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A million-dollar drug (cbc.ca)
298 points by rpledge 3 months ago | hide | past | web | favorite | 204 comments



People are fixated on the price for this drug, but the article itself is pretty clear on the rationale for the price tag: current alternative therapies have a price tag of up to $300k/yr, indefinitely. This drug is a one-time therapy. Presumably, any health system would jump at the chance to replace a $300k/yr recurring charge with a 1-time $1MM fee.

But they don't. Health systems in Europe apparently refuse to pay for this therapy. The reason for that, from reading other articles, appears to be that it is of questionable efficacy. Patients report fewer pancreatitis attacks, but clinical indicators like blood fat levels are apparently unchanged. The tiny market and efficacy concerns might explain why the therapy is no longer available at any price.


Actually, single payers in the EU are much better equipped to pay $1M now to save $300k/yr in perpetuity. All medical spending comes from one big pile.

In the US, not people don’t stay with the same health plan for more than 2-3 years. So why would an insurance company pay $1M when they get 2-3 years of pay back, then the next insurer gets a free ride?

I know there is an MIT prof who is pushing the idea of something like a bond. Some external party pays the $1M and the insurer makes X payments until it’s paid off.

A interesting idea that even the single payers like as they have a more predictable budget.


> In the US, not people don’t stay with the same health plan for more than 2-3 years. So why would an insurance company pay $1M when they get 2-3 years of pay back, then the next insurer gets a free ride?

One of the most compelling arguments for single payer which I’ve somehow never heard before now. Biding time in an effort to pass the buck should not be incentivized.


Yeah, I'm not saying it doesn't make sense or that the EU wouldn't do it. I'm saying they aren't doing it, because the treatment is of unclear efficacy.


But that doesn’t have much to do with the price. Your comment sounded like you were saying the eu was being cheap.


I thought it sounded like quite the opposite: he's not saying they aren't buying it because they're cheap (he points out that if it worked, and they were trying to be cheap, they would buy it). He's saying they're not buying it because it might not work very well.


Except as a result of the price tag, they priced themselves out of the market and any possibility of revenue. That is not a rational. And efficacy isn't really in question: Perfect cure or not, it has a vast increase in quality of life including the ability to have children, avoid pancreatitis, and enjoy alcoholic beverages to name a few. If insurance companies are covering replacement therapy to the tune of $300,000k/year, that would seem a pretty good sweet spot pricing that insurance companies would clamor to approve due to the savings over annual costs.


I don’t think they priced themselves out of a market. Uniqure set the list price at $1M. In Europe each country negotiates their own drug price, so the real price would have been even lower than $1M.

I’m going to speculate that the drug just wasn’t that good, so the demand wasn’t there and the program folded.

I know Germany pays close to $1M for a specific hemophilia therapy and they pay that annually. The price itself wasn’t the issue, this it must have been the drug itself.


according to the article, and a few google searches outside of it, the drug was that good. The article's implicit conclusion was that the drug was priced too high, and offers evidence to back that claim. You seem to be assuming a perfect rational market here that has a rational justification, but real markets don't always work that way.


As someone who works in the industry, the article was a 30,000 ft view and didn’t do a good job of digging into the issue.

Regardless, it looks like the drug does reduce pancreatitis attacks, but only by 50%. So it certainly doesn’t “cure” the patient.

The clinical trials were also quite small, so possibly the national payers said “$1M is reasonable if you do X, but you don’t have the data to convince me you can do X.”


Here is the problem with this statement - it assumes that the drug is worth the maximum amount that they could extract from the customer (insurance companies, patients and governments for it). Nothing says that they couldn't sell it for less, just that they thought they could get this much for it.


A thing is worth what another will pay for it.


And no one was willing to pay this much for the drug, but the inexplicably decided no revenue was better than lowering the price.


It's not "inexplicable". uniQure is a going concern with treatments in the pipeline for Huntingtons, hemophilia, and congestive heart failure. They have a finite amount of resources and are allocating them to projects that they're more optimistic about than this one. Glybera is of questionable efficacy and is very expensive to administer (they're on the hook for long-term monitoring for everyone they dose).

It's not at all hard to see why they'd stop production.


How much does it cost to manufacture the drug, and in such relatively low quantities? The article did not say but it pointed to this as part of their decision.


"Pay" goes both ways. The manufacturer wasn't willing to pay for a million dollars by making this treatment.


Maybe caving in and lowering the revenue would encourage future customers for other expensive treatments to boycott high prices and hold off for price drops. Refusing to negotiate and forgoing revenue now could be the rational strategy in the long term.


Yeah, but the drug also has weak efficacy. Who cares if it is "only" 100k instead of 1M if it do what it claims?


healthcare should never be one of those things.


"Your money or your life?" doesn't seem like a wonderfully ethical medical question when aimed at folks who probably cannot afford it even if it is a cure, adds decades to their life and you are willing to take installment payments.


[flagged]


It isn't a rant and there is nothing whatsoever "fun" about the topic for anyone who has a genetic disorder.


Interesting post. Hopefully some innovators can come through and figure out a way to make it more cheaply. Even if it's expensive now, if humans exists for 100's of years, then eventually the price will come down when this inventor is toast, right? Either that or people will figure out cheaper, DIY ways to do some of this biological manipulation.


Based on article the price is not at 1M because of high manufacturing costs, but because they want to have return on the investment made during the research and development phase.


TO be frank, it's not even that. If you read the article, they never priced it based on the what they invested in it, but rather off the the fact that they could replace something else that was expensive with it.


It's not even clear that this therapy is locked up because of IPR. If you read uniQure's filings, their patents appear to be for treatments for other conditions (notably Huntingtons), and their protection for the LPLD therapy is under "orphan drug" protection.


Yeah, seems ripe for someone to pick this up and charge $100k a dose. Insurance companies would look at that as a deal compared to $300k/year for the alternative replacement therapy.


another issue I have is with the claim from the article that they constantly have to produce new batches because the old product expires. but with such a small group, it would seem better to first make a comprehensive list of LPLD sufferers, then make a single batch for all of them, and repeat every say 5 years as new cases are found... yeah on average a patient waits 2.5 years...

If there is a long list of rare diseases, a company could specialise in manufacturing doses for rare diseases outside of the classical "order a dose (from continuous production) as a patient is discovered". So they might make a specific rare drug once every X years, but with enough rare drugs they might fill the rest of those years with preparing for and then making and testing single batches of other rare drugs...


> alternative therapies have a price tag of up to $300k/yr

So prices should all float to the maximum of the most inferior product, so that consumers do not have a choice?

How would you like that if it happened in your favorite consumer category?

That's like saying computer memory should never get cheaper (there is alternative memory priced at much higher rates!), or that electric vehicles should always be priced at the cost of the initial entrants, despite economies of scale


What are you talking about? The premise of this product was that it cost a fraction of what existing treatments cost, and was far better. That's the opposite of the dynamic you just described.


Even most of the folks described in the article did not have an initial reaction of "It only costs a fraction of existing methods!" Instead, their reaction was that the price was set by forces that had nothing to do with the R&D of the drug, and by that measure, it costs far much more that it otherwise could be. When the patent expires, a generic alternative will likely be made for far cheaper.


What patent are you referring to? Are you sure it's still under patent? Did you read anything about Glybera other than this story? Want some spoilers?


I've only read this story on it.

I assumed the patent information based on other commenters, perhaps those were incorrect.

I never watch the trailers before I go to watch a movie.


Here we are discussing the Real Events the movie was based on when all we've seen are the Movie Adaptation and Metacritic.


The article talks about turning white, fat-filled blood red, so presumably it would have an effect on blood fat level. Is the issue that humans with this disease have no choice but to remain on extremely strict diets, which does a reasonable job of controlling their blood fat level. This treatment (cure, essentially) would alleviate that, but not necessarily change the levels much, since the patients were already (laboriously) controlling them?


To learn about the efficacy concerns, you have to go read other articles about the treatment, which will come up right away when you Google it because the withdrawal of this treatment from the market was a big story.


I was recently one of the first recipients of gene therapy for my condition. I have Hemophilia A, which is a bleeding disorder that results in bleeding into joints, muscle and soft tissue due to lack of a naturally occurring clotting factor that my body can't produce due to a defective gene. I received my dose of 30 billion viral particles about 13 weeks ago as part of a phase II clinical trial at UCSF.

It is amazing to me that we can manufacture and program viral particles to target specific cells. In my case, my treatment is a non-nucleonic technique that didn't repair the actual chromosomal hereditary defect but inserted a working gene, additional and freely available genetic material into my liver cells. It's amazing that the body can just recognize this extra bit of code and just start producing the factor. The engineer in me is also impressed they can make so many copies of the engineered virus.

