Yes, but resolving this might be a case where the cure is worse than the disease. Take Colchicine for example, which is one of the first medicines ever. It was cheap and plentiful, and thousands of people used it daily to help control gout.
However, nobody ever actually did modern science on it. We all just assumed it was safe and effective, because it had been so for thousands of years.
So, in 2006 the US FDA started the Unapproved Drugs Initiative. The US government said they would give an exclusive right to the drug to anyone who did the science. So, URL Pharma did a tiny bit of research to prove what generations of physicians already knew, and the US Government let them have the exclusive right to sell Colchicine. The price immediately went from pennies a pill to $3 and up.
While I applaud the goal, it is far too easy to turn these well-meaning initiatives into cynical IP land-grabs that are distinctly anti-consumer.
another example is acthar gel. it was approved in the 1950s as a "miracle drug" for dozens of diseases. it is a hormone extracted from pig pituitary glands that stimulates corticosteroid production, and the research around the clinical use of this drug and corticosteroids won a nobel prize
in the 1950s, synthesizing steroids was expensive, so doctors used the pig-derived acthar (which was actually developed by armour & co, the chicago meat packing company). then cheap generic synthetic steroids gained use and acthar use declined, as they basically had the same effects.
except that acthar worked better than corticosteroids to treat a rare form of epilepsy in infants called infantile spasms, even though the drug was not FDA approved for this disease. however, there were too few patients for the drug to be profitable in that indication, so the manufacturer of acthar decided to take it off the market. physicians and patients revolted, as this was the only drug that worked for a serious disease, so the manufacturer kept selling it though they lost millions a year on it
enter questcor pharmaceuticals, which bought the rights to the drug for $100K. they cobbled together some existing publications and got FDA approval for infantile spasms. they increased the price of the drug from $30 / vial to $30K / vial, and then started marketing it in other indications like multiple sclerosis. there was no real evidence it worked in these indications, but because it was approved in the 1950s before modern FDA standards, it retained many approved indications
questcor was eventually acquired for $6B, and to this day there is no competition for acthar because there is no FDA pathway for making a generic version of a pig-derived drug
there is little backwards compatibility for FDA regulations
And yet another: Dimethyl Sulfoxide can be used to (cheaply) treat a ton of different things, but has been blocked by the FDA for use in all but a very small number of cases (bladder pain syndrome). Amongst other things, is extremely good at reducing swelling without the use of steroids, and is often used in gel form to treat inflammation.
If you want to use it, though, you have to leave the US or have a veterinarian as a friend. An acquaintance of mine gets DMSO gel used on horses to treat inflammation from a vet and uses it to reduce swelling in his back (has had multiple major spinal surgeries).
The common conspiracy theory is that DMSO is too cheap and treats too broad a category of ailments, so drug companies are lobbying against it with the FDA any time it comes up, as it would jeopardize the revenue streams from steroidal anti-inflammatory drugs, painkillers, etc.
But you can buy it over the counter easily? It's not hard to find locally or you can just pick up a bottle on Amazon. My mom has used it for years on her feet.
The problem is that in medicine, it's rarely the engineering that's valuable, it's knowing if it's safe and effective. I can see why that would rub people the wrong way, but it's also worrying that people were prescribing medicine based on tradition rather than science. Pennies to dollars for a period of time is better than pulling the drug off the market entirely until it was proven safe (which no one would have done).
> it's also worrying that people were prescribing medicine based on tradition rather than science
Why? New drugs have been getting less effective over time, even though the scientific requirements to get them approved have been becoming stricter. The majority of our most effective drugs were approved before there were any requirements for demonstrating safety and/or efficacy.
Does diminishing returns/low hanging fruit mean anything to you?
Also, from that pool of drugs you're referring to, we've eliminated a number of things that had strong effects but whose side-effects were later found after careful study to not outweigh the benefits.
