[HN Gopher] Drug Development Failure: how GLP-1 development was ...
___________________________________________________________________
Drug Development Failure: how GLP-1 development was abandoned in
1990
Author : bookofjoe
Score : 138 points
Date : 2024-08-30 16:45 UTC (6 hours ago)
(HTM) web link (muse.jhu.edu)
(TXT) w3m dump (muse.jhu.edu)
| tiahura wrote:
| In 1990, Pfizer and CalBio subsidiary MetaBio abandoned GLP-1
| drug development despite showing efficacy and holding patents.
| Pfizer misjudged the market for injectable diabetes drugs. CalBio
| redirected focus to a heart failure treatment. This decision
| preceded successful GLP-1 development by other companies by a
| decade. Novo Nordisk later succeeded with GLP-1 after research
| starting in 1992.
| oezi wrote:
| I guess they were aware how terrible and unpopular injections
| are for patients. These weren't the days of micro needles...
| layla5alive wrote:
| Source/elaboration?
| oezi wrote:
| This is just related that needle pens weren't available in
| the eighties. So people still were using single disposable
| syringes with needles which is more painful than using pens
| with micro needles which became available later.
| brianleb wrote:
| >>how terrible injections are for patients
|
| What is this belief founded upon?
|
| Disposable syringes and detachable needles have been around
| for over 50 years. We had 6mm needles in the 80s.
|
| Evolution of Insulin Delivery Devices
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261311/
| oezi wrote:
| This was just my understanding from seeing my grand-father
| 40 years ago having to drop his pants to use insulin
| syringe + needle, to the use today where you can lift your
| shirt and use a insulin pen in a couple of seconds.
| connicpu wrote:
| Personally I don't understand why so many people are so
| terrified of needles. Subcutaneous injection is so
| straightforward, even filling up the single use syringes
| yourself. I've done that once a week for the past nearly 7
| years. But still, from talking with other people who use
| similar pharmaceuticals to me, so many of them are terrified
| of needles to the point they choose less effective routes of
| administration, even though they wish they could have the
| benefits of the injection route.
| trogdor wrote:
| >I don't understand why so many people are so terrified of
| needles.
|
| The fear associated with specific phobias is by definition
| extreme, unreasonable, and irrational. If you could
| understand it rationally, it wouldn't be a phobia.
| Ekaros wrote:
| Personally I just don't particularly enjoy that type of
| pain... The type I associate with needles.
| johntb86 wrote:
| Maybe people just don't realize how little pain you can
| feel with a needle. I switched from the old formulation
| of humira to the new one (smaller needle and no citrate)
| and the difference is night and day. Before, I was
| dreading it every time (though objectively it didn't hurt
| that much), and after I sometimes don't even feel the
| needle.
| mannyv wrote:
| Back then people would have gone to the doctor's office for
| the injection. They would have done that because it wasn't
| quite pay-for-service back then.
| renewiltord wrote:
| It's been 34 years, so the original Pfizer patents are invalid
| and can just be copied? Clearly the primary factor in inability
| to do that has to be regulation in bringing drug to market,
| right?
| Pet_Ant wrote:
| This is tragic when you think about all the people that died of
| obesity in the mean time. By now, the patent would have expired.
| Many more people would have survived Covid.
| Someone1234 wrote:
| The patent thing in particular. The drug companies are
| currently charging $1000 per MONTH which is an unimaginable
| amount of money. Therefore, a lot of people who would otherwise
| benefit (e.g. obese, prediabetes) simply won't have the option.
|
| Unclear to me who has $12,000 extra they can spend on a non-
| immediate life-saving medication like these. There is
| technically market competition (wegovy vs zepbound), but
| surprisingly they all are charging $1K/month with a "discount
| card" which can be withdrawn at any time, and even that still
| makes is $6K/year.
|
| Currently, many people are benefiting via legal compounding
| from safe US licensed pharmacies due to the shortages/FDA
| shortage list, but that route is very soon going to be closed.
| Then back to $1K/month Vs. $1K/month.
| maxdemarzi wrote:
| It's $275 a month plus $99 every 6 months at SlimDownRX. The
| compounded pharmacies are helping.
| fnord77 wrote:
| $39/month from the top chinese vendors
| maxdemarzi wrote:
| Tell me more...
| Someone1234 wrote:
| It won't be for long. That can only exist because of the
| FDA Shortage List, and with the official manufacturers
| releasing single dose vials, it is only a matter of "when"
| not "if" it won't be classed as shortage, and you're back
| to paying $1K.
| HeatrayEnjoyer wrote:
| Why would classifying it a shortage make it expensive?
| Someone1234 wrote:
| Classifying it as a shortage makes it cheap. It will get
| expensive when it is off the shortage list.
| NotYourLawyer wrote:
| That makes no sense.
| Someone1234 wrote:
| The FDA shortage list allows compound pharmacies to
| produce it without paying for patents/licensing.
| TylerE wrote:
| Being on the shortage list is what allows compounders to
| sell it. Once that is no longer true, that option goes
| away.
| technofiend wrote:
| Compounded is amazingly cheap particularly when you start
| because a single bottle of compounded Wegovy is many doses at
| the lowest recommended dosage levels. I think the first
| bottle cost me $200 and lasted two months, possibly longer.
| Wegovy would be $1300/mo at Costco without insurance. Absurd.
| NotYourLawyer wrote:
| What actually _is_ the compounded stuff though? Where does
| it come from? What's in it?
| trogdor wrote:
| Their source for semaglutide is crushed Rybelsus pills.
|
| See my other reply to this post for sources.
| NavinF wrote:
| FYI 92% of Americans have health insurance. People are not
| paying $1k/month.
|
| > a "discount card" which can be withdrawn at any time
|
| if we're talking hypotheticals...
| Someone1234 wrote:
| FYI most health insurance won't cover the $1K/month cost of
| either weight loss medication currently (only for diabetes
| version with appropriate diagnosis). So people are,
| absolutely, paying out of pocket. I personally know two
| people that are and there have been multiple articles about
| it.