It appears to be working. My factor levels have steadily increased and I’m now no longer a severe or even moderate hemophiliac. I’m their first patient to have achieved these results for hemophilia A severe and it puts me well into the therapeutic range. It really feels like I have been given a new body, it’s indescribable. For the first time in my life, I’m pain free.

It’s a weird feeling. Pain, mostly from bleeds into my joints, has been my constant companion. I was never able to do sports as a kid and had to avoid many other activities that would put me at risk. I have mixed feelings about all of this. On one hand I’m extraordinarily grateful, and the other side I see what a huge disadvantage I’ve been at compared to others for all of my life. I thought this day would never come, I had resigned myself to my limitations but now they are gone in a matter of weeks through the miracle of a medical experiment.

My old medication, a replacement clotting factor that was synthetically produced in a lab, worked but not nearly as well as this. Not to mention the fact it cost over $100,000 per month and I had to give myself an IV every other day. It's truly been a life changing experience for me, and I hope that gene therapy becomes widely available to others.

Also, the thing that was a milestone in this case was that the Hemophilia A factor VIII gene has been notoriously difficult to create a genetic therapy for because of the complexity of the actual gene itself. On the scale of what the body produces, its one of the more complicated proteins. So it basically means many other genetic conditions will be able to be treated with and addressed with similar technology.

Such an exciting time to be alive, and yes there are amazing things happening right now despite all the bad news you may hear!


Thank you for sharing. My first undergrad studies were a double major in Science (Chemistry/Biology) 12 years ago and yet I had zero clue that we were at the stage currently to do what you described. To hear what you've just described is absolute music to my ears and it makes me very happy. While you may have lived a number of years dealing with your issues it means that we are likely approaching a time when children will be able to be cured early and live pain-free lives.


You’re welcome and yes I agree about this being most impactful for children. Hemophilia had a big effect on my life, both physically and psychologically, as well as my family. It’s hard to grow up knowing you’re so different from others. Now, someone born with hemophilia may never even have to know. It changes things dramatically.

In a single generation we’ve gone from being able to treat the condition at all (replacement factor was just becoming available when I was born) to being able to completely cure it.


a next step would be for the virus to fix the cells from which the gametes derive, then your future offspring would be cured as well


Delighted for you. I feel we're truly on the cusp of a revolution in medical understanding. We've been stabbing in the dark with destructive systemic treatments until now.


Did you need immunosuppressive treatment?


Nope, and I didn’t have any noticeable immune response. Literally no side effects to speak of, it was all very easy, just a simple injection and overnight stay in the hospital for monitoring.

They tested me before for immunity to the virus family they engineered, to make sure I didn’t already have immunity.

Other than that they are monitoring my liver closely but there hasn’t been any elevation in blood tests or structural changes (observed via MRI).


The hell with bioethics hand-wringers... we should be mending and improving people's genes whenever and wherever we can add net good.


not all "bioetchics hand-wringers" are against gene therapy ( in fact you too are taking a bioethical stance).

bio-ethicists aren't only interested in the net good of the patient of the therapy, but also in any harms onto others: perhaps child victims of organ trade (for example sourcing fibroblast stem cells from unnecessary circumcision of infants), perhaps harvesting organs from political, cultural or criminal prisoners, or from refugees, and yes, some of them are worried about viruses ...


How was the recovery process? Did you feel better immediately or was it in small amounts and over several weeks?


There was no recovery process to speak of in a traditional sense. Since this is a chronic condition, I’ve just simply gotten used to the aches and pains over the years. I really didn’t start to feel any different until a few weeks ago, when I realized I had forgotten to take my pain and arthritis mediciation, but I wasn’t having any pain that day. I went off it and I haven’t had to go back on it. My joints all feel noticeably better, there’s basically no pain anymore when I walk. I’d have some days like this before but nothing this long sustained before.

It’s too early to tell but my doctors think that with a sustained factor level, my body isn’t under as much stress from the bleeding all the time and can focus on repairing the damage caused from a lifetime of near constant bleeding.


That's awesome to hear. I'm so very happy for you. Looking forward to a world where these gene therapy solutions are available to more and more people for a wider range of illnesses.


Glybera was never sold in North America and was available in Europe for just two years, beginning in 2015

The patent will expire within a few years, setting the stage for generic manufacturers to step in, but the article doesn't mention it.

In the US, patent protection extends for 20 years after the earliest filing date for the application on which the grant is based. There can be adjustments to the term if the grant was delayed.

https://en.wikipedia.org/wiki/Term_of_patent

The article is fuzzy about the timeline of events, bu has this quote:

The stunning results of the mouse experiments were featured on the cover of the journal Human Gene Therapy in September 2004. The cover image showed how, week by week, the mouse blood changed from milky white to a clear, transparent red, illustrating just how effectively the gene therapy was working.

So it seems like a good first guess to put the patent filing at or before 2004.

If so, then the Glybera patent would expire sometime after 2024. At that point, generic manufacturers can step in to sell their version of the product, assuming regulatory approval.


As you can see from the lack of biosimilars in the US, manufacturing a biological is a hell of a lot more complex and expensive than doing it for a small molecule.

And in fact, since this is version 1.0, I’ll bet a better version comes out before any generic company launches.


If they come out with a new version, they must be expecting it to sell in a quantity that makes the investment worth it. So maybe the pricing worry is just a temporary concern.


This seems bizarre to me:

Van Deventer says the company never considered lowering the price. "Why would we? Pricing shouldn't be a political decision. It should be a rational decision based on merits and value."

If no one will pay $1 million, your revenue is $0. Assuming the drug costs much less than $1 million to make, surely any revenue number is better than $0?


I don't think he understands pricing at all. Market price isn't arrived at via a rational process. It's an inherently social process arrived at by negotiation between producers and consumers.

And it's especially weird that he thinks pricing shouldn't be political when his product has a government-granted monopoly and the bulk of its customers will be government-run health-care systems and government-licensed insurers.

Sure, there's a real question of how to pay for treatments for rare diseases. But the millions in development are a sunk cost. To take his ball and bat and stomp off would be disappointing in any circumstances. But when people will die because of it?


> Sure, there's a real question of how to pay for treatments for rare diseases. But the millions in development are a sunk cost. To take his ball and bat and stomp off would be disappointing in any circumstances. But when people will die because of it?

If people actually cared about treating patients, they would be crowdfunding that treatment rather than trying to fleece the people who invested man-decades of work into developing them, and who bear the mandatory cost of following these patients forever.

How about we just stop developing drugs, and live and die by the same ailments for the rest of time, as the patents expire. That would stop people from shifting the goalposts so dramatically every time somebody gets off their ass to actually produce a treatment.

The potential cost of care will continue to rise as long as we develop treatments for previously untreated or undertreated ailments; and it seems like the potential for care haunts people by giving the impression that they're being deprived of something, when the alternative is really that the treatment would not exist if insurers (government or private) would not be willing to pay something close to that much for it.

These people are dead without treatment, whether it's because of pricing (and insufficient social support [it could be literally impossible to fund all therapies of this sort for all patients]), or because the researchers were discouraged from ever developing it. The pricing is not arbitrary, so your only two options are a) don't develop it, and therefore never realize the moral hazard, or b) develop it, and market it to justify the work, so that you can do the same in the future, and treat at least some people, hopefully being able to reduce the cost of treatment in the future.


Oh, you think people should get together and pay for drug development and medical treatment of people with rare diseases? Good idea. In fact, maybe we should create some sort of system where funds are collected widely and then distributed through systems that judge merit, utility, and cost effectiveness.

Oh, wait! We already did! This literally exists in most countries. In the US the government funds about half of all basic research. In many biomedical fields, that number rises to 80-90%. Treatment too is covered by "crowdfunding" through government-supported health care systems.

The guy's grumble here is that he doesn't like the system. And there are plenty of fair arguments to make there. But his complaint isn't, "We need to do better funding cures over treatments," or "The government should support rare diseases better." It's a confusion of of free-market slogans inside a context that not only has little to do with a free market, but one where he only has something to sell due to extensive government funding and a government-granted monopoly.

Free-market approaches work well when figuring out the price of beans that you buy every week at the market. They are of very narrow utility in exotic, life-critical treatments for rare diseases. I'm still all for applying them where we can. But this guy's gripe sounds more like free-market fundamentalism (or straight greed) than any thoughtful understanding of how to fund public goods.


> I don't think he understands pricing at all. Market price isn't arrived at via a rational process. It's an inherently social process arrived at by negotiation between producers and consumers.

Are you suggesting that prices don't have anything to do with scarcity and are just set arbitrarily by social forces? That doesn't seem quite right.


What would make you think negotiation is arbitrary? I my experience, it's all about specifics.

I don't see a reason to think true scarcity matters at all here. The hard part about generally isn't making doses 100 through infinity. The hard part is making the first dose, and to a lesser extent the next few. This is why drugs get special patent protection. That is, artificial, government-enforced scarcity.


