Regulating Off-Label Prescribing

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Scholars and practitioners debate whether and how to regulate off-label drug use.

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In its recent case, FDA v. Alliance for Hippocratic Medicine, the U.S. Supreme Court rejected a challenge to the U.S. Food and Drug Administration’s (FDA) approval of mifepristone on the basis that the plaintiffs, a group of doctors, did not have standing to sue. Although the decision ensured that mifepristone, a common abortion drug, would be available in all states, it does not prevent future challenges brought by plaintiffs with standing—even though mifepristone boasts an excellent safety record.

Scholars warn that a successful challenge to mifepristone’s approval would threaten medication abortion access across the country. But a mifepristone ban would also affect the drug’s availability for uses other than abortion, such as treating miscarriages, Cushing’s Syndrome, and pregnancy complications, including ectopic pregnancy and preeclampsia.

Under the Kefauver-Harris Amendment to the Food Drug and Cosmetic Act of 1938, a drug must be safe and effective for a specific use to receive FDA approval. Mifepristone, for example, is approved to end a pregnancy through its tenth week, but not to treat the other conditions for which it is often prescribed. When doctors prescribe a medication for something other than its approved indication, the prescription is called an “off-label” use (OLU).

There are four primary reasons that a medication may be prescribed for an OLU: if it has been approved for use in a specific population but is being prescribed to another group; if a prescriber feels it is logical or necessary to prescribe the medication for a life-threatening medical condition; if a physician prescribes an OLU for a use that a similar medication is approved for; or if the medication is used to treat a condition similar to the one the medication is approved for.

OLUs are common, making up about 21 percent of all prescriptions. About 79 percent of pediatric patients discharged from emergency departments leave with an OLU prescription. OLUs are also the standard treatment option for common conditions such as headaches, neuropathic pain, and insomnia. Many OLUs are safe and supported by medical evidence, but others are prescribed without much data to support their use.

Current regulations of OLUs focus on prohibiting pharmaceutical companies’ labeling and marketing their drugs for OLUs. FDA enforces these regulations by monitoring for unapproved drug uses, disseminating information to consumers, and taking action against non-compliant pharmaceutical companies. And although these regulations give physicians broad discretion to prescribe medications for non-approved uses, OLU prescribers may still face civil liability in some cases.

Although a path exists to seek FDA approval of an OLU, drug manufacturers often choose not to pursue approval because it is a high-cost, time consuming process that may seem unnecessary when a medication is already approved for sale. The cost of the FDA approval process is especially prohibitive for generic medication manufacturers who often lack sufficient resources to conduct the necessary approval studies.

In this week’s Saturday Seminar, scholars and practitioners discuss OLU regulation and the implications of various strategies on different spheres of medicine.

  • In an article in the Journal of the American Academy of Psychiatry and the Law, Shariful Syed of Stony Brook University Medical Center and several coauthors discuss steps that physicians can take to limit their potential liability from OLU-related medical malpractice lawsuits. The Syed team recommends that physicians take four steps to reduce their potential liability: study the mental-health effects of prescriptions, obtain patient consent, document their reasoning for prescribing an OLU, and use caution when promoting OLUs. The authors argue that following these steps will help to ensure that patients understand the risks and benefits of OLUs and that physicians remain within the standards of acceptable practice, thus avoiding the two most common grounds for medical malpractice suits.
  • In an article for the Emory Law Journal, David A. Simon of Northeastern University School of Law argues for a graded system of regulation for OLUs based on their safety and efficacy. Simon proposes that FDA should work with other federal agencies to create a scaled approach that ties the strength of regulations to vetted evidence from drug compendia. He explains that the rigidity of the current off-label regulation limits doctors’ access to potentially useful information, and that FDA guidance is so unclear that drug manufacturers fail to understand its requirements. Simon claims that basing the stringency of an OLU’s regulation on the strength of its supporting evidence would be simpler while remaining consistent with FDA requirements.
  • In an article in the Food and Drug Law Journal, practitioner James M. Beck and several coauthors argue that federal preemption could challenge state abortion restrictions. The Beck team explains that preemption prohibits states from passing legislation that impedes a federal law’s purpose. Applied to abortion restrictions, the authors argue that limiting access to FDA-approved abortion medications conflicts with FDA’s purpose of ensuring access to safe and effective medications, thus curbing states’ restrictive power. Beck and his coauthors predict that preemption claims will defeat restrictions on abortion medications and procedures. They are less optimistic, however, that preemption will protect OLU access. Since OLUs are not directly regulated by FDA, states typically have discretion to regulate them, the authors explain.
  • The COVID-19 pandemic created an explosion of experimental OLUs, Andrea Parziale of the Netherlands’s Maastricht University claims in an article published in The Geneva Papers on Risk and Insurance – Issues and Practices. He explains that although this innovation was essential for managing the public health emergency, it also caused severe issues. To balance the need for innovation with the importance of continued research, Parziale argues for government regulation of OLUs. He explains that agencies should identify OLUs serving a public interest and fund research into those uses through the pharmaceutical industry. Parziale acknowledges that this framework would face strong industry opposition, but is optimistic that advocacy initiatives by patients, physicians, and agencies could effectuate this important regulation reform.
  • In an article in the International Journal of Clinical Pharmacy, Benedetta Guidi, formerly of Italy’s University of Pisa, and several coauthors discuss the pervasiveness of OLUs in pediatrics, and especially among early-childhood patients. Guidi and her team examine regulation of OLUs among European Union member states. They find that even when judicial proceedings target non-compliant OLUs, they tend to have little effect in deterring future noncompliant prescriptions. Guidi and coauthors suggest that the problem of pediatric OLUs is thus practical rather than legal. Accordingly, the authors argue that educating parents and training physicians against dangerous OLUs would be more effective than further regulation.
  • In an article in ESMO Open, George Zarkavelis of Greece’s University Hospital of Ioannina and several coauthors examine regulatory challenges for OLU usage. Zarkavelis and his coauthors identify several medications whose use in cancer treatment remain off-label despite unanimous agreement by experts that the medications’ effectiveness is supported by evidence. Yet 74 percent of practitioners hesitate to apply for OLU approval, a complex process that varies by country. The Zarkavelis team also finds that over 66 percent of practitioners assume that they would incur legal liability if an OLU were to harm a patient. Ultimately, Zarkavelis and coauthors acknowledge the burden of liability for OLU use but argue that the evidence of OLUs’ benefits justifies regulatory submission.

The Saturday Seminar is a weekly feature that aims to put into written form the kind of content that would be conveyed in a live seminar involving regulatory experts. Each week, The Regulatory Review publishes a brief overview of a selected regulatory topic and then distills recent research and scholarly writing on that topic.