FDA’s Biosimilar Labeling Guidance

By James C. Shehan –

On March 31, 2016 FDA released its promised guidance on labeling for biosimilar products. A few parts caught our eye, including another change of mind by FDA on the issue of whether a biosimilar’s labeling should identify itself as a biosimilar,

The guidance primarily affects prescribing information (a.k.a. the package insert) but a few sections affect patient labeling. FDA lays out a few general principles before proceeding to some specific recommendations.

Under general principles, FDA begins with the premise that, because the Biologics Price Competition and Innovation Act ("BPCIA”) requires that biosmilars have “no clinically meaningful differences from the reference product in terms of safety, purity, and potency, and because the labeling of the reference product reflects FDA’s findings of safety and efficacy, that labeling “may be relied upon to provide health care practitioners with the essential scientific information needed to facilitate prescribing decisions” for the biosimilar. Thus, biosimilar labeling should “include a description of the clinical data that supported safety and efficacy of the reference product as described in the FDA-approved product labeling” for that reference product, with appropriate biosimilar-specific modifications.

The guidance then makes some detailed recommendations on treatment of clinical study data in biosimilar labeling. These positions seem to coincide with positions advocated by biosimilar applicants. FDA states that clinical studies of biosimilars should not be included in their labeling, unless it is necessary to do so to “inform safe and effective use.” In support, FDA points out that clinical studies of biosimilars are usually designed to detect clinically meaningful differences between the biosimilar and the reference product and not to independently demonstrate safety and effectiveness. As a result, a biosimilar’s clinical studies may use different endpoints and different patient populations than were used in reference product studies. This leads FDA to conclude that information about such clinical studies is “not likely to be relevant to a health care practitioner’s considerations regarding safe and effective use of the biosimilar.” Including it “may cause confusion, resulting in an inaccurate understanding of the risk-benefit profile of the product.”

FDA also states that biosimialrs follow the content and format requirements of the physician labeling rule and the pregnancy and lactation labeling rule, regardless of whether the labeling of the reference product does or does not follow those rules.

Turning to specific issues, FDA states that those sections of the biosimilar product labeling based on the reference product labeling should be similar but need not be identical. For example, differences in administration, storage or safety information may require different labeling.

The guidance devotes several pages to describing when biosimilar sponsors should use their biosimilar’s name, the reference product’s proprietary name and the “core name” of the product, the latter term referring to that portion of the proper name that does not include the four letter suffix proposed in FDA’s draft guidance on biologics naming (see our post here). FDA recommends that:

• The biosimilar’s name (proprietary or proper) be used in labeling where information is (1) specific to the biosimilar product or refers solely to the biosimilar product, such as in Indications and Usage and Dosage and Administration sections; and (2) for directive statements and recommendations for preventing, monitoring, managing, or mitigating risks, typically included in sections such as black box warnings, Contraindications, Warnings and Precautions, and Drug Interactions.

• The reference product name be used when clinical studies or data of the reference product are described, e.g. in the Adverse Reactions and Clinical Studies sections.

• The core name should be used in labeling sections where risks apply to both the biosimilar product and the reference product, such as black box warnings, Contraindications, Warnings and Precautions, and Adverse Reactions. In such sections, the labeling should refer to the core name followed by the word “”

• More than one name be used where necessary to accurately convey information.

While this part of the guidance appears to be logical, it may result in labeling that is confusing to users, considering that the labeling will apparently switch back and forth between three different names to make distinctions whose subtlety may escape a busy or uninformed end user.

The guidance briefly addresses labeling for biosimilars that are approved for fewer indications than the reference product, noting that text regarding those indications should not be in the biosimilar labeling, except when necessary to ensure safe use. In those situations, FDA admonishes biosimilar applicants to write labeling “in a manner that does not imply that the biosimilar product is approved for a reference product indication(s) or use(s) that has not been approved for the biosimilar product.” Notably, the guidance does not address AbbVie’s request that the labeling of a biosimilar call out that it is not approved for all the indications of the reference sponsor (see our post here).

The section of the guidance that may generate the most discussion is the one calling for the labeling of biosimilar products to identify these products as biosimilars. FDA originally called for this to be done in a 2012 draft guidance, deleted that point in the 2015 final version of that guidance, but now has reinstated it here.

FDA “recommends inclusion of a statement, on the line immediately beneath the initial U.S. approval date in Highlights, that the product is biosimilar to the reference product.” This statement should read “[BIOSIMILAR PRODUCT’S PROPRIETARY NAME (biosimilar product’s proper name)] is biosimilar* to [REFERENCE PRODUCT’S PROPRIETARY NAME (reference product’s proper name)] for the indications listed.”

FDA provides precise wording and placement for the asterisked statement, essentially a paraphrasing of the BPCIA’s definition of a biosimilar: “Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. the a s