Well, yes, that’s how supply and demand (supposedly) works. The “correct” price is where the demand, at that price, equals the available supply.

If the product is scarce, that can drive up the price, but only as far as demand is willing to follow- there’s no inherent value in being scarce. “Price” is a social thing, so of course it’s determibed by social forces.


To illustrate your point: if I paint an unique painting of myself sitting on the toilet, that's quite a scarce item, there is only one in the world, yet, it's utterly worthless.

Purely social forces somehow came to the (in my opinion, debatable) conclusion that ladies with square faces painted by Picasso are art, while a representation of defecation by me is not.


Keep in mind the scarce few people that are actually affected by this disease. No doubt that this factored heavily into the high price.


Because if you signal to health systems that you're not serious about your pricing, why should they pay you fairly in the future, rather than just stubbornly waiting for you to give up and sell at a loss?

It's basically the same reason most businesses throw product away rather than just distributing it for free.


What I think is happening is that the number of affected people is so low and the cost of producing this small number is very large and the company does not want a profit but a BIG profit.


If a company does not make use of a patent they should at least loose their right to it.


Especially for lifesaving medical patents. If the drug isn’t being produced, or the price is too high (I don’t know how this would be defined), governments should be empowered to seize the IP and solicit bids to produce the invention. We move heaven and earth to save lives in natural disasters, why do we move so slowly with certain medical conditions?


Then nobody would ever bother investing in new drug development.

A better model would be for the state to fund this research and have the results be public domain.


Unfortunately, this happens all the time, but not for the public good. Research universities use patent portfolios to increase their revenue by licensing inventions to companies that can manufacture the product.

For example in 2014 NYU earned $214M in IP licensing and nationally led the period from 2004-2010.


Not nobody, just purely for profit rent seekers.


> Not nobody, just purely for profit rent seekers.

This is not an example of "rent-seeking behavior", which is a technical term with a specific meaning. It's not merely a synonym for "profit-maximizing behavior which I don't like".


I was thinking of situations like EpiPen, text book rent seeking.


> If a company does not make use of a patent they should at least loose their right to it.

Someone can always try and license the rights from them, if they think they can do a better job making money off of them. Problem is, I bet nobody else was interested in licensing it from them at any reasonable price, because they would have the same problem: the market just isn't there, at any price that would make it worth it to produce.


To be fair there is also a risk calculus in everything - even if completely shielded from bad drug liability the profits need to be enough to make taking the gamble repeatably sustainable. To take a deliberately extreme example companies won't try to buy out entire lotteries until the jackpot is big enough to pay off if nobody else wins (thus cutting the income percentage by N - where N is the number of winners).

Greed is a factor and a problem of course but without running the numbers it is hard to say what is the smallest acceptable profit for the outcome.

I wonder if ironically we'll eventually start to see health insurance companies cut out the middleman and do cure research directly to cut their sustained costs. A bit idyllic to hope for yet it also indicates several other problems.


NICE, which makes value for money decisions for the NHS, uses a threshold of £25k per Quality Adjusted Life Year for assessing cost effectiveness of treatments.

At that threshold, to pay for an £800k drug treatment you'd need to give someone 32 extra years of life (or 64 years at double the quality of life and so on). This is enough to pay that kind of amount for life saving gene therapies, especially if given to young children but not enough to treat something that can be largely managed through diet control.

Since the majority of the world's patients are in Quebec, I don't understand why the provincial government doesn't cut a deal for this drug. I'm sure they'd rather sell it $250k a dose to a nice big patient population than at $1m to nobody. Quebec has a lot of pricing power here as the only large potential buyer.


The fact that women can't have children without the drug, but apparently can with it adds a new complication to the QALY calculation I think.


RAMQ [Quebec Health] does negotiate separately from the rest of Canada... but they don't have the money. They don't have the money for top-line cancer treatments, and they so severely underpaid optometrists that the optometrist union opted out entirely. There is very little chance that even at $250K a dose (which is an imaginary figure! the sellers have said they will not reduce the price at all!) a negotiation could be reached.


The point of the patent system is that we are giving inventors a time-limited monopoly on their invention in exchange for them sharing it with the world. We all benefit because we have access to this new invention and soon can make it ourselves, and the inventor has an incentive to promote and sell as much as they can while they own the monopoly.

But it's not working here. The patent holder is effectively saying society isn't allowed to have the invention. They're using a legal means meant to share the knowledge with the world to instead horde it away from the rest of us.

When the system doesn't work, the system must be improved. How can we incentivize inventors to not do this?


It's bad to analyze this issue through the medium of a long-form article, which wraps the story up in emotional narrative. Here is a better write-up in the MIT Technology review: https://www.technologyreview.com/s/601165/the-worlds-most-ex....

The gist of the problem is this:

> The Amsterdam company spent more than $100 million testing the drug and carving a path through Europe’s medical rules and regulations, which weren’t geared to consider a new technology like gene therapy. Initially, for instance, regulators said they expected a clinical trial of 342 patients. Executives wryly noted that there were only 250 people with the disease in all of Europe.

> Nor has Glybera convinced the national regulators in Europe who decide what drugs get reimbursed. Last year, French authorities said they would not pay for the drug. Germany judged Glybera’s benefits “non-quantifiable.” It leaves doctors and insurers to make decisions on a case-by-case basis.

Here's a drug that cost $100 million to make, and will require even more money to move through clinical trials in the U.S. And the pool of potential patients is a less than 1,000 people, and oh many of then can't pay either because they lack insurance (U.S.) or the cost/benefit panel math doesn't work out (Europe).

Viewing this after-the-fact leads one astray, into thinking there is some problem with the system that leaves this potential cure out of the hands of patients. Patents, money, it's all just a proxy for effort in, benefit out. Even if you had the government make this drug, you're talking huge amounts of money per patient, which few governments would pony up. (And rightfully so, because you could save a lot more lives with that amount of tax dollars.) The answer is probably that this drug doesn't make economic sense, and the abandonment of it by the maker is just an indication that it was a misguided effort to begin with.


The drug didn't cost $100 million to make. It cost $100 million to prove that it works in order to get it approved for sale in Europe.

In a world where you could just put a drug on the market (where "the market" is, say, hospitals), the drug would have cost far less, and so the inventor would need to recoup far less.

Note that I'm not arguing for complete deregulation of drug manufacturing. Testing for product integrity through factory audits and the like is the original—and still core—purpose of bodies like the FDA and its EU equivalent(s). You want to know that your "ibuprofen, 20mg" indeed contains 20mg of ibuprofen in each pill, and nothing else.

But that's cheap! That doesn't cost a hundred million dollars to do. Proving product integrity is something that any food processing plant manages on the regular, not to mention manufacturers of generic/non-patented drugs.

If we stop with the need to prove—with overwhelming statistical power—the safety-and-efficacy of a molecule that we're planning to dispense to fewer than 1000 people (and even then only through doctors who can carefully monitor them for adverse reactions), the pharma industry would go back to being just another quiet industry that makes stuff, instead of the crazy behemoth it is.

Yes, certainly, there should be a stringent process before you stick something on a store shelf for OTC purchase. But most drugs never seek to be OTC anyway. Prescription drugs require an interaction with a prescribing doctor, a dispensing pharmacist, and possibly (in in-patient settings) a bunch of watchful nurses. Why, also, must they require an interaction with a standards body regulating the molecule they're composed of? The patients who were in the clinical trial itself got effectively the same treatment, minus the standards body, and they were all fine.

Maybe that's what I'm saying: why not just allow any random chemical to be given to people (without intention of standards-body registration) as long as the prescribing doctor is willing to do clinical-trial-like monitoring for adverse side-effects?


> (without intention of standards-body registration) as long as the prescribing doctor is willing

Unfortunately, the doctor (or scientist) cannot be allowed to make that decision on their own. There are far too many terrible examples in the not-very-distant past where doctors testing a new type of treatment drifted away from legitimate research into unethical experimentation[1], patient abuse, even torture and eugenics. Yes, most doctors wouldn't but the unusual-long length of the Wikipedia page [1] is why it's important to say "this is why we can't have nice things" require external approval.

That said, this approval are primarily concerned with preventing unethical experimentation and limiting the damage when the testing goes horribly wrong. Oversight of ethical issues and experimental technique should, in theory, be a lot simpler[2] and cheaper than the higher standard of proving that a new drug is "safe enough".

[1] https://en.wikipedia.org/wiki/Unethical_human_experimentatio...

[2] I know IRB approval isn't going to be "simple" for any type of experiment involving humans. It's easier than getting full FDA or EU approval.


>Maybe that's what I'm saying: why not just allow any random chemical to be given to people (without intention of standards-body registration) as long as the prescribing doctor is willing to do clinical-trial-like monitoring for adverse side-effects?

Snake oil, first. Imagine if e.g. Herbalife could claim their pills cure cancer? Good luck getting signal through all that noise.

