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Letter to the NEJM
The issue of off-label prescribing is heating up again. A recent article in the New England Journal of Medicine by Randall Stafford made the case for greater regulation. I am concerned that the benefits of off-label prescribing are not fully appreciated. Dan Klein and I wrote a letter to the NEJM - which they declined to publish - in response. Here's the letter:
Dear NEJM,
R.S. Stafford writes that off-label prescribing “permits innovation in clinical practice … offers patients and physicians earlier access to potentially valuable medications and allows physicians to adopt new practices based on emerging evidence.” Nevertheless, he calls for greater FDA regulation.
In contrast, we argue that the efficacy of off-label usage suggests that less FDA regulation of first or on-label usage would increase innovation and offer patients earlier access to new medications.
Off-label prescribing is regulated by the judgments of doctors, medical researchers, industry, the patient community, and patients. This system offers patients a more nuanced approach to care than a top-down approach. We should extend this approach to new drugs as well as to new uses for old drugs.
Our perspective is bolstered by a large survey of physicians which demonstrates strong support for off-label prescribing and considerable support for reducing FDA regulations on new drugs.
Daniel Klein
Alexander Tabarrok
George Mason University
Posted by Alex Tabarrok on May 9, 2008 at 07:43 AM in Economics, Medicine | Permalink
Comments
Everyone complains that drugs are kept arbitrarily expensive by the patent regime, and that may be true, as far as it goes. The drug companies make an excellent case that the FDA regs impose massive R&D costs on them (the $1-billion drug pipeline), and they need the extensive patent protection to guarantee recoupment of those investments. If the regs were dropped, say to the level of Europe, the costs would fall as well, and the needed patent protection would fall. Detente anyone? It's not like people are dropping dead in Europe from bad drugs (and, no, Vioxx should not have been removed from the market either).
Posted by: ephemeral druggist at May 9, 2008 10:02:49 AM
The fact that all of these articles are treating "off-label prescribing" as one real entity is absurd. Some off-label prescribing is bland and commonplace. Some is popular and yet borderline malfeasance.
There's no debate here unless we identify situations such as "we should regulate drug X for indication Y." Blanket regulations are obviously nonsensical and would largely shut down all of medicine in a two-hour time frame.
And that's a conversation far too nuanced for a non-specialist to be discussed effectively on a general audience economics blog.
Posted by: Pup, MD at May 9, 2008 10:20:19 AM
If anything, the FDA rules regarding off-label drug use are far too strict. Currently, a drug company representative is not allowed to market scientifically proven off-label uses to interested physicians. They aren't even allowed to disseminate articles from peer-reviewed journals that describe factually true material from unbiased third parties about off-label uses of their drug to physicians, even if such information would benefit patients and physicians alike.
(Ref: "F.D.A. Plan on Medical Articles Takes More Heat", NY Times, 4/19/2008:
http://preview.tinyurl.com/4cltoe)
This is a massive infringement of free speech. Unfortunately, it's the patients that pay the price.
Paul Hsieh, MD
Freedom and Individual Rights in Medicine: http://www.WeStandFIRM.org
Posted by: Paul Hsieh, MD at May 9, 2008 10:20:39 AM
The root problem of off-label utilization is that it makes cost containment even harder. Payers want to track what they are paying for. Restricting utilization to FDA indications allows for that. Off-label use can certainly be beneficial, and isn't inherently bad, the trouble is how to not stop innovation while not making it impossible for private and public payers to restrict manage what they pay for.
Posted by: Publius at May 9, 2008 10:39:22 AM
As with justice, treatment delayed is often treatment denied. Waiting for the regulator's approval often means treatment delayed. But only responsible, well informed people can assess the balamce of risk between treatment delayed and treatment whose effects are not fully known.
The NEJM article calls for the FDA to gather more information. That looks worth paying tax dollars for. But it also implies restricting informed choice because to make such choices might be risky. No case is esablished for such restriction.
The ancient inicial principle of Western medicine is "First, do no harm."; but as for centuries past doctors have to weigh up whether doing nothing or doing something is least likley to do avoidable harm. The classical resolution of that dilemma is that the doctor in charge of the particular case is responsible for deciding. Our modern case for restricting that discretion is based on the realisation that it is hard to be sure that the information reaching doctors is sound and impartial. We therefore entrust regulators with the decision on whether the risk of unsound "knowledge" in the medical system outweighs the risk of absence of knowledge.
Modern economics has produced a young mountain of evidence that decisions taken with some information tend to be superior to those taken with less information. We therfore tend to support strongly the classical reliance on decision by the informed person closest to the particular case; and we are right to press regulators on the costs of absence of knowledge in the medical system, and on the benefits of free dissemination of knowledge of uncertain quality. However, we do not yet assist the regulators with any assessments of the costs (in patients avoidably harmed) of eliminating "knowledge" from the system whyich later turns out to be unsound. For the regulators, those costs are important.
