On 21st January 2025, the U.S. Food and Drug Administration's (FDA) Center for Drug Evaluation and Research issued final guidance "Bioanalytical Method Validation for Biomarkers" focusing on the importance of robust bioanalytical methods for evaluating biomarkers in drug development.
This guidance helps sponsors of investigational new drug applications (INDs) and applicants of new drug applications (NDAs), biologics license applications (BLAs), and NDA and BLA supplements as well as abbreviated new drug applications (ANDAs), as applicable, to validate bioanalytical methods used to evaluate biomarker concentrations. This guidance also informs about developing bioanalytical methods for analyzing biomarker concentrations in nonclinical study samples.
A biomarker is defined as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.
Biomarkers play a pivotal role in:
Assessing pharmacodynamics and therapeutic responses.
Establishing safety profiles in early- and late-stage trials.
Supporting regulatory approval through reliable efficacy endpoints.
The guidance aims to provide clarity on how to validate bioanalytical methods used to measure biomarkers in biological matrices like blood and urine. These methods are critical for assessing safety, efficacy, and pharmacodynamics during nonclinical and clinical studies. Unlike drug assays, biomarker assays often require a fit-for-purpose validation approach tailored to their intended use in regulatory decision-making or internal pharmaceutical development.
Validation Approach
The extent of validation depends on the biomarker’s intended use:
Regulatory Decision-Making: Full validation is required, including accuracy, precision, sensitivity, selectivity, and reproducibility, aligned with M10 principles.
Internal Decision-Making: Partial validation may suffice for internal research purposes like candidate selection or proof-of-concept studies.
Key Validation Questions
Validation addresses:
Specificity and Selectivity: Does the assay specifically measure the biomarker without interference?
Accuracy and Precision: What is the variability in the measurements, and how reliable are the results?
Sensitivity and Range: What is the lower and upper limit of quantitation (LLOQ and ULOQ)?
Stability and Sample Handling: How do storage, collection, and transport conditions affect data reliability?
Key validation characteristics include:
Parallelism: Ensuring consistent results across concentrations.
Reproducibility: Establishing consistent results over repeated trials.
Stability: Confirming biomarker stability during handling and storage.
By addressing variability, sensitivity, and specificity, these methods support critical safety and efficacy evaluations, ultimately fostering better regulatory decisions and patient outcomes. For more details, refer to the official document on the FDA website.
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