|
| > if we're talking hypotheticals...
|
| We aren't. We've seen it with multiple very expensive US
| drugs that had generous "discount cards" that were
| withdrawn when they got popular. It is like a drug-dealer
| model, get them hooked, then jack up the price.
|
| The drug companies know this is a golden goose, and they
| only have 13 remaining years to squeeze it.
| ribosometronome wrote:
| Most health insurance will not cover these medications for
| the purpose of weight loss. Even for diabetics, many
| require you to go through other medications like metformin
| first, to show that can't help with your A1C (which it very
| well may, but without as much help losing weight). There
| are discount coupons that come and go and bring it down to
| like $500/mo if you have insurance that doesn't cover, but
| they come and go. A lot of people are definitely paying a
| $1k/mo for their skinny-as-a-service subscription.
| Spooky23 wrote:
| Most insurance plans are excluding the drugs for weight
| loss purposes.
|
| With a type-2 diagnosis, you can get Ozempoc, Zephound or
| Rybelsus covered. Wegovy, etc and off-label Ozempic is
| excluded by most formularies.
|
| Some big companies and government plans are covering it
| however.
| HeatrayEnjoyer wrote:
| Insurance only covers with a diabetes prescription. My
| sister in law is a pharmacist and 50% of her shop's fills
| are cash price because insurance will not help.
| wl wrote:
| You're probably getting a few things mixed up.
|
| Insurance generally only covers Ozempic if someone has
| diabetes. Some insurance plans cover Wegovy, the same
| drug with a different dosing labeled for weight loss, but
| many don't.
| Spooky23 wrote:
| A lot of the compounded stuff is nonsense. They charge you a
| few hundred dollars for vitamin B supplements with some
| shadily-sourced GLP drug that fell off the truck or was
| manufactured in some mysterious factory in Ukraine or
| wherever.
|
| Even in the drugs are real, most of the online compounders
| are out of Florida or other locals with a long history of
| shady behavior and poor regulation.
| ik8s wrote:
| Exactly! I've reasearched some semaglutide compounding
| pharmacies and it terrifies me that their semaglutide
| source is top secret; never disclosed. Where's it coming
| from and what are people really injecting?
| trogdor wrote:
| Their semaglutide source is crushed Rybelsus pills.
|
| See, for example:
|
| https://a4pc.org/2024-04/mass-confusion/
|
| https://subsema.com/wp-content/uploads/2024/05/White-
| Paper-S...
|
| https://mynextgenrx.com/wp-
| content/uploads/2024/03/Compounde...
| Spooky23 wrote:
| I doubt that's supporting the industry. Rybelsus is
| constrained from a supply pov and expensive.
| trogdor wrote:
| On the contrary. It's quite cheap, since compounding
| pharmacies are selling semaglutide for injection.
|
| Last week I purchased 90 tablets of 14mg Rybelsus for
| just over $700. My cost per milligram of semaglutide was
| just over 50 cents. Compounding pharmacies are preparing
| weekly injections containing _at most_ a few milligrams
| of semaglutide, and they are selling a one-month supply
| for ~$250. Their cost for active ingredient is well-under
| $10.
| andy_ppp wrote:
| In the UK Wegovy is PS200 per month privately, Why is it so
| expensive in the US?
| petercooper wrote:
| I pay PS169/mo for Mounjaro, but yeah, it seems a common
| thing for baseline prices for medication to be very high in
| the US, then often reduced significantly by insurance. I
| assume mostly because they can get away with it whereas
| next to no-one in the UK is going to pay PS1000/mo for it.
| 404mm wrote:
| Because we have shitty laws created by government that
| "represents the people" but runs on money from corporate
| donations. In other words, they charge $1k because they
| can.
| phonon wrote:
| Zepbound is $399-$650 per month, ordered direct, if insurance
| does not cover it. Not great, but at least a start.....
|
| https://www.help.senate.gov/chair/newsroom/press/news-
| sander...
| yieldcrv wrote:
| > Many more people would have survived Covid.
|
| Accurate, I periodically think about the standard here
|
| Over 1 million Americans are in the reported death tally, this
| is attributed to a failure of a lot of things under an
| administration's watch
|
| But if it was just 100,000 would the criticism or consternation
| be any different? if it was just 10,000 and matched the
| seasonal flu would it be any different? if it was just 3,000
| matching a tragedy of the magnitude of _9 /11_ would it be any
| different?
|
| if it is to be different, what would the threshold be
| HeatrayEnjoyer wrote:
| It would be very different if I didn't have to bury two
| people I cared very much about, yes.
| coderintherye wrote:
| >MetaBio went down because there were mistaken ideas about what
| was possible and what was not in the realm of metabolic
| therapeutics, and because proper corporate structure and adequate
| capital are always issues when attempting to survive predictable
| setbacks
|
| Like many startup failures, funding issues and corporate
| structure were more pivotal than the progress made on the actual
| problem.
| Mistletoe wrote:
| Obesity was about 17% in the USA in 1990 and is now at an
| incredible 40%.
|
| One wonders how many lives were lost by abandoning this in 1990.
| LarsDu88 wrote:
| Well, one could argue obesity has as much to do with
| deregulating the advertising of sugary cereals as a breakfast
| food for children in the 1980s as the non-existence of a
| $10,000+ shot that alters human metabolism!
| rootusrootus wrote:
| Look at the historical rate of obesity in Europe. Following
| the same trajectory as the US, as far as I can tell. Does
| deregulating advertising of sugary cereals also explain that?
| cassepipe wrote:
| Advertising probably not but the simple availability of
| ever sweeter cheap products and with time their integration
| in people's diet is a strong candidate. Especially since
| sugar is way less good than say fat at provoking the
| feeling of satiation (I can think only of evolutionary
| explanations for that, available sweet food in the wild,
| think fruits, are not very nutritive, especially ones not
| selected by humans over time)
| oezi wrote:
| > surgary cereals
|
| What else are kids eating these days for breakfast?
