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Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels

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Abstract

Boxed warnings—also known as “black box” warnings—can be a powerful tool in communicating drug risks to physicians and patients. The overall number of boxed warnings has grown in recent years as the US Food and Drug Administration (FDA) has approved more drugs on the basis of limited pre-marketing information and as new safety issues for marketed drugs have been identified. Two recent manufacturers’ petitions to remove boxed warnings on the drugs rosiglitazone (Avandia) and varenicline (Chantix) have led to divergent FDA decisions and revealed different considerations involved in boxed warning imposition and removal. For ethical and practical reasons, the FDA is justified in applying a higher standard for boxed warning removal than for imposition, as removal of a boxed warning may have unintended effects on physician and patient behavior. However, no guidelines on boxed warning removal currently exist. To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings.

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Authors and Affiliations

  1. Program on Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA

    James S. Yeh, Ameet Sarpatwari & Aaron S. Kesselheim

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  1. James S. Yeh
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  2. Ameet Sarpatwari
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  3. Aaron S. Kesselheim
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Corresponding author

Correspondence to James S. Yeh.

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Funding

Aaron Kesselheim’s work is funded by a Greenwall Faculty Scholar program grant, the Harvard Program in Therapeutic Science, and the Laura and John Arnold Foundation.

Conflict of interest

James Yeh, Ameet Sarpatwari, and Aaron Kesselheim have no conflicts of interest that are directly relevant to the content of this study.

Box 1. US Food and Drug Administration (FDA) requirement for inclusion of a boxed warning and adverse events of prescription drugs [21 CFR 201.57(c)(1)]

Box 1. US Food and Drug Administration (FDA) requirement for inclusion of a boxed warning and adverse events of prescription drugs [21 CFR 201.57(c)(1)]

Boxed warning. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box. The boxed warning ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. The box must contain, in uppercase letters, a heading inside the box that includes the word “WARNING” and conveys the general focus of the information in the box. The box must briefly explain the risk and refer to more detailed information in the “Contraindications” or “Warnings and Precautions” section, accompanied by the identifying number for the section or subsection containing the detailed information.

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Yeh, J.S., Sarpatwari, A. & Kesselheim, A.S. Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels. Drug Saf 39, 709–714 (2016). https://doi.org/10.1007/s40264-016-0419-8

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