The following originally appeared on The Upshot (copyright 2016, The New York Times Company).
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.
One out of five prescriptions is off-label. Some drugs, like those 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 costly clinical trials to demonstrate them are weak. So it’s not a surprise that off-label use is associated with a 44 percent greater risk of having an adverse event or side effect than with on-label use, according to a recent study. Side effects can be as mild as dry mouth or as severe as heart rhythm abnormalities.
“Clinicians frequently prescribe drugs off-label without knowing how well they work,” said Dr. Walid Gellad, a doctor at the University of Pittsburgh. “Sometimes it’s clinicians’ fault for not knowing the research. But sometimes the research just isn’t there.”
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 allow them to 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 metformin appears useful in treating breast cancer. Thalidomide, the morning sickness treatment that causedbirth 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 is little incentive to evaluate an existing drug for additional uses to the extent required for F.D.A. 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 F.D.A. 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.
“Why bother spending millions to get F.D.A. approval of a new use for a medication, when one small study, some key opinion leaders and an army of sales representatives can do the trick instead?” Dr. Gellad said.
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 could not otherwise afford them. But at those lower prices, companies cannot recoup the costs of clinical trials to test drugs for new indications. What’s in it for them?
But, by not exploiting existing 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 a focus of 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.
Moreover, 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.
This is a solvable problem, says Benjamin Roin, assistant professor of technological innovation, entrepreneurship and strategic management at M.I.T. He suggested a universal electronic prescribing system that tracks prescriptions and conditions for which they’re intended. This is feasibleand exists 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 others’ investments is common in health care. The sector is rife with relatively lower-cost ways toimprove health but with insufficient means of monetizing them, so they are understudied and underused. Solving the free-rider problem — including for new uses of existing drugs — could promote greater value for our health care dollar.
