends terminating pregnancy (“you are not ready for this”)
- unpleasant side effects set in, child decides she is not ready to handle pregnancy, or
- reality sets in, child decides she is not ready to be a mother/wants to finish school
- boyfriend abandons her
Basically increasing the number of pregnancies will necessarily increase the number of abortions.
* Fixed a bug in an existing "legacy system", deployed remotely without your knowledge. You have no logs or debug information, but you can speculate on cause and try it in small simulated / test environments (e.g. rodents). By introducing this fix you would also be changing the system in unknown ways.
* You only have a vague idea of how the code in the OS for this system works, your fix doesn't even change the code. Your only mechanism of change is injecting some foreign JS into a webform to cause ripple effects on the system for the user, meanwhile the system is setup to try to stop / avoid such "attacks" and will try to undo your fix if it can be detected by the system's "AI".
* if your fix fails in production for even one user, you may lose millions and potentially go jail, that person may die.
* You get one shot to release it to the public, after go-live it basically has to work or everything was for nothing. There is no "push this fix and everything gets better", even one small change is a complete restart (new molecule == new drug).
* If you accidentally release any information about the users, or lose their data, you lose millions and potentially go to jail.
* This software will take 10 years, a handful of scientists, a lab, some lawyers, lobbying, and a few billion dollars to make.
* Every user using your software will be on an entirely unique stack, processing all kinds of data in tandem with your software, and will not follow directions. Some will even have lots of other bugs in the system that are unrelated to your fix.
> The ability to identify medical reversals [practices that have been found, through randomized controlled trials, to be no better than a prior or lesser standard of care] and other low-value medical practices is an essential prerequisite for efforts to reduce spending on such practices. Through an analysis of more than 3000 randomized controlled trials (RCTs) published in three leading medical journals (the Journal of the American Medical Association, the Lancet, and the New England Journal of Medicine), we have identified 396 medical reversals. Most of the studies (92%) were conducted on populations in high-income countries, cardiovascular disease was the most common medical category (20%), and medication was the most common type of intervention (33%).
The original study can be found here: https://doi.org/10.7554/eLife.45183.001
https://elifesciences.org/articles/45183/figures#supp2
I don’t know if this is a permalink due to the hash parameter but I’ll try:
https://elifesciences.org/download/aHR0cHM6Ly9jZG4uZWxpZmVzY...
Modern medicine can't even agree in broad strokes on the proper ratio of macronutrients for humans. We give them too much power when we uncritically accept their judgement on any given treatment. For me, prayer would have no effect. For others it could be a life saving intervention. The efficacy of a particular molecule for a particular patient isn't much easier than that to determine. Therefore decision making should be as decentral and computationally parallel as we can make it.
Nothing is stopping decentralized decision making, you just need to market whatever non-effective but safe remedy you're selling as a food supplement, a tea or whatever. You just can't advertise that it's a drug.
Unfortunately, this is false. The FDA will still intervene in situations where it doesn't like what you're doing even if you don't advertise your work as a drug, medical procedure, or as having any particular efficacy.
https://www.technologyreview.com/s/603530/a-biohackers-plan-...
On another note, see the sensor pads story here: http://www.fdareview.org/devices.shtml
"We rarely get to try products that the FDA fails to approve, and we never get to try products that are never brought into existence because FDA rules and regulations have made research and development uneconomic. As a result, the public remains ignorant of the true costs of FDA power."
But yes, the FDA aren't complete morons. If you're selling genetically modified dogs you're obviously selling the results of an unapproved medical procedure to the public, even if all you say about it is that you're selling fluffy friends to the public.
The second story you've linked to is one where someone was clearly trying to sell a replacement for breast examinations to the public.
I've never heard about the "sensor pad" before, and there's probably a good case to me made for such a device being more beneficial than not, and that the FDA made a mistake etc.
But I think their process is more sound than not in demanding clinical trials of these sorts of products. This is because in practice people will use them as a replacement for going to their physician, so having some DYI breast cancer scanning kit doesn't just need to be harmless in isolation. You also need to consider the increased death rate from people not going to their doctor for an examination as a result.
This is completely false. Proof: homeopathy and chiropractic are very popular and still on the market.
How do you handle situations where the provider doesn’t know/care which is best either and just chooses the intervention that was the most heavily marketed to them?
