Category: Medicine
Off Label Prescribing as Good as On Label
Once a drug has been approved for some use it may be legally prescribed for any use. New uses for old drugs are discovered quite often so off-label uses can be very different from FDA approved uses. Mitomycin, for example, was approved to treat stomach and pancreatic cancer but is used off-label in laser-eye surgery. Drugs prescribed off-label have not been through FDA-approved efficacy trials for the off-label use. In Assessing the FDA via the Anomaly of Off-Label Drug Prescribing I pointed out that off-label prescribing, therefore, gives us a window onto a world with much less FDA regulation.
Since off-label prescribing is common and in rapidly progressing areas of medicine often the gold-standard, I argued that the behavior of physicians validated off-label prescribing and demonstrated that physicians were willing and able to draw upon non-FDA sources of information to make rational prescribing decisions. Dan Klein and I also showed that physicians are supportive of off-label prescribing saying, for example, that it would be “crazy” to require FDA approval for off-label uses.
The support of physicians for off-label prescribing is telling but not dispositive. Perhaps physicians make hubristic mistakes in prescribing off-label. A new paper by Ladanie et al. (including John Ioannidis) provides important information. The authors search the literature for all the RCTs when an off-label drug was pitted against an on-label drug. They conclude:
Our meta-epidemiological analysis of 25 different treatment indications for off-label drug use provides no empirical evidence supporting any assumption of generally inferior treatment
effects associated with off-label use. On the contrary, the summary effect estimates across all indications would even be compatible with more favorable effects, on average, of the off-label
treatment. However, the heterogeneity is substantial and the on-label comparators are not necessarily the best approved treatment option in all 25 topics. While some off-label
treatments are clearly better, others are clearly not.
The finding is especially impressive because although off-label treatments are sometimes the gold standard they are also often used when standard treatments have failed. Thus, in an RCT, off-label treatments could be worse on average and yet still provide a very useful weapon in the medical armory.
One might argue that if off-label treatments are as good as FDA-approved treatments then the FDA should have higher standards. FDA required clinical trials, however, already cost hundreds of millions of dollars and years of effort, creating drug lag and drug loss. Rather than condemning the FDA, what these results indicate is that the medical system–physicians, hospitals, insurers, scientists–does a good job at evaluating new uses for old drugs. As Dan Klein and I noted in our precis on off-label prescribing:
The off-label experience testifies to the fact that much knowledge about efficacy and safety is produced outside the FDA regulatory apparatus. The Pharmacopoeia’s recognition of off-label
indications years ahead of the FDA demonstrates that physicians and scientists have certified thousands of drug indications quite independently of the FDA, even when those indications are not
very closely related to the original indications. In addition to the Pharmacopoeia, there are several other forms of professional certification, including the American Hospital Formulary Service Drug Information, HMO formularies, and a wide array of specialist professional periodicals and information services. NIH studies, clinical results and determinations from other countries, and other professional, science-based judgments are examples of nongovernmental, non-mandatory certification.
Hat tip: Michelle Dawson.
Medicaid, asthma, and ADHD caseloads
There is a new NBER working paper on these topics, by Anna Chorniy, Janet Currie, and Lyudmyla Sonchak, here is the abstract:
In the U.S., nearly 11% of school-age children have been diagnosed with ADHD, and approximately 10% of children suffer from asthma. In the last decade, the number of children diagnosed with these conditions has inexplicably been on the rise. This paper proposes a novel explanation of this trend. First, the increase is concentrated in the Medicaid caseload nationwide. Second, nearly 80% of states transitioned their Medicaid programs from fee-for-service (FFS) reimbursement to managed care (MMC) by 2016. Using Medicaid claims from South Carolina, we show that this change contributed to the increase in asthma and ADHD caseloads. Empirically, we rely on exogenous variation in MMC enrollment due a change in the “default” Medicaid plan from FFS or MMC, and an increase in the availability of MMC. We find that the transition from FFS to MMC explains most of the rise in the number of Medicaid children being treated for ADHD and asthma. These results can be explained by the incentives created by the risk adjustment and quality control systems in MMC.
The economics of medical diagnoses remain a drastically understudied area.
Can We Stop Aging? Should We?
The great Tim Urban of Wait but Why has a deep dive into Why Cryonics Makes Sense.
