[HN Gopher] To improve medical trials, justify exclusion criteria
___________________________________________________________________
To improve medical trials, justify exclusion criteria
Author : klevertree
Score : 79 points
Date : 2022-04-26 13:39 UTC (9 hours ago)
(HTM) web link (trevorklee.substack.com)
(TXT) w3m dump (trevorklee.substack.com)
| duxup wrote:
| >There might well be good reasons for these exclusions that I'm
| not aware of.
|
| Is it possible that these reasons are more obvious or known to
| some folks and they just didn't list them, or they just wanted to
| see what happens without those groups, and it's not about
| shenanigans?
| halyax wrote:
| I do think there's a reasonably compelling case that drug
| companies could make for wanting to measure/demonstrate their
| drug's performance in an ideal population first - now the fact
| that they then go on to market the product with little to no
| care for the populations excluded from the trials undercuts
| this significantly. But it is at least possible that its not
| _entirely_ shenanigans...
| pfisherman wrote:
| 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.
|
| > 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.
|
| Absolutely!
|
| > However, there are other exclusion criteria that I don't
| understand at all. Why no oral contraceptive use? Why no smoking?
| Why no diabetes[...]?
|
| Smoking makes you lose weight. Diabetes is literally
| characterized by abnormal metabolism.
|
| > There might well be good reasons for these exclusions that I'm
| not aware of. [...] However, those reasons are not outlined here.
|
| Agreed. There should at least be a sentence in a supplement
| somewhere.
|
| 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.
|
| 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.
|
| If anything good has come out of Surveillance capitalism and
| those shitty EPIC / 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).
|
| 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.
| meowface wrote:
| >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].
|
| >[...]
|
| >[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.
|
| Wow, I had never heard of anything like this before. Does the FDA
| have a justification for why there isn't a requirement to mention
| significant exclusions like this?
| chmod775 wrote:
| I feel like I have to play devil's advocate here a bit.
|
| Obesity is an easily treatable condition. One might try to
| treat them in order: Obesity first, then the asthma. That would
| justify excluding that particular complication from the study.
| AlchemistCamp wrote:
| > Obesity is an easily treatable condition.
|
| Is it? I thought long-term success rates were very low and
| that prevalence was increasing all over the globe.
| bryan_w wrote:
| Also a person who has trouble breathing tends to not do
| significant exercise because they run out of breath too
| quickly.
| jallen_dot_dev wrote:
| While exercise is healthy, it isn't a great way to lose
| weight. Eating a healthier diet, in particular lower
| calorie, is how you lose weight.
| chmod775 wrote:
| prevalence != difficulty of treatment
|
| people's unwillingness to cooperate != difficulty of
| treatment
|
| Asthma also isn't the only condition that is hard to treat
| in morbidly obese people. For many conditions it will be
| too late to start paying attention to one's calorie intake,
| but asthma is one that is survivable in the meantime.
| Severe discomfort and _possible_ death tends to be a good
| motivator.
| throwthere wrote:
| Researchers generally analyze intervention success by
| _intention to treat_.
|
| If a treatment is telling people to "start paying
| attention to one's calorie intake," and that doesn't have
| the desired effect, whatever the reason, I think it's
| fair to say that intervention isn't useful.
| chmod775 wrote:
| Success rate _also_ isn 't the same as difficulty.
|
| It's very easy to fill out a lottery ticket, but success
| rate is very low.
|
| Success is a boolean condition that often first needs to
| be defined, while difficulty is a spectrum and a more
| rigid concept. Really the only complication is subjective
| vs. objective difficulty (what is objectively difficult
| may be subjectively easy to someone practiced).
|
| Difficult things require hard skills. Reducing someone's
| calorie doesn't require any hard skill that I am aware
| of.
| throwthere wrote:
| > Success rate also isn't the same as difficulty.
|
| > It's very easy to fill out a lottery ticket, but
| success rate is very low.
|
| > Difficult things require hard skills. Reducing
| someone's calorie doesn't require any hard skill that I
| am aware of.
|
| I don't really want to engage with those statements other
| than to say I think morbidly obese people do have quite a
| hard time losing weight.
| chmod775 wrote:
| > hard time
|
| With which you mean the process causes discomfort?
| Probably less so than being asthmatic and/or a host of
| other things, but yes.
|
| Other than that there can be some psychological issues
| that make self-controlled treatment subjectively hard or
| impossible. But then we'd have found another condition
| that would need to be treated first, getting us back to
| where we started: Somebody running a study on the
| efficacy of a diet probably would want to preclude people
| psychologically unable to stick to it...