| jajko wrote:
| Whatever you teach them to eat. But parents are often
| lazy, its supremely easier to buy addictive paper boxes
| and be done rather than wake up 10 minutes earlier (or 2)
| and cook or prepare something quick and healthy. Depends
| also where you live, US its exactly as we discuss, ie
| France or Switzerland its a completely different world,
| and its immediately obvious on people too. This approach
| also permeates many aspects of society.
|
| Kids also imitate what they see in parents, both good and
| bad. No point preaching healthy lifestyle if one is obese
| and spends hours daily in front of TV eating junkfood.
| Also, back in 80s I had maybe 4 years and I knew very
| well sweet stuff is bad for one's health, it was always
| as obvious as ie that cigarettes were very harmful and
| highly addictive.
|
| I _love_ how many folks desperately try to throw blame on
| literally anybody, anything for their failures in life,
| rather than taking a cold hard look at the mirror and
| accepting one 's own failures, as a parent but also
| generally as human in this case. Sure, it makes life with
| oneself a bit easier, instead of huge instant dose of
| misery and self-disappointment its slowly dripping
| through the cracks of illusions for the rest of their
| lives and people love feeling like a victim, but it very
| effectively prevents actually fixing anything.
|
| So sure, lets blame sugar industry (which is doing
| exactly what all other businesses do - sell to as many
| people as possible), lets blame tobacco industry or wine
| producers for people's failures. Lets wait till
| politicians will sweep away all obstacles and traps from
| our lives, of course that's a reasonable expectation.
| Anything but throwing away that 3rd cupcake or starbucks
| latte.
| oezi wrote:
| It was a serious question. Who is cooking in the morning?
| And what? Eggs and bacon (isn't that just replacing the
| sugar with fat/salt)? Porridge?
|
| Bread/toast also isn't particularly healthy (too high in
| salt, spikes your insulin too much).
|
| Fruit is also just very similar than sweets with a bit
| more fiber, isn't it?
|
| So, a plate of some veggies?
|
| And don't get me started on spreads which are available:
| you can choose between fat (butter/margerine/cheese/most
| other spreads), high salt (meat/salami) and sweet (jam,
| honey, nutella)
| TylerE wrote:
| Ironically, as a diabetic (or even a non-diabetic) fat is
| a pretty innocuous thing. Certainly compared to carbs...
| rootusrootus wrote:
| Fat is probably a better choice than sugar in nearly all
| instances. High calorie but it'll keep you full quite a
| while. Veggies definitely aren't any good for that. My
| strategy these days is to try and eliminate simple sugars
| and highly refined carbs whenever possible; everything
| else is fair game. When I see something advertised as
| "low fat" I instantly conclude it will probably make you
| fat and it's best to skip it.
| rootusrootus wrote:
| > I love how many folks desperately try to throw blame on
| literally anybody
|
| When I read opinions like this, I immediately have two
| thoughts.
|
| 1) What makes people think it's their right to shame
| anyone else? The 'look in the mirror' advice is pretty
| universal.
|
| 2) Is there even anyone qualified to make comments like
| this? Am I to assume that the folks who imply their
| superiority do not in fact have their own failings? Glass
| house and all that.
|
| I think perhaps it's more complicated, and declaring it a
| moral failing is not going to improve anyone's life.
| firesteelrain wrote:
| Obesity is a complicated problem and we can't blame
| corporations alone.
| catchnear4321 wrote:
| > ...we can't blame corporations alone.
|
| ok, but we can very much start with blaming corporations.
| sure, there are other factors at play, these are very large
| systems acting on individuals.
|
| that's the point. corporations are sufficiently complex and
| large to manipulate the system.
|
| individuals rarely are, and when they do, it is often by
| forming a corporation around themselves. influencers are
| faces for larger operations, they have employees,
| payroll... just like a more traditional brick and mortar.
| grouchomarx wrote:
| I'm willing to
| jjtheblunt wrote:
| it's not super complicated for most cases: grams of
| sugar(s) ingested versus grams of essential nutrients
| (proteins, fats) is too high.
| Someone1234 wrote:
| It isn't a coincidence though that back in the 1990s the sugar
| industry was spending/lobbying big to attack dietary fat. A lot
| of foods intentionally removed satiating fats with nutritional
| value and replace it with cheaper sugars that you can eat
| almost unlimited amounts of without feeling full.
|
| If I could only name two big "things" that contributed most to
| the obesity problem of today it would be:
|
| - Agricultural Act of 1970 and the polices of the 1970s,
| resulted in corn so cheap and abundant that other industries
| actively looked for usages. HFCS was obviously one such use,
| and it out-competed all other nutritional sources on price.
|
| - The 1990s "fat bad, sugar good" which resulted in
| reformulating a lot of staple foods and the beginning of
| standard sweet food allowing the cheap HFCS to flow.
|
| The US needs, and has needed, to offset the corn subsidies that
| get turned into HFCS by adding a "sugar tax" at the consumer
| side. That way it can still exist for animal feed, and be used
| where appropriate without being unnaturally and unreasonably
| inexpensive.
|
| The reason they don't is that it is political suicide to
| suggest sugar taxes in personal-freedom loving US that is
| pretty anti-tax regardless.
| cmiller1 wrote:
| https://slate.com/technology/2018/03/big-sugar-isnt-to-
| blame...
| Someone1234 wrote:
| Did you read that article or just the title? Because the
| article isn't focused on disproving any facts of the "big
| sugar bad" side but rather saying the facts as they stand
| are being unfairly characterized.
|
| The article is well written, and I WOULD recommend it for
| anyone interest in this topic. But ultimately I'd just
| point to the same facts presented in the article, and you
| determine if we're being mean to the sugar industry or
| fair.
|
| The result is the same either way, regardless of who gets
| the blame.
