Description
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Immunogenicity Testing of Therapeutic Protein Products—Developing and Validating Assays for Anti-Drug Antibody Detection.” This guidance provides recommendations to facilitate industry's development and validation of assays for assessment of the immunogenicity of therapeutic protein products during clinical trials. The guidance applies to assays for the detection of anti-drug antibodies (ADAs) and may also apply to some peptides, oligonucleotides, and combination products on a case-by-case basis. The guidance includes recommendations regarding the development and validation of screening assays, confirmatory assays, titration assays, and neutralization assays. This guidance finalizes the revised draft guidance for industry entitled “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products” issued in April 2016 and includes a revised title.
Scope & Applicability
Product Classes
8Focus of the guidance for determining when a CES may inform biosimilarity
especially important for mAb products because these products can have half-lives of several weeks
Specific type of therapeutic protein discussed for DDIs; Focus of biologics DDI evaluation.; ADCs consist of a small molecule drug component conjugated to an antibody.
Biological product shown to be highly similar to an FDA-licensed reference product; Biological product demonstrated to be highly similar to a reference product
Guidance on immunogenicity assessment and testing
Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
Licensed IVDs subject to stability requirements
Multi-domain products requiring multiple assays for different domains.
Stakeholders
2Samples from these individuals are used to statistically determine cut-points; Samples from treatment-naïve subjects that are collected, handled, and stored under study conditions.; samples from treatment-naïve subjects used for cut-point
Entity responsible for submitting applications under section 524B
Regulatory Context
Attributes
9Analysis by sex of clinical performance measures such as sensitivity
Measurement of antibody level based on risk
Property used to determine maintenance dose intervals and safety monitoring
Intra-assay and inter-assay precision as expressed by percent coefficient of variation (%CV) is expected to be lower than 20%.
A rate of approximately 5% is desirable for the initial screening assay.; One approach that allows for high assurance of a 5% false-positive rate.
Factor used to minimize matrix interference, recommended not to exceed 1:100
Ability to detect intended mechanism of action without interference; Performance characteristic to be validated
Ability to differentiate analyte in presence of matrix components
A key operating parameter of the assay affecting ADA incidence.; Performance characteristic to be established between laboratories
Identified Hazards
Hazards
3Signal suppression or non-specific signal caused by endogenous components
If the assay is subject to a prozone effect, the concentration of high-positive QC samples should be set
Reduction in signal caused by high concentration of analyte leading to false-negatives
Related CFR Sections (2)
- 21CFR809.3§ 809.3 Definitions.
(a) In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use Read full regulation →
- 21CFR201.57§ 201.57 Specific requirements on content and format of labeling for human prescription drug and biological products described in § 201.56(b)(1) .
The requirements in this section apply only to prescription drug products described in § 201.56(b)(1) and must be implemented according to the schedule specified in § 201.56(c) , except for the requirement in paragraph (c)(18) of this section to reprint any FDA-approved patient labeling at the end oRead full regulation →
See Also (8)
- Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable : Guidance for Sponsors, Institutional Review Boards, and Food and Drug Administration Staff (Status: Final)
- In Vitro Diagnostic (IVD) Device Studies - Frequently Asked Questions: Guidance for Industry and FDA Staff (Status: Final)
- Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Guidance for Industry and FDA Staff (Status: Final)
- Radiation Biodosimetry Medical Countermeasure Devices: Guidance for Industry and Food and Drug Administration Staff (Status: Final)
- Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product: Draft Guidance for Industry and Food and Drug Administration Staff (Status: Draft)
- Investigational IVDs Used in Clinical Investigations of Therapeutic Products: Draft Guidance for Industry, Food and Drug Administration Staff, Sponsors, and Institutional Review Boards (Status: Draft)
- Electromagnetic Compatibility (EMC) of Medical Devices: Guidance for Industry and Food and Drug Administration Staff (Status: Final)
- Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format (Status: Final)