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."
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.
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.
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.
Those are documented, but not necessarily in the paper. You can find the info at clinicaltrials.gov. Check out this current trial for breast cancer treatment by Merck Sharp & Dohme LLC for example. For the control arm, they are allowing doctors choice from a set of alternatives. Assuming the doctors are selecting control treatments to improve chance of survival, this test is comparing the new treatment to "the best known treatment for this specific cancer".
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.
A lot of companies essentially cherry pick healthy patients and write insane inclusion/exclusion criteria to rule out anyone except for the ideal participant, which is why more and more research sites are negotiating payment up front for pre-screening and higher screenfail % reimbursement for into their study budgets.
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.
This problem is actually even worse than the article identifies, because broad definitions of what a "risk" is, result in broad exclusions.
The most pernicious of these problems is that women--yes, more than half the earth's population--are considered a high risk group because researchers fear menstrual cycles will affect test results. Until 1993 policy changes, excluding women from trials was the norm. Many trials have not been re-done to include women, and the policies don't include animal trials, so many rat studies, for example, still do not include female rats--a practice which makes later human trials more dangerous for (human) female participates.
The exclusion of women from clinic trials is one of those things that makes me really angry, there's many women in my life who've been adversely affected by various medications and essentially palmed off about it, being made to feel like they're making it up when there's obviously a problem at hand.
It will be one of those things future historians of medicine will judge our time harshly for in my opinion, and rightly so.
I've personally been excluded from several depression clinical trials for having suicidal ideations, it makes me wonder just what kind of "depression" they are testing drugs on.
There are a few broad reasons this can happen. One possibility is that they want to know if the treatment causes suicidal ideation, and the effect is often small enough that people more likely to report those symptoms independent of the treatment confound the result. Another is that they don't want to have to deal with the safety protocols that come with screening in participants who have reported any history of suicidality. Another still is that higher likelihood of an active mental health crisis means that it's harder for study coordinators to determine if participants have provided informed consent.
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.
Because it would be unbelievably irresponsible to test drugs like that on someone experience suicide ideation. Like, they should be put in prison irresponsible.
May be you should try to contact people at metabolic mind (not for profit), they seem to be closely related to some treatment resistant depression trials.
They have a youtube channel with interview of researchers in the field.
Wonder if this is what happened to fluoroquinolones. They are likely mitochondrial toxins and some small percentage of patients get permanently harmed by them and sometimes in a severe way. Older versions were taken off the market and the current versions each have multiple black box warnings. Sadly, it seems many doctors aren’t even aware of this.
As a lay person, huh, that's something you don't think about. But still even if that were true, I don't see how society, patients and their caretakers will accept high risk patients in trails. And wasn't there news recently of UK phasing out animal trails too?
A relative of mine was in the late-stages of cancer, and was not able to find ANY trials willing to accept them. The worst of those trials was out of Baltimore (MD USA), and they ghosted my relative after initial in-person consults that required by relative to drive out of state. Despite the patient's repeated and dogged outreach to the trial authors after that point, there was never an explicit "no" that would let the patient move on, just radio silence instead and that felt cruel to me.
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[ 2.1 ms ] story [ 47.8 ms ] threadIntroducing 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.
https://clinicaltrials.gov/study/NCT07060807#study-plan
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.
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.
The most pernicious of these problems is that women--yes, more than half the earth's population--are considered a high risk group because researchers fear menstrual cycles will affect test results. Until 1993 policy changes, excluding women from trials was the norm. Many trials have not been re-done to include women, and the policies don't include animal trials, so many rat studies, for example, still do not include female rats--a practice which makes later human trials more dangerous for (human) female participates.
[1] Sort of one citation: https://www.aamc.org/news/why-we-know-so-little-about-women-... There's more than this--I wrote a paper about this in college, but I don't have access to jstor now, so I'm not sure I could find the citations any more.
It will be one of those things future historians of medicine will judge our time harshly for in my opinion, and rightly so.
Read "Invisible Women" by Caroline Criado-Perez for a strong take.
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.
I saw a new procedure available in Mexico for 8k for psychedelic treatment with Ibogaine. Still schedule 1 like MDMA in USA.
It looks like there has been a few MDMA trials for ptsd even though the FDA denied more widespread testing.
https://www.science.org/content/article/fda-rejected-mdma-as...