Second, the inevitable democratic anger of the masses when the next 'cure for the common cold' (which I'd be happy to sell you, btw) starts killing people.

Not to say there aren't (large) improvements possible to the regulatory process, but the process itself exists for some very important reasons.


So maybe it should be more like the UL model? Let the insurance companies fund the proof of safety/efficacy, but it's not mandatory.


If by UL you mean Underwriters Laboratories in the US or the other US NRTLs, compliance testing costs are borne by manufacturers, not insurance companies.


The number of drugs that have gotten FDA approval at a billion+ cost only to be later rescinded is pretty massive as well... so it's not like the current system is fool-proof.


There have been a number of FDA and even OTC approved NSAIDs which may have killed off millions... I don't know who profits from the present system, but it ain't patients.


But of that 100 million dollars the bulk was safety testing due to regulation.

So you're right it doesn't make economics sense but for a specific reason. As a society we have to strike a balance between safety and efficiency. And I don't think we've struck the right balance. Many times erroring too much on the side of safety, especially with rarer and more fatal diseases without good current treatments.


You’re focusing on the wrong thing.

Even if you ignored the cost of regulation and development, the company who was producing this drug would need to spend millions of dollars a year on production just to keep a safe supply available. With a pool of a few hundred patients, all of whom are “cured” for a decade, it’s going to be an expensive drug no matter what regulatory system is in place.


How do they make it in a lab to develop it initially? How is that possible, but it isn't possible to make small batches on demand?


They had a staff of skilled people who had been working on the project for years, most likely in an (expensive) laboratory that was purpose-built for the task of producing a transgenic virus destined for humans.

It’s not cheap to produce at any scale, and it’s typically more expensive to do small-scale production.

A million dollars can barely fund a startup for a year; it’s insane to think you can maintain a drug production facility on a tiny budget like that.


But if making a small batch costs $1M, how do they afford to do the research for years in an academic setting?

> It’s not cheap to produce at any scale, and it’s typically more expensive to do small-scale production.

This is correct, but we're not speaking in relative terms, we're speaking in absolute terms. How can they afford to produce it in a lab (unless each research project has many, many millions to play with each year)? It doesn't seem logical to me.


Per the article, the development project cost hundreds of millions of dollars. It wasn’t cheap to produce.


"But of that 100 million dollars the bulk was safety testing due to regulation."

How do you differentiate the cost of safety testing that should be done and the cost of safety testing due to regulation?


I think the answer is risk tolerance related for how much they would be sued without the testing. Many companies do risk analysis above and beyond what the minimal regulatory requirement if they feel it is more cost effective. That would be the number used in comparison.

That said the regulatory premium may still be the right thing to do given horrifying human costs and potential to leave everybody else holding the bag when they go bankrupt with expenses far beyond what they can pay. Even if you seize assets of the entire board in a criminal proceeding it is still possible to do more harm that can be repaired by the courts and thus make regulation the rational thing to do in addition to the right thing for a circumstance. Or the regulations could do more harm than good. In general regulations themselves aren't inherently good or evil but circumstantial.


The cost of safety testing due to regulation us the cost they spent. How much you think should be done would be based on your models.


Also the 100 million is used to distinguish between real medicine and snake oil.

Also, is this treatment better than the current treatment? How can you be sure without a clinical trial?


You cant even do a proper clinical trial if there are only 300 patients in the whole of Europe who have the disease. You are missing the point.


The point is to discover real medicine that really cures the people.

If there is no clinical trial, how are you so sure that this treatment is better than the previous one?

You can trust the gut feeling of the experts, but that is not enough. The rules for a clinical trial are complex, but they are created to avoid some mistakes (or frauds) of the past.

In particular of the recent changes is traying to force preregistration. https://en.wikipedia.org/wiki/Clinical_trials_registry Because it's too easy to massage the results after the trial to get a lot of results and then report only the "good" result and hide the others. The "good" result is an statistical fluke, so any attempt to reproduce the trial will fail.

Another older requisite is having a control group with a double blind setup if possible. For example, they tried this drug in 31 people. Did this 31 people get better average results than the other patients with the old treatment? They are probably applying the experimental treatment only to people that is not near death. If someone is going to die in a month and is very weak, you don't want to kill him because the new treatment has an unexpected side effect, or get blamed that the treatment killed him instead of the previous condition, or that the family later says that he was too weak to give an informed consent, or get random problems because the organs are too broken, or ... So there are some explicit and implicit filtration rules. Does the patient has any additional illness? Is s/he to young or too old? When you take the average result of the patients in the study and the patients with the normal treatment, are you using the same explicit and implicit filtration rules. What about long term effects? What about the periodic medical checks during the trial that detect early signs of other problems? Does they eat more healthy food during the trial?

So you need a control group chosen at random after you decide to include or exclude the patient in the study, so you try ensure that you have the same population. Preferably a double blind experiment because the patients may give inaccurate reports if they thing that the treatment is good, and the medics and nurses also are influenced by their expectations.

And in these trials, the control don't get a placebo, but the usual treatment, because using a placebo when there is some good treatment is unethical. This is a rule, because some people try to do this anyway, because it's easier to show that the new treatment is better than the placebo than to show that it's better than the current treatment.

Also, they have only 31 patients, that is barely usable to make statistics. The error bars for 31 subjects are huge (something like 5%). The difference must be huge to get a statistical significant result.

You can trust the gut feeling of the experts to think new treatments, but they must prove that the treatment is effective. Otherwise, you can't distinguish between a expert with good ideas, a moron and someone who wants to sell you snake oil.


You can indeed do a proper clinical trial. Effect size matters. Something that provides a complete cure will have a commensurately big effect size, especially since in this case, you have pretty clear markers of cure.

An RCT comparing fecal transplant vs. vancomycin for recurrent C. difficile infection, for example, was halted after recruiting only 43 patients because it was judged no longer ethical to keep people in the vancomycin arm.


This is an excellent response and you clearly understand the issue well. I'm curious though, what do you think about the long term effects of continuing to practice gene therapy? Sure, the cost for treating the first few patients will be exorbitant but wouldn't we expect researchers to find ways to bring costs down over time? How will we know if this is even possible if we abandon gene therapy at such an early stage? It might not make market sense to produce these therapies right now but I think there is a strong argument for governments to fund this type of research.


There’s a bigger issue than gene therapy. Precision therapies that work really well for a very small number of people are going to become increasingly common (whether gene based or otherwise). We are seeing this in cancer right now where there are finally true cures emerging. It’s clear current pricing models are not going to work in a world where you need lots of different therapies to treat small clusters of patients.

Outside of cancer (the only real place where there is a broad clinical application of precision medicine at scale) there’s an estimated 25-30 million people in the US with a rare disease (a disease that affects less than 200,000 people) [1]. There are an estimated 7,000 different rare diseases. That makes rare diseasss more common than cancer in the us which is at about 15 million people [2].

So what if we end up with cancer itself being subdivided into thousands of small diseases (something that is already well underway) in addition to all these “rare” diseases? The current model of developing therapies is just not going to cut it. We need new development methods that are not so cost-intensive and we need new payment models that create enough incentive that individuals and companies take enough risk to identify therapies. It’s a ferociously hard problem.

[1] https://rarediseases.info.nih.gov/diseases/pages/31/faqs-abo...

[2] https://seer.cancer.gov/statfacts/html/all.html


I don't know enough about gene therapy really say what could be improved. If there are common aspects of the process that could be "factored out" I think it would make sense for governments to research that and help streamline approval that way. But that's looking at it from a programming point of view--I don't know enough about the biology to know whether that makes sense.


The inherent cost of manufacturing the drug is relatively negligible. The problem is the cost of development and deployment, and the tiny customer (patient) population to spread that cost around to.

A gene therapy for a more prevalent disorder would not have the same problems, or at least not as badly.


No, its only negligible for small molecules. Making proteins/biologics is much more expensive, and this is where many new drugs are headed. Plus the investment required to design the process and build facilities is far from negligible either.


Relatively negligible. I don’t know what the precise price point for biologics are, but equivalent techniques are routinely used in research; a bit of Googling found a lab services page pricing a an AAV (the kind of vector used in Glybera) batch at the neighborhood of $1k [1]. Would be much more for a medical-grade preparation, I’m sure, but not an appreciable fraction of a million.

[1] https://sites.duke.edu/dvvc/services/adeno-associated-vector...


Thank you for raising this.

I think the reason this particular drug didn't make economic sense was touched on in the article but not highlighted: the drug approval process is designed for drugs, not new technology.

The price of a new gene therapy technology applied to a small pool of people can't justify it's cost of bring to market.

There are plenty of cases where drug company's inflating their margins using phantasmal threats of "R&D" costs on a condition that effects millions, but in this case it seems like the economics were unfortunately not feasible.


