Setting Up a CLIA Lab
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Setting Up a CLIA Lab

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Setting Up a CLIA Lab

Setting Up a CLIA Lab

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  • 1. to CLIA or not to CLIA(is there a question)Prof. Wim Van Criekinge, CSO9th of march 2013
  • 2. Agenda MDxHealth – Epigenetics – Business Model CLIA – Regulatory Agencies – Categorization – CLIA 88: QMS/QC/QA Howto – MDxHealth, a CLIA lab setup
  • 3. Defining Epigenetics Genome DNA  Reversible changes in gene expression/function  Without changes in DNA Chromatin sequence Epigenome  Can be inherited from precursor cells Gene Expression  Allows to integrate intrinsic with environmental signals (includingPhenotype diet)
  • 4. Actionable Epigenome
  • 5. (Epi)Genetic Editing ‘Root’ of Cancer GrowthTumor Tumor Development and GrowthEpigeneticallyaltered, self-renewing cancerstem cells
  • 6. Outside Oncology ?
  • 7. Genetics Whole-genome Probes MSP Bisulphite seq (450-27K)Full genome bp 109 108 107 106 105 104 103 102 101 1
  • 8. Genetics Whole-genome Enrichment seq EnrichmentG PCR sequencing (Exome) Targeted PanelsENE Full genome bpTI 109 108 107 106 105 104 103 102 101 1C
  • 9. Genetics Instrument and Assay providers Whole-genome Enrichment seq EnrichmentG PCR sequencing (Exome) Targeted PanelsENE Full genome bpTI 109 108 107 106 105 104 103 102 101 1C
  • 10. Genetics Instrument and Assay providers Whole-genome Enrichment seq EnrichmentG PCR sequencing (Exome) Targeted PanelsENE Full genome bpTI 109 108 107 106 105 104 103 102 101 1C CLIA Lab service providers
  • 11. Monetize EpigeneticCapabilities in Two Markets ClinicalMDx <-R&D-> PharmacoMDx Prostate, Lung Next Gen Sequencing Companion Diagnostics CLIA Lab Epigenetic PCR R&D Lab Direct sales force Business development Physicians IP Pharma companies Reimbursement Contracts + royalties Market size > $2 Billion Proprietary Tests Market size >$3.4 billion
  • 12. Agenda MDxHealth – Epigenetics – Business Model CLIA – Regulatory Agencies – Categorization – CLIA 88: QMS/QC/QA Howto – MDxHealth, a CLIA lab setup
  • 13. CLIA ?Congress established the ClinicalLaboratory ImprovementAmendments (CLIA) in 1988 toensure that patients laboratorytests were being handled by labsqualified to handle them. Every labin the United States that handleshuman test samples is required toobtain CLIA certification.Program administered byCDC,FDA, CMS
  • 14. Federal Regulatory Agencies U.S. Department of Health and Human Services (hhs.gov)
  • 15. Federal Regulatory Agencies U.S. Department of Health and Human Services (hhs.gov) – Food and Drug Administration (fda.gov)
  • 16. Federal RegulatoryAgencies U.S. Department of Health and Human Services (hhs.gov) – Food and Drug Administration (fda.gov) • Centers for Devices and Radiological Health (CDRH) • Eg CDx typically requires a Premarket Approval (PMA) submitted to FDA as 4 module
  • 17. The FDA is responsible for test categorizationCategorization applies to all laboratory test systems on materials derived from the human body conducted for the purpose of diagnosis, prevention or treatment, or assessment of the health
  • 18. What is Categorization? Process of assigning new commercially marketed tests to one of 3 CLIA categories: waived, moderate, high The key to understanding categorization; the analyst/operator and the complexity of testing Regulations that govern categorization – 42 CFR 493.17, categorization of specific laboratory tests by level of complexity • 7 Criteria: Knowledge, Training and experience, Characteristics of operational Steps, Calibration, QC, PT materials, Troubleshooting, Maintenance, Interpretation and judgment
  • 19. Moderate, High42 CFR 493.17• 7 criteria scored as 1, 2, or 3 • Score of 1 = minimum • Score of 3 = specialized• Total scores of 12 or less = moderate• 13 or higher = high• e.g. PCR = high complexity
