On July 6, 2018, the U.S. Food and Drug Administration (FDA) issued draft guidance to assist applicants in writing the Indications and Usage section of labeling for human prescription drug and biological products, “Indications and Usage Section of Labeling for Human Prescription Drug and Biological Products—Content and Format,” Draft Guidance for Industry (July 2018) (“Draft Guidance”).3 FDA’s recommendations in the Draft Guidance are intended to help ensure that the Indications and Usage section of labeling is “clear, concise, useful, and informative and, to the extent possible, consistent within and across drug and therapeutic classes.” Id. at 2. The Draft Guidance supplements FDA’s labeling rules and guidances.4 First, the Draft Guidance provides general principles to consider when drafting the Indications and Usage section of labeling.5 According to FDA, ”[t]he primary role of the Indications and Usage section … is to enable health care practitioners to readily identify appropriate therapies for patients by clearly communicating the drug’s approved indication(s).” Id. at 2. “Other sections of labeling (e.g., Dosage and Administration, Contraindications, Warnings and Precautions, Use in Specific Populations) … also provide essential details that enable safe and effective use of a drug, and labeling should be considered in its entirety for individual prescribing decisions.” Id. FDA cautions, however, that ”[i]ndications or uses must not be implied or suggested in other sections of the labeling if not included” in the Indications and Usage section. Id. at 3 (quoting 21 C.F.R. § 201.57(c)(2)(iv), (v)). Additionally, FDA may require a specific warning in the Warnings and Precautions section of the labeling to address unapproved uses “if the drug is commonly prescribed for a disease or condition and if such usage is associated with a clinically significant risk or hazard.” Id. (citing 21 C.F.R. § 201.57(c)(6)(i)).
Second, the Draft Guidance discusses what information to include in the Indicat ions and Usage section. Id. at 6-14. According to FDA, the section “must state that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a manifestation of a recognized disease or condition, or for relief of symptoms associated with a recognized disease or condition.” Id. at 8 (quoting 21 C.F.R. § 201.57(c)(2)). The disease, condition, or manifestation should be referred to using high-level, clinically relevant terms that are well understood and easily recognized by health care practitioners. Id. Additionally, other information necessary to describe the approved indication, when applicable, should be identified. Id. at 7, 8-9. For example, descriptors or qualifiers of the population to be treated, such as approved age groups, patients previously treated with other therapies, or patients with a certain classification of the disease, may be important to include. Id. at 7, 8. The Indications and Usage section may also provide information about adjunctive or concomitant therapy, or specific tests needed for patient selection. Id. at 7, 9.
The Draft Guidance also states that limitations of use, which are presented separately from the indication within the Indications and Usage section, should be included “when there is reasonable concern or uncertainty among FDA’s expert reviewers … about a drug’s risk-benefit profile” and “the awareness of such information is important for practitioners to ensure the safe and effective use of the drug.” Id. at 10. FDA distinguishes limitations of use from contraindications, which are “situations in which the drug should not be used because the risk of use …clearly outweighs any possible therapeutic benefit,” and recommends avoiding redundancy in the labeling by not restating contraindications as limitations of use in the Indications and Usage section. Id. (quoting 21 C.F.R. § 201.57(c)(5)). FDA also recommends incorporating “information that essentially narrows or further defines a drug’s approved indication and is used to direct appropriate therapy … directly into the indication whenever possible,” rather than including it as a limitation of use. Id. Limitations of use may be appropriate if there is reasonable concern or uncertainty about a drug’s effectiveness or safety in a certain clinical situation; if a drug is approved without evidence of benefits known to occur with other drugs in the same class; or if a drug has certain dose, duration, or long-term use considerations. Id. at 11-13. Limitations of use would generally not be appropriate, however, to restate information already included in the indication or to address the absence of data in populations in which the drug was not studied. Id. at 13-14.
Third, the Draft Guida nce makes recommendations about how to write, organize, and format the information within the Indications and Usage section. Id. at 14-17. FDA states that while a full description of how benefits of treatment were measured in clinical trials is generally unnecessary, a broad disease indication may be inappropriate where the drug affects only certain signs, symptoms, or manifestations of a disease. Id. at 14. The Indication and Usage section may include an indication identifying outcomes or endpoints when, for example, “the drug’s effect on the overall disease is not well understood; when different drugs have different effects on various manifestations of the diseases; when clinical trials evaluated only one or some of the manifestations of the disease; or when endpoints are different from the typical effectiveness measure.” Id. Additionally, governing statutory and regulatory provisions require or recommend language for certain products, such as systemic antibacterial drug products and products containing a single enantiomer of a previously approved racemic drug. Id. at 15. FDA notes that the phrase “reduce the risk of” is generally preferable to the word “prevent,” and that the words “only” and “also indicated” should generally not be used. Id. at 16.
Readers are encouraged to read the Draft Guidance in its entirety, as well as FDA’s re lated rules and other guidances, and to consult with legal counsel when making decisions about their product labeling.