| gumby wrote:
| As someone who has both designed and run clinical trials as my
| job, this assertion is likely* nonsense. First, the division
| you submit to will reject your recruitment criteria if they
| feel it does not accurately reflect the treatment population
| within the United States. They also reflect the specialty of
| the particular division (e.g. Oncology is allegedly far less
| worried about most side effects than, say, the Dermatology
| division, due to the kinds of indications they deal with).
|
| Second of all this kind of info _is_ on the label (prescribing
| information) even if it doesn't make it into the short summary
| (package insert, typically only a dozen pages or so) given to
| patients. Doctors do read those, you know, and within their
| specialities know what kinds of things to look for.
|
| There have been some notorious cases, but by and large I've
| found the people I worked with at the agency to be professional
| and solid. I'm no longer in that business and have no reason to
| say anything I don't believe.
|
| * I didn't bother to look up the label for this drug but they
| are all public info on the FDA web site and In the USP.
| ada1981 wrote:
| While you may not have financial incentives, the
| psychological incentives are often very strong to maintain a
| positive idea of an industry one was a part of.
| gumby wrote:
| That's a reasonable concern. All I can say is that I left
| that field for a reason (well reasons) and have some
| serious concern about some ethical issues and attempts at
| gaming the system.
|
| However by and large my concerns aren't around science
| (though there are exceptions, _cough_ alzheimers), they are
| mostly around the marketing, pricing manipulation with
| regards to medicare (ever wonder why drug companies give
| everyone coupons?) etc. The FDA has very little to do with
| some of these issues and none with others (e.g. scamming
| the taxpayer)
|
| In general I don't think pharma execs are necessarily nice
| people (though some are!) but most are not evil like the
| Sacklers.
| jahewson wrote:
| Oh the irony that you've excluded an investigation of the
| relevant example here, but made broad claims nonetheless.
| gumby wrote:
| My note was clear that the package insert is insufficient
| for prescribing. It is explicitly marked so -- see a
| comment I wrote to another reply to my GP comment.
| throwanem wrote:
| Totally unrelated, but just briefly to say, thanks for
| your work with Cygnus.
|
| I doubt I'd have been able to build a career for myself
| in software engineering without Cygwin being available
| and lively back in the days when I was required to use
| Windows fulltime, and along with that I learned a lot
| from working with it that's been of great help to me ever
| since. And I'm to this day running Cygwin on the one
| Windows box I still maintain!
|
| So, thanks for whatever hand you had in that. If you ever
| find yourself in Baltimore and thirsty, hit me up and
| I'll buy you that beer or other suitable beverage I owe
| you. :D
| lkey wrote:
| Why on Earth did you not bother to look it up before
| asserting your opinion...?
|
| https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/76.
| .. Body Weight Based on population pharmacokinetic analysis,
| higher body weight was associated with lower exposure.
| However, the effect of body weight on exposure had no
| meaningful impact on efficacy or safety and does not require
| dose adjustment.
|
| Assuming that grandparent comment is correct about morbid
| obesity exclusion, then you were the one spouting nonsense
| right? Doctors will definitely give this to patients
| regardless of weight with a note like that.
| gumby wrote:
| Both my note and the download you discuss are clear about
| this.
|
| You have linked to the the package insert, not the label,
| and it clearly states at the very top
| HIGHLIGHTS OF PRESCRIBING INFORMATION These
| highlights do not include all the information needed to use
| TEZSPIRE safely and effectively. See full prescribing
| information for TEZSPIRE.
|
| As I wrote in my comment:
|
| > ... this kind of info is on the label (prescribing
| information) even if it doesn't make it into the short
| summary (package insert, typically only a dozen pages or
| so) given to patients. Doctors do read those, you know, and
| within their specialities know what kinds of things to look
| for.
|
| You are simply quoting the short summary and drawing a
| conclusion based on the limited information that appears on
| it. Perhaps the author of the blog post made the same
| error. The doctor reads the actual prescribing information
| and the evaluation population must be specified there.
| [deleted]
| jmgrosen wrote:
| The second page starts the "FULL PRESCRIBING
| INFORMATION"; the body weight quote above comes from
| section 12.3 of it and there is no mention of a weight
| exclusion in the discussion of the clinical studies in
| section 14. AFAIK, "label" typically refers to this sort
| of ~20 page prescribing information, but is there a
| different label you have in mind? I believe the one-page
| package insert is the last page, page 17.
| lkey wrote:
| Am I losing my g _d_ mn mind here? You say look at the
| label not the insert, the FDA will have it. I link you to
| the FDA's label. The link literally had the word 'label'
| in it drugsatfda_docs >>> label <<<
|
| Inside the document there are _3_ things the 'HIGHLIGHTS
| OF PRESCRIBING INFORMATION', _AND_ the 'FULL PRESCRIBING
| INFORMATION' _AND_ finally 'PATIENT INFORMATION'
|
| I cite the relevant information about weight from them
| 'FULL PRESCRIBING INFORMATION: CONTENTS: PART 12 CLINICAL
| PHARMACOLOGY and you act like _I_ not you have performed
| some sort of bait and switch...
