Everything you needed and wanted to know about black boxed warnings.

• Author: Mullady, Raymond G., Jr.
• Position: Drug product labeling

The FDA has exclusive authority to require boxed warnings, but even if those warnings are present, courts may hold that they are inadequate

SINCE Charles Darwin first introduced the term "black box"--the way Darwin regarded the cell--into the scientific lexicon, the term has been used to denote an object whose inner workings are mysterious but that "is so unproblematic that we take it for granted.... How it works is ... not our concern."(1) Darwin would be the first to admit that his concept of the "black box" is not easily applied to the field of pharmaceutical product labeling, where the "black box" is seldom "mysterious" but often the source of complex liability issues confronting drug manufacturers.

What is the regulatory history and role of boxed warnings in drug product labeling? What is the apparent rationale behind the Food and Drug Administration's and the courts' boxed warning decisions? How should defense counsel defend boxed warning cases?

REGULATORY FRAMEWORK

In 1979, the FDA promulgated regulations that effected significant changes in the format and content of prescription drug labeling. The 1979 regulations are set forth at 21 C.F.R. [subsections] 201.56 and 201.57 and required that drug manufacturers adhere to a standardized vocabulary and structure when stating safety information pertaining to their products.(2) The 1979 regulations required that manufacturers provide specified information under each of the following mandatory subject headings, which were to appear in descending order of importance: (1) "Description," Section 201.57(a); (2) "Clinical Pharmacology," Section 201.57(b); (3) "Indications and Usage," Section 201.57(c); (4) "Contraindications," Section 201.57(d); (5) "Warnings," Section 201.57(e); (6) "Precautions," Section 201.57(f); (7) "Adverse Reactions," Section 201.57(g); (8) "Drug Abuse and Dependence," Section 201.57(h), (9) "Overdosage," Section 201.57(i); (10) "Dosage and Administration," Section 201.57(j); and (11) "How Supplied," Section 201.57(k).(3)

Under the "Warnings" heading, drug labeling was required to hazards, limitations in use imposed by them, and steps that should be taken if they occur." The provision further stated:

Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. If a boxed warning is required, its location will be specified by the Food and Drug Administration. The ostensible purpose of this "boxed warning" or "black box warning" provision, as well as of the other provisions of the 1979 regulations, was to create a standardized, uniform warning vocabulary and structure, thereby ensuring that safety information is readily and easily accessible to health care providers.(4) Adopting a standardized labeling format, the FDA posited, would eradicate the confusion engendered by decentralized labeling and would allow the "user of the information [to] develop expertise in processing the labeling information in a systematic manner.(5)

The required format and content for prescription drug labeling set forth in the 1979 FDA regulations remain in effect today and are codified at 21 C.F.R. [subsections] 201.56 and 201.57 (1999). The regulations are not confined to package inserts, but they apply to all drug labeling. In fact, the FDA in issuing the 1979 regulations declined to apply the regulations only to package inserts.

The Federal Food, Drug and Cosmetic Act, 21 U.S.C. [subsections] 301-395, which vested in the FDA the authority to enact the 1979 regulations, directs in Section 321(m) that "drug labeling" "means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." The regulations, 21 C.F.R. [sections] 202 (1) and (2) provide the following examples of "labeling":

Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio or visual matter descriptive of a drug and references published (for example, the Physician's Desk Reference) for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labeling ... The FDA maintains that it "reserves [the boxed warning] format, with the warning placed in a prominently displayed box, for the most serious warnings necessary to ensure the continued safe use of the product."(6) Jane E. Henney, M.D., the Food and Drug Commissioner, describes an FDA mandate for a boxed warning as a "dramatic" step that should be taken only if a new safety issue "really alters the risk-benefit ratio."(7)

An example of a recent boxed warning that could be lifesaving is carried by the drug Eulexin (flutamide capsules). It warns that the drug is contraindicated in patients with significant hepatic dysfunction and that the drug has been the subject of post-marketing reports of hospitalization and, rarely, death due to liver failure. The Eulexin boxed warning can be found at the FDA's Medwatch site.(8)

REGULATORY PROCEDURE

The FDA has not issued any guidance relevant to when or how it requires a boxed warning for a particular drug. Guidance can be gleaned, however, from an examination of the agency's drug approval process. That typically commences with an applicant's submission of an investigational new drug application, through which the applicant seeks permission to conduct human clinical trials for the new drug. If permission is granted, the applicant conducts several phases of human clinical trials. At the conclusion of the third of this four-phase trials process, the applicant submits a new drug application, called an NDA, to the FDA. The NDA is "a compendium of all available data on the drug's efficacy for the proposed uses, as well as its safety, and includes, among other things, proposed labeling for the drug."(9)

Following submission of an NDA, the FDA determines, over the course of a lengthy approval process, whether the proposed new drug complies with the Federal Food, Drug, and Cosmetic Act's requirements that safety be established, and that "substantial evidence" of efficacy be demonstrated according to 21 U.S.C. [sections] 355(d). In making this determination, the FDA strictly scrutinizes the drug's proposed labeling to ensure its accuracy and reliability, and to ensure that the labeling is based on scientific information. The FDA will permit proposed warnings on the labeling only to the extent that the potential health hazard reflected by the warning is supported by significant medical evidence. The FDA will not permit warnings of a drug's "unknown or theoretical adverse reactions."(10)

If, after reviewing an NDA, the FDA determines that the benefits of the new drug outweigh the potential risks, and, thus, that the product will ultimately improve the public health, the new drug is approved for marketing.

Thus, it is to be presumed that a determination as to whether a drug will carry a boxed warning will be made after human clinical trials and the submission of an NDA. This is not the only juncture at which the FDA may require a boxed warning, however. It also requires pharmaceutical manufacturers to engage in post-marketing surveillance by reporting individual adverse experiences and by conducting epidemiological studies.(11) If through this process the FDA becomes aware of new or formerly underappreciated risks associated with a particular drug, it may require a change in the drug's labeling, including the addition of a boxed warning. In addition, in rare instances, post-marketing developments may lead the FDA to restrict sales of a drug, or to mandate the drug's withdrawal from the market.(12)

The determination of whether a drug will be required to carry a boxed warning is typically made by the FDA's Center for Drug Evaluation and Research (CDER).(13) In making this determination, CDER often seeks the advice of an advisory committee, and although it is not bound by the decision of that committee, it is usually deferential to the committee's decision. The FDA's authority to use advisory committees in making decisions regarding black box warnings is conferred by 21 C.F.R. [sections] 14.171:

(a) Any matter involving a human prescription drug under review within the agency may, in the discretion of the Commissioner, be the subject of a public heating and continuing or periodic review by the appropriate standing technical advisory committee for human prescription drugs.

(b) High priority for such hearing and review by the appropriate standing technical advisory committee for human prescription drugs are given to the following types of human prescription drugs:

(1) Investigational drugs which ... are the subject of major scientific or public controversy, or which may be subject to special regulatory requirements such as a limitation on clinical trials, a patient follow-up requirement, post-marketing Phase IV studies, distributional controls, or boxed warnings.

(2) Marketed drugs which ... may be subject to important regulatory actions such as withdrawal of approval for marketing, boxed warnings, distributional controls, or newly required scientific studies. [Emphasis added]

Thus, the FDA may use an advisory committee at either the pre- or post-marketing stage to assist it in making a boxed warning determination. The FDA attempts to ensure that the committees, which are typically comprised of physicians, nurses, pharmacologists...