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A Survey of Applications of Biological Products for Drug Interference of Immunogenicity Assays

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Abstract

Purpose

Biological drugs in circulation can interfere with anti-drug antibody (ADA) assays and cause false ADA negatives. We surveyed the applications of biological products approved by FDA during 2005–2011 for prevalence of drug interferences and proposed approaches to address this issue scientifically.

Methods

The immunogenicity assay drug tolerance, steady-state drug concentrations, and immunogenicity rates were reviewed for 26 BLA/NDA and 2 sBLA.

Results

Many FDA approved biologics had higher steady-state drug concentrations than the drug tolerance of ADA assays, by 1.2- to 800-fold. Reported immunogenicity rates may be negatively impacted. Some sponsors triaged immunogenicity samples according to the drug tolerance, leaving some samples un-assayed or reporting them as inconclusive ADA; but these samples were interpreted as ADA− for calculating immunogenicity rates.

Conclusions

Implementation of ADA assays that can tolerate therapeutic drug concentrations is imperative. Given drug interferences, we propose in this paper the following practices: (i) to measure drug concentrations in ADA samples, (ii) to explicitly list all ADA status, including inconclusive ADA and un-assayed samples, (iii) to calculate population immunogenicity rates based on only subjects with confirmed ADA+ and ADA−, and (iv) to make available ADA assay specifics relevant to the use of ADA data in disease management.

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Abbreviations

ADA:

anti-drug antibody

BLA:

Biologics License Application

EMA:

European Medicine Agency

FDA:

Food and Drug Administration

NDA:

New Drug Application

TNFα:

tumor necrosis factor α

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Acknowledgments and Disclosures

The authors wish to thank Dr. E. Dennis Bashaw for the critical review of this manuscript and valuable comments.

The authors are employees of the FDA and did not receive external funding for this research project.

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Authors and Affiliations

  1. Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Yow-Ming C. Wang, Lanyan Fang, Lin Zhou, Jie Wang & Hae-Young Ahn

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  1. Yow-Ming C. Wang
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  2. Lanyan Fang
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Correspondence to Yow-Ming C. Wang.

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Wang, YM.C., Fang, L., Zhou, L. et al. A Survey of Applications of Biological Products for Drug Interference of Immunogenicity Assays. Pharm Res 29, 3384–3392 (2012). https://doi.org/10.1007/s11095-012-0833-2

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  • DOI: https://doi.org/10.1007/s11095-012-0833-2

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