title: Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products.
abstract: Most biological drug products elicit some level of anti-drug antibody (ADA) response. This antibody response can, in some cases, lead to potentially serious side effects and/or loss of efficacy. In humans, ADA often causes no detectable clinical effects, but in the instances of some therapeutic proteins these antibodies have been shown to cause a variety of clinical consequences ranging from relatively mild to serious adverse events. In nonclinical (preclinical) studies, ADA can affect drug exposure, complicating the interpretation of the toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) data. Therefore, the immunogenicity of therapeutic proteins is a concern for clinicians, manufacturers and regulatory agencies. In order to assess the immunogenic potential of biological drug molecules, and be able to correlate laboratory results with clinical events, it is important to develop reliable laboratory test methods that provide valid assessments of antibody responses in both nonclinical and clinical studies. For this, method validation is considered important, and is a necessary bioanalytical component of drug marketing authorization applications. Existing regulatory guidance documents dealing with the validation of methods address immunoassays in a limited manner, and in particular lack information on the validation of immunogenicity methods. Hence this article provides scientific recommendations for the validation of ADA immunoassays. Unique validation performance characteristics are addressed in addition to those provided in existing regulatory documents pertaining to bioanalyses. The authors recommend experimental and statistical approaches for the validation of immunoassay performance characteristics; these recommendations should be considered as examples of best practice and are intended to foster a more unified approach to antibody testing across the biopharmaceutical industry.
authors.affiliation: Clinical Pharmacology Sciences, Centocor Research & Development Inc., Radnor, PA 19087, USA.
authors.forename: Gopi
authors.initials: G
authors.lastname: Shankar
authors.forename: Viswanath
authors.initials: V
authors.lastname: Devanarayan
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Amaravadi
authors.forename: Yu Chen
authors.initials: YC
authors.lastname: Barrett
authors.forename: Ronald
authors.initials: R
authors.lastname: Bowsher
authors.forename: Deborah
authors.initials: D
authors.lastname: Finco-Kent
authors.forename: Michele
authors.initials: M
authors.lastname: Fiscella
authors.forename: Boris
authors.initials: B
authors.lastname: Gorovits
authors.forename: Susan
authors.initials: S
authors.lastname: Kirschner
authors.forename: Michael
authors.initials: M
authors.lastname: Moxness
authors.forename: Thomas
authors.initials: T
authors.lastname: Parish
authors.forename: Valerie
authors.initials: V
authors.lastname: Quarmby
authors.forename: Holly
authors.initials: H
authors.lastname: Smith
authors.forename: Wendell
authors.initials: W
authors.lastname: Smith
authors.forename: Linda A
authors.initials: LA
authors.lastname: Zuckerman
authors.forename: Eugen
authors.initials: E
authors.lastname: Koren
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis*; D001688:Biological Products / Q000276:immunology*; D001709:Biotechnology; D064420:Drug-Related Side Effects and Adverse Reactions; D006287:Health Planning Guidelines; D006801:Humans; D007118:Immunoassay / Q000592:standards*; D015203:Reproducibility of Results
chemical_list: D000906:Antibodies; D001688:Biological Products