Tuesday, March 21, 2017

Take that, Thiel

Oh.  Isn't one of Peter Thiel's policy ideas that the drug market should be opened up so that people can try them out before they go through all of the expensive testing?

Well, here's a short argument at Nature that there are good economic (and social) reasons to insist that drug companies show efficacy before they release drugs.  Some extracts:

Knowledge of the history is important. The 1938 US Food, Drug, and Cosmetic Act required only that drug safety be demonstrated. In 1962, new legislation demanded that marketed drugs also go through well-controlled studies to test for therapeutic benefit. More than 1,000 medical products were subsequently withdrawn after reviews found little or no evidence of efficacy1. The free market that existed before 1962 revealed no connection between a drug's ability to turn a profit and its clinical usefulness. The same is likely to be true of any future deregulated market....

An overly stringent system will err by withholding or delaying safe and effective 'good' drugs from patients. Critics of existing regulations often point to the case of a treatment for Hunter syndrome — a rare, inherited degenerative disease in which the absence of a crucial enzyme can be fatal. Trials of the enzyme-replacement drug Elaprase (idursulfase) meant that, for a year, a group of children received a placebo instead of the drug that was eventually shown to be effective2.

Conversely, a lax regulatory system will subject patients to 'bad' drugs that may be toxic. The iconic example is the more than 10,000 birth defects caused worldwide by the drug thalidomide, a late 1950s remedy for nausea during pregnancy. Even in the past dozen years, initially promising drugs, such as torcetrapib (for reducing cholesterol and heart-disease risk) and semagacestat (for improving cognition in people with Alzheimer's disease), were found to cause harm only after they had been tested in large, mandatory trials — effects that were not seen in the smaller trials3.

The most extreme proponents of deregulation argue that the market can serve as the sole arbiter of utility: if a medicine is selling well, it must be delivering value4. A more moderate view is that reliable information on efficacy can be collected after a drug goes on sale, through uncontrolled observational studies and other post hoc analyses.

There is a third type of error that these arguments neglect (see ‘The good, the bad and the useless’). Untested drugs can be reasonably safe but provide no benefit.
And here's the key point:
Arguments for deregulation fail to recognize that valuable information has a cost. Drug companies cannot afford to generate reliable evidence for efficacy unless their competitors are all held to the same high standards. Efficacy requirements level the playing field and ensure that the health sector receives the data needed to inform good therapeutic and economic decisions. The government, insurers, patients and others need to know whether medicines are likely to provide benefits. Patients and physicians must have access to reliable information to make educated and ethical choices.

Rigorous clinical studies are still the best way to learn whether a drug works, and regulation is essential to ensure that these studies are conducted. Pre-specified endpoints, controls, randomization and blinding cannot be discarded without sacrificing actionable clinical information5.

Once a drug is on the market, it is hard to gather solid efficacy data....

The FDA's gatekeeper role makes the medical marketplace function. The economic benefits of good research and a healthier population will be lost without incentives to find truly effective drugs.
Jason - that article is definitely tweet worthy, no?

Update:   I just Googled up an article at Vox from a couple of months ago that explained the pro FDA argument from a medical point of view.   A lot of this read like what John just said in comments:
Thiel, a libertarian iconoclast, has repeatedly made the case that the FDA gets in the way of drug innovation by making it too difficult for new medicines to get to the market. Some of the FDA candidates he’s identified — including Silicon Valley’s Jim O’Neill and Balaji Srinivasan — have similarly argued that the agency should dump its requirement that drugs be proven effective before reaching the market, and that we’d be better off if the FDA operated more like a “Yelp for drugs.” In other words, bringing the same speedy and disruptive approach to medical regulation that Silicon Valley brought to the taxi and hotel industries, for example, will unlock cures — fast. 