Why do we see new patent drugs replace the “old and boring” generics without any proven efficacy benefit?
It's not perfect, there are still abuses, but it's nowhere the circus we see in the US.
SSRIs being top of the list of drugs that "sometimes work sometimes don't" I think are a good example of why the FDA rubber stamping efficacy are still good. I'm not convinced I'd had those sheets of paper if drug makers had the run of the market.
I've never actually seen evidence that a "free market" (i.e. drug market with no FDA) results in a better world for consumers, unilaterally.
This may work if the decentralized decisions were made based on results. But they are often made based on profits and there is a lot of money to be made in doing useless therapies.
However, I do agree that it's a difficult topic, in general. Off-label drug uses is one example.
I have no problem with the FDA as a certification agency, whether they're certifying safety or efficacy or both. I do have a problem with their approval being mandatory in order for the product to be sold. If their stamp of approval means anything—if lack of FDA approval implies that a product is unsafe and/or ineffective—then doctors, insurers, and patients will all look for that approval and avoid products without it. The problem is that "safe and effective" is neither necessary nor sufficient to obtain FDA approval.
The existence of uncertified, or just differently certified, options should also put some downward pressure on the prices of the certified options compared to the current monopoly environment. When everyone has to obtain FDA approval there is no incentive to minimize the cost and plenty of reason for established incumbents to make approval as expensive as possible to lock out any potential competition. You can always push for "more safety" above and beyond the level of risk reasonable people would be willing to accept.
Downward pressure is nice from unapproved/unknown stuff, but any kind of price stratification inevitably leads to harm for those who are at risk the most.
People already order generics on "ebay" and a lot of those shipments are seized at customs, etc.
We know why prices are high in the US. And that's not because the need to go through FDA approved trials, but because of patents and because every other developed market got their shit together and negotiates in bulk with suppliers. (Thus the US market is what pays for most of R&D.)
> FDA approval there is no incentive to minimize the cost
Do you mean the cost of going through the approvals? I think it should be largely subsidized (and ratio should be computed from a reputation score of the requester - of course using the lower bound of the Wilson score interval, or something similarly fast converging).
> established incumbents to make approval as expensive as possible
True. But there are quite a lot of newcomers. VC money is pouring into medical tech. (Though usually small promising research projects [and sometimes the labs themselves too] are bought up wholesale by bigger companies that then do the preclinical and clinical trials and the FDA approval.) This of course incentivizes incumbents to consolidate.
Keeping the approval sane is largely the job of watchdog organizations (NGOs, other civil advocacy groups, expert groups). Of course filtering the lobbyist bullshit should be the job of everyone's beloved dear leaders. The incentives are not stacked in the common man's favor, as we already know it for some time.
Pushing for safety is of course the usual think of the children argument, but I'm not pushing for more. I'm pushing for the same amount that is currently there.
Furthermore, the FDA costs are almost negligible compared to the development cost of new drugs. (Seriously, it's less than one percent.) And running clinical trials themselves cost a lot of money. Which is something that cannot be simply avoided. Because human biology is very complex, and even with these trials getting the signal from the noise is not easy. Just look at the mess in psychiatry ( https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev... how basically targeting one gene is [almost?] completely uselss)
Well, if all you have to do is compare the patient's health outcome of, say, 3 days with water vs. 3 days without, I am sure you could find a very positive correlation between the two treatment paths.
In the same vein, I often get to read about an emerging approach called precision medicine.
Precision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology or prognosis of those diseases they may develop, or in their response to a specific treatment [1]
In dentistry/endodontics it was believed for a long time that installing a post helped keep a crown and tooth intact for longer. But long term studies showed posts can actually reduce longevity. In another case, a study showed that a common type of knee surgery for pain is actually less helpful than a placebo surgery.
The overarching problem is that it's (currently) very hard to evaluate the real effect of practicing medicine on large swaths of the population, and then using those results to change what doctors do. By getting doctors into a continuous improvement cycle, we could identify costly, useless practices, and improve health.
Seems to impact nearly all medical disciplines.. https://iiif.elifesciences.org/lax:45183%2Felife-45183-fig2-...