  • 20. Most Common Waived TestsUrine pregnancy – 34%All other tests – 20%Blood glucose (OTC) – 18%Urine dipstick/tablet chemistries-19%Ovulation tests – 5%Fecal occult blood – 4%
  • 21. FDA Databases
  • 22. FDA Databases
  • 23. Federal Regulatory Agencies U.S. Department of Health and Human Services (hhs.gov) – Food and Drug Administration (FDA) – Centers for Medicare and Medicaid Services (CMS) • Oversee regulations of all clinical laboratories (225,000) that perform testing on human samples for diagnosis, prevention or treatment, or for the assessment of an individual’s health.. • “CLIA” or “CLIA 88”
  • 24. Other Regulatory Agencies The College of American Pathologists (CAP) is an independent accreditation agency that has been awarded “deemed status” by CMS and performs accreditations inspections for CLIA State and Regulatory Agencies – Washington and New York State are exempt from CLIA
  • 25. CMS databaseTotal Number of Laboratories: 214,875 –Compliance 19,178 –Accredited 16,095 –Waived 134,778 –Provider Performed Microscopy 38,509 –Exempt 6,315 • NY 3,103 • WA 3,212 31
  • 26. CMS database
  • 27. Agenda MDxHealth – Epigenetics – Business Model CLIA – Regulatory Agencies – Categorization – CLIA 88: QMS/QC/QA Howto – MDxHealth, a CLIA lab setup
  • 28. Why CLIA? Enacted as result of reports of inaccurate test results from Pap smears (In U.S., estimated 44,000 to 98,000 deaths / year due to “medical errors”) Questions were raised about how labs functioned and what quality control procedures existed
  • 29. Error Source Ross and Boone1 Plebani et al.2 Pre-analytical 46% 68% Analytical 7% 13% Post-analytical 47% 19% 1Ross and Boone, Inst. of Critical Issues in Health Lab Pract, DuPont Press, 1991 2Plebani and Carraro, Clin Chem 43:1348, 1997
  • 30. Why CLIA?Enacted as result of reports of inaccurate test results from Pap smears (In U.S., estimated 44,000 to 98,000 deaths / year due to “medical errors”)Questions were raised about how labs functioned and what quality control procedures existedQuality results for Quality healthcareAdopt insights from Quality Management
  • 31. QCQuality Control (QC)A set of procedures designed to monitor the test method and test results toensure appropriate test system performance
  • 32. QC|AQuality Control (QC)A set of procedures designed to monitor the test method and test results toensure appropriate test system performanceQuality Assurance (QA)The practice that encompasses all procedures and activities directed towardensuring that a specified quality of product is achieves and maintained
  • 33. QC|A|MSQuality Control (QC)A set of procedures designed to monitor the test method and test results toensure appropriate test system performanceQuality Assurance (QA)The practice that encompasses all procedures and activities directed towardensuring that a specified quality of product is achieves and maintainedQuality management (QMS) is what the organization does toenhance customer satisfaction, and achieve continual improvement of itsperformance
  • 34. QMS evolving standards (CLIA-CLSI-ISO) 1988CLIA’88 2003 CLIA Final QC Rule
  • 35. Quality Management SystemEssentialsThese CLSI and ISO standards apply a core set of 12 qualitysystem essentials basic to any organization across alloperations in the health-care path of workflow that defineshow a particular product or service is provided.
  • 36. Quality Management SystemEssentialsThese CLSI and ISO standards apply a core set of 12 qualitysystem essentials basic to any organization across alloperations in the health-care path of workflow that defineshow a particular product or service is provided.• The laboratory must be part of an organization that has sufficient facilities to operate in a safe manner.
