Evidence and Extrapolation : Mechanisms for Regulating Off-Label Uses of Drugs and Devices

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 where such evidence is currently lacking. This “extrapolation” issue arises in the medicines context when a drug or device is being considered for (i) new conditions (such as treating off-label diagnostic categories), (ii) new patients (such as treating new sub-populations), (iii) new dosages or durations, or (iv) when the drug or device is itself new, but related to an approved counterpart. While the logic of pre-approval testing would counsel toward prohibiting extrapolation approvals until after traditional safety and efficacy evidence exists, such delays would unreasonably sacrifice some beneficial uses. This article instead proposes a more dynamic and evolving evidence-based regime. Just as probationary hiring can be dynamically efficient when ex ante due diligence is overly costly, a system that allows interim periods of use can provide physicians and patients greater treatment options while providing regulators with valuable evidence about the safety and efficacy of the proposed extrapolation. The harm of accessing unsafe products must be balanced against the harm of restricting access to beneficial products. 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 thorough-going reporting of off-label use (via the disclosure of diagnostic codes and “detailing” data) in manufacturer annual reports to the Food and Drug Administration (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 post-market testing, and we provide a novel framework for evaluating the need for post-market 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 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, without the need for new law-making. This evolutionary extrapolation framework could also be applied to other contexts