There is a similar effect from carefully studying devices/surgical interventions--not so much a raft of "new innovations" but rather the culling of a lot of things that were overused or actually harmful. Huge cost savings, big improvements in population health & lots of gored oxen.
> I can see why that would rub people the wrong way, but it's also worrying that people were prescribing medicine based on tradition rather than science.
I personally think FDA approval is dubious in cases like the OP mentioned.
We know from centuries of use that the plant is safe. Whether it helps their gout or not is irrelevant. Even if it's a placebo effect, who cares? Trying it out won't kill them, and if it doesn't work they can move on to something else.
Why waste tax payer money "proving" something like this?
I love the protections the FDA gives, but we need to use common sense, too.
Just because people "know" something is safe doesn't make it so. Below a certain percentage increase, or with more long-term effects, public perception of the issues that might come with a common treatment could be overlooking things.
We've known (for various confidence levels) that lithium salts are effective for some mood disorders since at least the 1870s (though there's various stories and one-off doctor recommendations that survive about lithium salts or natural water sources with high lithium levels being good for melancholy much older than that), then the FDA banned it in the 1940s due to the nasty discovery of lithium poisoning fatalities, and now we're using it again since 1970, with recurring blood tests to be sure you're not accumulating too much.
We used lead regularly in all sorts of things until, surprise, lots of people often exposed to lead turned up with nasty health issues.
We used asbestos all over the place until, decades after we started using it, we realized "hey, maybe all these easily-broken-off fibers that turn up in the shredded lungs of people might be related".
We used syrup of ipecac for hundreds of years, until we concluded "I _think_ the side effects from the ipecac are probably worse than the thing we wanted them to expel".
What do you do about all the flawed and weakly powered clinical trials of the past then? Do you consider them invalid at some point? If not, why have double standards then?
Rather than issue an artificial monopoly, what if a "reward" to the company that "did the science" was capped at 2x their costs or X years, whichever comes first. Then it's public domain.
Wouldn't that get SOMEBODY to take the nigh guaranteed investment? I think what rubs people the wrong way is the limitless profits that are guaranteed by government sanctioned monopoly for things that save people's lives. It's a strange perversion of the free market that benefits the wrong people disproportionately.
The profits aren't limitless. Pharma is an industry in decline, because drug r&d is so hard
As it currently stands, 60%+ of the new drugs that are developed in the world these days are for cancer or rare disease. Because for most other diseases, drug r&d is not profitable. Neuro is too risky because the biology is complex. Cardiovascular and metabolic disease is too costly because of regulatory and reimbursement hurdles. Infectious disease is a field where generics dominate, and the regulatory system is failing to support efforts to fight drug resistant strains
For-profit companies fund 3x what governments fund. We don't have the federal budgets to support a public drug industry. And we don't have the political will at least in the US to empower federal funding increases of that magnitude
It certainly isn't ideal that profit driven companies control which drugs get approved. But if profit driven companies didn't fund new drug development, no one else would
The general idea might be economically sound, but the exclusivity period would also need to account for the risk that research costs would never be recuperated, e.g. if the result of the research turns out to be ineffective or unsafe.
Between failure, placebo effect, and the possibility of being less effective than other treatments... that isn't guaranteed. Studying these drugs may just prove they aren't worth using.
If it's so straight forward to prove, the government should just fund the studies itself. There's no reason to grant any private company anything in that case.
> Even assuming government operates as efficiently as private industry, we are talking almost triple the NIH budget to accomplish that
So increase the budget? If we assume the government would operate as efficiently as private industry, then it would be cheaper overall. The other option is for private industry to recoup the costs plus profits from society at large.
Obviously increasing the budget is politically difficult, but let's not pretend the current method makes any real economic sense.