  • 37. Quality Management SystemEssentialsThese CLSI and ISO standards apply a core set of 12 qualitysystem essentials basic to any organization across alloperations in the health-care path of workflow that defineshow a particular product or service is provided.• The laboratory must be part of an organization that has sufficient facilities to operate in a safe manner.• Adequate personnel should be trained and competent to perform the procedure, and the equipment must be validated prior to patient testing and have regular ongoing maintenance.
  • 38. Quality Management SystemEssentialsThese CLSI and ISO standards apply a core set of 12 qualitysystem essentials basic to any organization across alloperations in the health-care path of workflow that defineshow a particular product or service is provided.• The laboratory must be part of an organization that has sufficient facilities to operate in a safe manner.• Adequate personnel should be trained and competent to perform the procedure, and the equipment must be validated prior to patient testing and have regular ongoing maintenance.• All supplies must be traceable by lot and shipment and performance verified prior to use on samples.
  • 39. Quality Management SystemEssentials The process of analysis must be controlled and documented.
  • 40. Quality Management SystemEssentials The process of analysis must be controlled and documented. Records of patient testing must be maintained and all procedures and policies must be under document control to prevent unexpected changes without supervisory approval.
  • 41. Quality Management SystemEssentials The process of analysis must be controlled and documented. Records of patient testing must be maintained and all procedures and policies must be under document control to prevent unexpected changes without supervisory approval. Management of information is thus important, both in protecting confidentiality and for providing traceability of the testing process from sample to reagent to result.
  • 42. Quality Management SystemEssentials The process of analysis must be controlled and documented. Records of patient testing must be maintained and all procedures and policies must be under document control to prevent unexpected changes without supervisory approval. Management of information is thus important, both in protecting confidentiality and for providing traceability of the testing process from sample to reagent to result. Finally, the laboratory must assess the quality of its results, and respond to complaints and occurrences. Customer satisfaction should be monitored and performance improved when issues are noted.
  • 43. Quality ControlQuality control is a set of procedures designed to monitor thetest method and test results to ensure appropriate testsystem performance.CLIA 67 was the first quality law for clinical laboratories in theUnited States that mandated the performance of two levels ofquality control, at a normal and abnormal concentration ofanalyte, each day of patient testing. CLIA 88 reinforced thisneed for two levels of controls at least every 24h of testingTwo levels of controls each day of testing have thusbecome the de facto historical standard for goodlaboratory practice.
  • 44. The Role of the Laboratory DirectorThe laboratory director plays a central leadership role inlaboratory management. The laboratory director holds aCLIA 88 certificate that allows the laboratory to performtesting under the directors supervision. The laboratorydirector must ensure compliance with all legal andregulatory aspects of CLIA88.The laboratory director has ultimate responsibility for thequality of laboratory results reported under his or herdirection. Although the laboratory director can delegate somefunctions within the laboratory, he or she is ultimatelyresponsible for ensuring compliance.
  • 45. The Role of the Laboratory DirectorThe federal government takes laboratory directorship seriouslyand wants directors to play an active role in laboratorymanagement rather than just apply their name to licensingpaperwork.Laboratory inspectors look for documentation of activeparticipation by the laboratory director, through meeting minutes,signatures on policies and procedures, review of control andproficiency test results, and participation in performanceimprovement or other laboratory committees and activities.For this reason, a laboratory director can only hold a maximumof five CLIA 88 certificates.
