[HN Gopher] Trials avoid high risk patients and underestimate dr...
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Trials avoid high risk patients and underestimate drug harms
Author : bikenaga
Score : 36 points
Date : 2025-12-08 19:07 UTC (3 hours ago)
(HTM) web link (www.nber.org)
(TXT) w3m dump (www.nber.org)
| bikenaga wrote:
| Abstract: "The FDA does not formally regulate representativeness,
| but if trials under-enroll vulnerable patients, the resulting
| evidence may understate harm from drugs. We study the
| relationship between trial participation and the risk of drug-
| induced adverse events for cancer medications using data from the
| Surveillance, Epidemiology, and End Results Program linked to
| Medicare claims. Initiating treatment with a cancer drug
| increases the risk of hospitalization due to serious adverse
| events (SAE) by 2 percentage points per month (a 250% increase).
| Heterogeneity in SAE treatment effects can be predicted by
| patient's comorbidities, frailty, and demographic
| characteristics. Patients at the 90th percentile of the risk
| distribution experience a 2.5 times greater increase in SAEs
| after treatment initiation compared to patients at the 10th
| percentile of the risk distribution yet are 4 times less likely
| to enroll in trials. The predicted SAE treatment effects for the
| drug's target population are 15% larger than the predicted SAE
| treatment effects for trial enrollees, corresponding to 1
| additional induced SAE hospitalization for every 25 patients per
| year of treatment. We formalize conditions under which regulating
| representativeness of SAE risk will lead to more externally valid
| trials, and we discuss how our results could inform regulatory
| requirements."
| refurb wrote:
| 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.
| randcraw wrote:
| It's understandable that unusual patients are seen as confounding
| variables in any study, especially those with small numbers of
| patients. Though I haven't read beyond the abstract, it also
| makes sense that larger studies (phase 3 or 4) should not exclude
| such patients, but perhaps could report results in more than one
| way -- including only those with the primary malady as well as
| those with common confounding conditions.
|
| Introducing too many secondary conditions in any trial is an
| invitation for the drug to fail safety and/or efficacy due to
| increased demands on both. And as we all know, a huge fraction of
| drugs fail in phase 3 already. Raising the bar further, without
| great care, will serve neither patients nor business.
| jrapdx3 wrote:
| 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.
| OutOfHere wrote:
| Move generally, whenever you read the percentage of patients that
| are noted as having a particular side effect from a medicine, the
| real percentage is much higher.
| SoftTalker wrote:
| 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.
| venturecruelty wrote:
| Strange how that line of thinking always winds up in places
| like "vaccines are bad" or "ivermectin cures COVID".
| Aurornis wrote:
| > whenever you read the percentage of patients that are noted
| as having a particular side effect from a medicine, the real
| percentage is much higher.
|
| 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?
| ortusdux wrote:
| Tangentially related, but I was surprised to learn about the lax
| attitude towards placebos in trials. Classes of drugs have
| expected side effects, so it's common to use medications with
| similar effects as placebos. Last I heard, there is no
| requirement or expectation to document placebos used, and they
| are often not mentioned in publications.
| Aurornis wrote:
| > 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.
| padjo wrote:
| You were surprised to learn this because it's not true.
| unethical_ban wrote:
| This was a plot in an early season of ER.
| nitwit005 wrote:
| This covers the trials not being fully representative, but
| largely neglects why that is the case.
|
| The paper defines a population "at high risk of drug-induced
| serious adverse events", which presumably means they're also the
| most likely people to be harmed or killed by the drug trial
| itself.
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