[meowface]

>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?

[gumby]

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.

[lkey]

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]

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.

[jmgrosen]

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]

Am I losing my gdmn 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'?

[ada1981]

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]

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]

Oh the irony that you’ve excluded an investigation of the relevant example here, but made broad claims nonetheless.

[gumby]

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]

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

[refresherd]

Much like sleep apnea in the morbidly obese, this is likely just a different condition entirely with a physical cause.

As to why it is prescribed anyways - like the MD who taught me about sleep apnea said, morbidly obese people get offended when you suggest that there aren't drugs that you can give them and they just need to take some extra weight off the strained organs. It's easier to give a person who is certain that it's not the weight, but some condition solvable with drugs, a drug.

[chmod775]

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]

> 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]

Also a person who has trouble breathing tends to not do significant exercise because they run out of breath too quickly.

[jallen_dot_dev]

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]

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]

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]

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]

> 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.

[photochemsyn]

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]

> 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]

> 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.

[photochemsyn]

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]

> 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'.

[samhw]

> 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.