| 462436347 wrote:
| Sugar consumption peaked in 2000 and has been in steady
| decline since, and not only that, but the decline has been
| led by a decline in HFCS consumption:
| https://news.ycombinator.com/item?id=38094768
|
| 30% of the US was obese in 2000, now it's over 40%, despite
| per capita sugar consumption reverting to what it was
| pre-1975.
|
| > The US needs, and has needed, to offset the corn subsidies
| that get turned into HFCS by adding a "sugar tax" at the
| consumer side.
|
| If anything, we need a tax on added fat and sodium, the two
| biggest drivers of food hyperpalatability, when added in
| excess of the thresholds identified in this paper (> 25% kcal
| from fat and >= 0.30% sodium by weight):
|
| https://onlinelibrary.wiley.com/doi/10.1002/oby.22639
|
| > The HPF criteria identified 62% (4,795/7,757) of foods in
| the FNDDS that met criteria for at least one cluster. Most
| HPF items (70%; 3,351/4,795) met criteria for the FSOD
| cluster. Twenty-five percent of items (1,176/4,795) met
| criteria for the FS cluster, and 16% (747/4,795) met criteria
| for the CSOD cluster. The clusters were largely distinct from
| each other, and < 10% of all HPF items met criteria for more
| than one cluster.
|
| (CSOD, carbohydrates and sodium; FS, fat and simple sugars;
| FSOD, fat and sodium; HPF, hyper-palatable foods.)
| fortran77 wrote:
| Why don't we just tax obesity?
| wolpoli wrote:
| So some kind of annual appointment where we get our BMI
| measured
| 462436347 wrote:
| Because adding fat (usually in the form of vegetable oil)
| and sodium is the cheapest, easiest way to make food
| hyperpalatable, and the share of the grocery store shelf
| space occupied by these products has exploded in the last
| 40 years, greatly contributing to the obesity epidemic.
| Ominously, this a trend that the researcher behind that
| paper I linked to attributes in large measure to the
| tobacco companies entering the packaged food business:
| https://onlinelibrary.wiley.com/doi/10.1111/add.16332
| happosai wrote:
| The American version would not be tax the Fat, but to
| make fat pay more for their health insurance.
|
| And the only result would be more people unable to pay
| their health insurances...
| ClarityJones wrote:
| > Though substantial progress was being made, Pfizer decided to
| pull support ... [t]he "gliptin" class of drugs peaked at annual
| revenues of around $10 billion and remains a major oral therapy
| for type 2 diabetes.
| ClarityJones wrote:
| > Pfizer found other routes to remain successful (some, such as
| their mRNA COVID19 vaccine, also in-licensed from smaller
| companies).
|
| > Even the biggest blockbusters can be dismissed ... by ...
| ambitious people, ... because ... ideas of how the market will
| react... .
|
| > These same dynamics are undoubtedly playing out today
| [seemingly referring to previous statements on their COVID-19
| vaccine], and it will likely take decades to determine just how
| costly some of today's mistakes will prove to be.
| nrb wrote:
| > then the implication is that they released the mRNA vaccine
| because it too would increase disease (and thus avenues for
| profitability)
|
| Sure, a disease that kills a patient very quickly is bad for
| business. Better for them to be alive and fall ill later on
| from a laundry list of profitable ailments.
| sweeter wrote:
| The problem with corporate driven drug development is on full
| display here, they are treating drugs (and by extension, human
| lives) like investors treat tech startups. It really pisses me
| off when people say that this drives innovation.
|
| The majority of corporate research money goes into patent
| extension methods (like slightly tweaking the delivery method, or
| slightly tweaking the forumal ala insulin being released as a
| free medicine, but costing thousands of dollars a month because
| of "evergreen" patent extension from corporate pharma companies)
| and on the other hand most novel compounds come from public
| research paid by taxpayers. Of which is then sold _back to us_ by
| coporate pharma companies that buy that research.
|
| There is an entire established pipeline, these researchers have
| no other options than to sell their research papers and findings
| to companies. It is disgusting on every level and indefensible...
| especially for the country that pays more than any OEC nation for
| healthcare, and has worse health outcomes than the majority of
| extremely impoverished "3rd world" countries. It kills millions
| every year, and is extremely shameful. It is the biggest
| embarrassment conceivable
| siliconc0w wrote:
| The catastrophic failure of FenPhen also cooled the industry's
| interest in obesity medication.
|
| Part of the problem is that it is so slow and expensive to bring
| a drug to market, which encourages risk aversion. It'd be
| interesting if we found better regulatory and financial
| engineering strategies here. There is a gigantic hidden graveyard
| of people who have died due not having access to medications that
| could have been produced and approved (which may have even been
| massively profitable) but were it just didn't make sense to try
| with today's incentives.
|
| Maybe FDA works in classes where class 0 is entirely experimental
| and only available to terminal patients, class 1 is shown to be
| safe in animals and approved only for extreme cases, class 2
| evidence of safety in humans and some evidence of efficacy, and
| class 3 is what we have today.
| Spooky23 wrote:
| That just pushes the moral hazard down to the providers and
| patients.
|
| Given how big the industry is that peddles mostly bullshit
| vitamins and supplements, I think society is best served by a
| conservative FDA.
| tgsovlerkhgsel wrote:
| Classes 0-2 could be experimental, non-commercial approvals
| that can be used as stepping stones to get long term data but
| not sold for profit.
| carlmr wrote:
| >not sold for profit.
|
| The only way to ensure no profit would be to provide them
| for free. Which, granted, may be good still for the
| pharmaceutical companies to lessen the costs for approvals,
| but Hollywood accounting makes it impossible to have any
| price depend on profits, because profits are more an
| accounting fantasy than a fact.
| selimthegrim wrote:
| Ring 0 for drugs?
| ajmurmann wrote:
| I personally like the idea of a "accredited ingestor". You get
| a certification indicating you understand enough about drug
| development and associated risks and then you are allowed to
| decide for yourself what you are willing to take.