|
| _You_ are the one claiming expertise here, so enlighten
| me, where is the the carve out for "we didn't test this
| at all on the morbidly obese" in place a doctor will find
| it if not in 'FULL PRESCRIBING INFORMATION'?
| photochemsyn wrote:
| I believe the FDA relies on the "maximum expected utility
| principle" - a cornerstone of free-market economic theory.
|
| > "By combining the concept of utility with the notion of
| rational decision making, economists in the mid-twentieth
| century established a basis for the maximum expected utility
| principle. This principle is a key concept behind the creation
| of autonomous decision-making agents."
|
| https://algorithmsbook.com/files/dm.pdf
|
| This has been expressed in the past as "Each portion of wealth
| has a corresponding portion of happiness, and of two
| individuals with unequal fortunes, he who has the most wealth
| has the most happiness."
|
| A good way to accumulate wealth and maximize happiness is to
| sell drugs, and preventing the sale of drugs because of
| concerns over ill effects reduces wealth and brings sadness to
| the pharmaceutical corporation and its shareholders and board
| members; such sadness prevents them from hiring ex-FDA
| employees as consultants or managers, thus defeating the
| principle of maximum expected utility.
|
| The autonomous decision-making agents at the FDA therefore have
| no choice but to rubber stamp everything that comes across
| their desk. Doing anything else would be irrational.
| gumby wrote:
| > The autonomous decision-making agents at the FDA therefore
| have no choice but to rubber stamp everything that comes
| across their desk. Doing anything else would be irrational.
|
| You have clearly never tried to get a drug or device approved
| nor have you looked at the number of drugs that fail,
| expensively, in Phase 2 or even Phase 3. Your statement is
| utter nonsense.
| toto444 wrote:
| > I believe the FDA relies on the "maximum expected utility
| principle" - a cornerstone of free-market economic theory.
|
| This has nothing to do with 'free-market economic theory'.
| It's about decision under uncertainty. The concept was
| expressed for the first time by Von Neumann and Morgenstern
| in a book that was supposed to explain how to play poker.
|
| > "Each portion of wealth has a corresponding portion of
| happiness, and of two individuals with unequal fortunes, he
| who has the most wealth has the most happiness."
|
| I have never ever read that anywhere. One could argue that
| rich people provide more value to society and then should be
| prioritise in some circumstances but what you are writing
| seems very unfounded.
| samhw wrote:
| > I have never ever read that anywhere. One could argue
| that rich people provide more value to society and then
| should be prioritise in some circumstances but what you are
| writing seems very unfounded.
|
| Nor have I. It's such a remarkably stupid statement that it
| strikes me as _stupid in itself_ to think anyone should be
| so stupid as to believe it.
|
| It's also nothing whatsoever to do with expected utility
| theory (I don't know where they _did_ get it from).
| 'Utility monsters' - per Rawls - are a valid objection;
| 'money monsters' are not, for the very reason that marginal
| economic gain is not equivalent to marginal gain in
| happiness/utility, nor would anyone think it is.
| photochemsyn wrote:
| You can get that quote from the linked text. Notice I'm not
| actually attacking 'free-market economic theory' per se -
| but we could adjust the behavior of FDA regulators and
| pharmaceutical corporate boards by (1) banning FDA
| regulators from ever taking jobs or gifts from the entities
| they're supposed to be regulating and (2) enforcing
| criminal penalties for fraud and deception in the
| pharmaceutical sector.
|
| There's nothing like a 5-10 year term in an American prison
| to reduce happiness...
| toto444 wrote:
| > You can get that quote from the linked text
|
| True. Utility is increasing with revenue. I misunderstood
| this part of your comment. I read it as : 'if we want to
| maximum social utility let's prioritise rich people'.
| puffoflogic wrote:
| 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.
| EEBio wrote:
| How is that questionable? Isolating to one relevant treatment
| per group is a standard procedure.
| puffoflogic wrote:
| It gives study staff the ability to exclude arbitrary sick
| patients from the trial. Combine this with a little harmless
| unblinding and the whole study outcome can be fabricated with
| plausible deniability.
|
| Notice that I'm referring exclusively to studies of
| prophylactics. The patient getting sick _is_ the data point.
| oversocialized wrote:
| TYPE_FASTER wrote:
| > Why no smoking?
|
| Smoking can be an appetite suppressant:
| https://www.npr.org/2011/06/09/137085989/the-skinny-on-smoki...
|
| > Why no diabetes, given that this is an overweight subject
| group?
|
| 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/variables.
|
| https://www.verywellhealth.com/diabetes-and-intermittent-fas...