But Thiel and his pals miss a very important point about developing new drugs: Manipulating biology isn’t the same as manipulating computer code. It’s much, much harder. Speeding up medical innovation will take a lot more than just stripping down the FDA — it’ll take huge leaps forward in our understanding of biochemistry and the body. Health care is also different from taxis and hotels in another key way: Consumers can’t really judge the safety and quality of medical products by themselves....
...I asked a longtime pharmaceutical scientist (and conservative), Derek Lowe, for his views. In his 28 years in the lab, Lowe has seen hundreds of thousands of compounds tested on a huge variety of drug targets, and never, not once, has he brought a drug to market.
The reason? “We don’t know how to find drugs that work,” he said.
For every 5,000 compounds discovered at this "preclinical" phase of drug development, only about five are promising enough to be tried in humans. That’s a success rate of 0.1 percent.
Drug innovation comes from painstaking tinkering and a dash of luck. “It’s very tempting for someone who has come out of IT to say, ‘DNA is code, and cells are the hardware; go in and debug it’,” Lowe said. “But this is wrong.”
In Silicon Valley, humans have designed the hardware, software, and computer code they’re working with. In medical research, scientists do not have that advantage, Lowe said. “We have 3 billion years of spaghetti-tangled gibberish to deal with. And unless you’ve done [drug development], it’s very hard to get across how hard it is. I don’t know of anything that’s harder.” Biochemistry and cell biology are “like alien nanotechnology,” he added.
So the real hurdle researchers face when it comes to finding new drugs for people isn’t overcoming a stringent regulator; it’s grappling with that “alien nanotechnology” in the lab.
Update 2:  from another article, talking about the effect of having an FDA that insists on showing efficacy as well as safety:

Pharmaceutical executives complain about the drug approval process, but usually don’t want to go anywhere close to a safety-only path. In practice, what they want is for the FDA to return their calls, for bureaucratic delays to be reduced, and to find the fastest and least expensive way to prove safety and efficacy.

Many biotech entrepreneurs are actually fans of a tough FDA. Pharmaceutical billionaire Leonard Schleifer, the founder and chief executive of Regeneron Pharmaceuticals, said that he was against “making it really easy to get your drug approved” at the Forbes Healthcare Summit last week, before news of that O’Neill was under consideration leaked.

Schleifer said that he couldn’t compete with companies like Pfizer or Eli Lilly, which have 10 to 100 times as many salespeople as Regeneron. But he can compete to get approved first, or to have a better drug that has more uses that the FDA allows it to advertise based on science.

“Having a high bar is a good thing, in my opinion, because it allows innovators to compete,” Schleifer said.


John said...

I'm currently dealing with this issue at a personal level. Just an hour ago I received some lab results for a friend of mine who for the last 15 years has been taking a prescription drug that can act as a nootropic. it is used in the treatment of Parkinson's and has been on the market for decades.

So one would be inclined to think it would have nothing to do with the heart. Just yesterday I found an animal study indicating it prolongs the QT interval, which has serious implications and can be fatal; often requiring a pacemaker. Several years ago my friend had a pacemaker inserted. Now he is struggling with other issues that may be related to this drug. His lab results are confounding, no-one knows what is going on. One of the most surprising things about this drug it that a major metabolite is methamphetamine!

The drug has been subject to thousands of studies but most people don't realise that most research done on drugs is not comprehensive, it is exploratory, teasing out the pharmacology with very little of that research directly addressing safety. That is why clinical trials are so important because trials specifically look at safety issues. In a deregulated system no-one is going to spend so much money investigating safety issues. They will spend more money on marketing than doing that. The trouble with free market mystics is that they don't understand the bottom line rules and if that means you can flog off a drug for a decade before the public becomes aware that it will kill you in 15 years they will do that. Dead people don't sue.

The current health craze and supplement frenzy raises related risks. Too many people out there think reading a few studies or worse internet pages on substance X is enough to inform of the safety of a supplement. Too many people still think of biological processes as pathway dynamics like those graphics in textbooks. Biological processes often are so complex that at present we can never know the full implications of tinkering with these. It may even be in principle impossible to know the full implications all the time.

As I previously stated my exception is in relation to terminal conditions. If such people wish to be guinea pigs fine, they are entitled to that choice.

Steve said...

