potentially pose greater risks than TCIs, particularly in light of decades of data which suggest that in transplant patients, oral calcineurin inhibitors are safer than oral systemic corticosteroids.
35
The tumor necrosis factor-alpha (TNF-α) inhibitors are biologic agents (eg, infliximab, etanercept, and adalimumab) that are increasingly used for the treatment of psoriasis and other dermatologic
diseases. A boxed warning was added to the entire class because of a potential malignancy risk based on AERS lymphoma reports in children and adolescents.37 A recent meta-analysis of 63 randomized controlled trials and nearly 30,000 patients with rheumatoid arthritis, however, revealed no significant
association between anti-TNF-α therapy and an increased risk of malignancy compared to other disease-modifying anti-rheumatic drugs or placebo.38 After years of conflicting data leading up to this study, this new information may influence prescribing practices unless dermatologists rely only on the package insert given that despite this new data, the black box warning on anti-TNF-α agents remains.
Regardless of the black box warning’s effect on legal liability, its intended purpose is to minimize severe adverse reactions in patients. Effective communication of new warnings to prescribers
from both the FDA and manufacturers is the pivotal point in making the black box warning a successful risk management tool. The best strategy for disseminating a new black box warning
is not known. Studies have shown that “Dear doctor†letters alone may have little impact on prescribing habits. These letters may be much more effective depending on their wording and whether they are accompanied by additional strategies such as media publicity.27 The FDA is interested in improving its overall
approach to this problem, and has made changes in recent years to improve physician and patient awareness of new drug information and labeling changes.39
Furthermore, adherence to boxed warnings is voluntary with no system of monitoring to guide use of drugs with such warnings.
Ambulatory electronic health records with computerized order entry and prescribing alerts related to boxed warnings do not improve clinicians’ overall adherence to boxed warnings,
although do improve adherence in specific clinically important subcategories.40 In a large study in outpatient practices,
0.7% of prescriptions (n=324,548) violated an aspect of a warning, such as a drug interaction, inappropriate patient selection,
or inappropriate monitoring. This was observed to be more common in patients over 75 years old and in those with multiple prescriptions. Despite this, fewer than 1% of these events resulted in an AE.41
Future of the Boxed Warning
Greater transparency is needed in the administration and clinical
application of the boxed warning. This was illustrated in the clinical case presented here using becaplermin. Many questions
remain regarding black box warnings. For example, how well does the current system work? How do dermatologists learn about boxed warnings? How does the knowledge of a boxed warning change dermatology practice? Do dermatologists
feel compelled to counsel patients more extensively before prescribing a drug with a boxed warning? Do dermatologists avoid prescribing these drugs altogether and choose alternative treatments to avoid the extra time needed for counseling and/or monitoring, or even to avoid potential liability? What is the magnitude of some of these unintentional effects of the boxed warning? What if there is no other effective alternative treatment available? Further research is needed to identify which methods of communication have the greatest impact on dermatologists’ awareness of new boxed warnings as well as changes to warning
data, thereby ultimately impacting patient safety.
In the context of prescribers’ schedules, variable learning methods
and practice styles, including use of electronic medical records and prescribing software, we would expect the “most effective†communication strategy to be a dynamic combination
of multiple simultaneous and staggered outreach efforts. The ideal combination of modalities is likely to change over time, requiring frequent reevaluation and adjustment to maintain
efficacy.
DISCLOSURE
The authors have no conflicts of interest to declare.
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