Posted by: David Heigham at May 9, 2008 12:15:50 PM
I wonder why they declined to publish your letter. It certainly can't be due to space considerations. Would it be too cynical of me to suggest petty fascism?
Posted by: KJC at May 9, 2008 12:59:31 PM
Of course they didn't publish the letter. It is ridiculously one-sided and doesn't even hint at the moral hazards that such deregulation would permit.
Drugs that actually DO something also have side effects. If an off-label treatment is ineffective, then patients are being harmed by those side effects. Without large trials, it is very difficult to know whether such an off-label treatment is effective. Doctors just can't know from their practice if a drug is effective or not, and routinely don't even care, judging from off-label prescriptions of antibiotics for viral diseases.
If the problem is that an off-label use is thought to be effective, then the solution is to prove it. Not to guess. Not to just wing it.
Posted by: Mike Huben at May 9, 2008 1:25:28 PM
They also probably didn't publish the letter because it didn't say anything than any undergraduate econ major couldn't have written off the cuff. The only "important" part of the article was the names attached to it. And those names (and especially that university) don't mean anything to physicians who don't nerd themselves out reading economics blogs.
Posted by: Pup, MD at May 9, 2008 1:31:45 PM
Mike Huben,
it seems to me that the question is not whether there are off-label uses that do more harm than good, but whether allowing off-label uses overall does more harm than good.
Posted by: LemmusLemmus at May 9, 2008 2:52:17 PM
Pup, MD and Huben missed the point. The point of the letter was to direct attention to the substantial research in the links.
Posted by: Alex Tabarrok at May 9, 2008 3:24:26 PM
If the problem is that an off-label use is thought to be effective, then the solution is to prove it. Not to guess. Not to just wing it.
It seems to me that if the problem is that off-label use is thought to be harmful, and requiring FDA approval is thought to be effective, then the solution is to prove it. Not to guess. Not to just wing it, and ban off-label prescription.
Problem is, Mike Huben, that Professor Tabarrok has actually studied the issue, as have many other researchers. Banning off-label prescription does more harm than good. Did you read any of the papers mentioned in the site he linked to, or are you just "winging it?"
Posted by: John Thacker at May 9, 2008 3:27:27 PM
To Mike Huben and others who would crack down on off-label use: You may be risk-averse, but not everyone is -- by what right do you propose that the government should force everyone to adhere to its standard of proof for safety and efficacy? Sure, for a headache I might want a drug that was proven in multiple clinical trials to be safe and effective, but if I'm a cancer patient and I know I'm going to die if I'm NOT treated, why should I wait for a clinical trial (not to mention the time it takes bureaucrats to review the results of that trial) to let my oncologist try something different?
There are simply not enough patients in the world to generate large clinical trials for every off-label use that could be useful. Why should patients suffer or die waiting for bureaucracy to run its course? (And why should pharmaceutical companies be guilty until proven innocent? I'm with John Thacker. Prove that off-label use is dangerous -- not the other way around.
-Stella Daily
ReasonPharm (http://reasonpharm.blogspot.com)
Posted by: Stella Daily at May 9, 2008 5:02:36 PM
Mike Huben said:
"Of course they didn't publish the letter. It is ridiculously one-sided and doesn't even hint at the moral hazards that such deregulation would permit.
Drugs that actually DO something also have side effects. If an off-label treatment is ineffective, then patients are being harmed by those side effects. Without large trials, it is very difficult to know whether such an off-label treatment is effective. Doctors just can't know from their practice if a drug is effective or not, and routinely don't even care, judging from off-label prescriptions of antibiotics for viral diseases.
If the problem is that an off-label use is thought to be effective, then the solution is to prove it. Not to guess. Not to just wing it."
I find this post to be offensive, one sided, and inherently ideological. To argue that all human beings shall produce the same "positive" response to the drug therapy before its approved borders on INSANE!
Try telling someone with pancreatic cancer that they may not use a potential therapy because it has yet to be approved. Why are you demanding regimentation, standardization, and top down approaches to problems that are so dire? What exactly does winging it mean to someone who is soon to die from cancer? Does that not seem unethical to you Mr. Huben?
Are we really so ideologically silly to think that the government must approve all drugs in a world where millions of people die from non-treatable diseases. It seems reckless.
Posted by: John Pertz at May 9, 2008 5:57:09 PM
Agreed, I did miss the point. Thank you for the gentle rebuff.
Posted by: Pup, MD at May 9, 2008 6:14:39 PM
One off-label use I am familiar with is Erythromycin being used as a gastric pro-kinetic:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2328193
Of course, I still don't understand why it is illegal to prescribe Domperidone for gastroparesis in the US...
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2328193
Posted by: Mr. Econotarian at May 9, 2008 6:55:31 PM
Very few drugs are tested for safety during pregnancy. Drug companies just are not going to take that risk. Some drugs are used off label for rare conditions that drug companies just arent going to investigate.
