Biosimilars: BIO Comments on Questions and Answers Regarding Implementation of BPCIA

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the Draft Guidance for Industry on Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (February 2012) (“Q&A Draft Guidance”).

BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations.  BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment. 

The implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) is of significant importance to BIO members, and we commend FDA’s efforts in developing the Q&A Draft Guidance to illustrate the Agency’s current thinking on certain aspects of the biosimilars approval pathway.  BIO has previously commented on biosimilars issues, and appreciates FDA’s consideration of our comments. We are pleased to provide the following comments on the Q&A Draft Guidance and provide recommendations on additional topics for consideration in future guidance.

Q.I.4. Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?

Manufacturing and quality aspects are critical components of a biosimilarity assessment that need to be assessed in relation to what knowledge lies in the public domain concerning the reference product, such as the formulation excipients, equipment, the raw materials used in the manufacturing process for the active ingredient, the container closure system and the cold chain distribution system.  A difference in any one of these can potentially have a significant impact upon safety or efficacy of the biosimilar product.  BIO urges FDA to exercise caution with respect to different delivery devices and closure systems and to require that biosimilar Sponsors affirmatively demonstrate that any design differences do not to result in a clinically meaningful difference between the biosimilar and reference product.  Further, if a biosimilar is deemed to be interchangeable, it is expected that the product would have an equivalent delivery device and container closure system to those of the reference product to ensure continuity in care and minimize the possibility of medication errors if a patient switches therapies.

Q.I.5. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?

Q.I.6. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?

Q.I.7. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?

Questions I.5, I.6, and I.7 address whether a biosimilar applicant can obtain licensure for a subset of what the reference product is licensedfor—in terms offewer than all routes of administration, fewer than all presentations, and fewer than all conditions of use.  FDA’s proposed responses to each of these questions describe the circumstances in which such approvals may be obtained, and describe the types of data that may be necessary to support such approvals.

FDA’s proposed answer to question I.5 states that an applicant may obtain licensure of a biosimilar for fewer than all routes of administration of an injectable reference product, provided that there are no clinical meaningful differences in safety, purity or potency.  The Q&A Draft Guidance further states that support for such a determination may include information from studies using a route of administration for which licensure is not requested.  FDA’s proposed answer to question I.6 states that a biosimilar applicant may seek approval for fewer presentations than the reference is licensed for, e.g., fewer strengths, delivery device(s), or container closure systems.  And FDA’s proposed answer to question I.7 states that a biosimilar applicant generally may obtain licensure for fewer than all conditions of use than the reference biological, provided that the 351(k) application includes information demonstrating that the proposed conditions of use have been previously approved for the reference product. 

BIO believes that, in addition to addressing the data and information that might support such applications, it is imperative that FDA address the product labeling implications of having biosimilars on the market with significant differences from the reference product.  For example, if FDA were to determine that a biosimilar could be licensed for fewer than all routes of administration than an injectable reference product is licensed for, it would be necessary to clearly and prominently identify such differences in the labeling for the biosimilar product to avoid confusion or misuse of the biosimilar. 

As stated in BIO’s 2010 Comments to FDA, the labeling for a biosimilar should flow from the fundamental premise that biosimilars are not expected or required to be structurally the same as the reference product.The biosimilar product labeling must clearly identify the differences from the reference product to avoid being misleading to healthcare providers and patients, and to minimize potential safety risks.  Clear, prominent labeling is necessary to inform healthcare providers and users of any important distinctions between the licensed uses or characteristics of the products.  Further, while off-label prescribing is a permissible practice of medicine, safety issues could arise if the off-label use has a different immunogenicity profile—one which has not been assessed in the biosimilar. 

Additionally, BIO believes that FDA guidance should address whether a product could be licensed as interchangeable with a reference biologic if the biosimilar is licensed for fewer routes of administration, presentations, or conditions of use than the reference product.  We believe an interchangeability determination in that case would present safety risks.  Among other concerns, users would likely presume a product to be interchangeable for all routes of administration, presentations, and conditions of use of the reference product.  Further, as stated in BIO’s 2010 Comments, given the strictness of the legal standard that applies to interchangeability, “the same clinical result…in any given patient,” clinical data must be provided for each labeled indication. Extrapolation of indications may be acceptable for determination of biosimilarity if the mechanism of action is very well understood and is the same for those indications.  However, to be deemed an interchangeable biosimilar, the same efficacy and safety should be shown in clinical trials in each of the indications included in the reference product labeling.  It may not always be necessary, however, to have a chronic switching study for each indication.

Finally, the Q&A Draft Guidance does not address the circumstance in which a reference biologic Sponsor obtains approval of a new indication after a biosimilar has been approved.  BIO requests that FDA guidance address this issue, including what nature and extent of supplements to a 351(k) will be allowed (i.e., post approval indications for which the reference product is licensed) and the contents of a supplement to a 351(k) application seeking approval of the new indication or other modification.