The NIH budget has declined 20% in the last 15 years. Not only is there a strong downward trend, but the movements in funding levels are gradual. I'd say that tripling the NIH budget is not just politically difficult, but politically impossible
Then just leave the drugs grandfathered. If we view something as a problem (i.e. the lack of formal drug approval processes on old drugs), but we are not willing to solve the problem right (i.e. providing funding to government agencies to do the research), then we shouldn't do anything at all. Continuing the status quo is also a reasonable action.
That would be the best thing to do IMO, but the problem is politics. Congress loves wasting money on toys that kill people, but when it comes to things that saves lives and advance science, all of a sudden budgets are tight or we need a new round of tax cuts.
I think the US government should just directly pay for the studies/tests. If (as would be assumed), the drug meets the current requirements after this testing, all drug companies can continue selling them. If not, then great we can take a dangerous and/or ineffective drug off the market. And if the government isn't willing to pay, they should just continue leaving it grandfathered.
The Unapproved Drugs Initiative sounds much worse.
As someone who is prescribed colchine for life for 3x/day, I remain blown away that a generic drug I'd taken for a better part of my life went from costing pennies to costing ~$6 per pill.
"So, in 2006 the US FDA started the Unapproved Drugs Initiative. The US government said they would give an exclusive right to the drug to anyone who did the science."
This right here is the problem. The US government could easily have put a 1 cent tax on every pill and used it to have the FDA contract out the safety research.
But instead it chose to grant a private venture yet another monopoly.
This would still leave the question of deciding which, of an huge number arguably medical human activities to subject to scrutiny. Various commercial interests will find ways of sticking their noses into the game of maybe-maybe-not banning something.
To date, it is still not fully understood how paracetamol/acetaminophen works. Due to the fact that it was sold long before understanding the mechanism of action was required by the FDA, and there are little adverse effects in the history of the drug, it's permitted to be sold today.
This is a silly piece and it misrepresents the space.
For starters, the 510(k) pathway only applies to moderate risk class 2 devices. It's not like every device on the market prior to 1976 was automatically granted 510(k) status which is what this piece implies.
Second, holding medical devices to the same safety standards as drugs is unnecessary. The reason drugs are held to a higher standard is because they present a high risk of acute injury and they are more novel. Most medical devices won't kill you suddenly if they are faulty, and the ones that can are class 3 devices which require a clinical trial component.
Third, the 510(k) pathway exists because the safety risks for device classes are relatively similar whereas for drugs there can be high variability depending on structures. If you design a dental implant that is made of the same material, has a similar design, and has a similar purpose as a pre-existing device which has been shown to be safe, it will generally be safe to assume the new device will also be safe. Most new devices that cannot be shown to be similar to something already on the market are automatically deemed to be high risk and require a trial.
Finally, you can't have your cake and eat it too. Want devices to be as safe as drugs? Apply the same safety standards and watch device costs skyrocket. Then nyt will be back to incorrectly blaming product manufacturers for sky high healthcare costs. The FDA is already in a position where they do not have the funding or manpower to even review all the 510(k)s they get every year. If you make every device submission a premarket approval (highest level of scrutiny + a clinical trial) then devices will never get approved in a timely fashion.
Clarification: upon further digging, it turns out that all devices >= class 2 in production before 1976 were granted 510(k) with the intention of transferring class 3 devices to pma once regulations were developed for them. Most of these devices were transferred by the time I entered the space and make up a small percentage of the total class 3 devices which is why I was not familiar with this. Ignore that part of my previous statement.
It was one of 19 devices that were class 3 (high risk) but granted 510(k) exemptions due to precedent. Ultimately all of these devices were intended to be transitioned to the higher standard pma approval process normally associated with class 3 devices, but were allowed to leverage moderate risk 510(k) pathways typically granted to class 2 devices until pma processes were developed for them. FDA was slow in orchestrating the change, and so this was allowed to continue until these safety concerns manifested, forcing FDA's hand.
I was actually not aware that this had happened as by the time I entered this space almost all of the class 3 devices in question had transitioned to pma. To my knowledge there are very few devices left where this is still the case.
