Investigation of Factors Associated With Immunogenicity Labeling Updates and Characteristics of Biologics License Applications

Abstract

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Immunogenicity is a critical concern in developing biological products, yet the immunogenic response in animals does not necessarily reflect that in humans. WHAT QUESTION DID THIS STUDY ADDRESS? The present study aimed to investigate the evolution of immunogenicity information in the labeling of Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER), US Food and Drug Administration between 2008 and 2017 based on the CDER Drug and Biologic Calendar Year Approvals lists. The investigation was focused on the identification of attributes associated with immunogenicity labeling updates.

Investigation of Immunogenicity Assessment of Biosimilar Monoclonal Antibodies in the United States

“…1,13,25 These findings highlighted the unpredictability and complexity of immunogenicity evaluation. 24,26 The remaining uncertainty of immunogenicity concerns in the reference biologics makes the development of biosimilars more challenging. 12,27,28 Therefore, both the European Medicines Agency (EMA) and the FDA have published guidelines for biosimilars providing recommendations for immunogenicity assessment.…”

“…Uncertainties remained in the labeling documents of reference biologics awaiting PMRs for more evidence. 26 In terms of PK and efficacy, most of the original labeling documents of reference products did not mention the impact of ADAs. 26,46,47 The uncertainties made the interpretation of the findings of biosimilars more challenging.…”

“…26 In terms of PK and efficacy, most of the original labeling documents of reference products did not mention the impact of ADAs. 26,46,47 The uncertainties made the interpretation of the findings of biosimilars more challenging. Often, it was less likely to reach statistically significant differences for ADA/NAb impact in the trials conducted for biosimilar applications due to small sample sizes.…”

“…However, the information provided in the labeling of reference products about the impact of ADA and NAb might not be comprehensive enough, leading to uncertainties about their implications and long-term effects. 1,26,42 Our research, based on the analysis of approved biosimilar applications, has shed light on the importance of revisiting immunogenicity assessment and the challenges of obtaining sufficient evidence before approval. Regulatory considerations for immunogenicity studies prioritize assessing the impact on clinical consequences over differences in ADA incidence.…”

“…However, studies implied that there was a lack of sufficient critical information, such as the clinical significance of being ADA‐ or NAb‐positive, or the long‐term immunogenicity, in many reference biologics labeling documents and an over‐reliance on further post‐marketing evidence 1,13,25 . These findings highlighted the unpredictability and complexity of immunogenicity evaluation 24,26 …”