The Value of the Black Box Warning in Dermatology

There is no one official or central black box warning resource. Labeling information may be found in the Physicians' Desk Reference (PDR), Drugs@FDA.gov, manufacturer websites, and drug interaction databases. However, of the major drug interaction databases, Facts & Comparisons 4.0, MICROMEDEX DRUG-REAX, and Lexi-Comp Lexi-Interact, significant discrepancies in detecting boxed warning drug contraindications were found.²⁵ Furthermore, only half of newly discovered serious AEs are detected and documented in the PDR within 7 years after drug approval.¹² Therefore, clinicians are forced to consult a number of different sources for accurate information. The current package insert of a particular drug may be the most up-to-date and definitive resource for boxed warnings.²⁵

Once a warning is added, there is no official protocol for disseminating this information to prescribers. In recent years, however, the FDA has worked to improve drug safety. In 2004, the FDA issued the Development and Use of Risk Minimization Action Plans (RiskMAP Guidance) that describes how to minimize the risks of drugs and address specific risk-related goals and objectives.²⁶ A new black box warning may be accompanied by “Dear Doctor” letters sent by the manufacturer, press releases, postings on the company and/or FDA websites, notices to pharmacies or inclusion in commercial pharmacy databases, and detailing by pharmaceutical representatives directly to individual practitioners.²⁷ There are two separate parties involved in writing and communicating these warnings. While the FDA is the regulatory government body involved, the manufacturers are primarily responsible for sending letters, making press releases, and dispatching representatives to deliver information to individual physicians. RiskMAP Guidance also suggests the use of “Reminder Systems,” which involve ways to prompt providers to double-check their prescribing procedures, and “Performance-Linked Access Systems,” which link drug access to laboratory results or other documentation.²⁶

The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave the FDA the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, for certain high-risk drugs. This may include a Medication Guide, package insert, communication plan, implementation system, and timetable for future assessment of REMS, which are required 18 months, 3 years, and seven years after initial approval.²⁸ Under the FDAAA, the FDA can require post-approval trials to further investigate known AEs, assess AE signals, and to further identify future AEs. The FDA can mandate approved product labeling changes based on new safety data. It also allows for monitored access to drugs with known AEs that would otherwise be unavailable.²⁹

The FDA’s goal is to protect the public from serious adverse events, while the manufacturer stands to lose substantial revenue depending on how a boxed warning impacts physicians’ prescribing habits. Although a boxed warning doesn’t always reduce drug sales, the FDA’s intention may be just that.³⁰ In the year after the antihistamine terfenadine (Seldane®) received a black box warning against its use in certain settings and for particular drug-drug interactions, its sales dramatically dropped from “around $700 to $450 million.”³¹ Terfenadine and terfenadine- containing drugs were later permanently withdrawn from the market.³² Some medications with boxed warnings are withdrawn from the market, while others are still commonly used, such as the TCIs. However, the TCIs continue to have associated stigma from the warning, with usage and sales never again reaching levels of their 2003-2004 peak. In fact, insurance companies and third party payors responded to the boxed warnings on TCIs by changing reimbursement rates, formulary status, and requiring pre-authorization and other obstacles to prescription.³³

In some cases, the warning may apply only to a specific patient population. In this scenario, even though a physician is aware of the boxed warning, it may be safe to continue prescribing the drug to patients outside of that group. However, the existence of any black box warning may have more widespread and unintentional effects. Patients’ concerns and fears may lead to non-adherence to the prescribed regimen. With increased patient awareness of drug labeling, physicians may have to spend additional time counseling patients who may be appropriate candidates for the drug, but who are wary of using any medication with a “black box warning.” This may potentially alter physician prescribing habits. Patients may therefore be denied access to a potentially beneficial drug with a boxed warning if physicians are unwilling to prescribe it due to concern about the time needed for additional counseling or even potential liability. The physician stands to be liable with or without a defendant drug manufacturer. For example, in a 1995 case, the court determined that the black box warning was sufficient to fulfill the “learned intermediary rule,” protecting the manufacturer (Hoffmann-LaRoche) from product liability by informing physicians via a black box warning of the potential birth defects caused by Accutane® (isotretinoin).⁸ However, some courts have more recently ruled that the learned intermediary doctrine does not apply in the setting of direct-to-consumer advertising.34 Furthermore, the boxed warning provides little detail about the AEs including incidence information.

More than 40% of surveyed dermatologists reported that over 20% of their atopic dermatitis patients were not adequately controlled since the boxed warning for TCIs was introduced.³⁵ The American Academy of Dermatology Association Task Force reported no causal proof that TCIs caused nonmelanoma skin cancer or lymphoma, and recommended their use for atopic dermatitis and other inflammatory disorders.³⁶ Those dermatologists who have been using alternative therapies to TCIs have resorted to chronic topical corticosteroids, systemic corticosteroids, cyclosporine, and other systemic immunosuppressive agents in addition to phototherapy.³⁵ These agents can