A key argument:
Here’s an interesting way to think about it: Imagine a patient arriving in an ambulance to Hospital A, a typical modern hospital. The patient’s heart stopped 15 minutes before the EMTs arrived and he is immediately pronounced dead at the hospital. What if, though, the doctors at Hospital A learned that Hospital B across the street had developed a radical new technology that could revive a patient anytime within 60 minutes after cardiac arrest with no long-term damage? What would the people at Hospital A do?
Of course, they would rush the patient across the street to Hospital B to save him. If Hospital B did save the patient, then by definition the patient wouldn’t actually have been dead in Hospital A, just pronounced deadbecause Hospital A viewed him as entirely and without exception doomed.
What cryonicists suggest is that in many cases where today a patient is pronounced dead, they’re not dead but rather doomed, and that there is a Hospital B that can save the day—but instead of being in a different place, it’s in a different time. It’s in the future.
Kurzgesagt and CGP Grey also have a new two part video series on why we should stop aging forever. The first one is below. The second is here.
Am I seeing a trend? I hope so. To quote CGP Grey:
Humans must discard the learned helplessness that the reaper and their own brains have imposed on them.
*The Fate of Rome*
That is the new and very important book by Kyle Harper, with the subtitle Climate, Disease, & the End of an Empire. I am just reading through this now, but it appears to be an significant revision of our views on the decline of Rome. p.21 offers a capsule summary, which I will summarize in turn:
1. During the reign of Marcus Aurelius, a pandemic “interrupted the economic and demographic expansion” of the empire.
2. In the middle of the third century, a mix of drought, pestilence, and political challenge “led to the sudden disintegration of the empire.” The empire however was willfully rebuilt, with a new emperor, new system of government, and in due time a new religion.
3. The coherence of this new empire was broken in the late fourth and early fifth centuries. “The entire weight of the Eurasian steppe seemed to lean, in new and unsustainable ways, against the edifice of Roman power…and…the western half of the empire buckled.”
4. In the east there was a resurgent Roman Empire, but this was “violently halted by one of the worst environmental catastrophes in recorded history — the double blow of bubonic plague and a little ice age.”
Here is a key passage from the book:
The centuries of later Roman history might be considered the age of pandemic disease. Three times the empire was rocked by mortality events with stunning geographical reach. In AD 165 an event known as the Antonine Plague, probably caused by smallpox, erupted. In AD 249, an uncertain pathogen swept the territories of Roman rule. And in AD 541, the first great pandemic of Yersinia pestis, the agent that causes bubonic plague, arrived and lingered for over two hundreds years. the magnitude of these biological catastrophes is almost incomprehensible.
Here is the book on Amazon. Here is Kyle Harper on Twitter. Here is Harper on scholar.google.com; he is also Provost at the University of Oklahoma.
I do not feel I can assess the veracity of this thesis, but it does seem to be intelligently and reasonably argued.
My Conversation with Mary Roach
Here is the transcript and podcast, here is the summary introduction:
She joins Tyler for a conversation covering the full range of her curiosity, including fear, acclimating to grossness, chatting with the dead, freezing one’s head, why bedpans can kill you, sex robots, Freud, thinking like an astronaut, the proper way to eat a fry, and why there’s a Medicare reimbursement code for maggots.
Here are a few excerpts:
ROACH: It is never uncomfortable. People sometimes say, “The questions that you ask people, is it an awkward interview? When you went to Avenal State Prison for the rectum chapter of Gulp, and you, talking to this convicted murderer about using his rectum to smuggle cellphones and other things, was that not a very awkward conversation to have?”
A little bit, but then you have to keep in mind, this is somebody for whom hooping, as it’s called, is . . . everybody does it. It’s just something that you do; it’s everyday to him. Like for a sex researcher, talking about orgasm is like talking about tire rotation for a car mechanic.
And:
COWEN: To do a whirlwind tour of some of your books, you have a book on corpses. If you could chat with the dead, what would you ask them?
ROACH: Oh, if I could chat with the dead. Are we assuming the personality or the body?
COWEN: Well, both.
ROACH: The corpse?
COWEN: The corpse.
ROACH: Oh, is this a research corpse or . . .
COWEN: It’s a research corpse.