Steve
Posted by: steve at May 9, 2008 11:37:59 PM
Mike Huben misses the point, as usual (hint: it's on the top of his head). The point is not that nobody should test drugs. The point is that the federal government (which was granted permission to regulate drugs through section XXXYYY WAIT TO POST THIS UNTIL YOU FIND IT IN THE CONSTITUTION of the Constitution) ensures drug safety at the cost of keeping beneficial drugs off the market. That's like ensuring automobile safety (for all those people driving on post roads) by keeping everybody off the road (which you'll notice the DOT doesn't do).
Posted by: Russell Nelson at May 10, 2008 1:36:43 AM
"And that's a conversation far too nuanced for a non-specialist to be discussed effectively on a general audience economics blog."
Nuanced, or revealing? I'd like to see that discussion. Trust me, I can take it.
I guess respectable establishment economists have to do things a certain way.
My letter would have read something like this.
Dear NEJM,
Bite me.
Well, not really, but it should. At most, why can't I just sign a consent form for off-label use? There could be an independent function that pays me for the information yielded from self-experimentation.
What if the NIH regulated experimental methods only for approved applications in the laboratories? You'd have almost no experimentation.
The only difference is that doctors can hurt people, and labs aren't supposed to hurt anyone, except grad students, but they are hardly people, after all.
Do we really want to stop experimentation?
We already have human experimentation. We just don't acknowledge it and it's uncompensated. Some people are used to find out what happens when they take drugs only after animal testing. Some after limited human trials. Some for off-label applications. Other people are used to find out when they are denied drugs. Pregnant women for example. The question is, from where do we collect the evidence?
The thing about chemicals is, who knows what they are going to do a priori? The body is complex. That's the real problem here. There will be unforeseen benefits and unforeseen drawbacks.
"from off-label prescriptions of antibiotics for viral diseases"
The only problem, if patients are aware of potential side effects, with this is developing drug resistance that threatens others. Malfeasance is what we created courts for.
Well, what if side-effects aren't known? That's a problem. However, every body is slightly different, so why expect side-effects to ever be fully known? And is the "approved" process so great that we should propagate it far and wide? Vioxx showed that apparently the pre-approval trials were not big enough for statistical parity with the ultimate usage. There is a correlation between amount of rollout and potential for damage. Off-label is likely to remain a small percentage with limited damage potential. Perhaps there might be better use of scarce regulatory resources than addressing off-label. But, perhaps opportunity cost is too nuanced a subject for regulators and MDs.
"If the problem is that an off-label use is thought to be effective, then the solution is to prove it."
No, the problem is you have a patient begging for relief and you have nothing "approved" in the cabinet. The solution is you fully inform them, give them your best advice, and then if you are nice, observe the outcome, inform the people who would force pump you for your information on the outcome.
There is the issue of collecting the information. Or, more accurately, that the regulators want the information for free. I don't know what doctors get for publishing other than a warm fuzzy feeling, but how 'bout rewarding physicians more for publishing their results?
I'd say the procedure is fairly unoptimized. Why give prescriptions in all cases? Why not give people trial dosages and monitor the effectiveness and watch for any early warning side-effects? I sometimes do this for myself whenever I get a prescription. It doesn't seem like a concept that is built-in. Usually, it's "here's your 30 days worth of pills."
I'd say the big problems in medicine are the deaths caused by medical errors, diseases having no obvious treatment, organ shortages, multidrug resistance developed in the "hospital as incubator," and high costs associated with sparkling new technologies that extend end of life by fractions of a year. I also hear tales that pharmacists are going nuts from the pressure of workload and the stress of worrying about errors. Maybe my list is wrong, or not nuanced, but "solving" this "problem" does nothing for the biggies.
I'm not a doctor, or an economist, only a customer, so as a non-expert, I recommend completely disregarding my thoughts as unnuanced. Okay, the jabs are meant in good humor. I really do appreciate input from doctors. What we really need is synthesis.
Posted by: Andrew at May 10, 2008 5:03:17 AM
Pup, MD's gracious comment is appreciated.
Posted by: Alex Tabarrok at May 10, 2008 10:35:00 AM
Alex wrote: "Pup, MD and Huben missed the point. The point of the letter was to direct attention to the substantial research in the links."
Well gosh, perhaps the NEJM doesn't consider one-sided, pseudo-academic, quote-mined, think-tank propaganda to be "substantial research". How could they possibly have higher standards than articles in CATO?
As for the various twits who denounce me (supposedly because I want to deny cancer patients a chance to try the latest unproven fraudulent cure), they are the ones who miss the point. Alex is proposing"less FDA regulation of first or on-label usage", and that is what I'm denouncing.
Posted by: Mike Huben at May 12, 2008 6:37:56 PM