Interesting, John. I just updated the post with an extract from a Vox article that backs up your point.

Jason Soon said...

Thiel's argument is to get rid of the requirement for effectiveness and have caveat emptor for that. Under his proposal drugs would still be tested for safety. so those arguments aren't that relevant to debunking Thiel

Steve said...

What about the economic argument in the Nature article, Jason?

Steve said...

And, I would add - as someone who is interested in medicine needing to be more rigorous and rational when it comes to putting money into treatments that actually are shown to benefit (like the controversy over whether certain operations are really effective overall), the point made in the Nature article should be of particular concern to you, no?

That is, if drug companies are free to make lots of money on drugs with no proven efficacy, why wouldn't they do that like they have in the past, making the health spending less efficient just at the time, particularly in the US, it needs to be more efficient?

Steve said...

The vitamin and supplement industries show that people are gullible enough as it is on spending money on treatments based on mere hearsay - through drugs into the mix too, and it sounds like a lot of money to be wasted, and with drug manufacturers with less incentive to find drugs that do work.

Steve said...

"throw drugs" not "through drugs"...

John said...


That is what happens in the supplements industry and Pharma will do exactly the same. They will create many useless drugs and then use marketing to flog those to the masses. How can the buyer beware when even scientists and doctors cannot be aware of whether a drug works without undue side effects? Thiel is just another free market mystic who thinks that somehow it will all work out if we let market magic do its stuff. Thiel is an ideologue, he is not putting forward an empirical argument he is asserting a philosophical viewpoint. Great, the FDA being run by a philosophical mystic. They are so screwed.

not trampis said...

Soony just wants to go back to the good old days of having quacks treat you.

Try this drug for your cancer, We do not say it is effective but nudge nudge wink wink!

Steve said...

I like a good Thiel pile on. :)

Jason Soon said...

If it's their own money that they waste I don't have a problem with it. there could be a dual track system where if a drug is to qualify for a public subsidy then it has to pass both safety and effectiveness. If it doesn't want to then only effectiveness and buyer beware. After all, I don't advocate banning acupuncture, chriopracty and homeopathy

Steve said...

Well, the question may come down to how much money drug companies think they can make from "safe but unproven" drugs compared to "safe, works and has public subsidy" drugs. Because, like I said, if they can make plenty on the former (and maybe the public subsidy is not so important, because they haven't had to pay for the efficacy trials?) they actually may lose incentive to make more of the drugs that work...

Jason Soon said...

Big pharma's main intellectual capital and the value of its IP will be tied up in treatments that work. But a Thiel like approach may encourage early release of trial products that would otherwise simply not be accesssible

Steve said...

"Big pharma's main intellectual capital and the value of its IP will be tied up in treatments that work."

Well, the three authors of the Nature article would not seem to agree:

"Drug companies cannot afford to generate reliable evidence for efficacy unless their competitors are all held to the same high standards. Efficacy requirements level the playing field and ensure that the health sector receives the data needed to inform good therapeutic and economic decisions."

Like that other libertarian/small government idea that competition between countries for the lowest tax rates is inherently a good thing, it seems those authors are suggesting freeing drug companies from proving efficacy will encourage a race to the bottom - if no one really has to prove efficacy, why should any company go to the expense of doing it? Just spend more money on advertising and olde time testimonials from satisfied customers instead...

John said...

it seems those authors are suggesting freeing drug companies from proving efficacy will encourage a race to the bottom

That will happen. The other issue here is the need for pure research. If we can spend so much money on the LHC for zero capital potential we certainly need to invest much more heavily in research that attempts to address some of the conceptual challenges. Drug research will never do that, it operates at another level entirely. That can help, to some extent, but there is very little market incentive to developing new strategies for basic research. So you won't find many drug related articles in the Journal of Biological Chemistry but it is a journal that has many fascinating articles. This is why I think we always need governments supporting the sciences to some degree, to provide the freedom necessary for research that if often neglected because market forces are about profit not understanding; though the two goals are not mutually exclusive there is a clear bias towards profit.