Trials avoid high risk patients and underestimate drug harms

Most trials have long lists of excluded conditions. As you say, one reason is reducing variability among subjects so effects of the treatment can be determined.

This is especially true when effects of a new treatment are subtle, but still quite important. If subjects with serious comorbidities are included, treatment effects can be obscured by these conditions. For example, if a subject is hospitalized was that because of the treatment or another condition or some interaction of the condition and treatment?

Initial phase 3 studies necessarily have to strive for as "pure" a study population as possible. Later phase 3/4 studies could in principle cautiously add more severe cases and those with specific comorbidities. However there's a sharp limit to how many variations can be systematically studied due to intrinsic cost and complexity.

The reality is that the burden of sorting out use of treatments in real-world patients falls to clinicians. It's worth noting level of support for clinicians reporting their observations has if anything declined over decades. IOW valuable information is lost in the increasingly bureaucratic and compartmentalized healthcare systems that now dominate delivery of services.

We see this "no no's" in VC investing, job hunting, and now your anecdote, medical trials.

People don't want to be responsible for children. The elderly. Owning a home. Maintaining society. Or to each other. Saddening really.

People are adverse to just trying often times. The responsibility of potentially failing is something they don't want...

When nobody is responsible for anything, society crumbles.

First off it ignore the fact that if you include frail patients you’ll confound the results of the trial. So there is a good reason for it.

Second, saying “rate of SAE is higher than rate of treatment effect” is a bit silly considering these are cancer trial - without treatment there is a risk of death so most people are willing to accept SAE in order to achieve treatment effect.

Third, saying “the sickest patients saw the highest increase in SAE” seems obvious? It’s exactly what you’d expect.

Sometimes studies are specifically for treatment-resistant depression, and I expect those studies are more likely to screen in participants with a history of suicidality, so I would recommend keeping an eye out for those if you would like to participate in clinical trials.

They have a youtube channel with interview of researchers in the field.

Study design is sometimes optimized so only the "best" most enticing participants will actually be eligible, I've seen as low as 2% - 12% but frequently 50% randomization rates. Some studies also have 100 to 150 day screening period, a limited AND full screening period, etc.

Overly restrictive inclusion/exclusion criteria to super narrowly defined ideal populations hinders enrollment, causes a large burden to sites for prescreening and ends with trial results that fail to reflect real-world demographics.

It will be one of those things future historians of medicine will judge our time harshly for in my opinion, and rightly so.

This would be called an "active placebo" and would certainly be documented.

It's common to find controlled trials against an existing drug to demonstrate that the new drug performs better in some way, or at least is equivalent with some benefit like lower toxicity or side effects. In this case, using an active comparison against another drug makes sense.

You wouldn't see a placebo-controlled trial that used an active drug but called it placebo, though. Not only would that never get past the study review, it wouldn't even benefit the study operator because it would make their medication look worse.

In some cases, if the active drug produces a very noticeable effect (e.g. psychedelics) then study operators might try to introduce another compound that produces some effect so patients in both arms feel like they've taken something. Niacin was used in the past because it produces a flushing sensation, although it's not perfect. This is all clearly documented, though.

https://clinicaltrials.gov/study/NCT07060807#study-plan

If the risk is primarily due to, or made worse by, the disease being treated, wouldn't they want to join the trial?

The patients self-report their own side effects, then the numbers go into the paper.

Are you suggesting the study operators are tampering with numbers before publishing?

https://www.fda.gov/safety/medwatch-fda-safety-information-a...