Pharmacogenetic Tests: Premarket Submission Requirements and Performance Validation
This guidance aims to facilitate progress in pharmacogenomics and genetics by providing recommendations for preparing and reviewing premarket submissions (PMA and 510(k)) for pharmacogenetic and genetic tests, including single markers and multiplex tests. It focuses on nucleic acid-based analysis for heritable markers but excludes gene expression and somatic mutation testing.
Recommended Actions
- Consult with OIVD early to determine appropriate submission type and study design
- Develop comprehensive validation protocols covering analytical and clinical performance
- Establish robust quality control measures and validation procedures
- Document detailed device design and methodology
- Perform thorough precision/reproducibility studies at multiple sites
- Compare device performance to bidirectional sequencing
- Validate software according to FDA guidance
- Prepare comprehensive labeling addressing all required elements
- Consider population demographics in study design
- Establish clear protocols for handling discrepant results
Key Considerations
Clinical testing
- Clinical validation studies needed to establish safety and effectiveness
- Define “clinical truth” for evaluating device performance
- Validate genotype/phenotype correlations on statistically determined number of specimens
- Include all matrices in intended use statement
- Establish and validate clinical cut-offs where applicable
- Consider retrospective/prospective studies with appropriate consultation
Non-clinical testing
- Compare results to bidirectional sequencing as reference method
- Evaluate all matrix types intended for use
- Report positive/negative percent agreement
- Calculate confidence intervals for performance measures
- Identify and report failure rates and incorrect results
Human Factors
- Include training programs recommendations in labeling
- Consider skill levels of intended users in reproducibility studies
- Multiple operators should perform testing during validation
Software
- Provide software validation according to level of concern
- Verify computational methods
- Address probe saturation, background correction, normalization
Labelling
- Include clear instructions for device use
- Provide quality control measures
- Specify result interpretation key and nomenclature system
- State device limitations
- Include stability information
- Describe performance characteristics
Safety
- Evaluate potential interfering substances
- Assess sample carryover risks
- Include controls to monitor critical reactions
- Validate sample preparation methods
Other considerations
- Characterize device design thoroughly
- Validate instrumentation specifications
- Consider population demographics and ethnicity
- Address rare variants/mutations sampling
- Evaluate precision and reproducibility
Relevant Guidances
- Dual Use Molecular Diagnostic Instruments with FDA-Approved and Non-Approved Functions
- Content of Premarket Submissions for Device Software Functions
- Applying Human Factors Engineering and Usability Engineering to Medical Devices
- Use of Genetic Variant Databases as Sources of Valid Scientific Evidence for Clinical Validity of Genetic Tests
- Use of Next Generation Sequencing in the Diagnosis of Germline Diseases
Related references and norms
- CLSI EP5-A2: Evaluation of Precision Performance of Clinical Chemistry Devices
- CLSI EP12-A: User Protocol for Evaluation of Qualitative Test Performance
- CLSI EP7-A: Interference Testing in Clinical Chemistry
- CLSI EP9-A2: Method Comparison and Bias Estimation Using Patient Samples
- CLSI EP14-A: Evaluation of Matrix Effects
Original guidance
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