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Though you may not have realized it, there's a good chance that a doctor has prescribed you a medication for a use other than what it was approved for. This off-label use is perfectly legal, but isn't as safe as it might be, in part because incentives to invest in costly clinical trials to test such uses are weak.

Efficient use of off-label drugs is the topic of this week's Healthcare Triage.

This episode was adapted from a column Austin Frakt wrote for The Upshot. Links to further reading and references can be found there:

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Though you may not have realized it, there's a good chance that a doctor has prescribed you a medication for a use other than for what it was approved.  This off-label use is perfectly legal, but isn't as safe as it might be, in part because incentives to invest in costly clinical trials to test such use are weak.  With the help of my colleague Austin Frakt, efficient use of off-label drugs are the topic of this week's Healthcare Triage.


One out of five prescriptions is off-label.  Some drugs, like those used for cardiac conditions and anticonvulsants, are used off-label at a much higher rate.  One study found that an average drug is used for 18 different conditions, but the vast majority of off-label use lacks strong evidence of safety and effectiveness.  The monetary incentives to invest in very expensive clinical trials to demonstrate them are weak, so it's not a surprise that off-label use is associated with a 44% greater risk of having an adverse event or side effect than on-label use, according to a recent study.

Side effects can be as mild as dry mouth or as severe as heart rhythm abnormalities.  The incentive to discover a useful new drug is clear.  Patents and exclusive marketing rights granted by the Food and Drug Administration enable drug companies to profit from a monopoly.  The monopoly prices often allow them to more than earn enough to recover the cost of developing new drugs, the ones that succeed and the attempts that fail as well as profit.

There is no comparable incentive to investigate the use of existing drugs as solutions for other health issues, what the University of Michigan law professor Rebecca Eisenberg termed, "the problem of new uses."  Despite the limited financial incentives and investment, over time, some valuable new uses of previously developed drugs have been found.  Sometimes new uses are discovered by accident or through publicly sponsored studies.  The diabetes drug (?~1:53) appears useful, for instance, in treating breast cancer.

Thalidomide, the morning sickness treatment that caused a lot of birth defects, is now approved for the treatment of multiple myeloma, a type of blood cancer.  In 2012, researchers experimenting on mice discovered that a cancer treatment drug showed encouraging early signs of effectiveness against Alzheimer's disease, but there's little incentive to evaluate an existing drug for additional uses to the extent required for FDA approval.  Though obtaining that approval would be cheaper than developing a new drug, drug companies can encourage off-label prescribing with even cheaper studies than the FDA requires.

Additionally, more rigorous testing of drugs for new uses might illuminate harms, hampering drugs' marketability rather than helping it.  With little to gain and a lot to lose, companies aren't eager to invest in new use studies, and once a drug's market exclusivity period expires and generics enter the  market, companies have even less incentive to test their products for new uses.  Generic competition pushes down prices of drugs, which is good for patients who cannot otherwise afford them, but at those lower prices, companies can't recoup the costs of clinical trials to test drugs for new indications.  What's in it for them?

But by not exploiting drugs to their fullest, we may be denying ourselves many useful treatments, even for conditions for which there are none.  One approach to encourage safer off-label discoveries is to spend more on government sponsored studies.  This might be done with direct grants for new use research, already focus in the National Institutes of Health, or through the sponsorship of prizes for the discovery of or execution of clinical trials for new uses.  

There may also be a more market-based approach.  The government could, and already does, grant patents and periods of market exclusivity for new uses of generic drugs, but without other changes, this is of little value.  Today, pharmacists typically can't tell for what affliction a prescription is being filled.  It's therefore of little consequence that one generic version of a drug has market exclusivity for a particular medical problem if a different one would work just as well.  The pharmacist has no reason not to substitute one for the other and is often legally or contractually bound to do so.  

If a drug company cannot ascertain the problem for which a prescription is written, it lacks the means by which it can enforce its new patent.  Therefore, it cannot recoup through higher prices expenses for investing in new use research, but according to Benjamin (?~4:16), assistant professor of technological innovation, entrepreneurship, and strategic management at MIT, this is a solvable problem.  He suggests that a universal electronic prescribing system that tracks prescriptions and conditions for which they're intended.

This is feasible.  It even exists already in Quebec.  With such a system in place, a new use innovator could charge more for the patented new use and it would be easier to tell when a competitor is breaking the law by selling its product for that use.  The problem of free riding by competitors on other investments is common in healthcare.  The sector is full of relatively lower cost ways to improve health, but there are insufficient means of monetizing them, so they end up understudied and underused.  Solving the free rider problem , including for new uses of existing drugs, could promote greater value for our healthcare dollars.

Healthcare Triage is supported in part by viewers like you through, a service that allows you to support the show through a monthly donation.  We'd especially like to thank our research associate Joe Sevits and our surgeon admiral Sam.  Thanks Joe!  Thanks Sam!  More information can be found at