To improve medical trials, justify exclusion criteria
trevorklee.substack.com
To improve medical trials, justify exclusion criteria
1–10 of 55 posts
Re: To improve medical trials, justify exclusion criteria
#2>These unjustified exclusions can have real clinical implications, too. For example, most asthma studies exclude morbidly obese people, as morbidly obese asthma is notoriously resistant to treatment and there aren’t good explanations as to why. However, once asthma drugs are approved, they’re approved for all asthmatics equally. As a result, morbidly obese people get prescribed asthma drugs that were never tested on people like them [1].
>[...]
>[1] This is literally going on today by the way. The FDA approved Tezpire as a breakthrough drug for asthma in December 2021. Tezspire excluded morbidly obese people from their efficacy trials. This fact is not mentioned anywhere in Tezspire’s labeling.
Wow, I had never heard of anything like this before. Does the FDA have a justification for why there isn't a requirement to mention significant exclusions like this?
Re: To improve medical trials, justify exclusion criteria
#3> While they have utility as tools to make running trials on interventions easier or more straightforward, they’re too often used to run different trials altogether than what’s promised in the abstract.
Yes, this makes it a lot easier to find something to publish. If they stop doing this they hurt their career prospects, it might be good for science but it isn't good for the individual.
In order to improve science you need to see it from a capitalist perspective where the researchers are desperately fighting over resources. As long as that fight is won by performing bad science we will mostly get more bad science. The most critical part to change is peer review, today we treat peer review as the main cornerstone of the scientific method, even though it is very unrelated, it is only to help filter out the worst of spam, it doesn't say much at all about the validity of the paper.
Re: To improve medical trials, justify exclusion criteria
#4Based on the record of the pharmaceutical industry and their entirely captured regulatory agency, the FDA, it's not entirely unwise to wait about ten years after the introduction of a 'breakthrough drug' to see if it actually has negative side effects that were not discovered in the clinical trials. See Vioxx, etc.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534432/
> "Dr Graham, associate director in the FDA's Office of Drug Safety, said an estimated 88,000 to 139,000 Americans had heart attacks and strokes as a result of taking rofecoxib. The number, he said, far exceeds earlier disasters such as the 100 children killed in the United States by an elixir of sulfanilamide in the 1930s and the 5,000 to 10,000 children born in the 1960s with birth defects related to thalidomide. Both events led to sweeping regulatory changes in the United States."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534432/
This is an unfortunate situation as relatively safe and effective medicines (i.e. Sars-CoV2 vaccines) end up mixed in with ineffective and even dangerous ones, and the public has no real way of distinguishing between them. As the whole opiate epidemic (driven by pharmaceutical corporations pushing their FDA-approved products via shady doctors and pill clinics) demonstrates, these outfits only care about profit margins, and since there are no criminal penalties and any fines are sure to be much less than their profits, they have no incentive to change their behavior.
Re: To improve medical trials, justify exclusion criteria
#5I think the author makes a fair point, but the analogies and examples in this piece offended my aesthetic sensibilities to the point that I find myself wanting to disagree with him purely out of spite.
> Some of these exclusion criteria are pretty straightforward. […] you’d want to avoid any participants with conditions that make them predisposed to gain or lose weight, as that would make an apples-to-apples comparison across groups more difficult.
Absolutely!
> However, there are other exclusion criteria that I don’t understand at all. Why no oral contraceptive use? Why no smoking? Why no diabetes[…]?
Smoking makes you lose weight. Diabetes is literally characterized by abnormal metabolism.
> There might well be good reasons for these exclusions that I’m not aware of. […] However, those reasons are not outlined here.
Agreed. There should at least be a sentence in a supplement somewhere.
One things about trials and extrapolation is that trails are tightly controlled and will never reflect real world conditions in terms of the patient population, the intervention, or the context in which the intervention is performed.
This is a double edged sword. It’s good because you can get “cleaner” measurements and data by getting rid of cofounders and such. But it’s bad because your trial scenario may be unrealistic and your results may not translate into the clinic.
If anything good has come out of Surveillance capitalism and those shitty EPIC / Cerner EHR systems that everybody (except for hospital quality people) hates, it is a drastic improvement in capabilities for post market data collection (i.e. real world data).
RWD is increasingly a thing at FDA. I think the big issue there which needs public discussion is the extent to which post market data collection should either replace or augment clinical trials. If you replace clinical trials with RWD then you are essentially running mass experiments on sick people with untested drugs, which is monstrous. If you purely augment, then it is basically like a tax and you are driving up the cost and complexity of drug development.
Re: To improve medical trials, justify exclusion criteria
#6>These unjustified exclusions can have real clinical implications, too. For example, most asthma studies exclude morbidly obese people, as morbidly obese asthma is notoriously resistant to treatment and there aren’t good explanations as to why. However, once asthma drugs are approved, they’re approved for all asthmatics equally. As a result, morbidly obese people get prescribed asthma drugs that were never tested on…
I believe the FDA relies on the "maximum expected utility principle" - a cornerstone of free-market economic theory.