|
| In general I am a big fan of FDA approval just becoming a stamp
| on a product like the Nintendo Seal of Approval and letting
| consumers and insurers decide what they make of it, but that
| would never fly
| vips7L wrote:
| I write software for this industry, the thought of not
| involving the FDA genuinely scares me.
| ajot wrote:
| I do admin work for a pharma-related company. I would never
| want to be in charge of verifying with my own body what
| treatment is safe and/or effective.
|
| Drug development and clinical trials are expensive for a
| reason. Not doing them in an orderly manner is more
| expensive.
| CamperBob2 wrote:
| Fortunately, the position would be voluntary.
|
| You might be a big fan of the work the FDA does to keep us
| safe in light of past industry abuses, but keeping good
| drugs off the market - whether by outright fiat or by
| making them too expensive to develop, test, and deploy --
| also has a terrible human cost. It's not clear that the FDA
| has found the right balance between risk reduction and
| upside potential.
| 0cf8612b2e1e wrote:
| Drug development is a conservative industry. Even with
| researchers/companies/FDA all doing their best to develop
| good treatments, there are still many drug failures due
| to efficacy or safety.
|
| Being more lassiez faire is going to lead to direct harm
| of some patients. Is it a worthwhile tradeoff vs
| potentially addressing some unmet need is a tough
| calculus.
| hobermallow wrote:
| What criteria would you suggest to measure in an effort
| to make it _clear_ that the FDA _has_ >found the right
| balance between risk reduction and upside potential?
| CamperBob2 wrote:
| I don't think there's a good answer to that question,
| unfortunately. What we're doing now seems to be working
| for most people most of the time, but it'd be absurd to
| think there's no further room for optimization. And it
| seems unlikely that the best approach is more restrictive
| regulation, given that extremely-useful drugs are going
| undeveloped for decades.
|
| So... that leaves more flexible regulation as a
| worthwhile approach going forward. I like the idea of
| making limited human trials easier to carry out and less
| costly in general.
| BurningFrog wrote:
| One far less scary version is to allow drugs approved by
| other reputable agencies (EU, Japan, UK, maybe) to be used
| in some limited capacity in the US.
| ajot wrote:
| From what I've heard from some friends working with
| regulatory agencies worldwide, this is currently the case
| or is about to happen. FDA-EMEA-(whatever the japanese
| regulatory agency's called) have agreements for
| treatments approved in one of the other two agencies to
| be easily approved.
| zerkten wrote:
| There is a history of these agencies later withdrawing
| approvals and FDA conservatism protecting US healthcare
| consumers. The same pattern applies with these other
| agencies not basing decisions on FDA approval. Overall,
| the combination of approval authorities and global
| surveillance delivers the best results by ensuring the
| broadest coverage and continued research.
| BurningFrog wrote:
| The rarely understood tradeoff in this arena is that no
| matter what you do, your decisions kill people!
|
| Everyone understands the case when (A) you approve
| something that later turns out to kill people.
|
| The other case (B), when you _don 't_ approve something
| that _would_ have saved lives is much less understood,
| but those people are just as dead as those from case A.
|
| One famous case B is when the FDA only approved beta
| blockers 17 years after other major countries. This cost
| ~10k US lives per year, or ~170k lives total.
|
| Because A errors produces headlines and scandals, while B
| errors are just the normal deaths we are used to, the FDA
| is heavily incentivized to minimize A errors, regardless
| of the B error rate.
| bobthepanda wrote:
| The incident around thalidomide is basically FDA mythos
| at this point.
| dwattttt wrote:
| We all love a good trolley problem
| the8472 wrote:
| https://web.archive.org/web/20210125231725/https://blog.j
| aib...
| selimthegrim wrote:
| Not just lives also DALYs from glaucoma.
| MostlyStable wrote:
| An important thing to remember when thinking about this
| thing: the downside of approving a drug that was
| dangerous is bounded: it kills people or causes some
| unexpected side effect and then it gets pulled.
| Meanwhile, the downside of _failing_ to approve something
| that could have saved /improved lives is at least
| potentially unbounded: if it never gets approved that's
| the entire futures worth of humanity who is unable to
| take advantage of it (although admittedly I'd like to
| imagine that _eventually_ tech will improve to the point
| that we either figure out we should approve the drug
| and/or invent something else that obviates the need).
|
| The point is that case B is both harder to notice and at
| least potentially _much_ worse than case A. And it's the
| case that the FDA currently errs towards.
| rich_sasha wrote:
| I believe European regulators approved Boeing 737 Max on
| this principle. And in turn FAA approved it because
| Boeing said it's safe an compliant.
| paulmd wrote:
| that already exists, it's called doing research chemicals.
| You can do survodutide or whatever other next-gen drug right
| now and "do your own research" on the supply chain and
| efficacy and safety. They're everywhere and functionally the
| FDA can't stop you.
|
| should that be officially legitimized in any way by the FDA?
| _fuck no._
|
| As soon as you break down the barrier in any way, companies
| will spring up exploiting it and promising miracle cures etc.
| even if you want to do RCs the FDA keeping a minimal wall
| there benefits you.
| 0cf8612b2e1e wrote:
| It is a philosophical question: Would you rather people die due
| to taking a harmful compound or die due to lack of access to
| something that may have helped them.
|
| Access to experimental treatments also opens up more perverse
| incentives where desperate people are likely to try anything.
| ajuc wrote:
| You can have a class of drugs allowed if you're going to die
| anyway.
| PaulHoule wrote:
| People in that state are highly vulnerable to fraud. See
| https://en.wikipedia.org/wiki/Amygdalin
| donbateman wrote:
| They are also vulnerable to dying. They should be able to
| try whatever drug they need and the government shouldn't
| be allowed to stand in their way.
| 0cf8612b2e1e wrote:
| The pharma companies are not clamoring for a huge surge
| in compassionate use (emergency use of unapproved drugs)
| either.
