Academic journal article Washington Law Review

The Law, Economics, and Medicine of Off-Label Prescribing

Academic journal article Washington Law Review

The Law, Economics, and Medicine of Off-Label Prescribing

Article excerpt

(ProQuest: ... denotes formulae omitted.)


There is a major dissonance in the current structure of regulating new drugs that have more than a single medical indication. Physicians are authorized to prescribe these drugs for all indications including those beyond their approved purposes. However, product manufacturers are expressly prohibited from marketing or promoting their drugs for any purpose other than those which have been specifically indicated.1 Thus, while prescribing physicians are encouraged to gain medical information on any additional indications, the information that physicians can obtain from the most likely source-the drug's supplier-is substantially constrained.2

Although the Food and Drug Administration (FDA) originally accentuated this dissonance, it has more recently retreated from that posture; first under pressure from the statutory admonitions of 1997,3 and subsequently due to the Second Circuit's opinion in United States v. Caronia.4 However, the issue remains in flux and is the subject of this Article.

In succeeding Parts, we review the legal, economic, and medical aspects of this dissonance: between what physicians are authorized to prescribe and what information drug manufactures are permitted to provide about their products. A critical feature of this dissonance is its connection to the two separate types of information about the therapeutic properties of pharmaceuticals, so we start with a discussion of this distinction. Finally, we suggest some policy conclusions to be drawn for this discussion.


The U.S. drug approval process is a multi-stage process involving the identification of a potential drug and various trials that must be met to discern its safety and efficacy. The formal approval process requires manufacturers to submit a New Drug Application (NDA), which the FDA reviews in its decision-making process on whether to approve a drug for sale. Critically, drugs are approved only for the specific indications disclosed in the firm's NDA.

An essential part of the NDA is its report on the three formal stages of testing required by the FDA. Phase I, usually conducted on healthy volunteers, focuses on safety and potential side effects, and may also be used to understand how the drug is metabolized.5 Phase II examines whether the drug appears to be effective for a specific indication, where the proposed drug is compared to a placebo or another drug.6 Safety and side effects continue to be assessed in these trials.7 Phase III is a much larger trial which assesses the efficacy of the drug in different subpopulations and at different dosages.8 Such trials can vary in their complexity, but their inferences of efficacy are fundamentally based on the statistical tests of the differences in outcomes in the patients treated with the drug and those treated with placebos or alternatives.9 Given the expense of Phase III trials and the numbers of patients required to assure that differences in outcomes are unlikely to be the results of sampling variation between the treated and control groups, the outcomes and indications studied in these trials are often quite limited.10

At the heart of the ongoing policy debates concerning off-label prescribing lies the distinction between pharmaceutical "efficacy" and "effectiveness." That distinction follows from the different types of information that can potentially be gleaned on the therapeutic benefits gained from taking pharmaceuticals. Consider the difference between the information obtained from a formal clinical trial of a prospective drug and the information gathered from medical practice and experience resulting largely from observational studies.

The clinical trials required by the FDA to be included in a company's NDA make little use of any substantive knowledge of the drugs being studied. The judgment that a drug is efficacious or not is based on the results of a randomized control trial, in which judgments on efficacy are made by ruling out, via statistical theory, that difference in outcomes between the treatment and control group are simply due to sampling variation. …

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