To improve medical trials, justify exclusion criteria

&gt;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].<p>&gt;[...]<p>&gt;[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.<p>Wow, I had never heard of anything like this before. Does the FDA have a justification for why there isn&#x27;t a requirement to mention significant exclusions like this?

&gt; Why no smoking?<p>Smoking can be an appetite suppressant: <a href="https:&#x2F;&#x2F;www.npr.org&#x2F;2011&#x2F;06&#x2F;09&#x2F;137085989&#x2F;the-skinny-on-smoking-why-nicotine-curbs-appetite" rel="nofollow">https:&#x2F;&#x2F;www.npr.org&#x2F;2011&#x2F;06&#x2F;09&#x2F;137085989&#x2F;the-skinny-on-smoki...</a><p>&gt; Why no diabetes, given that this is an overweight subject group?<p>Given the goal of intermittent fasting is to get insulin levels low enough that your body burns fat instead of sugar, and based on this article at least IF requires closer monitoring of your diet, maybe they wanted to eliminate a variable&#x2F;variables.<p><a href="https:&#x2F;&#x2F;www.verywellhealth.com&#x2F;diabetes-and-intermittent-fasting-4844452" rel="nofollow">https:&#x2F;&#x2F;www.verywellhealth.com&#x2F;diabetes-and-intermittent-fas...</a>

&gt;The FDA approved Tezpire as a breakthrough drug for asthma in December 2021. Tezspire excluded morbidly obese people from their efficacy trials.<p>This statement is very misleading because morbidly obese people were only excluded from the Phase 2 PATHWAY trial[1] and were not excluded from the larger Phase 3 NAVIGATOR trial[2]. The FDA approved Tezpire based on both trials demonstrating efficacy, not just the PATHWAY trial.<p>[1] <a href="https:&#x2F;&#x2F;clinicaltrials.gov&#x2F;ct2&#x2F;show&#x2F;NCT02054130" rel="nofollow">https:&#x2F;&#x2F;clinicaltrials.gov&#x2F;ct2&#x2F;show&#x2F;NCT02054130</a><p>[2] <a href="https:&#x2F;&#x2F;clinicaltrials.gov&#x2F;ct2&#x2F;show&#x2F;NCT03347279" rel="nofollow">https:&#x2F;&#x2F;clinicaltrials.gov&#x2F;ct2&#x2F;show&#x2F;NCT03347279</a>

I 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.<p>&gt; 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.<p>Absolutely!<p>&gt; However, there are other exclusion criteria that I don’t understand at all. Why no oral contraceptive use? Why no smoking? Why no diabetes[…]?<p>Smoking makes you lose weight. Diabetes is literally characterized by abnormal metabolism.<p>&gt; There might well be good reasons for these exclusions that I’m not aware of. […] However, those reasons are not outlined here.<p>Agreed. There should at least be a sentence in a supplement somewhere.<p>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.<p>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.<p>If anything good has come out of Surveillance capitalism and those shitty EPIC &#x2F; 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).<p>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.

&gt;There might well be good reasons for these exclusions that I’m not aware of.<p>Is it possible that these reasons are more obvious or known to some folks and they just didn&#x27;t list them, or they just wanted to see what happens without those groups, and it&#x27;s not about shenanigans?

Based on the record of the pharmaceutical industry and their entirely captured regulatory agency, the FDA, it&#x27;s not entirely unwise to wait about ten years after the introduction of a &#x27;breakthrough drug&#x27; to see if it actually has negative side effects that were not discovered in the clinical trials. See Vioxx, etc.<p><a href="https:&#x2F;&#x2F;www.ncbi.nlm.nih.gov&#x2F;pmc&#x2F;articles&#x2F;PMC534432&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.ncbi.nlm.nih.gov&#x2F;pmc&#x2F;articles&#x2F;PMC534432&#x2F;</a><p>&gt; &quot;Dr Graham, associate director in the FDA&#x27;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.&quot;<p><a href="https:&#x2F;&#x2F;www.ncbi.nlm.nih.gov&#x2F;pmc&#x2F;articles&#x2F;PMC534432&#x2F;" rel="nofollow">https:&#x2F;&#x2F;www.ncbi.nlm.nih.gov&#x2F;pmc&#x2F;articles&#x2F;PMC534432&#x2F;</a><p>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.

Other questionable exclusion criteria: removing patients from trials of a prophylactic drug if they are seen by medical staff outside the trial for any reason, especially for the condition being studied.

&gt; 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.<p>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&#x27;t good for the individual.<p>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&#x27;t say much at all about the validity of the paper.