1. Regulation of Consumer Tests in California AAAS Meeting June 1-2, 2009 Beatrice OKeefe Acting Chief, Laboratory Field Services California Department of Health Services

2. Brief History of Lab Regulation in CA 1923-voluntary Certification of laboratories 1923-voluntary Certification of laboratories 1938-Licensing of clinical labs and 1938-Licensing of clinical labs and personnel personnel 1990-Non diagnostic health assessment 1990-Non diagnostic health assessment 2002-Expansion of self ordered tests 2002-Expansion of self ordered tests 2004-Consumer tests offered over 2004-Consumer tests offered over internet internet 2009-Genetic tests offered over internet 2009-Genetic tests offered over internet

3. Future of Genetic Tests Washington G2 Report June 2008 Global molecular diagnostic industry Global molecular diagnostic industry 5.5 Billion in 2008, 8 billion by 2010 5.5 Billion in 2008, 8 billion by 2010 Lab market increase 5% per year, Lab market increase 5% per year, molecular diagnostics growth 20% molecular diagnostics growth 20% per year per yearChallenges Laboratory validation Laboratory validation Regulators review and acceptance of validation Regulators review and acceptance of validation

4. Regulation in California of Genetic Tests and Risk Analysis Definition of clinical laboratory test very Definition of clinical laboratory test very broad broad Genetic risk analysis considered part of Genetic risk analysis considered part of laboratory test laboratory test Requires physician order, licensure of Requires physician order, licensure of laboratory, qualified director and review of laboratory, qualified director and review of report by licensed person report by licensed person

5. Diagnostic/Predictive Genetic Tests Generally Consists of Two Parts: Determination of genetic profile of the patient Determination of genetic profile of the patient Determination of the risk or other parameters using a soft ware algorithm Determination of the risk or other parameters using a soft ware algorithm

6. Three Types of Labs offering Genetic Tests in CA Genetic analysis only Genetic analysis only Genetic analysis plus risk assessment Genetic analysis plus risk assessment Risk assessment only Risk assessment only

7. Performance Characteristics Accuracy Accuracy Precision Precision Reportable Range Reportable Range Reference Range Reference Range Analytical Sensitivity Analytical Sensitivity Analytical Specificity Analytical Specificity

8. Performance Characteristics Accuracy Closeness of the agreement between the result of a measurement and the true value Closeness of the agreement between the result of a measurement and the true value Verification or establishment of accuracy Verification or establishment of accuracy Testing reference material Testing reference material Comparing results of test against a reference Comparing results of test against a reference method method Compare split sample results with a method Compare split sample results with a method shown to provide clinically valid results shown to provide clinically valid results Submit test results for independent analysis Submit test results for independent analysis Correlation with clinical results Correlation with clinical results

9. Performance Characteristics Precision Closeness of agreement between independent Closeness of agreement between independent test results test results Repeatability-measured under same Repeatability-measured under same conditions conditions Reproducibility-measured under changed Reproducibility-measured under changed conditions conditions Verify day-day, run-to-run, within run, operator Verify day-day, run-to-run, within run, operator variance variance Repeat testing of patient samples over Repeat testing of patient samples over time time Test known reference samples over time Test known reference samples over time

10. Performance Specifications Analytical Sensitivity Proportion of biological samples that Proportion of biological samples that have a positive test result or known mutation have a positive test result or known mutation and that are correctly classified as positive and that are correctly classified as positive Determined using samples with known Determined using samples with known test results or mutation status test results or mutation status Results should include confidence Results should include confidence intervals intervals

11. Performance Specifications Analytical Specificity Ability of a test to distinguish target sequence(s), Ability of a test to distinguish target sequence(s), allele, mutation(s) from other sequences/alleles in the allele, mutation(s) from other sequences/alleles in the specimen/genome specimen/genome The proportion of samples that have no The proportion of samples that have no identified mutation and that are correctly identified mutation and that are correctly classified as negative classified as negative Use samples with known test results, or samples Use samples with known test results, or samples from target population with all positive results from target population with all positive results confirmed by reference method confirmed by reference method Estimates should include confidence intervals Estimates should include confidence intervals

