Scott Gottlieb, MD
U.S. Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
RE: Comment on Food and Drug Administration Draft Guidance “Considerations in Demonstrating Interchangeability with a Reference Product” [Docket ID FDA-2017-D-0154]
Dear Commissioner Gottlieb:
As members of the Biologics Prescribers Collaborative (BPC) and professional organizations with members who are biologics prescribers, we welcome the availability of biosimilars in the United States. Biosimilars will provide greater access to more therapeutic options for the millions of patients who rely on biologic medicines.
We thank the U.S. Food and Drug Administration (FDA) for its thoughtful draft guidance “Considerations in Demonstrating Interchangeability with a Reference Product.” When final, the guidance will provide important scientific information for manufacturers to consider when seeking licensure for proposed interchangeable products. Once available, it is critical that we, as prescribers, have all of the information we need to make informed decisions with our patients.
BPC believes data required to demonstrate biosimilarity should be robust and risk-based to build prescriber confidence in this new class of medicine. Such confidence is particularly important for interchangeable biosimilars as these products may be substituted for the reference product without intervention from the prescribing healthcare provider.
In determining its final guidance on interchangeability, BPC poses the following considerations to promote transparency and patient safety:
- Data required to demonstrate interchangeability should be more extensive than that required for determining biosimilarity. BPC supports FDA’s recommendations that data to support interchangeability should be set at a general standard. We would extend this by asking that the agency consider a baseline of what percentage of an identical response level should be seen as a bare minimum for each condition. Rather than relying on clinical endpoints, we agree that pharmacokinetics (PK) and pharmacodynamics (PD), when available, and drug trough levels, are more appropriate endpoints as these assessments are generally more likely to be sensitive to changes in immunogenicity and/or exposure that may arise due to alternating or switching. Additionally, there should be special considerations in the case of insulin interchangeability. Finally, the agency should mandate that complex biochemical measures (binding, etc.) be identical, especially with interchangeable biosimilar products, as these analyses are more technical and could give prescribers additional confidence.
- Clinical switching studies should be robustly designed and include a minimum of three switches between the reference product and proposed interchangeable product. BPC supports the approach to clinical switching studies presented in the draft guidance and believes it should be the standard and not be lowered. However, there are several methods for immunogenicity testing, each having different technical issues and implications. Therefore, FDA should consider standardizing this testing for manufacturers to use for all products submitted for interchangeability. Finally, BPC prescribers support the draft guidance’s requirement that clinical switching studies be performed only with a U.S. licensed reference product. It has been noted that differences in antigen binding and other technical aspects in E.U. biologics as compared to U.S. biologics. These differences could impact patients differently resulting in clinical studies that do not reflect the patient experience appropriately.
- FDA should be cautious in granting indication extrapolation. Diseases with different mechanisms of action (MOAs), immunogenicity differences among patients, and implications for misprescribing or inadvertent switching, if the biosimilar is not deemed interchangeable for all of the reference product’s indications, are all reasons for caution. BPC supports FDA’s requirement that sponsors: 1/ provide a scientific justification for extrapolating data to support a determination of interchangeability for each condition, and 2/ seek licensure for all of the reference product’s licensed conditions of use. BPC understands that the guidance is written to allow manufacturers flexibility for innovation. However, if interchangeability is only demonstrated for one indication and not the other(s), this will cause challenges for prescribers and pharmacists, potentially affecting patient safety as interchangeable biosimilars may be inadvertently substituted for a non-interchangeable indication.
- The label should include a statement of whether the biosimilar is interchangeable with the reference product and/or other biosimilars on the market and for which specific indications interchangeability was demonstrated.Health care providers may confuse a finding of biosimilarity with a finding of interchangeability. Explicit labeling and transparent communications are needed to ensure the appropriate use of biosimilars and interchangeable products in accordance with the statute. FDA should also consider what information should be included for dispensing pharmacies and pharmacists to support clear prescribing, such as specific patient diagnosis, as this information is not noted electronically on e-scripts.
- Sponsors seeking to develop presentations for proposed interchangeable products that differ from the presentation of the reference product should provide scientific data demonstrating interchangeability for all presentations for which they seek licensure. A variety of end users may administer these products, including physicians, patients, or caregivers. Differences in presentation could impact the ability of the end user to appropriately administer them. Additionally, since products deemed interchangeable may be substituted without the intervention of the prescribing provider, the presentation could also be substituted in the same manner, raising concerns for patient safety. As such, BPC believes that in addition to the threshold analysis outlined in the draft guidance for all proposed presentations, sponsors should be required to conduct comparative human factors studies to determine whether differences in design affect the use error rate between the reference product and the proposed interchangeable product. Also, to prevent confusion among physicians and pharmacists, and to prevent inappropriate substitution, sponsors should be required to seek interchangeability designation for all presentations of the biosimilar for which they are seeking licensure.
We commend FDA for its careful consideration in developing the draft guidance and information that should be considered to demonstrate interchangeability.
Alliance for Patient Access
American Association of Clinical Endocrinologists
American College of Rheumatology
American Gastroenterological Association
Biologics Prescribers Collaborative
Coalition of State Rheumatology Organizations
Dr. Janet Woodcock, Director, Center for Drug Evaluation and Research
Dr. Leah Christl, Associate Director, Therapeutic Biologics, Center for Drug Evaluation and Research
Dr. Steven Kozlowski, Director, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research
Sandra Benton, Senior Policy Coordinator, Office of Medical Policy, Center for Drug Evaluation and Research
Steven Ripley, Center for Biologics Evaluation and Research