This isn't really news for people familiar with medical device regulation. Depending on exactly what the new technology is, you can get approval based on a predicate device.
Otherwise, your most basic medical devices (bladder catheters) would be crazy expensive as the manufacturer would need to run a clinic trial to test a piece of tubing.
It seems pretty crazy that new alloys and materials for long term implants wouldn't have to do any bio-compatibility testing.
I also wonder what the culture is like for orthopedic surgeons. What risks and benefits did the doctor-patient in the article perceive came with the particular implant?
They would have to do biocomp testing. Every 510(k) requires an analysis of device compliance to ISO 10993, regardless of whether or not its predicate is preamendment. The premise of the article is alarmist and acts as if FDA requires no testing whatsoever, when the list of standards is as long as my arm: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/cla...
Now one could argue that biocomp testing, which is done on animal models for the most part, is insufficient for any implanted device. That's a fair argument and one worth having. But the linked op-ed is a polemic.
Agreed. This article is pretty alarmist. I would ask the author to actually go through the process and report back. It's not for the weak of pocketbook or compliance.
>I also wonder what the culture is like for orthopedic surgeons.
It is among the worst specialties as far as being based on tradition/folklore/marketing. When you see one of their own being injured this badly you realize how wholeheartedly they buy into their own BS about "new innovations" that can "help" people.
There was an episode of Reveal awhile back about Essure, a permanent, implantable female contraceptive that, due to unforeseen nickel leakage, caused severe long-term reactions (and in some cases, even pregnancy) in a significant subset of its patients. Essure underwent clinical trials prior to FDA approval, but there was no control group, and its ~400 women studied for one year were compared against a long-term study of 10,000 tubal ligation patients.
My father's last position before retirement was as a civil servant responsible for approving equipment for medical use.
One of his last cases concerned a businessman who insisted, that a vacuum cleaner produced by his company should be certified as a medical device - ostensibly its use was to deliver drugs(via reverse action and inhalation).
My father rejected this notion on the grounds that, among other things, it was impossible to control the dosage. Unfortunately once my father retired that man eventually found somebody who would give in to pressure.
What I'm trying to say is that there's a decent amount of "medical" devices on the market that serve no such purpose so, a non-conformant artificial hip joint is only the tip of the iceberg.
Maybe we should just give up on privacy for medical records and require that all prescriptions, tests, symptoms, etc. are thrown into a large database where they can be analyzed.
Then approval is given for X number of patients, when hypothesis is defined. And further approval follows automatically as long as on-the-fly analysis of all health records supports the hypothesis.
Okay, I'm naive, and we integrating all health records is certainly non-trivial. My point is every prescription is an experiment that could be used as further evidence.
Any time you care about the results of a set of actions, you should measure those results. If we care about the results of medical care, we should measure those results.
It's irresponsible not to. I would venture to guess that millions of people are dying early because we don't have this as a mandatory, built in part of the process.
But let's put this in terms of not just science but economics. A working market depends on having information about the normalized value of a particular proposition. To understand that value, you need to know the proposition's cost and its benefit. Insurance and other systems remove us from information about cost. Throwing away results data obscures the benefit. Is it any shock then that prices spiral out of control?
Could you point to where this number comes from more precisely? I'm incredibly curious, given that it is an order of magnitude different from what I've seen. For example, there's the Tufts study:
which arrives at $2.6B. And if you are interested in keeping up with some of these studies from someone in the industry, I highly recommend Derek Lowe's blog -- he's a medicinal chemist. For example, http://blogs.sciencemag.org/pipeline/archives/2017/09/12/it-...
The tufts study is the definitive source I usually hear as well. But most of the $2.6B is cost of failed candidates. The actual cash costs of developing a successful drug are probably more like $100-200M minimum from start of lead optimization to FDA approval, based on the tufts data and also anecdotally if you track venture funding raised from companies that get drugs approved
In some indications however one phase 3 study can be $300M+
Why shouldn't we consider the cost of failed candidates? That's like saying lottery tickets are a great investment, if we only look at the winning ticket.