ROACH: …So what I’d say to the cadaver is, “Is this embarrassing for you? Are you OK with this? Are they treating you respectfully? Do you wish you had some clothes on?”
And:
COWEN: Why do only 18 percent of people who are in the position to have a life-after-death experience actually have one? What’s your view on that?
ROACH: The trouble seems to be remembering the near-death experience.
And:
COWEN: Why are bedpans dangerous?
There is much, much more at the link. Jonathan Swift, Elvis, Adam Smith, and Jeff Sachs all make appearances, in addition to Catholicism, bee larvae, Mozambique, whether people know what they really want in sex, and whether it should be legal to harvest fresh road kill in Oregon.
Megan McArdle on the collapse of Obamacare
Her earlier prediction:
Obamacare would not, and could not, be the program that had been promised or intended. It had already failed to deliver on key promises for coverage, affordability and of course, the infamous promise that “if you like your doctor, you can keep your doctor.” It was also dangerously unstable, requiring steady executive intervention just to keep the program from collapsing. I argued that these executive interventions, enthusiastically supported by the law’s proponents, were setting a precedent that would eventually be used against it. Worried that health care was too hostage to the vicissitudes of the markets, Democrats had instead made it the prisoner of politics.
“Essentially they’ve made it so that Republicans can undo two-thirds of this law with a stroke of the presidential pen,” I said at the close of my opening statement. “Obamacare is now beyond rescue. The administration has destroyed their own law in order to save it.” Four years later, we are watching those dominos fall.
Here is the full Bloomberg piece.
Vaping Saves Lives
E-cigarettes are less dangerous than cigarettes but are equally effective at delivering nicotine. Levy et al. estimate that if smokers switched to e-cigarettes millions of life-years would be saved, even taking into account plausible rates of non-smokers who start to vape. (It’s worth noting that the authors are all cancer researchers, statisticians and epidemiologists concerned with reducing cancer deaths.)
A Status Quo Scenario, developed to project smoking rates and health outcomes in the absence of vaping, is compared with Substitution models, whereby cigarette use is largely replaced by vaping over a 10-year period. We test an Optimistic and a Pessimistic Scenario, differing in terms of the relative harms of e-cigarettes compared with cigarettes and the impact on overall initiation, cessation and switching. Projected mortality outcomes by age and sex under the Status Quo and E-Cigarette Substitution Scenarios are compared from 2016 to 2100 to determine public health impacts.
Compared with the Status Quo, replacement of cigarette by e-cigarette use over a 10-year period yields 6.6 million fewer premature deaths with 86.7 million fewer life years lost in the Optimistic Scenario. Under the Pessimistic Scenario, 1.6 million premature deaths are averted with 20.8 million fewer life years lost. The largest gains are among younger cohorts, with a 0.5 gain in average life expectancy projected for the age 15 years cohort in 2016.
Vaping saves lives but the FDA has in the past tried to impose severe regulations on the industry and to make vaping less pleasurable. (Aside: It’s interesting that liberals tend to favor other risk-reducing devices such as condoms in the classroom but disfavor vaping while conservatives often take the opposite sides. I don’t think either group is basing their choices on the elasticities.)
The FDA, for example, has tried to ban flavored e-cigarettes. In a new NBER paper, Buckell, Marti and Sindelar calculate that:
…a ban on flavored e-cigarettes would drive smokers to combustible cigarettes, which have been
found to be the more harmful way of getting nicotine (Goniewicz et al., 2017; Shahab et al., 2017).
In addition, such a ban reduces the appeal of e-cigarettes to those who are seeking to quit; ecigarettes
have proven useful as a cessation device for these individuals (Hartmann-Boyce et al.,
2016; Zhu et al., 2017), and we find that quitters have a preference for flavored e-cigarettes.
Fortunately, the new FDA commissioner Scott Gottlieb has signaled a more liberal attitude towards vaping. It could be the most consequential decision of his tenure.
Hat tip: The excellent Robert Wilbin from 80,000 Hours.
Intellectual fallout from the likely failure of Graham-Cassidy
1. The Democrats were debating single payer while this bill, which they dread, nearly passed (and still has some chance of passing). This was not a random mistake, rather it reflects a more general tendency of the Democratic Party to focus on the wrong kind of expressive values, in a manner which does not seem remediable. We need to re-model what they are, and build this kind of un-educability into the new model.
