(T1030-10-65) A Review of Immunogenicity and Its Effect on Efficacy and Safety of Biologics as Reported on the Prescribing Label to Support Strategic Assessment and Planning Labeling Communications

Purpose: Food and Drug Administration (FDA) published a draft guidance (2022) incorporating immunogenicity information into a new section, 12.6. This section under the Clinical Pharmacology section of the drug product labeling summarizes immunogenicity (anti-drug antibody (ADA)) incidence and its effect on safety, pharmacokinetics (PK) and pharmacodynamics (PD). We investigated currently available labeling information for biologics to summarize ADA impact on drug efficacy and safety and thus improve strategic assessment of the immunogenicity of biologic drugs during drug development and in labeling communications.

Methods: Extensive labeling and literature searches were conducted to collect immunogenicity information on biologics approved before June 2023 through FDALabel, Drugs@FDA, and PubMed databases. A database was built by searching FDALabel content using keywords including “Biologics License Application (BLA)” and “New Drug Application (NDA)” for “human prescription drug”, and the term “immunogenicity” for drug labeling full-text search. Subsequently, the database was delineated by excluding repetitive results, biosimilar drugs, and non-ADA-related results via Drugs@FDA validation. Multiple indications with multiple formulations for each active pharmaceutical ingredient (API) were included in this database. Last but not least, the immunogenicity profile for each product was summarized and categorized based on the following results using BLA or NDA: ADA incidence and ADA effect on drug safety and efficacy.

Results: There was a total of 388 results returned by FDALabel search. By investigating product labels available on Drug@FDA website as of June 2023, the results were delineated down to 267 products including 230 BLA and 37 NDA products. Covariates such as age, gender, indications, duration, and route of administration were found to be related to the development of ADAs. Incidence cut-off of 10% was found as a statistical representation of relatively low ADA incidence due to most approved products (50.4% BLAs and 59.5% NDAs) falling into the category of ADA≤10%. Higher ADA incidence was found to correlate with a greater risk of developing safety and efficacy concerns in BLA products generally. Out of 267 approved BLAs and NDAs, 28.5% (68 BLAs and 8 NDAs) reported ADA impact either on drug efficacy and/or safety. Safety concerns were associated with injection-site reactions (5 products), infusion reactions (6 products), hypersensitivity (17 products), cross-reactivity to endogenous proteins (8 products) or in more severe cases, anaphylaxis (11 products). Altered exposure concerns such as decreased clearance (5 products) or increased clearance (54 products) and the subsequent effect on treatment effect also rise with ADA incidence, with a resulting recommendation of alternative treatments or efficacy monitoring along the drug treatment.

Conclusion: With more refined requirements for reporting immunogenicity effects on biologic/peptide drug efficacy and safety, the potential impact of the ADA incidence on approvability and label can be better understood. This analysis may support ADA-based risk assessment and mitigation for biologics and peptide molecules with high ADA incidence.

Figure 1. Maximum ADA incidence reported for (A) NDAs (N=37) and (B) BLAs (N=230). NR: ADA incidence not reported in the label.

Figure 2. Correlation of ADA incidence rate with percentage of BLAs with safety (A) or efficacy (B) concerns in each category.