|
| Who is going to pay? Early stage drugs are still figuring
| out their manufacturing process, and quantities can be
| extremely limited. Say you give drug X to a sick patient
| and they die, what then? Was it because of the novel
| drug? Not a favorable position to have more deaths
| associated with your treatment. Can you draw any data
| from these patients to inform further trials? Also
| complicated because end stage patients have already
| exhausted other options and the interaction with other
| compounds can make disentangling this harder.
| jayd16 wrote:
| It feels like the odds a drug is perfect and a few years too
| late for you unless you skip the tests is exceedingly low
| compared to the odds that a drug will not pan out or might
| even be unsafe.
|
| The perverse incentives is also a very real issue.
| Ekaros wrote:
| With drugs there is also the option that something is not
| harmful, but also not effective and thus lead to something
| effective not be taken...
| AceJohnny2 wrote:
| https://en.wikipedia.org/wiki/Trolley_problem
| slacka wrote:
| How is this the trolley problem for someone with a terminal
| disease? I assume the sick population are the people in the
| trolley and the experimental patient is the person on the
| track? In this scenario, by not pulling the lever you just
| extend the life of the people on the trolley to the end of
| the ride for a dangerous drug. Where as, pulling the level
| could save the life of the person on the track and the
| people in the trolley if the drug is successful.
|
| What am I missing? For non-terminal diseases, it's a bit
| murkier, but still I don't follow the analogy.
| cameronh90 wrote:
| Some people do go into remission from a terminal cancer
| diagnosis, either because the diagnosis was wrong or
| because they live long enough for an approved treatment
| to come on the market. Also, that you have terminal
| cancer doesn't say anything about how long you're going
| to live. You can live for many years with terminal
| cancer.
|
| I do think we're overly cautious with drug approvals and
| I think we should be more open to leaving the decision to
| patients and their medical teams, but it's not as simple
| as saying someone's terminally ill, so just do whatever.
| Reducing it down to the trolley problem makes it seem
| much more black and white and immediate than it really
| is.
| BurningFrog wrote:
| If the public could be made aware of the millions of Americans
| who have died from FDA being so restrictive, things would
| change quickly.
|
| I don't think that has any chance of happening though.
| jermaustin1 wrote:
| The public is aware of the millions of Americans who have
| died from the FDA being so lax.
| doctorpangloss wrote:
| Can you provide some examples?
| Something1234 wrote:
| Thalidomide
|
| The therac-3
|
| That one alzheimers drug a lot of people were pissed
| about cause it didn't work and was expensive.
| doctorpangloss wrote:
| Those killed millions of people?
| cj wrote:
| If the goal is to shock people into thinking a certain
| way, 20,000 deformed infants has more or less the same
| shock-value as 1 million deaths.
|
| (Obviously talking about Thalidomide here)
| doctorpangloss wrote:
| Thalidomide was used and approved around the world, not
| just in the US. It's an interesting example of
| _something_ but not millions of deaths.
|
| But I get a sense that the original poster isn't
| sincerely interested in talking about the complex
| question, how should the FDA regulate drugs?
|
| One thing's for sure: High drama personalities have
| always had a tenuous understanding of the facts behind
| their "shock" and outrages. Or maybe one of the
| commenters has learned a valuable lesson about copy and
| pasting from chatbots.
| tredre3 wrote:
| Speaking of factual drama, Thalidomide was not approved
| in the US during all the drama in the 60s.
|
| It has since been approved for cancer where its benefits
| outweigh the side effects, but it doesn't negate that the
| FDA prevented harm to babies by blocking it in the 60s.
| devilbunny wrote:
| Thalidomide was not approved in the US until long after
| the birth defect scandal, FWIW.
| dannyobrien wrote:
| The FDA famously _didn 't_ approve Thalidomide, which
| meant only 17 people were affected in the United States.
| https://en.wikipedia.org/wiki/Thalidomide#History
|
| (I don't think this affects your argument directionally,
| but worth noting.)
| carlmr wrote:
| >(I don't think this affects your argument directionally,
| but worth noting.)
|
| Aside, but this is high class discussion culture I
| haven't seen on the Internet in a while.
| BurningFrog wrote:
| That Thalidomide was _not_ approved by the FDA, while it
| hurt thousands of babies around the the world is probably
| a big reason that FDA has been very restrictive in the 60
| years since, and often bans drugs that are available in
| the rest of the world.
| pfdietz wrote:
| The Therac-25 (where did the -3 come from?) killed four
| and seriously injured 2.
|
| I supposed 6 is kind of like 1 million, for large values
| of 6.
| SilasX wrote:
| Yeah -- that's the problem. You can't make the right
| decision when you only look at the costs of a yes but never
| the costs of a no. _Both_ matter!
|
| Politicians _can_ puff themselves up by only grandstanding
| about the former -- but that doesn 't make for good policy!
| xkcd-sucks wrote:
| Or even a graduated approval scale with categories of limited
| liability, etc.: For example, when Vioxx and other cox-2
| inhibitors were withdrawn from the market, some employees
| really stocked up on the reps' samples. And in the present it
| is said that some vets prefer the off-label-for-humans options
| per [0]
|
| [0]
| https://www.merckvetmanual.com/pharmacology/inflammation/non...
| zoklet-enjoyer wrote:
| I found some phentermine tablets next to my neighbors trash
| bin, still in the blister pack. So I thought maybe if I snorted
| one I'd get high. I didn't. Just got really jittery and
| nauseous then puked on a tree while a woman who looked like she
| worked for the government walked by (this was in the capitol
| city of another country). Would not recommend. And then I
| accidentally brought it back with me through customs.
| mewse-hn wrote:
| So just a normal weekend then?
| morkalork wrote:
| Not knowing what FenPhen was I checked the wiki page and wow,
| it looks remarkably similar to those sketchy amphetamine
| analogs people sell on the internet like 3-FA, of course
| selling that as an anti-obesity drug was going to go sideways.