| cperciva wrote:
| _maybe they wanted to eliminate a variable /variables._
|
| There's an even simpler explanation: Fasting can provoke
| dangerous hypoglycaemia in diabetics. The first priority for
| trials is the safety of the participants.
| vericiab wrote:
| >The FDA approved Tezpire as a breakthrough drug for asthma in
| December 2021. Tezspire excluded morbidly obese people from their
| efficacy trials.
|
| 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.
|
| [1] https://clinicaltrials.gov/ct2/show/NCT02054130
|
| [2] https://clinicaltrials.gov/ct2/show/NCT03347279
| Jensson wrote:
| > 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.
|
| 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't good for the individual.
|
| 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't say much at all about the validity of the paper.
| [deleted]
| photochemsyn wrote:
| Based on the record of the pharmaceutical industry and their
| entirely captured regulatory agency, the FDA, it's not entirely
| unwise to wait about ten years after the introduction of a
| 'breakthrough drug' to see if it actually has negative side
| effects that were not discovered in the clinical trials. See
| Vioxx, etc.
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534432/
|
| > "Dr Graham, associate director in the FDA'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."
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534432/
|
| 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.
| WalterBright wrote:
| You may not have 10 years to wait if you're dying of some
| disease.
| TameAntelope wrote:
| You dying to a disease is nobody's fault (usually). You dying
| to a bad drug is arguably someone's fault, and I suppose
| there are probably not any number of documents you can sign
| that will completely abdicate the responsibility for your
| death from the corporation that created the chemical compound
| that resulted in your demise.
|
| And probably for good reason? I _really_ don 't want to live
| in a society that gives people the ability to sign their life
| away so corporations can run scientific experiments on them
| that have a real chance of death.
|
| I think there are some exceptions to this, but _generally_ it
| makes sense to not let people go from "dying of a disease"
| to, "dying of a drug".
| avgDev wrote:
| I just want to add some anecdotal evidence and what my
| experience has been like with a popular antibiotic. Cipro has
| wrecked my connective tissue and nervous system. This family of
| drugs has been around for a long time. The side effects have
| been discussed in medical studies for years. The drug has a
| black box warning label. Yet it gets prescribed very often
| against the current FDA recommendation to only be used for life
| threating infections. I have talked to top physicians in the US
| and they literally just ignore the problem like it doesn't
| exist. I have connected with physicians, chemists and other
| people with PhDs from all over the world who suffered the same.
| A pharmacists I know was called crazy by her colleagues when
| she said what happened to her.
|
| My primary physician has stopped prescribing the medication, I
| send pages of research to him, which he probably didn't have
| time to read but it validated what is going on with me. He was
| surprised I actually took the covid vaccine, as not only did
| cipro screw me up but the whole medical community also
| completely ignored me and kept asking about anxiety. When I
| clearly had mechanical issues with tendons. They ran a bunch of
| tests and told me I was healthy.
|
| Recently, Dr. Stefan Piper released a book on FQAD
| (flouroquinolone associated disability) and discussed
| pathogenesis, possible causes and therapies he has been using
| on hundreds of patients by now. He is an actual MD. From his
| experience a subset of people who are diagnosed with fibro, cfs
| developed it after taking the an fq antibiotic. Currently,
| there is no way to test for it. However, Mayo clinic is doing a
| study right now, to see if flouroquinolones are causing damage
| to mitochondria.
| pdonis wrote:
| _> relatively safe and effective medicines (i.e. Sars-CoV2
| vaccines)_
|
| By your own logic, we don't know this, because these vaccines
| haven't been in use long enough.
| photochemsyn wrote:
| I personally went and got vaccinated the second month the
| Pfizer vaccine was released (but not the first) and even so I
| viewed myself more as a guinea pig in a clinical trial than
| anything else. As I had no immediate negative symptoms, I
| then got the second dose on schedule. Had some minor muscle
| stiffness in the arm after that one that persisted for a few
| months. I then got the booster when it came out, as at that
| point the data seemed pretty clear: side effects were
| minimal, and the risks of hospitalization and long Covid
| justified vaccination.
|
| Notably however I certainly didn't expect that the vaccine
| wouldn't be 'sterilizing' and at the time the FDA was keeping
| quiet about the fact that vaccinated people could be
| asymptomatic carriers and spreaders of Sars-CoV2, which now
| seems widely accepted. The clinical data from the original
| trials has yet to be released as I understood it, and it
| likely showed that as well.
| hallway_monitor wrote:
| Exactly this. In this case it does seem like emergency speed
| was justified. However, every year over 1,500 drugs are
| pulled off the shelves because, like vioxx, they were
| discovered later to have terrible side effects. Maybe some of
| these would have been found with different study
| demographics. Maybe not. Drugs are dangerous.
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