This is a serious problem. We cannot let health be dominated by cost


> And the pool of potential patients is a less than 1,000 people, and oh many of then can't pay either because they lack insurance (U.S.)

How many people with lipoprotein lipase disorder in the US actually don't have health insurance?

I get that it's a common meme to talk about people in the US not having health insurance, but instead of just throwing that around as a presumed fact, it needs substantiation, especially when we're talking about a very small number of people in the first place, all of whom are suffering from a congenital, chronic condition that already requires expensive treatment to manage.


To be sure, if you're testing the new platform for a medical technology and can't scrounge up 350 people for your study, there's no faith that you're going to make something that actually works.

It would be far wiser to build a treatment for something where you can get a significant sample size to prove out the platform, and then move into smaller populations from there, building on the newly gained knowledge.

Data speaks, and statistics are how we listen. If you can't do the stats, you shouldn't try to claim an advance.


> Viewing this after-the-fact leads one astray, into thinking there is some problem with the system

> The answer is probably that this drug doesn't make economic sense

You don't see it? The problem with the system is that we let economics drive these decisions.


What would it look like for economics not to “drive decisions”? Spend unbounded money to save each life? That doesn’t make sense either.

What decision mechanism do yo prefer, and how would it work differently here? Why would that outcome be better?

Remember, even the much-lauded European health care systems didn’t feel it passed the cost benefit test, and they’re supposed to be the model of “not letting people die for lack of money”.

Rejecting economic thinking doesn’t suddenly solve the problem of opportunity costs and trade offs.


You quoted me, but missed the important word - these decisions. It's a tragedy of the commons type thing, and we can carve out specific solutions to that, as we do for these types of situations. Where the European healthcare bureaucracy draws their specific moral lines has no bearing on my overall argument.


But what is “these” and why would the same points not apply?

The fewer people that are suffering a given disease, the lower return to curing it. Moralizing doesn’t change that; it just means you’re willing to prioritize it over cures that help more people.

Yes, creation of disease cures is a tragedy of the commons, but the point is that there are worse tragedies of the commons. What consistent, defensible decision procedure favors a different response to this one?


It seems we agree in principle on tragedies of commons - that in edge cases where normal rules of economics produce lethal externalities, we should intervene.

My original comment was simply pointing out that it is not inconsistent to blame the system for these lethal externalities.

Where and how we draw the lines on where to break from economic decisionmaking and into moral decisionmaking is a way, way bigger topic.


I'm sorry, but no, you don't have a basis for concluding that from my responses or the thread.

In my previous comment, I just explained to you why -- even accepting that there are these disease victims you want to care for -- you still wouldn't necessarily have a justification for allocating resources toward a cure for this disease. After all, there are far worse tragedies of the commons: diseases that affect far more people, and that even European governments believe merit a higher priority.

To wave a wand and say "oh, we should throw money at this rare disease", you're saying "we should throw less money at the things that are impacting far more people". (Or, worse, you're saying we should throw unbounded money at all problems, the very charge I originally made!)

And you still haven't even explained under what criteria you would do anything differently, let alone why those criteria would be any better.

So no, you don't get to claim a moral high ground, or that "economic thinking" led to the wrong decision. Not when you can't even explain what exactly the moral error is, or why.


Economics drives all decisions. Economics is ultimately about allocation of a finite set of resources.


Okay. Let's say you were the dictator of the world. What model not involving "economics" would you propose for deciding how many resources to assign to which medical research projects?


If a patent holder is not producing the patented thing, and not licensing it to someone else who is, the patent should expire. Kind of like a trademark that is not defended. Seems that would fix the problem?


It still wouldn't get the drug to the people who need it. Most of the cost involved is in getting it approved by the authorities for human use.

There's nothing stopping people from manufacturing the drug for personal use, other than that it's likely extremely hard to make.


In this case it's already been approved for human use. So that's a non issue. But yes, I'm sure that is a hurdle for plenty of other pharmaceutical research


for drugs you usually patent them about 10 years before you can have them on the market. That would be not very compatible with the current requirements of regulatory bodies.


No, not here.


If the drug is patented, then by definition the best known mode of implementation has been disclosed. That's what a patent is.

The problem with alipogene tiparvovec probably isn't the IPR†. Rather, it's that the treatment is extraordinarily expensive to administer (ironically, because it's something close to a total cure with a long-term impact, the drug seller is required to provide long-term monitoring to patients), has a microscopic market (that's why it's so expensive), and is of questionable effectiveness --- it improves quality-of-life metrics but not necessarily clinical ones like blood fat levels. Many (all?) national health systems in Europe, where it is approved, refuse to pay for it.

If the drug had a clear market, even if the current owner no longer wanted to provide it, it could license to some other drug company. But it's likely that no other viable concern wants to shoulder the costs and uncertainty of this particular drug. That's not the fault of the patent system.

In fact, it's possible that the patent here has expired; I'm still trying to confirm that, but it would explain why the treatment had "orphan drug" status in Europe.


> is of questionable effectiveness --- it improves quality-of-life metrics but not necessarily clinical ones like blood fat levels

"Although based on a small number of patients and episodes, overall pancreatitis incidence up to 2 years post-alipogene tivarvovec injection decreased by 5-fold"

"However, several signs of clinical efficacy independent of plasma TG were noticed up to 2 years after LPL gene transfection and raised the possibility that TG-rich lipoprotein characteristics, particularly the size, lipid content and kinetics of CMs, rather than plasma TG concentration per se, are the best surrogate markers of pancreatitis risk in LPLD."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956470/#!po=37...

From what I read, 2-year follow-ups seem to find continued (post-26 week) activity of the inserted gene.

So it's inaccurate to say there were no clinical improvements.


I worried about the word "clinical" here, which might not be what I meant. It is not, however, inaccurate to say that concerns about efficacy were behind EU health system refusal to pay, and behind the therapy being taken off the market.


True. The question seems to be correlating the long-term decrease in serious episodes and gene expression (observed, albeit in a low sample size) with a marker (plasma TG did not change, but centrifuged TG composition by weight did).

The injustice here, if it exists, seems to be that the system is poorly configured to treat rare diseases.

Afaik, the FDA (regulatory side, for non-US readers) began granting more permissive experimental waivers for this sort of thing.

But the insurance side seems well within their rights to not pay by saying "This treatment has not been demonstrated effective to our standards." Something which is likely impossible given the cost of running normal trials and target population (small).

Hopefully, in the future, this will be addressed as more gene therapies become available and individualized medicine becomes the norm (similar to the revolution oncology has gone through in the past 30 years).


It's also such an easy fix too. If a company isn't actually using a license or copyright they should loss all claim to it.


... Or punish them when the do do this.


Patent was and is always like that. We have a massive improvement on 3D printer and VR display because... the patent expired.

Patent is a system to freeze the invention from society for 20 years.

But in this case, patent alone is not on the blame. Still we need to change the patent system something like the patent holder must offer patented product or license the patent for reasonable price or face losing the patent.


Getting a drug approved for use is an expensive proposition, but that doesn't mean that it is impossible for a nonprofit organization to step in and get the job done when the target treatment group is too small or too poor to make it worthwhile for those with a profit motive.

The Drugs for Neglected Diseases Initiative, a nonprofit which grew out of Doctors Without Borders, just received approval for a pill that successfully treats African Sleeping Sickness.

>Ultimately, the drive for approval cost $63 million and involved clinical trials including 750 patients in Congo and the Central African Republic. Two million villagers were screened.

The costs were paid by seven European countries, the Bill and Melinda Gates Foundation, Doctors Without Borders and other donors.

https://www.nytimes.com/2018/11/16/health/sleeping-sickness-...


in society, we have another large, one-time purchase people often make in which there are special financial arrangements and rules: buying a home. it seems to me that gene therapies (high priced, one-time use drugs) are going to warrant alternative financial instruments. there's absolutely no reason this drug should have failed when the amortized cost over 10 years is less than an inferior product. regardless of the other questions this is a pure market failure by the financial industry.

edit: the downvotes probably assume I mean the patient is going to pay out of pocket. of course not. the insurance companies would be paying. the only inferiority between gene therapies and non-cures is their pricing structure. we invented a solution to this problem thousands of years ago: debt.


The problem is with a house / car / TV / phone you can always reposes it.


We have loans for education even though lenders can't repossess knowledge.


It just backs out to interest rates commensurate with the risk. Lack of collateral doesn't mean you can't get a loan.

Perhaps the economics wouldn't work, but it sure sounds like nobody tried in this case. What it would boil down to is if the insurance company expected a larger net cost on a traditional drug regimen for the life of the patient, vs servicing a loan at the market rate over N years. Interest rates are still very low so in general debt is seeking out risk.


Insurance companies don't cover total health costs over the life of the patient. They cover the next month of health costs, and a certain percentage of their customers churn afterwards. For insurance companies, providing treatment that lasts a longer amount of time can often be a terrible business decision - if the customer switches insurance providers afterwards, then they're essentially subsidizing the insurance company they switched to.