I completely agree you have to include cost of failed candidates and did not mean to suggest I did not
I mentioned the cash costs for developing an approved drug as an additional data point to that illustrate GPs $35M is too low even excluding cost of failure
The actual cost of developing a successful drug includes failed candidates. If you knew what chemicals would be effective medicines from the start, you wouldn't need to do research.
> If you knew what chemicals would be effective medicines from the start, you wouldn't need to do research.
I mean that's not really accurate, even if you know a drug will be effective you're still legally required to do the research. There are plenty of drugs we know will be effective in advance, but they still need to be tested. Similarly, there are lots of drugs that we know will have maybe only a 5% likely chance of being effective, but it's worth spending money to test them anyway because of the potential profits. So including the costs of failed drug trials doesn't really make any sense.
If you knew it was effective what's the point of the research? The research is what's used to demonstrate efficacy. The FDA requires research because it cannot be known if a drug is safe and effective without research. They don't require you submit all the research that found a drug didn't work. They only require it of the one that did. It doesn't change the fact that you have any number of chemicals that could do any number of things, and you do research to demonstrate which ones have the desirable properties. Not that no one has to constructively invent a process to manufacture a drug, but what a drug patent typically grants is exclusive manufacture for proof of medical utility.
I don't know the details of the nexium approval but for novel drugs you don't know it's effective until you test it
The biggest driver of the high cost of drug development are failed late stage (phase 2 and 3) studies. Things look effective in the lab, then look effective in animals, then look potentially effective in exploratory human studies, then when you test rigorously for effectiveness in humans, they often fail. And these late stage human studies are the most expensive
For generic drugs where you "know" it is safe and effective, there's an expedited pathway with fewer / smaller studies. And for slight tweaks to approved drugs there is another process that's more burdensome than the generics approval process but not as bad as a full new chemical entity path
Because doing controlled trials is how you come about that knowledge. Otherwise you're just guessing. You can guess something is safe, but until you try it for real in a systematic way, that's all it is, a guess. That's not knowledge.
The upper bound isn't really relevant though, because of course any company can spend infinitely much on anything, and will if they're trying to maximize the amount of time they can sell the drug while it's under patent. The only thing that matters is how much the least expensive drug approvals cost.
I'm probably taking you too literally but companies can't spend infinite amounts because they don't have infinite money
The upper bound is actually very relevant. Those $300M studies are cardiovascular outcomes studies, which are required for many diabetes / cardiovascular drugs, and those expensive studies have basically stifled innovation in those areas because the cost of developing those drugs is too high compared to the expected profits
Not sure I understand the statement that the only thing that matters is how much the least expensive drug approvals cost?
I'm sure there are other folks on here who know more on the subject, but the last time I looked into data from that Tufts group, it smelled fishy to me: closed source analysis of closed source data.
It seemed to hardly count as verifiable academic research. The raw data was seemingly made available privately to the researchers by way of their close relationship with the companies they're studying, the raw data is not made available by reproduction of their analysis, and there's no way for others to acquire similar data for comparison.
They may be honest, and the data and analysis may be accurate, and it may not be trying to paint a picture that favors its benefactors, but I did not conclude any of those things.
The oft-cited $2.6B cost to develop a drug from the tufts studies pertains to r&d costs up to FDA approval. You need FDA approval to market a drug and the tufts studies don't include any pre-approval market research costs from what I can tell
However a big part of the $2.6B is the money invested into drugs that don't end up getting approved, ie cost of failure. The actual cash cost of getting a drug approved is probably an order of magnitude less
Once approved most drugs do 90%+ gross margins so are quite profitable
On the flip side, most drugs don't actually do anything. Or have side effects that are worse than the thing they're trying to cure.
sure, i'm on board with lowering the cost, but not at the expense of lowering the efficacy.