E.g., there are some reports on how much data was needed by the Large Hadron Collider (LHC) to conclude that the Higgs Boson DOES exist -- the amount of data needed was beyond belief. Sooooo, anytime well short of that much data they could have conluded that the Higgs did not exist, that is, so far their data failed to show that it DID exist. Same for any treatment: If don't collect enough data, use poor measures, let the data get corrupted, etc., i.e., do sloppy work, then will fail to find where the treatment did work and conclude that it didn't.
Australia has a study that's pretty damning. Is that one of these practices listed?
The pharmacological industry resistance to these findings is unsurprising.
Most of it didn't work, and caused severe side effects.
This is from the British Medical Association: https://www.bmj.com/content/357/bmj.j2097
This is from the Royal Society of Medicine: https://journals.sagepub.com/doi/full/10.1177/01410768187968...
Medicine is not like trying out a new coding framework - in some cases, like cancer:
i) There is no ability to "try it out for your self" - you are either all in or not
ii) There are extreme risks to taking the drug (most cancer drugs are actually somewhat to extreme toxic...just less toxic than cancer)
iii) You only get a few tries (since, you know, cancer will kill you).
iv) People are very desperate and will try anything
v) Data sharing is very very hard given the sensitivity of the information (patient data) - making it effectively impossible to have an open data exchange. (This is also due to the billions of dollars at stake on the pharma side).
Try designing a system to overcome those challenges...and you will likely end up with a central governing body that looks like the FDA. Anything else you are going to get way way more drugs that don't work, which waste time and money and kill people, which endanger patient privacy, or which are not satisfactory to pharma or, ...
The fact is, the FDA is full of many of the smartest and hardest working doctors and scientists in all of medicine. They take their jobs extremely seriously. They are far more careful and rigorous than most academic or even pharma-level researchers.
Do they get it wrong? Yes, occasionally. Not frequently. Occasionally. But that also, is science. The FDA follows rigorous statistical procedures, but even p<0.05 (or <0.001) still means false positives can happen.
Honestly the worst parts of dealing with them are direct consequences of people trying to game the system. We went out of our way to make sure nothing we did could give that impression and got excellent guidance and response.
Been through that process with a couple products from a medical imaging software startup. Extreme professionalism and competence was the lasting impression I got from my time interacting with them. We were making software that could be used in oncology for diagnosis, analysis, and treatment planning, so yeah, we got the regulatory proctology exam. But I wasn't annoyed at all. They were highly competent people who took their duty to protect the public from me seriously.
I took no offense at all.
It's called "Expanded Access" (also known as "Compassionate Use") https://www.fda.gov/news-events/public-health-focus/expanded...
The other reason why data sharing is hard is because it costs on average over $1,000,000,000 (1 billion USD) and 10 years of time to whittle over 10,000 drug candidates into a single new FDA approved NME (new molecular entity).
If you spent a billion dollars and a decade on a project, you will consider the data you collected to be a trade secret and would protect it with everything you can, because you have to now take this drug to market and make up the billion you spent making this drug. If you simply shared all your results, foreign competitors will simply copy your work without paying you, and will then offer your product without the cost of R&D and regulation built in: AKA they will charge 1/10 or less than you and you will struggle to profit anywhere they are in the market.
You would also be heavily incentivized to make sure the numbers show that your drug is effective, with very limited side effects..
And, the FDA monitoring of drugs requires more than Phase 1-3 clinical trials (which cost hundreds of millions of dollars to produce some of the most rigorous science in human history), but they also do post-release data analysis (so called Phase 4), and have even recently pulled drugs which are not meeting the Phase 2 and 3 standards for safety and efficacy over existing treatments (not efficacy over placebo, the results must show efficacy also over existing drugs).
Not to mention, the FDA fines of pharma corporations are some of the largest fines in American history.
So with the FDA you have
* A regulator using science forcing big business to spend 10 years creating scientific evidence that their product is safe and effective. No other industry on the planet has these requirements.
* A regulator using market data to actively govern products and pull products which aren't safe and effect (pretty normal)
* A regulator assessing multi-billion dollar fines pretty regularly https://en.wikipedia.org/wiki/List_of_largest_pharmaceutical...