This more commonly happens with prescription quantities. Medication compliance is far better when people can pick up a three-month supply of medication. Insurance companies want patients to pick up one month supply instead, so that they aren't paying for two months of medication for every patient who switches insurance companies.


Right, so what is necessary is for Gene therapy to have similar financial characteristics to an insurance company as a monthly perscription for a chronic illness. There is no reason this cant be securitized properly, unless a) the lifetime healthcare costs for a person are higher with the therapy than without (unlikely for most chronic illnesses) or b) the interest rate would need to be so high as to make it so. If gene therapy provides a more optimal use of resources and capital than continual therapy for chronic illness than the up-front high price tag nature of it being a problem is an opportunity for someone to come along and make the market more efficient.


Insurance is how the US deals with health care. It isn't how all countries do it. There are other models and there's no reason we couldn't invent new ones if none of the existing ones work.


> "Why would we? Pricing shouldn't be a political decision. It should be a rational decision based on merits and values," he said. "Hundreds of millions of investor money has gone into the company, and if there is no return for those investments, there will be no new drugs because nobody's going to do that in the future, right?"

As terrible as it sounds, this logic seems sound to me. If we think having this type of drug is worth the > $100MM it took to develop, then health systems should either fund the $100MM research, or they should let private companies do it and pay them fairly for their work. $1MM for something so expensive to develop with so few possible users doesn't seem crazy to me.

If the $100MM is in fact not worth it, then, well, you get the situation we have now.

I'm sure a lot of people will read this article and think the owners/funders of the drugs are the bad guys. But nobody can be expected to work for free.


Yeah, people just look at the price and think that's terrible, but it's a business not a charity. It's up to the government to step up if people really deem this to be a problem worth solving. With their tax dollars. I bet a lot of critics would go quiet at the point they actually have to pony up.


There another way to read that sentence :

>>> Hundreds of millions of investor money has gone into the company, and if there is no return for those investments,

Considering that there are patients who needs it, you can divide the price by 10, this way you make sure everybody will pay and the only sacrifice you make is your ROI to be on a 10x longer period.

The problem with investors is that they want tons of benefits and in a very short time.

They could as well sell the IP if they don't use it anymore.

I understand that this is business, but here I see at as "if we fail, then everybody will fail".


"Well, one pharma company has the patent, and we need to let them charge what they think the market will bear. Sorry LPLD carriers, you have to die now." Apparently, this is the best the world can manage in 2018.


The last sentence of the article sums it up pretty well:

"If it's not commercially viable to produce a certain therapy, unfortunately, in our Western society, it does not happen."

And it is far from clear that this is not as it should be, because it's not just LPLD carriers about whom tear-terking stories can be told. $1M can be deployed in other ways that could potentially save more lives. Instead of "Sorry LPLD carriers, you have to die now", it might be, "Sorry, 100 poor African children without access to clean water, you have to continue to die of dysentery so we can save this one LPLD carrier."


You can play this moral dilemma forever. If the one LPLD patient happens to be an expert in 3rd world diseases, then his death would lead to an even bigger tragedy.

In reality, there is no dilemma. The people who can help are morally obligated to help in non-theoretical situations.

If a child is drowning, and by jumping in I have to ruin my $5,000 watch which I would have otherwise later sold to help 100 children, my moral obligation is still with the immediate need of this drowning child.

There is a very good podcast about this very issue: https://itunes.apple.com/us/podcast/philosophy-bites/id25704...


> You can play this moral dilemma forever.

Yes, of course. That's the whole point. It's a very hard problem.

> In reality, there is no dilemma. The people who can help are morally obligated to help in non-theoretical situations.

Really? How much money have you donated to help provide clean drinking water to poor children in third world countries?

> If a child is drowning, and by jumping in I have to ruin my $5,000 watch which I would have otherwise later sold to help 100 children, my moral obligation is still with the immediate need of this drowning child.

Really? You would sacrifice 100 to save 1? That's a very peculiar moral calculus you have there.


Seriously?

Tell me how a person watches a child drown.

Sorry fam, next week I plan on donating to save 100 kids living in worse places than your dead kid lived in...

Actually facing a scenario like that, and the people involved plays out very differently.


There is no argument here other than an appeal to emotion.

Yes, it's true that no normal person would actually avoid jumping into a pool to save a drowning child, even at the cost of $5000 that could save 100 other people. That is the entire point -- human moral faculties are not based on logic, and overweight the interests of people you can see, or whom you can help in obvious, concrete ways, relative to diffuse total global happiness. But the fact that humans are wired to think in a particular way doesn't prove that it's rational or correct.


News flash!

Emotion, character and reason are all valid in this discussion.

Let me put it to you just a bit more directly:

An aggrieved mother and father are there, facing you and their dead child.

Now, having made this call to let their kid die, what do you say to them?

I will wait...

Actually, I won't. It is one thing to speak of optimal choices when one is seperated from, or above, disassociated.

Real life, where the actual humans are plays out much differently.

Above, when I asked, "Seriously?" it was this I was getting at.

The claim of strange morals, based on some 100 to one, as if!

I found the whole thing deeply disturbing. Not a negative to the participants. Not my intent.

No, what I found disturbing was the detached nature of the whole thing.

Maybe Liberal Arts education remains more relevant than I realize.

Again, not a negative toward anyone. Context matters, that's all.

I very seriously question the general wisdom in having some percentage of us so far isolated from people overall, and any sort of meaningful policy, moral debate being beneficial.

You completely failed to make a meaningful rebuttal. Correct... ?

Like I said, seriously?


> Now, having made this call to let their kid die, what do you say to them?

This wouldn't happen, since I'm a (non-sociopath) human.

You seem to have missed the point of the argument completely.

> Real life, where the actual humans are plays out much differently.

Nobody disagrees here.


The person questioning morality did.

And that is OK. Let me be clear. It was thought provoking!


> Really? How much money have you donated to help provide clean drinking water to poor children in third world countries?

I was born and raised in a third world country, and I assure you the problem is much bigger than simply throwing money at their problems.

> Really? You would sacrifice 100 to save 1? That's a very peculiar moral calculus you have there.

The sacrifice is only hypothetical, while the drowning child is something of immediate concern. If a person were to stand by watching a child drown in exchange for throwing money at a problem that is neither directly visible nor immediate, I would conclude there is something fundamentally wrong with that person.


Not that uncommon. Seeing how many gadgets get sold e.g. iphones where the money could go to charity to save kids.


>If it's not commercially viable to produce a certain therapy, unfortunately, in our Western society, it does not happen.

Are there new and innovative drugs for rare conditions coming from non-Western societies?


Excellent point. Everybody in this thread who thinks that the most outrageously expensive branches of medical research will continue to happen without a profit motive would do well to think about how many examples of that we have, empirically.


Actually close to none. And the socialist/communist countries do way worse in caring for their actual population so the only hope is with the West. Its a miracle to see what we already have now compared to 50 years ago.


Except $1 millon is not the entire economy.

It's easy to hide resources by equating them to their monetary value.

The fact is that there exist many millions of dollars, and the way each dollar is spent does not determine the way another dollar is spent.


So what? Dollars are still proxies for finite resources, and there are only three possible ways to procure them: their owners can give them voluntarily, they can be forcibly seized by the government through taxation, or the government can print them, which produces inflation and effectively seizes a little bit from everyone who holds dollars (essentially a tax on savings). If you can't get someone to voluntarily spend $1M to save a life, which of the other two processes do you propose to use?


This isn't complicated. Say there are 1,000 LPLD patients in North America (a wild overestimate). Then treating them with this therapy costs us $1Bn. If we limit ourselves to health care problems, is $1Bn better spent on these 1,000 LPLD patients, or on increasing penetration of existing therapies for other conditions? It seems likely to be the latter.

To believe LPLD therapy objectively deserves the allocation you're talking about, you have to believe that there aren't other cohorts of patients that are currently underserved. But we know that isn't true.


You make some good points.

I'm not anti- all patents. Let's say, for example, a pharma patent worked more like a trademark: if you aren't going to use it (or maybe, if you abuse it), you lose it. Then we wouldn't have to trust this one company's opinion on whether it is "commercially viable" or not.

Maybe that's a bad idea. I'm not a lawyer, and I don't work in medicine. I just doubt what we have now is the best of all possible worlds. Intellectual property laws are supposed to be a net benefit.


They complain about the cost of research, development, and approval... so why not migrate those aspects to state entities which are not beholden to a profit motive?

Drug manufacturing is a very different business than drug discovery. We bundle them together hoping that the profits in one will bankroll the massive loss risk in the other.

