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Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance for Industry on Immunogenicity Assessment for Therapeutic Protein Products.” BIO commends FDA on the release of this Draft Guidance, which will help Sponsors to identify and mitigate risks of adverse immunological reactions during the development and marketing of therapeutic protein products.
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.
In general, the Draft Guidance is very well written and provides a useful review of the numerous factors that can affect immunogenicity. BIO generally agrees with the risk-based approach presented in the Draft Guidance but recommends that FDA set a minimum level of required immunogenicity testing for all therapeutic protein products to provide clarity for potential Sponsors and to ensure safety and efficacy for patients.
A. Improving Organization and Flow by Aligning with International Guidelines for Risk Management
BIO encourages FDA to reorganize the Draft Guidance in alignment with the established format of international guidelines for risk management, including International Organization for Standardization (ISO) 31000 – Risk Management Guidelines and Principles and International Conference on Harmonization (ICH) Q9 – Quality Risk Management. This general format can be summarized as  :
This could be achieved simply by moving Section V. Patient- and Product-Specific Factors That Affect Immunogenicity ahead of Section III. Clinical Consequences, to be followed by Section IV . Recommendations for Immunogenicity Risk Mitigation in the Clinical Phase of Development of Therapeutic Protein Products.
B. Improving Utility by Providing Further Recommendations and Examples from Literature
BIO encourages FDA to add greater detail to the recommendations sections to provide Sponsors with meaningful advice on how to identify and address the risk factors for potential immunological reactions, which would greatly improve the utility of the Draft Guidance. For example, the Draft Guidance briefly mentions in Section V.A.2 the potential impact of prior exposure to a therapeutic protein, but the accompanying recommendation in this section does not provide any suggestions as to how Sponsors should assess this factor in their development programs.
Additionally, BIO believes that further citation of updated examples from the relevant literature would support the requested expansion of the recommendations sections and provide important clarity to potential Sponsors.
C. Addressing Variations Between Specific Classes of Therapeutic Protein Products
BIO requests that FDA provide additional details for the recommendations made within the Draft Guidance to address the specific issues associated with certain therapeutic protein product classes, where appropriate. While well-understood therapeutic product classes may likely present little challenge when conducting immunogenicity assessment, the less familiar or more structurally complex therapeutic protein product classes (such as fusion proteins or monoclonal antibodies, respectively) may require more complex analytical assay methodologies to detect all chemical modifications. Additionally, these novel or more structurally complex product classes may require a more sophisticated clinical monitoring program, in part due to the required prerequisite of maintaining high levels of manufacturing purity and avoidance of chemical degradation.
D. Clarifying Applicability of the Draft Guidance to Biosimilar Development
While BIO recognizes that the topics discussed in the Draft Guidance apply generally to the development of biological products, BIO encourages FDA to address the specific concerns related to immunogenicity assessment for biosimilar biological products in a separate Guidance document that bridges the principles presented in this Draft Guidance with the Draft Guidance on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product .  Immunogenicity is a critical issue for biosimilar development and marketing because of the potential for differences between the reference product and the biosimilar. Additionally, since biosimilars are expected to have a less robust package of preclinical and clinical testing data, the opportunity to understand the impact of various product characteristics on immunogenicity before marketing will be limited. Therefore, BIO believes the following principles should be considered carefully by FDA regarding immunogenicity testing that will be recommended and/or required for biosimilar biological products:
First , the immunogenicity of therapeutic protein products is unpredictable. As this draft guidance notes, many factors, including a protein’s degradation, misfolding, microheterogeneity, and microaggregation, can influence the molecule’s immunogenicity.
Second , product differences that are difficult or impossible to detect can lead to differences in immunogenicity. State-of-the-art analytical testing may be capable of showing that two complex protein products are very highly similar in structure, but such testing cannot show that those products will have the same immunogenic responses in humans.
Third , similar rates of immunogenicity with an innovator biologic and a potential biosimilar do not necessarily equate to similar immunogenicity profiles. Two similar complex protein products may be immunogenic in different patients and/or elicit antibodies to different epitopes, with different titers or kinetics (time to onset and transient/persistent).
Fourth , differences in immunogenicity can result in differences in safety and efficacy in ways that cannot be predicted without clinical testing.
Fifth, pre-market clinical testing is inadequate to exclude clinically important differences in immunogenicity. Post-market surveillance measures will be necessary.
Sixth, the human immune system is highly sensitive to some types of differences between products (but not others), so differential immunogenicity may be a clue to clinically meaningful product differences not detected by other testing. Therefore, serological cross-reactivity must be taken into consideration, especially for biosimilar biological products seeking an interchangeable designation.
BIO has presented detailed concerns related to immunogenicity of biosimilar products in previous public comments to FDA ,,, and looks forward to the opportunity to continue to work with the Agency to address these concerns in the future.
E. Employing Standardized Nomenclature to Replace the Generic Term “Aggregate”
BIO believes that the use of the term “aggregate” throughout the Draft Guidance to refer exclusively to oligomers in the nanometer size range is confusing and that FDA should move to a standard, less ambiguous terminology. For specific species, BIO believes that the size being discussed should be used (in this case nanometer-sized aggregates), or alternatively, the nanometer-sized aggregates could simply be referred to as “oligomers.” Scientists from industry, academia, and regulatory authorities have extensively reviewed this proposed standardized terminology, which was developedat the meeting of the American Association of Pharmaceutical Scientists (AAPS), co-sponsored by FDA, on Protein Aggregation and Immunogenicity in Breckinridge, Colorado in July 2010. 
BIO appreciates this opportunity to comment on the “Draft Guidance for Industry on Immunogenicity Assessment for Therapeutic Protein Products.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.
International Organization for Standardization (2009) ISO 31000:2009 Risk Management – Principles and Guidelines
Narhi LO, et al. (2012) Classification of Protein Aggregates. Journal of Pharmaceutical Sciences, 101(2): 493-498.