Evidence and Extrapolation: Mechanisms for Regulating Off-Label Uses of Drugs and Devices
Ryan Abbott & Ian Ayres
A recurring, foundational issue for evidence-based regulation is deciding whether to extend governmental approval from an existing use with sufficient current evidence of safety and efficacy to a novel use for which such evidence is currently lacking. This "extrapolation" issue arises in the medicines context when an approved drug or device that is already being marketed is being considered (1) for new conditions (such as off-label diagnostic categories), (2) for new patients (such as new subpopulations), (3) for new dosages or durations, or (4) as the basis for approving a related drug or device (such as a generic or biosimilar drug). Although the logic of preapproval testing and the precautionary principle—first, do no harm—would counsel in favor of prohibiting extrapolation approvals until after traditional safety and efficacy evidence exists, such delays would unreasonably sacrifice beneficial uses. The harm of accessing unsafe products must be balanced against the harm of restricting access to effective products. In fact, the Food and Drug Administration's (FDA's) current regulations in many ways reject the precautionary principle because they largely permit individual physicians to prescribe medications for off-label uses before any testing tailored to those uses has been done. The FDA's approach empowers physicians, but overshoots the mark by allowing enduring use of drugs and devices with insubstantial support of safety and efficacy. This Article instead proposes a more dynamic and evolving evidence-based regime that charts a course between the Scylla and Charybdis of the overly conservative precautionary principle on one hand, and the overly liberal FDA regime on the other.
Our approach calls for improvements in reporting, testing, and enforcement regulations to provide a more layered and nuanced system of regulatory incentives. First, we propose a more thoroughgoing reporting of off-label use (via the disclosure of diagnostic codes and "detailing" data) in manufacturers' annual reports to the FDA, in the adverse event reports to the FDA, in Medicare/Medicaid reimbursement requests, and, for a subset of FDA-designated drugs, in prescriptions themselves. Second, we would substantially expand the agency's utilization of postmarket testing, and we provide a novel framework for evaluating the need for postmarket testing. Finally, our approach calls for a tiered labeling system that would allow regulators and courts to draw finer reimbursement and liability distinctions among various drug uses, and would provide the agency both the regulatory teeth and the flexibility it presently lacks. Together, these reforms would improve the role of the FDA in the informational marketplace underlying physicians' prescribing decisions. This evolutionary extrapolation framework could also be applied to other contexts.
Property is closely associated with freedom. Following the demise of the feudal property system, property ownership in Anglo-American law came to imply an individual's freedom to act as she pleases on her land. For their part, modern property theories—whether right-based, utilitarian, or relational—employ the normative value of freedom to justify ownership. Courts and scholars have always acknowledged the fact that this freedom of the owner cannot be absolute: an owner's freedom to do as she pleases on her land is often limited to protect other owners. However, the consensual assumption remains that an owner is not subject to affirmative duties. She is free, according to conventional wisdom, to choose to do nothing with her property. This Article argues that this assumption is simply wrong. Owners are not free to ignore their land. Property law has always subjected them to an obligation to maintain their land up to a specific standard. This obligation, dubbed here "the duty to maintain," is enforced through an array of legal rules and practices. This Article chronicles these rules and practices for the first time, classifying them in accordance with the enforcement mechanism they employ. It then justifies these diverse rules and practices—and the general duty to maintain—in light of the different theories of property. In this fashion, this Article illustrates that ownership, both as a legal institution and as a normative concept, inherently and inevitably incorporates a duty to maintain.
Recently, federal prosecutors' increased interest in criminally charging foreign organizational defendants has revealed a "jurisdictional gap" in Rule 4 of the Federal Rules of Criminal Procedure. Rule 4, which has operated largely unchanged since its adoption in 1944, requires that a copy of a compulsory summons be served on an organizational defendant by mailing it either to the defendant's "last known address" in the relevant district or to its "principal place of business elsewhere in the United States." The courts have divided over how to confront jurisdictional challenges brought by certain foreign corporations—those without domestic principal places of business and addresses—that appear to be legally incapable of receiving service. As it stands, the jurisdictional gap threatens to effectively immunize large swaths of illegality over which the United States would otherwise have jurisdiction. The Department of Justice and the Advisory Committee on Rules of Criminal Procedure have responded to this concern with dueling proposals to close Rule 4's jurisdictional gap.
This Note agrees that the jurisdictional gap should be closed, but in a narrowly fashioned manner. Relaxing the service regime for foreign organizational defendants too much may enable, for the first time, prosecutions of wholly extraterritorial conduct that would violate the Fifth Amendment's Due Process Clause. This Note sketches the contours of such a case, and concludes that any risk is best cabined by reasonably limited means of service under Rule 4 coupled with the responsible exercise of prosecutorial discretion.
The Health Insurance Portability and Accountability Act (HIPAA) is nearly synonymous with patient privacy. In contrast, the National Instant Criminal Background Check System (NICS), a provision of the Gun Control Act of 1968, demands the disclosure of information about individuals, including mental-health information, that may prohibit their purchase of firearms.
These two statutes raise the following question: what if NICS requires or recommends the reporting of information protected by HIPAA? In the wake of recent gun violence by mentally disabled individuals, governmental and nongovernmental organizations have questioned whether HIPAA's privacy provisions have stultified national gun-control measures by prohibiting the reporting of mental health information. In early 2014, the Department of Health and Human Services responded to these concerns by proposing a rule that would grant an exception to HIPAA's privacy protection to allow the reporting of relevant mental-health records to NICS.
This Note questions whether there is an insurmountable conflict between HIPAA and the Gun Control Act that warrants the proposed exception. It analyzes the NICS-reporting practices of certain states to explain how existing federal NICS-reporting laws can be used to clarify federal NICS-submission standards and argues that the proposed rule is legally trivial.