But it doesn't work-- we end up with situations like this-- drugs that don't cover their upfront R&D costs, and also issues with questionable market-oriented priorities (I tend to think of the galaxy of me-too erectile-dysfunction medications that hit the market almost immediately after Viagra)

If we shoved a bunch of research dollars into public labs and universities, they could manage research, development, and certification, with the goal to produce a non-patented product that the manufacturers can compete to produce at scale as cheaply and reliably as possible. If the up-front science is paid for, maybe that 1,000 patients are economically viable to produce the actual pills.


I don't understand how anyone can think patents are a good idea.


I don't have a problem with the idea of patents. I just think we could be a whole lot more pragmatic about them. They're supposed to incentivize useful behavior.


Who should decide what's a useful behavior? What's a fair price? What's a reasonable lroduction/distribution strategy?

I think the free market should decide, not the government and its enforced monopolies.


Not a fan of it either, but how do we incentivize companies to research and create new drugs if they can't make back the huge cost of clinical trials?


Did you read the article? The company that charged that absurd price acquired the patent, they had nothing to do with developing it.


While I don't disagree with your point, the company that bought the patent paid a lot of money for it from the company that developed it. Patents being exchangeable is not necessarily a bad thing.


How do you incentivize environmental research? How are we supposed to find solutions to climate change if they can't be patented?

Copyrights are just as bad as patents, and musicians/writers shouldn't make people pay for their music/books.

We should start giving money to causes we support, whether it's art, medical research, software projects, etc. It's a mistake to think we should only give money if we're forced to by law (through pricing something that's not scarce).


What if governments paid for the clinical trials?


The government does frequently fund the discovery of new drugs. The problem is that the return on that investment is usually abysmal and the taxpayer ends up not only paying to fund the drug’s discovery, but also paying absurdly high prices to buy it from pharmaceutical companies who passed some or all of their risk onto taxpayers.

One example: https://abcnews.go.com/WNT/YourMoney/story?id=129651


If you read the article, the drug was in fact discovered at UBC, which is a publicly funded university.

But it turns out that discovering the drug wasn't the expensive part. The expensive part was privately funded.


Of course. Most of basic science in the US is government funded. I'm wondering what the OP thinks about removing the barrier that they identified (private corps paying for the trial vs gov paying for the trial) and how that would affect their thinking.


The article has a section that talks about the difficulty of getting the drug even approved for testing by governments in the first place.


The government is the whole reason the clinical trials are required before patients can be treated with a working drug. They are the cause of the problem, not the solution.


Reading the article has convinced me that drug patents in particular are a great idea. Isn't it wonderful that we live in a world where futuristic new treatments like this can be developed?

Yes it's true that people can't get the drug now, but at least someday it might be available.

Without patents, who would you find to work for free developing something like this?


> Isn't it wonderful that we live in a world where futuristic new treatments like this can be developed?

This futuristic new treatment can no longer be developed or produced by ANYONE in the world, without the consent of this company. Before the patent, anyone could. Do you think that's not a problem?

We'll incentivize researchers the same way we'll do with musicians and writers in a post-copyright society. People who think this disease is important will crowdfund the research, and those who want to receive experimental and personalized treatment will pay for it.

How do you think we should incentivize things like environmental research? Is our knowledge about climate change patentable? What if someone found a cure?


> Before the patent, anyone could

Anyone could, but nobody did, or would have without either a profit motive or massive state funding.

> Do you think that's not a problem?

Well it’s certainly not the most ideal thing you can imagine, but I don’t see a better way in a capitalist society to incentivize medical research. Do you?

> People who think this disease is important will crowdfund the research

I’m not aware of any crowdfunding campaign that has raised hundreds of millions of dollars.

> How do you think we should incentivize things like environmental research?

It should be funded by the state

> What if someone found a cure?

That’d be awesome. We should pay them incredibly handsomely for their work.


There should at the very least be a law that states that a patented technology should be made available in reasonable ways to make the patent valid.


We don't need more laws. The problem is caused by the government. They're the one that enforce patents and regulate clinical trials. You think they should decide what "made available in reasonable ways" means? What could go wrong...


Would you rather have this drug exist and be patented, or never have existed at all?


I see you arguing that things went just the way they should have all over this thread.

This point in particular is completely wrong. The two doctors who made the drug do not even hold the patent and basically gave it away for free to the company trying to distribute it.

So yes, if not for the patent this drug would definitely still exist, and probably be available to people who actually freaking need it.


> I see you arguing that things went just the way they should have all over this thread.

Actually, I never said that anywhere. I think what happened is basically a no-op. Without a profit motive, the drug would never have been developed, and therefore not available to anyone, and we'd be in the same boat we're in anyway.

What I do think is one of two things should happen: Either (1) we decide that the drug is worth it, in which case health systems should pay the owner of this drug fairly for their investment. Or (2) it's not worth it, in which case we're no worse off than we would have been without this company, other than the fact that they wasted a bunch of their money.

(As an aside, note that I said we should pay the owner, fairly for their invention, not the original developer who voluntarily gave up the rights. This is an important distinction as the ability to voluntarily transfer property rights is pretty central to the whole concept. Imagine if after you bought a car, anyone could take it, because you're not the original manufacturer. It's not hard to see the path from this society to one where nobody bothers making cars.)

> The two doctors who made the drug do not even hold the patent and basically gave it away for free to the company trying to distribute it.

Those two doctors did the least expensive part of the whole operation. The more expensive part was funded privately. If you want to fix this you can either have the government fund that expensive part, or you can have it done privately and pay the owners what they want.

> if not for the patent this drug would definitely still exist, and probably be available to people who actually freaking need it

Sure, maybe the doctors still would have done the research, but there would be no money either for the clinical trials, and so manufacturing and distributing the drug would be illegal.


To me, this is akin to a game company raising the price of a game. The costs are already sunk. The only thing that counts is setting a price on copies of that game. Those who pirate copies of the game incur to loss of revenue because those people would've never been able to pay for it. It becomes a question of projecting the maker's morals onto those who did not pitch to the coffer instead enjoying the game like a dirty thief. This is crazy, the only loss to the manufacturer is the uncomfortable idea people are enjoying or benefiting from your creation for free. Yet there are developers who happily contribute to open source projects and games with little to no recognition or reward.

Likewise with drug manufacturing, it's the same idea. It's illegal to copy a pharmaceutical drug and take it yourself and others without the approval of the patent holder. Yet, it is the patent holding party that determines how many licensed copies it is willing to sell. Thus, they are able to take the moral high ground in pricing this drug, but it's the same principle as above-pony up for my idea, shame on you for benefitting from it and not contributing to my wealth.

I really do think this company is out of touch with reality. All in all, I feel like this only earns them bad press, especially after Martin Shrekli debacle. There's also a potential for a lawsuit, based on human rights I'm sure.


>"You need to maintain the factory, you need to do the paperwork, you need to test the product, you need to make new product batches all the time because product expires," he said.

I'm pretty confident LPLD sufferers around the world would be prepared to move to the LPLD hot spot in Quebec, and work part time in the factory under proper supervision?


You can't put a bunch of untrained people in a drug factory and expect them to make a good job. You need some people with a Chemistry/Biology/Pharmaceutical degree, or some kind of specialization, or many years working in the industry.

Specially if it is a cutting edge factory with a technology that is being invented now and changes every month. Whatever that can be automated so anyone can make it without knowledge is probably automated.

It's like thinking that the Supreme court can fire all the technical staff, and the judges themselves can administer the web and mail server (perhaps with a little of help from some experts that come only once in a while).


So I was expecting another story about some IP troll buying the rights to a drug with a monopoly and then jacking up the price (like the whole EpiPen fiasco) but this wasn't that.

There's an old Chris Rock bit about Big Pharma where he says there'll never be another cure for HIV like there was for polio because there's no money in that. The money is in getting you to the next stop.

It's poignant because this isn't a theoretical scenario. Gilead recently was downgraded on declining revenues because they're wiping out the disease (Hepatitis C IIRC?).

So, back to Glybera. There are plenty of low-incidence diseases that are treated by expensive drugs to manage them. This is a lifelong commitment. Covering such drugs in company health plans can significantly increase the per-member costs.

If you have a drug that essentially cures the drug in one dose shouldn't that be weighed against the lifelong cost of covering a regime to manage the disease that is inferior? Multiply that by the disease being quite rare and sure, you end up with a $1 million price tag.

As further evidence for how screwed up the US health insurance system is: companies enroll in plans for their members typically for a period of a year or maybe a few years. Let's say your drug's price of $1m compares favourably to $100k/year for 40 years to manage the disease. How can a company who might only be covering the employees for 1-3 years be expected to cover that higher cost?

To be clear, this is further evidence of how stupid the US model is. In a single payer model this particular concern goes away.

How many rare genetic disorders are out there where $1 million per patient for an essentially complete cure isn't a bargain compared to the cost of managing the disease? Probably a lot. Is it fair to decry such expensive drugs just on their price tag without looking at the facts? Probably not but I bet you it will happen.