2. One lesson of Graham-Cassidy failure is that American health care, at the state level, is a race to the bottom not to the top. Recall that the Canadian health care system also leaves key decisions to the provinces + block grants, but American Progressives love the results. Most observers know the American states would not copy the Canadian provinces in their policies, and it is not only because fiscal equalization is weaker to the south. The reality is that spending much more on health care would not make most American states much more desirable places for most people to live in. If it did, Graham-Cassidy would be a better idea than in fact it is and a race to the top would ensue. Better health care would brighten up states all around, attract more population, and increase the revenue going into governor’s coffers.
Democrats and Republicans both find this inadequacy of state-level outcomes difficult to accept, though for opposing reasons. Democrats hate having to recognize that all the extra health care spending might be mainly redistribution rather than remedying a market failure or providing a broad-based social public good. Republicans hate to see that giving states control over health care policy, and allowing them to revise Obamacare, won’t improve those states and probably would make most of them worse.
Of course my points #1 and #2 relate. I agree Graham-Cassidy is a bad idea, but every time I hear the critics say it is heartless, or would “take away” people’s health insurance, or “kill people,” what I really hear is “If we let everyone vote again on Obamacare, with a real time balanced budget constraint, they wouldn’t vote for nearly as much health care next time around.”
Which is why you should not be obsessing over single-payer systems.
Across the board, pondering Graham-Cassidy, including its failure, should make you more pessimistic about economic and social processes.
Winners and losers under Graham-Cassidy
…the greatest winners in 2026 would be Mississippi and Kansas, where federal health-care funding would more than triple and double, respectively. On the other hand, Connecticut’s aid would be cut by just over half.
And:
…the Kaiser Family Foundation…concluded that 35 states would lose $160 billion under the bill. The Kaiser study, like two earlier this week, looked at the cumulative effect from 2020 to 2026.
Here is the Amy Goldstein and Juliet Eilperin piece at WaPo.
Japan (America) fact of the day
So consider the amount of standard daily doses of opioids consumed in Japan. And then double it. And then double it again. And then double it again. And then double it again. And then double it a fifth time. That would make Japan No. 2 in the world, behind the United States.
That is from German Lopez at Vox.
The economics of Graham-Cassidy
It is good for forcing some fiscal discipline on health care, but state governments are fiscally too weak to take over America’s public sector health care finance. That is the message of my latest Bloomberg column. Here is one excerpt:
There is another problem with state experimentation in this context. So many health-care problems are on the supply side, namely weak incentives for quality care, barriers to entry and innovation, and regulations that raise costs but don’t improve safety. Ideally policy experimentation could cover all of these dimensions, but almost all of the debate is on the side of financing and insurance coverage. With a more or less fixed set of supply-side institutions, simply pushing more financing decisions into state governments may not produce much, if any, improvement.
So overall the reform doesn’t seem to be feasible. But here is the part to bug you:
It is a legitimate worry that Graham-Cassidy might cut health-care benefits in an unequal fashion, but the bill may be more egalitarian than it at first appears. Due to the embedded formulas, the bill redistributes resources to red states, in particular states that have not already accepted the Medicaid expansion from Obamacare. Often those are rural states, some of them in economic decline. Favoring such states does have an egalitarian aspect, even if the Republican Party isn’t very effective in explaining the policy in those terms.
The biggest losers from Graham-Cassidy are likely New York and California, two states with very costly Medicaid rolls. That might appear anti-egalitarian, but is it really? The beneficiaries in those states tend to be relatively young, and thus their human capital endowments, in the form of future life enjoyment, are usually quite high. All things considered, a 28-year old lower middle-class immigrant in Los Angeles is arguably better off than a 61-year-old in Nebraska with $100,000 in the bank. Giving a benefit to the red state individual actually may reflect the more egalitarian sentiment, although that’s not usually how health-care policy discussions are framed by either Democrats or Republicans.
Like it or not, the forward-looking perspective is probably the correct one here. One not altogether illogical response is to treat this as a reductio ad absurdum on egalitarian ideas. Another response is to base health care policy more on efficiency, and again to discard the egalitarian ideal, which in turn would resurrect some chance of being able to defend redistribution toward the young. What doesn’t make sense is to invoke egalitarian ideals only selectively, as people are fond of doing.
