[mabbo]

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?

[rayiner]

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.

[derefr]

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?

[pdkl95]

> (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.

[thereisnospork]

>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.

[panzagl]

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.

[howard941]

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.

[mrnobody_67]

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.

[scottlocklin]

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.

[JamesBarney]

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.

[irq11]

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.

[mistermann]

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?

[irq11]

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.

[mistermann]

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.

[rileymat2]

"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?

[Nasrudith]

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.

[JamesBarney]

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.

[gus_massa]

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?

[ekianjo]

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.

[gus_massa]

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.

[Fomite]

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.

[skadamou]

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.

[JunkDNA]

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

[rayiner]

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.

[maxander]

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.

[ekianjo]

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.

[maxander]

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...

[iaw]

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.

[rorykoehler]

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

[chimeracoder]

> 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.

[sdenton4]

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.

[ericflo]

> 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.

[SilasX]

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.

[ericflo]

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.

[SilasX]

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?

[ericflo]

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.

[infinite8s]

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

[umanwizard]

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?

[ams6110]

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?

[d4l3k]

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.

[ineedasername]

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

[ekianjo]

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.

[tptacek]

No, not here.

[tptacek]

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.

[ethbro]

> 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.

[tptacek]

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.

[ethbro]

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).

[jswizzy]

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.

[teekert]

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

[ezoe]

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.