You might find this surprising but pharmaceuticals is a money losing industry in the long term. Most of these companies are looking pretty bad, they're spinning off any division which could potentially be profitable (biologics, medical devices maybe) but your average business of finding new drugs? It's not profitable, the regulation is so intense and the work is so hard and competition which ignores intellectual property is so damaging that it's very likely most major pharma companies will go bankrupt in the coming decades.
When you compare how much science the FDA makes drug companies do to any other industry, food, finance, supplements, makeup, cars, houses, anything at all... nothing else compares. A forensic audit is nothing compared to a Phase 3 clinical trial. Far less goes into proving a car is safe than a drug. Etc.
The FDA is doing incredible scientific work with an extremely thin budget.
They cost a ton of money and take forever to create, so the product becomes very expensive, and rights to it are owned by the creating company. The government empowers a body to regulate the flow of new drugs on the market, and once the drug meets regulatory requirements, the government - in many cases - pays on behalf of the patient.
A company is interested in making a profit on their time investment, whereas the government could be content to break even (for the good of their citizens).
If the government instead paid a company to do the R&D, maybe even providing access to approved facilities where the work is to be done, the government could then retain ownership of that product and then create agreements with drug manufacturers to produce those drugs.
This solves a couple of problems, like sole producers of a product arbitrarily increasing prices (it is expensive and time consuming to set up production for a new drug, even if it is off patent), as well as supply issues (I don't think right now the FDA has any rules saying a drug company must be able to supply a certain amount of a drug to get their license to distribute).
AIDS/HIV(originaly called GRID) was originally considered a punishment for gay men who were seen in the 80's as being immoral and sinful by the establishment. Government-funded R&D for AIDS drugs would have been unlikely for decades.
Another example is hormonal birth control. Birth control in general is a huge political football with portions of the establishment wanting no access to birth control at all. If R&D were government funded it's possible for these people to prevent access simply by making funding of certain lines of research illegal.
I think you have to look beyond the price of treatment to really see the benefit of a healthy private enterprise here. There are still a ton of ways that government contributes to new treatments, like grant funding for basic research and development. But I can see your proposed future becoming a dystopia, where whoever is in power in government makes it illegal to sell certain patented drugs to their particular underclass of the week.
There is promising work going on in this area to allow the sharing of models while maintaining privacy. (Differential privacy, homomorphic encryption, multi-party computation, etc.)
Historically treatments were based on some theory of how the body works, and a plausible intervention either based job that model, or based on tradition and anecdotal experience.
As people tried to implement more empiricism it hits all the difficulties you mention and others ... it’s an extremely difficult ugly challenge.
We should have lots of medical reversals. It means we are slowly getting better. Probably things could move faster if there was some giant anonymized database of every patient treatment, with documentation of symptoms, intervention, and outcome.
There are so many reasons why that is impractical, I’m astonished we are making the progress we are.
Why should they be? It's not like European regulators have a better track record than the FDA here.
This has literally nothing to do with FDA approval of NMEs.
Which is illegal in itself, for reasons that have nothing to do with FDA approval or the issues relevant to this article.
The issue is that there is a huge lack of transparency. When a third of the studies involved in approval of anti-depressants were withheld from the public [0] and even some withheld at the insistence of the FDA [1], what good do low P-values do?
Hard to trust the science when you're not even allowed to review the papers for yourself.
[0]: https://www.nytimes.com/2008/01/17/health/17depress.html
[1]: http://www.washingtonpost.com/wp-dyn/articles/A9802-2004Sep9...
Actually you can read all the papers you want, you have no guarantee that what's on paper is what happened. Academic and industrial misconduct and epidemiological ignorance are so prevalent in the field that it's more akin to a religious cult.
No, unfortunately I'm not being pessimistic. This is also the case for the FDA people. They can't know, even by doing good work and to a very large extent, whether something will prove harmful or useful.
Can't speak for others, but we were deathly afraid of submitting anything dependent on papers that we had not verified ourselves to 100% satisfaction. This actually held us up a lot, but it was safer than taking a chance that you would get it by those people at the FDA. Now of course, we were making software, and when you deal with computer science research, there are a lot of BS papers out there. I remember reading through papers on ray tracing, which had supposedly been peer reviewed, but were presenting arithmetic that was entirely incorrect. Literally every paper we found on this particular algorithm was riddled with almost identical mathematical errors. It was crazy. (I would say that computer scientists have got to be the worst mathematicians I've seen during my time in the sciences.) In any case. I knew that one of the people we were dealing with was a pretty good math guy. Yeah, we decided not to chance it.