Canada Imports Precious Bodily Fluids
In 2004 Canada prohibited paying Canadian sperm donors, leading to a tremendous shortage as I had predicted in 2003 (see also my post, The Great Canadian Sperm Shortage). Canadian Peter Jaworski has an update (oddly enough published in USA Today):
Canada used to have a sufficient supply of domestic sperm donors. But in 2004, we passed the Assisted Human Reproduction Act, which made it illegal to compensate donors for their sperm. Shortly thereafter, the number of willing donors plummeted, and sperm donor clinics were shuttered. Now, there is basically just one sperm donor clinic in Canada, and 30-70 Canadian men who donate sperm. Since demand far outstrips supply, we turn to you. We import sperm from for-profit companies in the U.S., where compensating sperm donors is both legal and normal.
Note, by the way, that contrary to what you might expect from Titmuss et al. US sperm is considered to be of high quality because it comes with information about the donor.
And sperm isn’t the only precious bodily fluid that Canada imports.
Canada has never had enough domestic blood plasma for plasma-protein products, such as immune globulin. Our demand for those products, however, is increasing. Last year, we collected only enough blood plasma from unremunerated donors to manufacture 17% of the immune globulin demanded. The rest we imported from you, in exchange for $623 million, or $512 million U.S.
Reliance on your blood plasma looked like it might change a little bit when, in 2012, a company called Canadian Plasma Resources announced plans to open clinics in Ontario dedicated to collecting blood plasma. The trouble is that its business model included compensating donors. Almost immediately, groups such as the Canadian Union of Public Employees and the Canadian Health Coalition began to lobby the Ontario government to pass a law to stop CPR from opening clinics. Ontario obliged in 2014, passing the Safeguarding Health Care Integrity Act, which among other things made compensation illegal.
…As for safety, the fact that we import products made with remunerated donors should tell you that it is emphatically not an issue. Health Canada has said that there is no health concern. The CEO of Canadian Blood Services, Graham Sher, took to YouTube to explain that “it is categorically untrue to say, in 2015 or 2016, that plasma-protein products from paid donors are less safe or unsafe. They are not. They are as safe as the products that are manufactured from our non-remunerated or unpaid donors.”
As Jaworski writes:
What Canada should do is legalize compensation for renewable bodily fluids in our own country. It would be the morally right thing to do. It would help make and save more lives, without harming anybody.
Is single-payer health care a feasible evolutionary option?
I say no, in my latest Bloomberg column. For some of the arguments here, I am indebted to earlier work by Megan McArdle.
Silphium
Long ago, in the ancient city of Cyrene, there was a herb called silphium. It didn’t look like much – with stout roots, stumpy leaves and bunches of small yellow flowers – but it oozed with an odiferous sap that was so delicious and useful, the plant was eventually worth its weight in gold.
That’s the opening to an excellent story about silphium, a herb widely-used and loved by the Romans but that hasn’t been seen for nearly two thousand years. Part of the problem was biological, the plant grew only in a tiny region of modern day Libya:
Its entire range consisted of a narrow strip of land about 125 miles (201km) by 35 miles (40km).
Try as they might, neither the Greeks or the Romans could work out how to farm it in captivity. Instead silphium was collected from the wild, and though there were strict rules about how much could be harvested, there was a thriving black market.
Even today there are plants, like huckleberry which resist all efforts to farm them. (Ala Jared Diamond’s Guns, Germs and Steel). Part of the problem was also economic–a tragedy of the commons–as prices shot up and property rights weren’t strong enough to prevent over-farming.
And might silphium still be found somewhere in remote regions of Libya? Read the whole thing.
Alan Krueger on opioids and labor force participation
I haven’t had a chance to look at this one, but here is the headline summary from Brookings:
The new paper, published in the Fall 2017 edition of the Brookings Papers on Economic Activity, makes a strong case for looking at the opioid epidemic as one driver of declining labor force participation rates.
In fact, Krueger suggests that the increase in opioid prescriptions from 1999 to 2015 could account for about 20 percent of the observed decline in men’s labor force participation during that same period, and 25 percent of the observed decline in women’s labor force participation.
Here is the Brookings link.