  • 46. Quality assurance (QA)Quality assurance (QA) is an objective assessment of a laboratoryscapability and commitment to produce repeatable, defendable, andaccurate data. QA includes regulation of the quality of raw materials,assemblies, products, and components; services related to production; andmanagement, production, and inspection processes. Two key principlescharacterize QA: "fit for purpose" and "right at the first time." It isimportant to realize also that quality is determined by the intended users.Appropriate measures for QA should be• Using validated methods of analysis• Using internal quality control (QC) proceduresParticipating in proficiency testing schemes• Becoming accredited to an International Standard
  • 47. Biomarker Fit-for-Purpose ValidationDefinition Verification Development Validation Accuracy (final Regulatory / Phase Phase Phase Phase clinical studies) Product Sequence area Choose regions Initial Designs Design Verification Final design Transfer to CLIA as service
  • 48. Biomarker Fit-for-Purpose ValidationDefinition Verification Development Validation Accuracy (final Regulatory / Phase Phase Phase Phase clinical studies) Product Phase II/III / Pre-IDE Preparation for phase II/III study: • Move product to development phase • Start FFP validation for clinical studies • Obtain IDE • Accuracy based on therapeutic responses
  • 49. Biomarker Fit-for-Purpose ValidationDefinition Verification Development Validation Accuracy (final Regulatory / Phase Phase Phase Phase clinical studies) Product Preparation for Regulatory submission: • Finalize manufacturing • Supply agreements, reagents, instruments, software etc • Produce multiple lots • Validate as final assay “fit” for the recruitment of patients • Submit with drug as CDx
  • 50. “right at the first time” –> Method ValidationValidation of methods is an integral part of QA to demonstratethe applicability for the intended use. According to IUPACtechnical report, typical performance characteristics ofanalytical methods are applicability, selectivity, calibration,trueness, precision, recovery, operating range, limit ofquantification, limit of detection, sensitivity, andruggedness. Additional parameters may be relevant forparticular analytical purpose.For quantitative bioanalytical procedures, at least thefollowing validation parameters should be evaluated :selectivity, calibration model, precision, bias, limit ofdetection, the lower limit of quantification (LLOQ),statistical process control, and measurement uncertainty.
  • 51. PrecisionPrecision can be the "within-laboratory reproducibility,where operator and/ or equipment and/or time and/orcalibration can be varied, but in the same laboratory." It isusually specified as standard deviation (SD).Method: Analysis of five to six replicates per level underrepeatability conditions. Control samples at low and highconcentrations relative to calibration range.Acceptance criteria: Relative standard deviation (RSD)within ±15% (±20% near LLOQ).
  • 52. Limit of DetectionThe limit of detection (LOD) is the smallest amount orconcentration of an analyte that can be reliably distinguishedfrom zero. Depending on the intended use, it must not be partof the validation procedure. For practical use, the LOD can bedetermined with a simple procedure. The values for this"practical" LOD were greater than the possible "instrumental"LOD.Method: Analysis of the LOD using spiked samples withdecreasing concentrations of the analyte.Acceptance criteria: Checking for compliance withidentification criteria or a signal-to-noise ratio (SNR) >= 3.
  • 53. The Lower Limit of QuantificationThe LLOQ defines the concentration below which theanalytical method cannot operate with an acceptableprecision.Method: Control samples with an analyteconcentration near the LOQ. Alternatively, analysis ofspiked samples with decreasing concentrations of theanalyte.Acceptance criteria: Compliance with accuracy andprecision data of control samples near LLOQ or aSNR >= 10.
  • 54. CDx: Fit-for-Purpose / Minimizing ErrorDefinition Verification Development Validation Accuracy (final Regulatory / Phase Phase Phase Phase clinical studies) Product Manufactured Components No LOD LOD, LOQ, LLOQ, LLOD LOQ Precision Selectivity Reproducibility Precision Robustness Linearity Linearity Accuracy Cutoff determination Accuracy
  • 55. CLIA vs ISO/CLSICLIA –more specific in some areas, eg – Personnel – Quality control – PT – Record retentionISO/CLSI –more general, e.g. – Applies to all laboratories, regardless of test complexity – Management system – Internal and external assessment
  • 56. Agenda MDxHealth – Epigenetics – Business Model CLIA – Regulatory Agencies – Categorization – CLIA 88: QMS/QC/QA Howto – MDxHealth, a CLIA lab setup
  • 57. to CLIA or to CLIA(there no question)Prof. Wim Van Criekinge, CSO9th of march 2013