I could see a good argument for balancing clinical trials vs toxicity, commonality and threat. Perhaps a drug that's only useful for .0001% of the population that would die otherwise, and isn't toxic, well maybe we can lower the bar there. but something that half the population takes, and overdoses will kill you, that should require really high standard. this approach is tough with the current system of off-label prescriptions though.
I would say that a high bar for toxicity and side effects is good. Leave it there.
But there can be a more graded approach for effectiveness. There is little reason to completely forbid the commercialization of a drug because it's effectiveness isn't certain to a very low p-value.
But, as I understand, they aren't independent considerations; toxicity, side effects, and effectiveness (and the nature of the condition they treat) are weighed together, not evaluated independently. The acceptable toxicity and side effects of a drug that's near 100% effective at treating quickly-fatal condition with no other available treatment is not the same as for something with only moderate effectiveness at treating headache pain.
Second, I'm not so convinced by a science writers rather magical, in that we can't see his variables (just trust me I got it all right!), napkin math from 2013, and the complaints of a drug industry power player.
> We should be finding better ways to do clinical trials to help companies lower the cost.
I'm sure the rich drug companies can find ways to do this. Like cut ridiculous compensation packages when apparently your operating costs are skyrocketing?
I'm not inclined to "help out" companies doing their share to dig themselves into a financial shitshow.
They have enough power, including, apparently, an SC decision that let's them expropriate private property on vague promises of jobs, then providing no jobs:
And let's not forget the freedom they have to tweak a generic (with no change to the effect of the drug) and earn a fresh patent claim.
I keep hearing pundits go on about how government can't seem to control it's costs, and is ridiculously inefficient -- we best just shut it down. Then in the next breath, they proclaim giant corps are having a hard time managing theirs, but obviously WE MUST HELP THEM.
Personally I would consider being even more strict on medical device testing. My mother who had a stroke about a decade ago was using a device designed to test the PT/INR levels of her blood. The stroke had made her body less capable of properly balancing her blood, so she has to constantly test her levels to ensure she doesn't suffer from either fatal bleeding or internal clotting.
The device she was using had to be recalled after years of use because it could report a low value, causing her to over-balance her medication into dangerous levels. Not only that, but they chose not to inform my mother after the recall and made no efforts to fix the issue.
It's even worse if software is involved. Radio controlled heart implants that rely on security through obscurity is tragedy waiting to happen. I recommend Karen Sandler's talk about her own experiences with that kind of device.
This sounds like individuals or groups of individuals covering their own rears instead of facing the problem for themselves.
It's very difficult to see product defects from behind a desk. And it's impossible to recognize the personal complications and difficulties that arise for people on the receiving end while looking at statistics and financial reports.
What is a medical device? Are we talking about things like thermometers, wheelchairs, and surgical knives. Is this saying you need a double-blind study for every new design of wheelchair?
Sometimes the medical device is software. In fact, there are many software products on the markets whose makers don't even realize are unapproved medical devices. However, the FDA just doesn't have the manpower to investigate that on a wide scale.
I hear that that's true of other things in medical practice as well. For eg: are surgical procedures validated by any kind of controlled clinical trails?
However, nobody ever actually did modern science on it. We all just assumed it was safe and effective, because it had been so for thousands of years.
So, in 2006 the US FDA started the Unapproved Drugs Initiative. The US government said they would give an exclusive right to the drug to anyone who did the science. So, URL Pharma did a tiny bit of research to prove what generations of physicians already knew, and the US Government let them have the exclusive right to sell Colchicine. The price immediately went from pennies a pill to $3 and up.
While I applaud the goal, it is far too easy to turn these well-meaning initiatives into cynical IP land-grabs that are distinctly anti-consumer.
https://www.jwatch.org/jw201006100000001/2010/06/10/spotligh...