> "By combining the concept of utility with the notion of rational decision making, economists in the mid-twentieth century established a basis for the maximum expected utility principle. This principle is a key concept behind the creation of autonomous decision-making agents."
https://algorithmsbook.com/files/dm.pdf
This has been expressed in the past as "Each portion of wealth has a corresponding portion of happiness, and of two individuals with unequal fortunes, he who has the most wealth has the most happiness."
A good way to accumulate wealth and maximize happiness is to sell drugs, and preventing the sale of drugs because of concerns over ill effects reduces wealth and brings sadness to the pharmaceutical corporation and its shareholders and board members; such sadness prevents them from hiring ex-FDA employees as consultants or managers, thus defeating the principle of maximum expected utility.
The autonomous decision-making agents at the FDA therefore have no choice but to rubber stamp everything that comes across their desk. Doing anything else would be irrational.
Re: To improve medical trials, justify exclusion criteria
#7>These unjustified exclusions can have real clinical implications, too. For example, most asthma studies exclude morbidly obese people, as morbidly obese asthma is notoriously resistant to treatment and there aren’t good explanations as to why. However, once asthma drugs are approved, they’re approved for all asthmatics equally. As a result, morbidly obese people get prescribed asthma drugs that were never tested on…
I believe the FDA relies on the "maximum expected utility principle" - a cornerstone of free-market economic theory. > "By combining the concept of utility with the notion of rational decision making, economists in the mid-twentieth century established a basis for the maximum expected utility principle. This principle is a key concept behind the creation of autonomous decision-making agents." https://algorithmsbook.c…
> I believe the FDA relies on the "maximum expected utility principle" - a cornerstone of free-market economic theory.
This has nothing to do with 'free-market economic theory'. It's about decision under uncertainty. The concept was expressed for the first time by Von Neumann and Morgenstern in a book that was supposed to explain how to play poker.
> "Each portion of wealth has a corresponding portion of happiness, and of two individuals with unequal fortunes, he who has the most wealth has the most happiness."
I have never ever read that anywhere. One could argue that rich people provide more value to society and then should be prioritise in some circumstances but what you are writing seems very unfounded.
Re: To improve medical trials, justify exclusion criteria
#8>These unjustified exclusions can have real clinical implications, too. For example, most asthma studies exclude morbidly obese people, as morbidly obese asthma is notoriously resistant to treatment and there aren’t good explanations as to why. However, once asthma drugs are approved, they’re approved for all asthmatics equally. As a result, morbidly obese people get prescribed asthma drugs that were never tested on…
As someone who has both designed and run clinical trials as my job, this assertion is likely* nonsense. First, the division you submit to will reject your recruitment criteria if they feel it does not accurately reflect the treatment population within the United States. They also reflect the specialty of the particular division (e.g. Oncology is allegedly far less worried about most side effects than, say, the Dermatology division, due to the kinds of indications they deal with).
Second of all this kind of info is on the label (prescribing information) even if it doesn’t make it into the short summary (package insert, typically only a dozen pages or so) given to patients. Doctors do read those, you know, and within their specialities know what kinds of things to look for.
There have been some notorious cases, but by and large I’ve found the people I worked with at the agency to be professional and solid. I’m no longer in that business and have no reason to say anything I don’t believe.
* I didn’t bother to look up the label for this drug but they are all public info on the FDA web site and In the USP.
Re: To improve medical trials, justify exclusion criteria
#9>These unjustified exclusions can have real clinical implications, too. For example, most asthma studies exclude morbidly obese people, as morbidly obese asthma is notoriously resistant to treatment and there aren’t good explanations as to why. However, once asthma drugs are approved, they’re approved for all asthmatics equally. As a result, morbidly obese people get prescribed asthma drugs that were never tested on…
I believe the FDA relies on the "maximum expected utility principle" - a cornerstone of free-market economic theory. > "By combining the concept of utility with the notion of rational decision making, economists in the mid-twentieth century established a basis for the maximum expected utility principle. This principle is a key concept behind the creation of autonomous decision-making agents." https://algorithmsbook.c…
> The autonomous decision-making agents at the FDA therefore have no choice but to rubber stamp everything that comes across their desk. Doing anything else would be irrational.
You have clearly never tried to get a drug or device approved nor have you looked at the number of drugs that fail, expensively, in Phase 2 or even Phase 3. Your statement is utter nonsense.
Re: To improve medical trials, justify exclusion criteria
#10>There might well be good reasons for these exclusions that I’m not aware of.
Is it possible that these reasons are more obvious or known to some folks and they just didn't list them, or they just wanted to see what happens without those groups, and it's not about shenanigans?