> Let's say your drug's price of $1m compares favourably to $100k/year for 40 years to manage the disease. How can a company who might only be covering the employees for 1-3 years be expected to cover that higher cost?

Yes, it's essentially a Prisoner's Dilemma. If every insurance company agreed to pay for this drug, the total cost of treatment overall would be lower (and the patients would be healthier and happier). If my company decides to pay it and no other insurance company does, then when the patient leaves our network (in less than 10 years) and joins another insurance network, my company will have paid the cost but can't reap the financial benefits.

There's two major differences between this scenario and classic PD, though.

First, companies are allowed to communicate. We could conceivably get everybody in a room together and come up with some agreement by which everybody agrees to pay for this drug, even if patients switch insurers. Everybody wins. Patients are healthier, and insurers save money.

Second, it's not a one-time decision. An insurer can change their mind from "no" to "yes" at any time. So it's more like "iterated PD", with an indefinite number of rounds. In that game, interestingly, there is no strictly dominant strategy, and altruism tends to do better in practice! So maybe you don't even need an agreement.

> To be clear, this is further evidence of how stupid the US model is. In a single payer model this particular concern goes away.

How do you figure? The article points out that they also had trouble convincing European governments to pay for it. You can't get Glybera anywhere in Europe or Canada today, either.

The US model is arguably a poor one, but this isn't a good example of that, because every other country in the world failed at Glybera, too.


This article brings up a thought experiment I've been pondering for a good while now...

So what would you charge for a drug that guaranteed you would live 30 extra years after you spent 20 million to develop it?

For an added twist, let's say it's NOT FDA approved but you have solid clinical evidence that it's efficacy was solid and can your "street cred" (whatever that means in biotech) allows you access to the world's most successful (ie richest) people.

I have my answer...what's yours?


That's a really interesting thought experiment, and I don't really know what my answer is.

The following choices assume that more people living an extra 30 years is a good thing ethically, and that there are no devastating effects environmentally or otherwise. The following choices also assume that you'll always have a monopoly on the production of the drug.

1. Assuming that the supply is practically unlimited, an altruistic actor should probably give it away for as close to free as possible. A purely selfish actor should probably try to sell to each individual for as much as they can afford (though this can be hard pricing strategy to enact). I suppose you might actually want to charge less than that even as a purely selfish actor, since you wouldn't want to somehow destroy the world economy by making everyone really poor except for yourself (would this actually destroy the economy though? I'm not sure... probably not relevant for the purposes of this thought experiment).

2. Assuming supply is limited, a purely altruistic actor will have to choose the most fitting recipients. This is a really tough choice. How do you define the most fitting recipients? Those who are most likely to contribute to the betterment of humanity with their extra 30 years? It seems like an almost impossible task to pick out who these people would be. A purely selfish actor should charge the richest as much as they're willing to pay.

If it were me and supply were unlimited, I'd like to think that I'd sell it for as little as possible but enough to still never have to worry about money again. Making $10 million in profit would probably be more than enough (though if you can make more and still help everyone, that'd be even better). If supply were limited, I don't know what I would do.

One thing I just realized though, is that even if supply were unlimited, if you had this godly power, you might choose to withhold it those you deem unworthy, which is a whole other ethical can of worms. I'm guessing this kind of deviates from the intent of your thought experiment though.

What's your answer?


This is exactly the reason we have governments. Theoretically in a liberal democracy, we don't allow people to do actions that enrich themselves at unreasonable societal cost. Allowing only the rich to have access to longer life is one of those basic things that governments are supposed to be here.


Does anybody know which virus vector was used?


The adeno-associated virus serotype 1 (AAV1) viral vector delivers an intact copy of the human lipoprotein lipase (LPL) gene to muscle cells.

source: https://en.wikipedia.org/wiki/Alipogene_tiparvovec


> But it's the only way scientific discoveries ever get to patients, because universities don't make drugs.

Why not?

If there are so very few patients, a lab could easily produce enough for them.


Yeah, they had to make some quantity to run their trials. presumably it cost much less than $1mil/dose or they'd not have research funding at their level


Indeed. A lot less than $1million per dose, I bet.

I understand that there are regulatory issues.

But it seems pretty clear that the standard pharma industry model doesn't work for drugs like this.



TBH, it sounds like the govt regulation for the drug to even get approved are what drove the cost up. The product was essentially made before pharma even had to lift a finger, but they made them jump through a lot of hoops to get it to market. That's the $100mm they are trying to recoup. Also, I think a lot of folks are missing that the disease is not necessarily lethal when diet is controlled. Just saying, that's all.


If it works but it's not economically-viable: the moral and ethical choice is to open-source it or give it to a non-profit medical foundation. It sucks to have a rare disease because there isn't enough profit to recoup r&d; this is where non-profits, NGOs and GSEs should advance medicine where big pharma trades lives for profits.


Will other scientific or technological advances (like gene therapy drugs for more common disorders) cause the price of this drug to come down in the future?

Say, if gene therapy became common, there wouldn't be as much red tape for approving this particular one, and there might be machines or research that could be shared with other drugs to amortize the cost?


> Pricing shouldn't be a political decision. It should be a rational decision based on merits and values," he said.

The money quote. A rational decision? Maybe. Exactly what merits? Exactly which values?

"Hundreds of millions of investor money has gone into the company"

But none of that led to the development of the drug.


This is what we call “market failure”.


That's probably the greatest example of the issue that Open Longevity was going to solve by combining patient organization with ICO funding to conduct clinical trials without profit driven big pharma. Unfortunately, that didn't happen…


> The problem was the price.

I thought that drug patents were basically illegal in India. It seems there’s a huge market there for this kind of thing. An abandoned drug with a huge price tag.

Also I’m not terribly worried. The patent will wear off eventually and then anyone can make it.


As sad as this story is, the silver lining is that patents expire, and 20 years from the patent filing point (probably 5-10 years from now?), patients will be able to be affordably cured. It sucks but is better than nothing.


The story is clear: the problem is not the patent itself but the cost of passing regulation hurdles and maintaining a plant producing the drug when there is suck low demand.

No one will invest in this even after the patent expires. The best the patients could hope is to group togethr to get some done produced?


Regulation hurdles were met, and the cost of a plant is overblown. Most specialty pharmacy are made in small labs with a few pharmacy techs, and they can make other things in between this drug. I think the issue is that of pharma alows the price to drop on this drug, they lose negotiations on other drugs. They don't want a precedence to be set where they drop thier price if insurance companies refuse to pay.


The article is fascinating, but the format with the

one sentence

at a time

system is incredibly hard to read and digest


On the contrary, I find that easier to read! Except for the font, that's just way too light.


What’s up with this drug now?

Sounds like it’s patents and IP protection should be up.

I’d imagine you could get a single dose manufactured 1 off for $100k by a lab.


This is kind of a common issue with genetic disorders. When I was active on cystic fibrosis lists, sometimes articles were posted that said stuff like "It costs an average of $100k annually to treat CF" and parents would discuss it and go "That sounds low to me" and some older patient would chime in and say "Last year, my drug prescriptions alone were $100k. That's not counting the cost of doctor's visits and hospitalizations."

(Estimates in articles vary wildly. I searched briefly and just trying to find something that makes sense for like two minutes just makes me tired. So if you want to jump up and dispute that with some googled up article, I don't feel like arguing with you about it. I've already told you actual people living with the condition read those articles and go "Where on earth are they getting these ridiculous low ball figures???")

So then they come out with some very expensive drug that costs like a quarter million or more annually and it only treats around five percent or so of patients with CF. The price on Wikipedia [1] is currently listed at over $300k annually.

[1] https://en.wikipedia.org/wiki/Ivacaftor

And then who can afford that? If you have been sick your whole life, you probably don't have a lot of savings or a lot of ability to come up with big bucks, etc. You are probably deeply in debt and not making much money.

I don't know the answer. Conventional medicine doesn't really work for people with genetic disorders. It tends to be crazy expensive and also merely mitigates things somewhat. The standard expectation is that you will suffer a bit less and maybe live a bit longer, but you won't ever really be well.

So such people understandably want a cure. That's the holy grail for folks coping with genetic disorders.

I think there are potentially other avenues for some portion of people with genetic disorders. But I don't currently have the words for that and I get tired of being ganged up on by boatloads of internet strangers who want to inform me that I'm imagining things and my entire life experience is a hallucination and I don't actually know nothing about genetic anything. So let's just leave it at "I have this opinion and maybe it provides a way out of this trap and maybe it doesn't."

Because the current approach of inventing incredibly expensive drugs that might provide a cure is essentially failing as a method. And all other approaches are so awful it's why such things get labeled "dread diseases" -- because what it does to your life is so terrible that if a doctor were not prescribing it, it would be in violation of the Geneva Convention. It's just not humane.




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