Having been an "investigator" in a few phase 3 and 4 trials, it is true that all actions involving subjects must strictly follow protocols governing conduct of the trial. It is extremely intricate and labor intensive work. But the smallest violations of the rules can invalidate part of or even the entire trial.

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.

> Classes of drugs have expected side effects, so it's common to use medications with similar effects as placebos.

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.

This seems like an odd criticism.

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.

And this just goes to reinforcing the beliefs of those who are skeptical of medical research. "Trust the science" is all well and good in theory except when the scientists are telling you a selective, cherry-picked story.