| hmottestad wrote:
| Norway is big on oil and gas. One of the incentives we give out
| is a cost sharing model for the initial exploration phase.
|
| Not sure how that would translate, but an important factor
| would be that the health care providers (private or state) have
| some say in what kinds of illnesses need better drugs.
| pnw wrote:
| That's a nice incentive but Norway's tax policy is a major
| disincentive to any new venture. I'm currently helping a
| founder relocate his Series A company as a result.
|
| https://www.bloomberg.com/news/articles/2024-05-08/norway-
| ri...
| doctorpangloss wrote:
| > The catastrophic failure of FenPhen also cooled the
| industry's interest in obesity medication.
|
| In the 90s, more Americans were willing to have an eating
| disorder to stay thin compared to today.
| skyyler wrote:
| Fen-phen was an obesity medication that caused valvular heart
| disease and pulmonary hypertension. If you've never heard of
| fen-phen, check out this article from Sept. 23, 1997 in the
| New York Times: https://archive.is/ottWQ
|
| Wyeth set aside $21.1 billion to cover the lawsuits.
| https://archive.is/k3Go4
|
| It was kind of a big deal. Not many people younger than ~30
| have heard of it for some reason.
| hilux wrote:
| That article could be greatly shortened without losing any useful
| content. The author seems to be guilty of resulting, i.e. judging
| a decision by its ultimate outcome, rather than by the quality of
| the decision-making, considering knowledge and constraints at
| that time.
| ck2 wrote:
| Also they've noticed oddly GLP-1 seems to prevent people from
| dying of covid
|
| Doesn't prevent infection but rather death from it
|
| https://www.nytimes.com/2024/08/30/health/wegovy-covid-death...
|
| https://www.jacc.org/doi/10.1016/j.jacc.2024.08.007
| brianleb wrote:
| GLP-1 => weight loss => decreased obesity, improved
| cholesterol, improved blood pressure, improved glucose control,
| etc. etc. => better survival rates (all causes)
|
| There is no presumed clinically relevant mechanism for GLP-1s
| to be protective specifically against COVID death. It is simply
| protective against all death, of which COVID is a type.
| Healthier people are less likely to die, statistically. The
| same benefit can be (and is being) said about GLP-1s and heart
| attacks, heart failure, stroke, kidney failure, etc.
| wswope wrote:
| Rather arrogant of you to spew forth unfounded conjecture
| without even bothering to skim the high-level details of a
| six paragraph article.
|
| > the protective effect occurred immediately -- before
| participants had lost significant amounts of weight.
|
| > the participants taking the drug were not healthier than
| the others, said Dr. Harlan Krumholz, a cardiologist at Yale
| and the editor in chief of the journal.
| brianleb wrote:
| I understand how you came to your conclusion, however what
| you are quoting is journalism (and it is factually
| incorrect). I read the actual peer reviewed article.
|
| The patients in the COVID group, _when they got COVID_ had
| already begun losing significant amounts of weight. The NYT
| article is 100% incorrect on this matter. See:
|
| >>The change in weight between randomization and reported
| COVID-19 in patients who died of COVID-19 according to
| treatment was -6.4 kg in the semaglutide group vs -0.9 kg
| in the placebo (P < 0.001) group and -8.4 kg vs -1.25 kg (P
| < 0.001), respectively, in patients who did not die.
|
| They go on to say that there is a correlation between
| obesity and adverse COVID outcomes:
|
| >>There was an associated increased risk of respiratory
| decompensation and mortality in patients with COVID-19 and
| obesity16,17 and plausible biologic hypotheses associating
| obesity with adverse COVID outcomes, including impaired
| respiratory status, lower cardiometabolic reserve, or
| immune hyperreactivity or dysregulation.18
|
| And they double down on the fact that the patients
| absolutely had weight loss at time of COVID.
|
| >>Accordingly, it is plausible that the decreased risk of
| infectious deaths is caused by weight loss, which was 5 kg
| greater in patients assigned to semaglutide compared to
| placebo by 1 year, the average time to COVID-19 diagnosis
| after randomization.
|
| I will leave you with the note that nowhere in the journal
| article do they make any claims whatsoever about
| semaglutide's effect on COVID outcomes. They exclusively
| discuss outcomes as related to metabolic health.
| Semaglutide is a means to an end. The means is weight loss.
| The end is better health.
| wswope wrote:
| I read the JACC article too, and thought the NYT claims
| were decently supported:
|
| > The second unexpected observation was the lower rate of
| non-CV death with semaglutide vs placebo, particularly
| infectious deaths, including in patients with reported
| cases of COVID-19. The mechanism by which semaglutide is
| associated with lower CV or non-CV mortality is unknown.
| Weight loss improves traditional cardiometabolic and
| kidney risk factors,3 such as hypertension, dyslipidemia,
| renal function,26 and dysglycemia. However, the blood
| pressure and lipid reductions in SELECT with semaglutide
| were relatively small compared with those in dedicated
| risk factor-lowering trials, and the observed reduction
| in major adverse cardiovascular events is more than would
| be expected based on those changes.
|
| You could absolutely be right that body weight is a
| lagging indicator, and these patients are getting a
| bigger improvement in systemic inflammation/their
| hematologic profile than weight loss alone would
| suggest... but running immediately to that conclusion is
| major hubris in my book. I don't think it's remotely
| implausible that there are one or more yet-unknown
| metabolic pathways tweaked by GPL1 agonists that could
| explain the effect.
| thehappypm wrote:
| I wonder if this has anything to do with blood sugar -- even
| before you start losing weight, you're eating way less calories
| (and probably less junk) and so you might have health benefits
| just from starting the regime.
| jmount wrote:
| It goes in phases. Anything other than pill use to be a hard no,
| but now we see injections moving beyond just vaccines. I've also
| heard from a friend that large pharma internal R&D is "pretty
| much just cancer for now."
