Assay Development and Validation Requirements for Lamotrigine and Zonisamide Testing in Clinical Laboratories
This guidance addresses lamotrigine and zonisamide assays that: - Employ immunoassay technologies - Are for use in central clinical laboratories - Are for use with serum or plasma samples - Are regulated under 21 CFR 862.3350 as Class II devices
Recommended Actions
- Design comprehensive validation protocol covering all performance characteristics
- Conduct precision studies over 20 days with multiple concentrations
- Perform recovery/bias studies using reference materials
- Evaluate linearity across entire measuring range
- Validate lower limits of quantitation
- Complete interference testing for endogenous and exogenous substances
- Test cross-reactivity with key metabolites
- Conduct method comparison with minimum 100 patient samples
- Validate stability of calibrators and controls
- Prepare detailed labeling addressing all required elements
- Document traceability of calibrators to reference materials
- Consider need for external site studies based on assay complexity
Key Considerations
Clinical testing
- Method comparison study with minimum 100 patient samples across measuring range
- Samples should be from intended use population with unaltered patient samples
- Multiple specimens from individual patients should be appropriately analyzed statistically
Non-clinical testing
- Precision evaluation over 20 day period for 3+ drug concentrations spanning reportable range
- Recovery/bias studies using reference materials spiked into drug-free clinical samples
- Linearity evaluation across entire reportable range with 7-9 concentration levels
- Lower limits evaluation including precision and bias relative to reference materials
Software
- Follow FDA guidance for software contained in medical devices if device includes software
Labelling
- Must satisfy requirements in 21 CFR 809.10
- Include specimen collection/storage instructions
- Detail quality control and calibration procedures
- List warnings and precautions
- State limitations of procedure
- Provide reference ranges with appropriate context
- Summarize performance characteristics
Safety
- Test blood products for communicable disease agents per 21 CFR 610.40
- Include appropriate warnings for hazardous materials
Other considerations
- Evaluate endogenous and exogenous interference following CLSI EP7-A2
- Test cross-reactivity with drug metabolites
- Validate matrix comparison for all recommended matrices
- Demonstrate calibrator and control materials stability
- Consider external site studies for complex assays
Relevant Guidances
- Content of Premarket Submissions for Device Software Functions
- Recommended Format and Content for Non-Clinical Bench Performance Testing in Medical Device Premarket Submissions
- Content and Decision-Making Process for 510k Submissions: Determining Substantial Equivalence
- Refuse to Accept Policy for 510k Submissions: Minimum Threshold Requirements for Administrative and Technical Review
- The Abbreviated 510k Program: Using Guidance Documents, Special Controls, and Standards for Substantial Equivalence Demonstration
Related references and norms
- CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods
- CLSI EP7-A2: Interference Testing in Clinical Chemistry
- CLSI EP9-A2: Method Comparison and Bias Estimation Using Patient Samples
- CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures
- ISO 17511: Metrological Traceability of Values Assigned to Calibrator and Control Materials
Original guidance
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