12. Other Performance Characteristics Documentation of clinical performance characteristics? Documentation of clinical performance characteristics? Clinical/diagnostic sensitivity Clinical/diagnostic sensitivity Clinical/diagnostic specificity Clinical/diagnostic specificity Positive and negative predictive values in Positive and negative predictive values in target population target population Professional practice guidelines Professional practice guidelines Peer-reviewed studies in recognized scientific Peer-reviewed studies in recognized scientific literature literature Retrospective epidemiological review Retrospective epidemiological review

13. Validation of Software Algorithm SNP microarrays Increasing density, >900,000 SNP Increasing density, >900,000 SNP available available Genotyping errors Genotyping errors Low rate >0.5% per single SNP gives large Low rate >0.5% per single SNP gives large number of false positives number of false positives Requirements Requirements Eliminate unreliable SNPs Eliminate unreliable SNPs Use a robust SNP calling program to extract greatest Use a robust SNP calling program to extract greatest amount of information from raw data amount of information from raw data Identify poor quality chips Identify poor quality chips

14. Types of Data Leading to Software Algorithm Data Source Clinical data, randomized trials, variables Clinical data, randomized trials, variables controlled controlled Banked samples, not randomized, Banked samples, not randomized, variables not controlled variables not controlled Population based registry Population based registry Literature searches Literature searches

15. Two different approaches-Risk of Breast Metastasis Clinical Trial Utilize tumor tissue from randomized, controlled clinical trial for treatment for Estrogen Receptor +, node negative breast cancer Utilize tumor tissue from randomized, controlled clinical trial for treatment for Estrogen Receptor +, node negative breast cancer Determine genetic profile of tissue Determine genetic profile of tissue Epidemiologic analysis over 5 yr period led to software algorithm for risk of metastasis Epidemiologic analysis over 5 yr period led to software algorithm for risk of metastasis Strong association between risk and disease recurrence Strong association between risk and disease recurrence

16. Two different approaches-Risk of Breast Metastasis Banked Samples Banked samples, patients and tumor Banked samples, patients and tumor samples had variable clinical samples had variable clinical characteristics characteristics Determine genetic profile of tissue Determine genetic profile of tissue Develop software algorithm for risk Develop software algorithm for risk Ratio associated with poorer disease Ratio associated with poorer disease free survival free survival

17. Other Approaches Population based Registry Advantage Advantage Reduces amount of time required for Reduces amount of time required for study study With certain assumptions, provides With certain assumptions, provides adequate estimate of life time risks adequate estimate of life time risks Used to measure tests sensitivity, Used to measure tests sensitivity, specificity, positive and negative specificity, positive and negative predictive value predictive value

18. Other Approaches Case Control Study May not take into account other risk May not take into account other risk factors-such as smoking or other factors-such as smoking or other environmental factors environmental factors Any single gene may increase risk only Any single gene may increase risk only moderately and the genotype frequency moderately and the genotype frequency in the population may be high in the population may be high Population stratification may lead to invalid Population stratification may lead to invalid results results

19. Validity of Genetic Tests Only as good as initial sample selection and validation efforts Garbage in, Garbage out Garbage in, Garbage out Clinical efficacy may be required for Clinical efficacy may be required for reimbursement reimbursement Publication in peer review journals is Publication in peer review journals is important for acceptance important for acceptance Some genetic risk assessments may be Some genetic risk assessments may be no better than standard methods no better than standard methods Standardization and reproducibility important Standardization and reproducibility important

20. Regulation in California of Genetic Tests Definition of clinical laboratory test very Definition of clinical laboratory test very broad broad Genetic risk analysis considered part of Genetic risk analysis considered part of laboratory test laboratory test Requires physician order, licensure of Requires physician order, licensure of laboratory, qualified director and review of laboratory, qualified director and review of report by licensed person report by licensed person