By Abdul Sattar Sohrani
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.
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. 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 utilization would undoubtedly also occur 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.
Another factor driving off-label use is that there are entire populations in which new drugs are seldom tested. Drug companies are understandably reluctant to test new drugs on pregnant women or children. If a drug trial in such populations were to go wrong, liability could be large and publicity disastrous. Nor are many drugs tested in the very old: their metabolic rates differ from those of younger, healthy people, they often have multiple medical conditions and conflicting drug prescriptions, and they may drop out of a costly study prematurely due to illness or death. No surprise, then, that pediatricians, obstetricians, and geriatricians often prescribe drugs that have only been tested in and approved for use by young and middle-aged adults.
Finally, off-label drug use is driven by the fact that pharmaceutical science moves on well after all incentive for regulatory approval has vanished. Once a drug has lost its patent protection, its profit margin may not be high enough to warrant the trouble and expense of getting FDA approval for it, even for the most promising of new uses.
Off-label drug utilization can certainly be of great benefit to patients. It is no exaggeration to say that “In oncology, pediatrics, geriatrics, obstetrics, and other practice areas, patient care could not proceed without off-label prescribing.” Medicare and private insurance companies recognize this and routinely reimburse for off-label drug utilization.
But off-label drug utilization has important downsides. There are risks inherent in the off-label use of any drug because the drug has not gone through the same rigorous testing for that use as it has for its on-label indication. While many off-label uses of drugs are scientifically valid, the evidence for off-label utilization is quite variable, both in quantity and in quality. And any offlabel use carries risks—even when the departure from the label is as “simple” as prescribing for children a drug approved for use in adults. (Just adjusting a dosage for weight differences may not address other important differences between how children and adults metabolize the drug.) Finally, there is ample evidence that physicians’ knowledge of the scientific validity of various off-label drug uses is poor.
The main governmental efforts at controlling off-label drug use have been aimed at regulating off-label drug marketing. But marketing is speech, and however laudable their goal of ensuring patients’ safety, marketing regulations may offend the First Amendment, which protects nondeceptive commercial speech. The drug companies argue that they have every right to share factual information about their drugs’ potential off-label uses with physicians; there is nothing wrong with nondeceptive commercial promotion of legal activity. Critics respond that, without someone in the room to monitor the marketing conversation, there is no guarantee that what’s said is not deceptive. The drug industry points to the recent spate of off-label marketing suits as evidence of unfair and unpredictable prosecution, while critics regard the suits as further evidence of industry greed and unscrupulousness.
The dispute over the recent change in FDA guidance governing the distribution of scientific reprints to physicians illustrates the complexity of this safety-versus-free-speech clash. First, that the new FDA policy is framed as a nonbinding guidance document rather than as a binding regulation is itself probably a nod to the free-speech rights of drug marketers. Second, the terms of the guidance are a series of compromises between the goals of respecting free speech and ensuring scientific validity. The guidance lets drug marketers give physicians peer-reviewed articles on off-label drug use. The articles must come from journals with conflict-of-interest disclosure policies; articles from in-house drug company journals won’t do. They may not be marked up in any way and must be accompanied by the FDA label for the drug in question. No other drug promotional material can be attached. The studies in question must be “scientifically sound.” All of these restrictions appear to be aimed at permitting free speech while assuring quality. Critics, predictably, allege that they will do no such thing. The new policy, they argue, will permit marketers to cherrypick from among numerous published articles and use only the most positive studies. At least one critic has voiced the fear that less prestigious journals now have an incentive to accept new studies favoring off-label drug use because those studies will bring in lucrative reprint orders from drug marketers. Finally, a few notorious cases have illustrated that the bulk of the available peer-reviewed literature on a particular drug was produced by the drug manufacturer and disseminated by unethical practices such as “ghostwriting”; if the medical literature is itself deceptive, then distribution of reprints from that literature is only more of the same.
Given the complexities of the free-speech problem, it may be more fruitful for the government to refocus its attention on the regulation of conduct. Recent commentators have suggested, for example, that the FDA could be empowered to require manufacturers to gather data on particularly common or problematic off-label uses. Less intrusively, the government could expand its own efforts to evaluate common off-label uses and publicize lists of the best- and worst-supported among them. Finally, some have proposed that independent researchers, disease groups, medical specialty societies, or government entities could be authorized to seek regulatory approval for off-label uses of the drugs, perhaps under special guidelines. All of these reforms would help increase the safety of off-label use.