Commentary Solicited on Immunogenicity Draft Guidance

Commentary Solicited on Immunogenicity FDA Draft Guidance

FDA announced the availability of a draft guidance for industry entitled “Immunogenicity Assessment for Therapeutic Protein Products.” Assessing the risk of immunogenicity is a standard component of the clinical development of a protein therapeutic, including those products that are now being considered as biosimilars. The clinical risks from immunogenicity are real: the notorious demonstration many years ago of pure red cell aplasia induced by cross-reactivity to endogenous hormone in patients treated with erythropoietin, and the common loss of responsiveness to coagulation factor replacement therapy in hemophilics. However, the most common scenario associated with administration of protein therapeutics is that of non-neutralizing antibody production, a finding which presumably confers no clinical risk.

The draft guidance describes a risk-based approach in both the preclinical and clinical phases of product development of therapeutic protein products to evaluate immunogenicity risks, and the present announcement solicits stakeholder commentary. The guidance is clear that the requirements for risk assessment data and risk mitigation strategies may need to be individualized based on the biochemical nature of the products being developed, the extent of similar known risks for related marketed products, and the availability of biomarkers or other assays that may help quantify the risks. Although the recommendations provided in this draft guidance are acknowledged to be nonbinding, sponsors would be wise to carefully consider the various topics covered by the guidance when presenting product development programs to the Agency. Some of the topics mentioned in the guidance are quite exploratory and are probably premature in nature (e.g., HLA mapping studies to identify patients subsets at particular risk), but other topics including recommendations for postmarket surveillance will almost certainly find their way into many products’ approval letters. While we agree that FDA’s concern regarding immunogenicity assessments is an important step for product safety, sponsors should realize that addressing these risks may involve considerable expense, e.g., development of discriminatory assays, greater powering of clinical trials than that strictly necessary for demonstration of efficacy and general safety, and proactive postmarket safety programs.

Posted by Bob Roth, Vice President and Worldwide Medical Director. For more information, please contact Bob at