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T-31: Characterizing the Clinical Impact of Immunogenicity in Prescription Drug Labeling

Poster Presenter

Daphne Guinn

Regulatory Health Project Manager
FDA
United States

Objectives

Adequate prescription drug labeling is critical to safe and effective use of biological and drug products. We assessed immunogenicity information in current FDA labeling, how that information conveys clinical impact, and where lack of evidentiary standards may have impacted risk communication.

Method

We performed a systematic evaluation of the current labeling of 71 CDER biological and drug products with immunogenicity concerns initially approved between 2014-2018 using a structured tool capable of capturing and characterizing immunogenicity-related labeling information. Co-Authors - Rajnikanth Madabushi, Issam Zineh, and Kimberly Maxfield (Madabushi R., Zineh I., and Maxfield, K.)

Results

Evaluating Consistency in Reporting: Labeling for most products provided anti-drug antibody incidence (96%), and neutralizing antibody incidence (66%) data. Most labels were consistent with the recommendations in the Labeling for Biosimilar Products Final Guidance to provide immunogenicity information (99%) and include a general immunogenicity (97%) statement in the Adverse Reactions section. Conveying Immunogenicity Clinical Impact: Of the reviewed labels, 56 (79%) provided some information about the clinical impact of immunogenicity on pharmacokinetics, safety, or efficacy. The remaining 15 labels (21%) did not communicate any immunogenicity clinical impact information. Of note, an immunogenicity-related post-marketing requirement or commitment (PMR/PMC) accompanied the approval of 28 of the 71 products reviewed (39%) to gain more clinical experience or increase the sensitivity of the assay to characterize immunogenicity risk. The types of clinical impact labeling information related to PK, safety, or efficacy, as well as how this information correlated with the need for a post-marketing assessment, was further characterized. An immunogenicity-mediated impact on PK, safety or efficacy was reported in 25 labels (35%). Of these 25 labels, 12 (48%) had a PMR/PMC associated marketing approval to optimize an assay, collect clinical data, or further assess clinical impact. For 23 products (32%), the labeling stated there was no known clinical impact of immunogenicity and further study through a PMR/PMC has been requested for 7 of those products. The labeling language stated that clinical impact was unknown for 8 products (11%), 3 of which had an immunogenicity-related PMR. The uncertainty was generally attributed to a lack of clinical experience or an inadequate immunogenicity assay. Lastly, for the 15 product labels that did not contain any clinical impact information, 6 had an immunogenicity PMR/PMC, 3 of which requested an assessment of clinical impact.

Conclusion

Incomplete or inconsistent communication of immunogenicity clinical impact information can contribute to the over- or underestimation of the risks associated with immunogenicity. In present labeling, there is a high level of consistency in reporting immunogenicity incidence and adhering to labeling recommendations associated with general immunogenicity reporting. The communication of clinical impact, however, and the evidence that is included in those labels to support the labeling statements is not always transparent. This may be due to limitations in the assays used to evaluate immunogenicity or the lack of clinical experience throughout the product lifecycle. Additionally, the evidentiary thresholds underlying the review and inclusion of immunogenicity data in labeling are not well established and lead to inconsistent reporting of limitations and immunogenicity risk, as well as inconsistent requirements for post-marketing assessments. Defining and consistently reporting immunogenicity clinical impact information with the appropriate limitation statements will allow for healthcare professional to better identify when there is a significant risk. Future work will focus on further defining current evidentiary thresholds that inform labeling of immunogenicity clinical impact and to provide recommendations on best practices for communicating the clinical impact of immunogenicity in the labeling at the time of product approval and throughout post-marketing. The views expressed in this article are those of the authors and do not necessarily reflect the official position of the FDA.