FDA's final labeling rule defers revisions to labeling issues such as the content and format of the Pregnancy subsection, inclusion of in vitro data and the requirements for container labels.

While the physician labeling rule establishes broad format changes, several aspects of drug labeling are left unresolved in the final version until FDA completes a thorough evaluation of the specific issues.

For example, FDA will reevaluate its policy on the inclusion of in vitro data in the Pharmacokinetics subsection of the Clinical Pharmacology section.

"The agency has reconsidered its proposal to exclude from the 'Clinical Pharmacology' section in vitro data for anti-infectives that are not supported by clinical data," the "Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products" final rule states.

"While comments conceded that in vitro data have their limitations, the comments maintained that in vitro data for anti-infective agents can be an important component of the total information available for making prescribing decisions in some situations, including: in the absence of susceptibility testing, in treating drug-resistant pathogens...and in treating rare infections," the rule states.

FDA's December 2000 proposed rule would have required all in vitro data not supported by clinical data to be removed from labeling within one year of the rule's effective date. The Pharmaceutical Research & Manufacturers of America suggested in response that removal of in vitro susceptibility data could cause an increase in inappropriate antibiotic use (¹ Also see "Antibiotic In Vitro Data Needed In Labeling For Appropriate Use, PhRMA Says" - Pink Sheet, 16 July, 2001., p. 8).

"The agency is considering a broad range of issues concerning the development and labeling of anti-infective products, including the types of data that should be obtained to support indications, the way that indications and anti-infectives data should be presented in labeling, and ways to meaningfully address resistance to anti-infective drugs," the final rule says.

"The agency believes a comprehensive and coordinated approach is needed to address these issues," the rule states. "Thus, FDA is deferring any action on the in vitro data proposals in the 'Clinical Pharmacology' section of labeling until the agency has developed a comprehensive plan."

Consequently, the final rule does not include the proposed requirement that sponsors obtain a waiver to include in vitro data for anti-infective drugs in labeling. Until FDA has developed its intended plan, in vitro data for anti-infective drugs must be preceded by the statement: "The following in vitro data are available but their clinical significance is unknown."

The final rule also defers proposed changes to the content and format of the Pregnancy subsection.

"The agency is developing a proposal that would revise the requirements for the 'Pregnancy,' 'Labor and delivery,' and 'Nursing mothers' subsections of prescription drug labeling," the rule states. "For this reason, the agency has reconsidered the need to make minor, interim changes to the warning statements for pregnancy categories D and X in this final rule."

Pregnancy-related labeling reforms have been under consideration for several years; FDA established a Pregnancy Labeling Subcommittee in 1999.

The Pregnancy, Labor and Delivery, and Nursing Mothers subsections will appear in the Use in Specific Populations section of labeling; that information previously was located in the Precautions section. FDA says it does not expect changes to the Pregnancy subsection to impact the new Highlights section - the most prominent change to the drug labeling format.

The agency also postponed implementing changes to its requirements for container labels.

FDA had proposed eliminating from container labels: the list of inactive ingredients for non-oral products; instructions to pharmacists about the proper container type for dispensing; and a statement directing healthcare professionals to the package insert for additional information. Under the proposed rule, such information would have appeared in the How Supplied/Storage and Handling section of drug labeling.

FDA has decided that further evaluation of the content and format for container labels is necessary and plans to conduct a comprehensive review of its requirements.

FDA also is developing guidances on the content and format of the Clinical Pharmacology and Dosage and Administration sections. The agency issued four supporting guidances with the final labeling regulation Jan. 18 (² Also see "Labeling “Highlights” To Depend On Data In Relation To Clinical Setting" - Pink Sheet, 23 January, 2006., p. 3).

Unfinished Labeling Business: Pregnancy, In Vitro Data, Containers

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