Since safety concerns regarding prescription drugs are often discovered only after a medicine has been approved and released on the market, FDA regulatory advisories serve as an important means of communicating risk information to providers and to the general public. Although there are a variety of methods that the FDA uses to communicate such information, black box warnings are reserved for those deemed of highest public health importance. In many cases, risk information may be available for only select drugs within a therapeutic class, and thus the Agency often has to decide how broadly an advisory should be applied when faced with incomplete information. Should a warning derived from data about a single agent be similarly applied across drugs within the same chemical class or across agents with similar pharmacologic effects? Why or why not? What factors should guide this decision?
As with many decisions that the Agency makes, this deliberation can be complex, since it requires the combination of facts and judgments in the setting of incomplete scientific information. To complicate matters further, advisories focused on a single agent may have substantially different effects than advisories focused on an entire therapeutic class. For example, applying an advisory to a single member of a class may erroneously suggest superior safety of other members of the class in the absence of evidence to the contrary, and may also erode a particular agent’s market share and thus be met with resistance by industry stakeholders. The lack of specificity of a class-wide warning may blunt the impact of an advisory.1 Too many advisories may lead to “alert fatigue.” Poorly worded or framed advisories may increase their spillover to untargeted populations. Indeed, as the history of risk communication has shown us, poorly managed messages about risks can become risks themselves.2,3
In this issue of JGIM, Panagiotou et al. assess the application of black box warnings across drugs within the same chemical classes.4 The authors identified 20 top-selling drugs (index drugs) representing 20 chemical classes in 2008, selecting 10 medicines with a black box warning and 10 medicines without one. They then searched the labels for each drug in the defined classes, including those members that had been withdrawn from the market, and quantified the extent to which these labels reflected similar warning information as the label of the index drug.
These 20 classes yielded 176 therapies for which the authors could obtain FDA labels. Among these classes, the authors identified seven therapies that had been withdrawn from the market for safety reasons, but with little overlap between black box warning information on these agents and available same-class agents. For example, while troglitazone was withdrawn from the market because of its hepatotoxicity, no other glitazone label examined had a similar black box label for this toxicity. Among the drug labels reviewed, the authors identified 15 drugs for which black box warnings were not applied equally across other members of the class. The authors indicate that 10 of these 15 warnings were included in some form on the other agents within the class, but 5 warnings were completely excluded from same-class agents. The authors concluded that differences in labeling within a treatment class may shape impressions about drug safety and that more systematic labeling is needed.
The authors examine an important topic—how systematically the FDA regulatory advisories are applied across agents within a chemical class—and their analysis provides an opportunity to consider a variety of factors that the Agency must consider when issuing such advisories. Their first conclusion, that differences in labeling may shape perceptions of safety, is unobjectionable. However, their second conclusion, that more systematic labeling is needed, raises a much more complicated set of issues. This is because it requires a consideration of the specific clinical circumstances of each advisory, and these examples demonstrate the complicated nature of applying black box warning information across chemical classes. Table 1 describes three of the five settings where the authors indicate that black box warning information on one or more drugs within a chemical class was absent from other agents within that class. We use these three cases to highlight the importance of considering the clinical context when applying black box warnings to agents within the same chemical class.