Do Off-Label Drug Practices Argue against FDA Efficacy Requirements? A Critical Analysis of Physicians' Argumentation for Initial Efficacy Requirements

I Introduction THE FOOD, DRUG AND COSMETICS ACT of 1938 with amendments in 1962 forbids new drugs from being sold unless they have passed FDA-approved tests for safety and efficacy in a specified use, called the "on-label" use. Physicians are allowed, however, to prescribe an FDA-approved drug not only for its on-label use but also for other, "off-label," uses. It often happens that physicians and researchers discover new uses for a drug after it has been permitted, so off-label use is quite common. Amoxicillin, for example, has an on-label use for treating respiratory tract infections and an off-label use for treating stomach ulcers. For the on-label treatment of respiratory tract infections, amoxicillin has been tested and certified in all three phases of the FDA's Investigational New Drug clinical study; phase I trials for basic safety, and phase II and phase III trial for efficacy. For the treatment of stomach ulcers, however, amoxicillin has not gone through FDA phase II and phase III trials and thus is not FDA certified for this use. Amoxicillin will never go through FDA efficacy trials for the treatment of stomach ulcers because the basic formulation is no longer under patent. Yet any textbook or medical guide discussing stomach ulcers will mention amoxicillin as a potential treatment, and today a physician who did not consider prescribing amoxicillin or other antibiotics for the treatment of stomach ulcers would be considered negligent. Off-label prescribing is very common in all areas of medicine. It is not uncommon for a drug to be prescribed more often off-label than on-label. Thalidomide has been approved for use in treating leprosy but is much more commonly used to treat multiple myeloma and AIDS. Most cancer and AIDS patients are given drugs that are not FDA certified for the prescribed use (GAO 1991; Brosgart et al. 1996). In a large number of fields, a majority of patients are prescribed at least one drug off-label (Tabarrok 2000: 26). To explore the policy lessons of off-label usage, we tapped the knowledge and judgment of actual practitioners. We asked physicians whether the FDA should hold drug uses to efficacy requirements, both as the question applies to initial (on-label) uses and as it applies to subsequent (off-label) uses. Virtually all opposed imposing efficacy requirements on subsequent uses. But the majority of respondents supported the FDA efficacy requirements on initial uses. Is it inconsistent to favor efficacy requirements for new drugs but not for new uses of old drugs? We asked the physicians to justify their responses in an open-ended format, and received hundreds of justifications of their opinions about FDA policy. The key feature of our study is asking physicians the justification question. II The Consistency Argument: If Off-Label Uses Should Not Require FDA Efficacy Certification, Why Should On-Label Uses Require FDA Efficacy Certification? AGAIN, WHEN THE FDA EVALUATES a new drug, the evaluation of safety and efficacy is made with respect to a specified use. Once a drug has been permitted, physicians often come to prescribe the drug for other uses. But there seems to be a logical inconsistency in allowing off-label uses and requiring proof of efficacy for the drug's initial use. Logical consistency would seem to require that one either (1) be in favor of allowing physicians to prescribe off-label and allowing physicians to prescribe (and pharmaceutical companies to make and sell) new drugs that have not been FDA efficacy certified, or (2) be against allowing physicians to prescribe off-label and allowing physicians to prescribe (and pharmaceutical companies to make and sell) new drugs that have not been FDA efficacy certified. But even if logic dictates as such, it would not tell us whether to favor (1) or to favor (2). Tabarrok (2000) argues that off-label usage provides a natural experiment. …