| brcmthrowaway wrote:
| Could this be true for LK99
| adamontherun wrote:
| Acquired had a great episode earlier this year that really
| connects with this. They talked about how Novo Nordisk stuck with
| GLP-1 research for decades, even when it didn't seem like a sure
| thing.
|
| A big part of that was Mads Krogsgaard Thomsen, who pushed for
| GLP-1 research at Novo even when he faced a lot of skepticism and
| wasn't always treated well for it. Compare that with MetaBio--
| mentioned in the study--where Pfizer pulled the plug early and
| missed the boat entirely. Novo's persistence, especially
| Thomsen's, led to Ozempic and Wegovy
| unavoidable wrote:
| So much of this is hindsight bias though. There were no
| shortage of people with ideas and companies pursuing obesity
| drugs through a number of different pathways. Only in hindsight
| does it seem "genius" that Thomsen persisted and succeeded
| where nobody else did. But there are dozens, hundreds, of other
| smart people who were pursuing other pathways who did just as
| much stubborn work but didn't get a result. That's just
| pharmaceuticals.
|
| Take, for example, another high profile disease - Alzheimer's.
| First there was the beta amyloid theory, then there was the p.
| gingivalis theory (this one was talked about so highly on this
| very forum, but ended in an equally high profile failure* of a
| pivotal clinical trial by Cortexyme). Now there are viral and
| metabolic theories. Each of these theories have a few dozen
| companies and armies of PhDs stubbornly pursuing a miracle
| drug, but so far it remains elusive.
|
| * We also like to talk about "failures" of clinical trials,
| which is technically correct language, but evokes in the public
| imagination the wrong idea. A clinical trial failure doesn't
| mean there was something wrong with the idea or process (long
| before it ever gets there, a drug candidate would have been
| proven to be very effective in lab tests and animals). It's
| just that 90% of clinical trials don't end up working due to
| complex disease pathways and numerous unknown factors. It would
| help if we talked about "negative proofs" (i.e. proving
| something doesn't work is also valid), but it's not quite as
| catchy.
| ZoomerCretin wrote:
| > First there was the beta amyloid theory
|
| First? Isn't the beta-amyloid cabal still blocking all
| Alzheimer's research unless the researchers find a way to
| even tangentially support that long disproven theory?
| light_hue_1 wrote:
| It was not a cabal. It was scientific fraud.
|
| Karen Ashe and Sylvain Lesne at Minnesota published a fake
| paper that redirected billions of research into the trash
| bin. https://www.science.org/content/blog-post/faked-beta-
| amyloid... Amazingly both still have their jobs for life,
| both still publish, Ashe is still a member of the National
| Academy of Medicine, both are still getting grants.
| atombender wrote:
| This is a mischaracterization of the scope of the fraud.
| Lesne clearly committed fraud, but his work was not
| foundational. The fraud did not "redirect billions".
| eesmith wrote:
| As unavoidable mentioned, there are viral theories.
|
| In Science, from July, "Can infections cause Alzheimer's? A
| small community of researchers is determined to find out.
| Following up tantalizing links between pathogens and brain
| disease, new projects search for causal evidence",
| https://www.science.org/content/article/can-infections-
| cause...
| pfdietz wrote:
| Yet another reason to get your shingles vaccine.
| unavoidable wrote:
| I mean, that's the point - in pharmaceutical sciences
| there's _so much noise_ including fraud that it's really
| only easy in hindsight to pick out "the guy" who was the
| "genius". It's hard to take one story like this and make it
| a repeatable success.
| condiment wrote:
| https://pubs.acs.org/doi/pdf/10.1021/acsptsci.9b00048
|
| ^^ Here's an article written by Lotte Knudsen, referenced in
| the original post, that further tells the story of how GLP-1
| was first developed into a drug (as liraglutide) and approved
| for human use. There were a lot of false starts and additional
| practical problems that needed to be solved in order to yield a
| viable medication.
|
| After reading the OP I was surprised to learn that Novo Nordisk
| picked up the research only a couple of years after GLP-1 was
| abandoned by Pfizer, after which it took 5 years to develop the
| initial medication and another 12 years to make it through FDA
| approval. Even after all that, the primary indication was for
| diabetes. It took another 7 years for semaglutide to make it
| through approvals and bring GLP-1 into the public
| consciousness.
|
| When you consider the amount of time involved, and the
| sustained investment required, it's difficult to fault the
| execs at Pfizer for their decision to shut the project down.
| Obesity wasn't nearly as prevalent then as it is now, and it
| seems likely they had funded the startup specifically because
| of the author's prior research into nasally-administered meds.
| It's even possible that the shutdown decision had little to do
| with the primary area of research.
| light_hue_1 wrote:
| Since this is YC, it's worth looking at this from the perspective
| of a failed startup that made several mistakes. In particular,
| the authors take the view that Pfizer killed their startup. But
| buried on page 333 is the real reason. And if you're going to
| start something, this is worth learning from.
|
| The founders gave up their ability to control their company when
| they agreed to become a wholly owned subsidiary from day 1. There
| was no need for that. And no one would ever tell you to do this
| today. This was done to be nice and collegial, something that
| broke down the moment money was involved.
|
| The company they created this fatal alliance with had other
| priorities, their own drug development pipeline.
|
| Then they got investors who were profiting from the status quo,
| and for whom a new drug didn't look great.
|
| But the real reason is that the founders half-assed it. None of
| them left their academic jobs. They didn't have any skin in the
| game. Oh well, they walked away with a little money. Had the
| founders done what YC tells you to do, commit, this never would
| have happened. (bottom of page 333)
|
| The whole article blames Pfizer and others for the failure of the
| startup. But it's really this last point that was the determining
| factor. The authors say there were confused by the buyout and
| just took it to move on. There would have been no confusion and
| no buyout if they were committed to the startup.
|
| Even if you have the right idea, even if you are the right person
| in the right place, even if you're about to break through and
| change the world, you can fail if you don't commit.
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