By Kevin E. Noonan --
The Biologic Price Control and Innovation Act (BPCIA), enacted as part of President Obama's Affordable Care Act (better known as "Obamacare," Public Law 111-148), provided for the first time in the U.S. a path for FDA approval of biosimilar drugs, i.e., "generic" versions of biologic drugs that, unlike generic versions of conventional small molecule drugs are not identical but similar. Congress did not, however, prescribe the standards for establishing biosimilarity or other aspects of the biosimilar pathway, leaving the details up to the FDA. As part of fulfilling its mandate under the BPCIA, the FDA has issued a series of Guidances (both in draft and final form) with respect to the procedural and scientific protocols to be followed in filing and pursuing a biosimilar drug application (see "FDA Releases 'Final' Guidances for Industry regarding the Biosimilar Approval Pathway"). On Friday, the FDA issued its latest Guidance, which has to do with labeling of biosimilar drugs. Far from being merely a technical aspect of the biosimilar program, this Guidance has been subject to pressures from both the innovator biologic drug makers and companies pursuing (or planning to pursue) their own biosimilar drugs. These pressures have everything to do with the hoped-for acceptance of these drugs (particularly by the U.S. government, the biggest payor for biologic drugs) and fears by innovator biologic drug companies that their drugs might be mistaken for a biosimilar version (especially in the event that a biosimilar is associated with an adverse event).
The Guidance (which is but a draft Guidance for now) on its face is being distributed "for comment only" and in this way reflects the manner in which the FDA has approached its task of implementing the Act, by soliciting public and industry feedback by issuing draft Guidances and holding hearings and other meetings. In a "black box" at the beginning of the document it states:
This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.
There are eight sections, providing the Background, General Principles, Specific Recommendations, FDA-approved Patient Labeling, Revised Biosimilar Product Labeling, instructions on how to submit initial and revised labeling, and a short section on Interchangeable Biological Products that does not provide labeling recommendations for interchangeable products (consistent with the agency's refusal to provide Guidance on obtaining approval for interchangeable versions of biologic drugs). In the short Background the agency explains the context of the biosimilar provisions of the Act and then moves immediately to the General Principles. There the FDA notes that the biosimilars pathway is provided "to demonstrate biosimilarity between the proposed [biosimilar] product and the reference product, not to independently establish safety and effectiveness of the proposed [biosimilar] product." Accordingly, the information on the biosimilar label should be the "relevant data and information from the reference product labeling, with appropriate product-specific modifications." Indeed, "[i]nformation and data from a clinical study of a proposed biosimilar product should be described in its labeling only when necessary to inform safe and effective use by a health care practitioner" and should not include "a description of these data," on the grounds that any clinical study undertaken by the biosimilar applicant should be aimed at establishing biosimilarity (defined as there being no clinically meaningful differenced between the biosimilar product and the reference product) and not at assessing the safety and efficacy of the biosimilar per se. The Guidance also recites several other labeling rules not limited to the biosimilar context that a biosimilar label is required to follow (see, 21 CFR 201.56(c)(1), 201.56(d) and 201.57, and 21 CFR 201.57(c)(9)(i) through (iii)).
With regard to the Specific Recommendations for biosimilar products, the Guidance accommodates circumstances where the biosimilar product label differs from the reference product label (for example, depending on whether the biosimilar applicant is seeking approval for all or just a subset of indications for which the reference product has been approved). The Guidance reaches the crux of the matter with regard to product identification; an earlier version of the agency's thinking in this regard was disclosed previously. The agency recommends using the biosimilar product name "[i]n sections where the information described is specific to the biosimilar product" and "[f]or directive statements and recommendations for preventing, monitoring, managing, or mitigating risks." The reference product name should be used "[w]hen clinical studies or data derived from studies with the reference product are described in biosimilar product labeling," particularly with regard to clinical studies and adverse reactions. The "core" name (which is the nonproprietary name without the source-specific suffix) should be used when the property or risk applies to both the reference and biosimilar products (exemplified in the Guidance as "BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience)" which would reflect the commonality of these properties for both products. The FDA also apprehends situations where "[t]here may be text appropriately based on the reference product labeling where more than one of these product identification approaches should be used to accurately convey information." For instances where a biosimilar has sought (and been approved for) fewer than all the indications approved for the reference product, information relating to these indications should not be included unless it is necessary for safety or efficacy (whilst ensuring that it is clear that the biosimilar is not approved for such uses).
The Guidance then recites the recommendation for specific language regarding a biosimilar:
[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.
The INDICATIONS AND USAGE section of the label "should be specific to the approved indications for the biosimilar product and should be consistent with language previously approved for the reference product for those indications" including text from the reference product related to Limitations of Use. The FDA also recommends specific language related to immunogenicity:
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to [reference product's proper name] in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
Not surprisingly, the agency recommends that Patient Labeling follow the reference product except when differences are necessary to properly describe the biosimilar product.
The agency also recognizes that changes may arise during the life cycle of a biosimilar product and provides mechanisms for updating safety information, particularly when "new information" relating to use of the product under "more widely or  diverse conditions." Specifically, "[a]s with any biological product, a biosimilar product application holder must promptly review all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological studies/ postmarketing adverse event surveillance, reports in the scientific literature, and unpublished scientific papers; and the biosimilar product application holder," citing 21 CFR 600.80. And if any information is found to be inaccurate, prompt correction is mandated by the statute (see, 21 CFR 601.12). The Guidance also provides for post-approval licensure for additional indications for which the reference product has been approved.
How such labeling information should be submitted is set out as requiring:
• A clean version of reference product labeling that was used to develop the biosimilar product labeling
• A tracked changes and annotated version of proposed biosimilar product labeling explaining the differences from the reference product labeling
• A clean version of the proposed biosimilar product labeling
Finally, the Guidance indicates that, while "FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product" that Guidance will not be found here.
As noted above the FDA is soliciting comments; as the face of the Guidance states, "[c]omments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance," with electronic copies to be sent to http://www.regulations.gov and questions to Sandra Benton at 301-796-1042 or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.