Speaking Off Label

In the United States, while it is legal for physicians to prescribe drugs for “off-label” indications (uses for which the drugs do not have Food and Drug Administration approval), it is largely—though not entirely—illegal for drug manufacturers to promote off-label uses of their drugs to physicians. In recent months, the rules against off-label marketing have been rigorously enforced: in October, Allergan reached a $375 million settlement over off-label promotion of Botox; in September, Novartis settled an off-label marketing dispute for $422.5 million, and Forest Laboratories settled one for $313 million. These were only the latest in a series of criminal and civil settlements on off-label promotion, the most dramatic being last year’s $2.3 billion settlement by Pfizer. And there are more to come: the Justice Department just joined a private whistleblower suit against Wyeth—an indication that the government thinks the suit has merit. Lawyers for the whistleblowers predict recovery in the hundreds of millions of dollars.¹

But even as the Justice Department was busily prosecuting off-label marketers, the FDA last year finalized a guidance document that expands manufacturers’ off-label marketing opportunities and makes them more difficult to oversee. The nonbinding guidance, originally advanced by the Bush administration and finalized under President Obama, permits drug company marketers to give physicians reprints of published scientific articles describing new off-label uses for their drugs.² This marketing is permitted regardless of whether the manufacturer intends to seek on-label status for the use being marketed. And in a departure from previous policy, the distributed articles no longer need advance vetting by the FDA.

For the uninitiated, this strange, simultaneous mix of strict enforcement and rule-liberalization may raise a number of puzzling policy questions. At the most basic level, one may wonder why off-label use of drugs is permitted at all. But if it is permitted, why prosecute firms for encouraging physicians to engage in a legal activity? And why worry about the distribution of published scientific articles to physicians?

To get a grip on this set of issues, one must understand the phenomenon of off-label drug use. Such use is in fact extremely common, particularly in certain areas of medical practice. There are a number of reasons why this is so.

The most complex of these reasons has to do with the fact that obtaining FDA approval for any given drug use is both costly and time-consuming. Manufacturers want the approval process to move as quickly as possible, maximizing the number of years their drugs can be on the market before the patent expires, at which point they face competition from generic manufacturers and their profit margins drop. Manufacturers therefore concentrate on gaining regulatory approval for those indications for which they have, or can most easily gather, the best data in the shortest time. Oncology drugs, for example, are often approved only for particular varieties of cancer. If the manufacturer wants to market its drug for an additional use, the law requires that it go to the trouble and expense of demonstrating the drug’s safety and efficacy for that new use.

But in an ideal financial scenario, a drug manufacturer bypasses the process of adding new uses to the drug’s label. If it can get its drug to market for one use but sell the drug for many uses, it saves the expense of gaining regulatory approval for those other uses. Hence the temptation to promote off-label uses. But a certain amount of off-label drug cur without any effort on the manufacturer’s part. Medical researchers and practicing physicians understand that the mechanisms that make a given drug work against one sort of cancer, for example, may work against others as well. Physicians regularly experiment with off-label drug use for their patients, and some independent researchers study off-label efficacy. These factors lead to widespread off-label prescribing. Experts have estimated that as many as 50 percent of cancer drug prescriptions are for off-label indications.³

Another factor driving off-label use is that there are entire populations in which...