On May 13, the FDA published a revised draft guidance entitled “Biosimilars:  Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.”

The draft guidance complements the FDA’s final guidance on biosimilars released on April 28, 2015, “Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCI),” adding new questions and proposed answers as well as revised answers to questions that had been included in the 2012 draft guidance but omitted in the final guidance. A brief summary of the changes included in the newest draft guidance is provided below.

1)  Biosimilarity and interchangeability

  • Revised Q&As from the 2012 Draft Guidance Part I
    • Q&A 1.9: Is a clinical study to assess the potential of the biological product to delay cardiac repolarization (a QT/QTc study) or a drug-drug interaction study generally needed for licensure of a proposed biosimilar product?
      • Previously, the FDA stated “No.” The revised answer, however, provides that in certain circumstances, the FDA  may impose “postmarket requirements [studies] on the biosimilar applicant.”
    • Q&A 1.10: How long and in what manner should sponsors retain reserve samples of the biological products used in comparative clinical PK and/or PD studies intended to support a 351(k) application?
      • The revised answer clarifies that the sponsor of a proposed biosimilar product should retain reserve samples for at least 5 years. In addition, the FDA provides the recommended quantities and dosage units of samples.
    • New Q&As
      • Q&A 1.16:  How can a proposed biosimilar product applicant fulfill the requirement for pediatric assessments under the Pediatric Research Equity Act (PREA)?
        • The FDA first addresses the differences in the use of the term “extrapolation” in the context of a proposed biosimilar product under the BPCI Act and in the context of PREA. “Under PREA, extrapolation of efficacy (but not safety or dosing) from adult populations to pediatric populations [as well as from one pediatric age group to another pediatric age group] in a single drug or biological product or drug or biological product line may be permitted if the adult and pediatric [or the two pediatric groups] indications are the same indication and the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric [or the two pediatric groups] patients.” The FDA also addresses the effect of adequate and inadequate pediatric information in reference product labeling.
      • Q&A 1.17:  When should a proposed biosimilar product applicant submit an initial pediatric study plan (PSP)?
        • The FDA provides that the deadline is no later than 60 calendar days after the date of an end-of-Phase 2 321 (EOP2) meeting, or at another time agreed upon by the FDA and the applicant. The FDA addresses circumstances in which the FDA and applicant have not yet reached an agreement on the initial PSP, including a review of what an initial PSP must include.
      • Q&A 1.18: For biological products intended to be injected, how can an applicant demonstrate that its proposed biosimilar product has the same “dosage form” as the reference product?
        • For the purposes of the PHS Act only, the “FDA considers the dosage form to be the physical manifestation containing the active and inactive ingredients that delivers a dose of the drug product.” For example, FDA considers an “injection” (i.e. of a solution) to be a different form from “for injection” (i.e. a type of powder) and the same with regard to emulsions and suspensions of products intended to be injected. If the dosage form is different, the applicant will not be able to obtain licensure for the biosimilar product.
      • Q&A 1.19:  If a non-U.S.-licensed product is proposed for importation and use in the U.S. in a clinical investigation intended to support a proposed biosimilar development program (e.g., a bridging clinical PK and/or PD study), is a separate [Investigational New Drug] IND required for the non-U.S.-licensed product?
        • The FDA provided that a “sponsor may submit a single IND for its proposed biosimilar development program, and may submit information supporting the proposed clinical investigation with the non-U.S.-licensed comparator product under the same IND. ” Further, “If a sponsor intends to conduct a  clinical investigation in the United States using a non-U.S.-licensed comparator product, the IND requirements in 21 CFR part 312 also would apply to this product (see, e.g., 21 CFR 312.2).”

2)  Provisions related to requirement to submit a BLA for a “biological product”

  • New Q&A
    • Q&A II.3:  What type of marketing application should be submitted for a proposed antibody-drug conjugate?
      • The FDA provided that a BLA under section 351 of the PHS is the most proper application for a proposed monoclonal antibody that is linked to a drug (antibody-drug conjugate).

3)  Exclusivity