FDA Guidance on Foreign Reference Products and Indication Extrapolation

In April 2015, the FDA released three updated non-binding guidances regarding the process for biosimilar approval under section 351(k) of the Public Health Service Act (“PHS Act”) as amended by the Biologics Price Competition and Innovation Act of 2009. These publications, Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (“Biosimilars Q&A”); Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (“Scientific Considerations”); and Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (“Quality Considerations”), provide important information for developers of biosimilars as they prepare their application for FDA approval. Among the critical topics discussed in these guidances are: (1) the use of data from foreign comparator products to demonstrate biosimilarity with a U.S. reference product; and (2) the extrapolation of data regarding one therapeutic indication to another. These topics are the subject of today’s post.

Use of Data Generated with Foreign Reference Products

The PHS Act defines “biosimilar” as a biological product that is “highly similar to the reference product notwithstanding minor differences in clinically inactive components.” PHS Act at 351(i)(2) (emphasis added); see also Biosimilars Q&A at 3. There must be no clinically meaningful differences in terms of “safety, purity, and potency” between proposed and reference products. Id. Further, a biological product may also be “interchangeable” with the reference product, in which case they can be substituted for the reference product without the intervention of a prescribing healthcare provider. See Biosimilars Q&A at 3 (citing PHS Act at 351(i)(3)).

To demonstrate biosimilarity, a sponsor must compare the proposed product to a reference product that has previously been licensed by the FDA. See Scientific Considerations at 6. The comparison should include analytical studies, at least one pharmacokinetic (“PK”) study, and potentially at least one pharmacodynamics (“PD”) study. Id. The sponsor may, however, rely on data from animal or clinical studies comparing a proposed product with a foreign comparator product to address the requirements of 351(k)(2)(A). Id.; Quality Considerations at 9–10. In order to use the foreign comparator product, the sponsor must provide scientific justification and demonstrate a connection between the foreign comparator product and the U.S.-licensed reference product. Id.

The Biosimilars Q&A publication lists several issues that a sponsor may need to address to “bridge” the data for a foreign comparator product with the U.S.-licensed reference product, including:

  • The relevance of the design of the clinical program to support a demonstration of biosimilarity to the U.S.-licensed reference product for the condition(s) of use and patient population(s) for which licensure is sought;
  • The relationship between the license holder for the non-U.S.-licensed comparator product and BLA holder for the U.S.-licensed reference product;
  • Whether the non-U.S.-licensed comparator product was manufactured in a facility(ies) licensed and inspected by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., International Conference on Harmonisation (ICH) countries);
  • Whether the non-U.S.-licensed comparator product was licensed by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., ICH countries) and the duration and extent to which the product has been marketed; and
  • The scientific “bridge” between the non-U.S.-licensed comparator product and the U.S.-licensed reference product, including comparative physicochemical characterization, biological assays/functional assays, degradation profiles under stressed conditions, and comparative clinical PK and, when appropriate, PD data, to address the impact of any differences in formulation or primary packaging on product performance.

Biosimilars Q&A at 8–9. Further, the sponsor would also need to address “any other factors” that would affect the comparison. Id. at 9.

In making its determination regarding whether the bridging data is sufficient, the FDA will consider a number of factors including:

  • the complexity of the product;
  • the degree of heterogeneity associated with the product;
  • whether the formulations, dosage forms, and strengths of the U.S. reference product and the foreign comparator product are the same;
  • the routes of administration of the U.S. reference product and the foreign comparator product;
  • the design of the testing and assessments sensitive enough to detect differences between the products; and
  • the selection of lots of the comparator product so that product variability is captured.

Id. at 9–10.

The Biosimilars Q&A also notes that, “[a]t this time, as a scientific matter, it is unlikely that clinical comparisons with a non-U.S.-licensed product would be an adequate basis to support the additional criteria required for a determination of interchangeability with the U.S.-licensed reference product.” Id. at 10. Thus, the FDA appears to be contemplating that biosimilarity may be demonstrable with a foreign comparator product, but not interchangability.

The use of data generated with a foreign reference product is an important consideration for companies who are developing products for more than one jurisdiction. The FDA guidance on this issue makes clear that providing a scientific justification for the reliance on data generated using a foreign reference product comparator will be critical in evaluating the propriety of that data for obtaining approval for a biosimilar to a U.S. reference product. FDA has encouraged biosimilar applicants to discuss with FDA during the development program the adequacy of the scientific justification and bridge to the U.S.-licensed reference product, but noted that a final decision about the adequacy of the scientific justification will be made by FDA during review of the 351(k) application.

Indication Extrapolation

The FDA’s recent guidances also makes clear that the agency will permit an applicant to extrapolate clinical data intended to support biosimilarity in one condition of use, to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed. Therefore, if a proposed product meets 351(k)’s licensure requirements in one appropriate condition of use, the applicant may seek licensure for additional conditions of use for which the reference product is licensed. See Biosimilars Q&A at 10; Scientific Considerations at 21. In order to extrapolate to other indications, the sponsor will need to provide a scientific justification sufficient to support a determination of biosimilarity for each indication. Id.

FDA’s guidance states that the justification for extrapolation should address issues including:

  • The mechanism(s) of action in each condition of use for which licensure is sought, which may include:
    • the target/receptor(s) for each relevant activity/function of the product;
    • the binding, dose/concentration response and pattern of molecular signaling upon engagement of target/receptor(s);
    • the relationships between product structure and target/receptor interactions;
    • the location and expression of the target/receptor(s);
  • The PK and bio-distribution of the product in different patient populations (relevant PD measures also may provide important information on the mechanism of action);
  • The immunogenicity of the product in different patient populations;
  • Differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to “off-target” activities); and
  • Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought.

Biosimilars Q&A at 11; Scientific Considerations at 21. FDA has stated that differences between conditions of use will not necessarily preclude extrapolation provided that the totality of the evidence supports biosimilarity. Id. When a reference product has only been approved for a condition of use on an accelerated basis, and post-marketing trials are required for verification, an applicant should consider studying a different indication for which the reference product is licensed. That strategy will minimize the risk of complications in the event the post-marketing trials fail to verify the clinical benefit of the reference product for a particular indication.

FDA’s recent guidances provide important considerations on the design of studies and the generation of data for demonstrating biosimilarity with a U.S. reference product. Applicants should consider these criteria in preparing their development plan and strategy for obtaining FDA approval.