FDA would restrict the use of nonspecific safety claims such as "well tolerated" under its draft guidance on adverse event labeling.

"In characterizing overall adverse event experience, subjective and nonspecific terms (e.g. well tolerated) should be avoided, as they have no precise meaning and can be misleading," the draft guidance states. The document was published in the Federal Register June 20.

Qualifying terms such as "rare, infrequent and frequent" should also be avoided, FDA said. "If the terms are used, their use should be consistent with their regulatory definitions."

FDA said that it would still consider such language on a case-by-case basis. However, the agency is seeking to move away from those types of nonspecific claims and AE descriptions in labeling in order to decrease their use in promotional messages.

The draft guidance, "Content and Format of the Adverse Reactions Section of Labeling for Human Prescription Drugs and Biologics," is the first in a series of guidance documents on the content and format of individual labeling sections.

The agency is also developing guidances for the Clinical Pharmacology, Clinical Studies and Warnings/Precautions sections of labeling. The guidances are slated for publication "in the coming months," FDA said. "Guidances for other labeling sections may be developed later."

The new guidelines for individual labeling sections are part of a broader FDA effort to revise the overall format of prescription drugs labeling.

The agency is developing a rule that will "propose reordering the sections of the labeling, based on the importance of the information to practitioners, and the frequency with which practitioners refer to a section."

The proposed rule would also create a "highlights" section of labeling and an index.

The Pharmaceutical Research & Manufacturers of America task force on paperless labeling has proposed that an electronic labeling system capable of being updated within 24 hours of a labeling change would make possible features such as a "What's New" section of product labeling (¹ Also see "Paperless Labeling Could Save Companies Up To $5 Mil. Each Year" - Pink Sheet, 5 June, 2000.).

The adverse events labeling draft guidance suggests that that data be presented in two sections, a general "Overview" section and a more detailed "Discussion of Adverse Reaction Information."

The overview "is intended to briefly highlight the information in a drug's adverse reaction profile that is most important to prescribing decisions and to observing, monitoring and advising patients."

The section should include listings of the "serious and important adverse reactions described in other labeling sections, the most commonly occurring adverse reactions [and] the adverse reactions most frequently resulting in clinical intervention," the draft guidance states.

The draft guidance specifies that the "discussion of adverse reaction information" section should include a table displaying adverse event data; commentary elaborating on the data; a description of the database used, including control groups, number of patients and duration of exposure to the product; a discussion of less common adverse events; and adverse event data from spontaneous reports.

The draft guidance also proposes that adverse event information generated from spontaneous reports should be presented separately from clinical trial adverse event data.

Rates or number of spontaneous reports should not be cited "unless they are meaningful and informative (usually not the case)," the document states.

Labeling should include a disclaimer regarding the significance of data obtained from postmarketing spontaneous reports, FDA said.

The statement should inform readers that "because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure."

The draft guidance also suggests that all labeling carry a disclaimer on the significance of adverse events observed in clinical trials. A disclaimer is needed to "help place in perspective the significance of adverse reactions data obtained from clinical trials," FDA said.

The draft guidance would require labeling to include the statement: "Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice."

"The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates," the statement continues.

In order to keep the adverse events section of labeling up to date, FDA is recomending a regular review of AE labeling. "Sponsors are urged to periodically review (at least annually) the content of the adverse reactions section to ensure that it remains accurate," the draft guidance states.

"The labeling should be reviewed to ensure consistency with newly acquired information from controlled trials or spontaneous reports and with the evolution of labeling in the pertinent drug class, and to seek out any defects in labeling that may have accumulated with time."

Although FDA labeling workgroups have discussed requiring an annual review of labeling to be documented in an annual report, the draft guidance does not go that far.

In order to increase the utility of the adverse event data included in labeling, FDA suggested that adverse events included in labeling should be carefully chosen.

"Long, exhaustive lists of every reported adverse event, including those that are infrequent and minor, commonly observed in the absence of drug therapy or not plausibly related to drug therapy, should be avoided," the draft guidance states.

FDA will be accepting comments on the guidance until Sept. 20.

FDA Adverse Event Draft Guidance Would Restrict "Well Tolerated" Claims

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