Having bogus research out there is one thing, getting lucky enough to slip it by the FDA is something entirely different. Don't mistake those two things for the same issue, it could cost your company. Or worse, if you do manage to slip it by the FDA, it could cost your freedom when your bass ackwards ortho normal basis calculation switches left and right, and the surgeon goes in after the wrong kidney.
There was one specific signal change (a + to a - in an equation) that took me almost a month of hitting my head against a wall to figure out...
https://en.wikipedia.org/wiki/History_of_the_Food_and_Drug_A...
We do work with the Government in a different context, and I've found nothing but professionalism and deep expertise. In fact the people I've met in the agencies we're working with are some of the smartest I've encountered in my entire career.
In a single department, we don't know.
As a whole, it's been shown over and over that like any organization, government becomes corrupt.
Between defense and universities, I've heard depressing ancedotes as well.
It's lucky and temporary you had a good experience.
But this time will be different.
Very interesting take.
I hate to say it, but every one of these folks I have encountered falls into two categories: 1. Recent college graduates who don't know much if anything, 2. People who have worked a government job for a long time but have little intellectual capacity to understand complex subjects.
Haven't met many recent college graduates, as they don't usually have the experience to land a government job. Have met a few old-timers. But otherwise almost all of them were efficient, helpful, and good at their jobs. In the specialized departments, they definitely had the intellectual capacity to understand complex subjects and could have earned significantly more money in private practice if they wanted to waste their lives in a rat race.
On one point people are making specifically -- unlinking safety with efficacy is really tough -- an immunooncology product that causes serious AEs/hospitalizations in a quarter of the population and costs $250k and only extends life by 6 months may be approved because the alternative is almost certain mortality; whereas another drug may not be approved simply because it increases bleeding risk in a small percentage of people because there are good alternatives already.
Sam Peltzman's "Regulation of Pharmaceutical Innovation" does an evaluation of this based on statistics, and concludes that the efficacy requirements are a net negative.
It's not about the FDA scientists being incompetent. It's about the increase in cost is so large that far fewer new treatments are even attempted. Conditions that affect a smaller number of people are simply not worth finding a treatment for.
does this mean private sector pharma studies are to blame?
What is the best learning rate for updating physicians (our models) from the results of RCT's (part of our loss)?
The authors reviewed all articles in three journals from (generally) between 2003-2017. They didn't, afaict (please point me if they did), review the time-to-correction (if any correction has been made). It takes some time before the results of an RCT end up in established practice. I'm actually surprised it's so small in many cases.
It's not like there's a database where the results of every RCT are immediately updated and the physician model is retrained overnight on the new data.
Even if there were, imagine if the learning rate (so to speak) were so high that every discipline immediately changed their published best practices on the basis of a single RCT?
Here's a cautionary paragraph from one of the excellent reversal studies they use:
Several limitations of the study warrant discussion. First, because we enrolled only 26% of eligible patients, our findings must be generalized cautiously. The most frequent reason that patients declined enrollment was a strong preference for one treatment or the other. Since patients' preferences may be associated with treatment outcome, our trial may be vulnerable to selection bias. Participating surgeons may not have referred potentially eligible patients because they were uncomfortable randomly assigning these patients to treatment; this form of selective enrollment may also create bias.26 Second, because the trial was conducted in academic referral centers, the findings should be generalized carefully to community settings. Third, we did not formally assess the fidelity of the physical therapists or surgeons to the standard intervention protocols. Finally, our study was not blinded, since our investigative group did not consider a sham comparison group feasible. [0]
I'm less concerned about RCT to Best Practice time than from Best Practice to Typical Physician Practice time. There is a cascaded model connected to the 'complex RCT loss' and it's discipline published practice down to individual physician treating patients. Compressing the time from RCT to individual physician is fraught with difficulties, but could be improved.
Finally, RCT is the gold standard, but it's not perfect and it doesn't always clearly translate to the individual physician's model of practice. Many best practices weren't established from RCT's either.
And an inconclusive result from an RCT is not the same thing as proving that there's no difference in outcomes, but a proper statistician can chime in there.