setting up a clia lab
DESCRIPTION
Setting Up a CLIA LabTRANSCRIPT
to CLIA or not to CLIA(is there a question)
Prof. Wim Van Criekinge, CSO9th of march 2013
Agenda
MDxHealth– Epigenetics
– Business Model
CLIA– Regulatory Agencies
– Categorization
– CLIA 88: QMS/QC/QA
Howto– MDxHealth, a CLIA lab setup
Defining Epigenetics
Reversible changes in gene expression/function
Without changes in DNA sequence
Can be inherited from precursor cells
Allows to integrate intrinsic with environmental signals (including diet)
Genome
DNA
Gene Expression
Epigenome
Chromatin
Phenotype
Actionable Epigenome
(Epi)Genetic Editing ‘Root’ of Cancer Growth
Tumor
Epigenetically altered, self-renewing cancer stem cells
Tumor Development and Growth
Outside Oncology ?
107 106 105 104 103 102 101 1108109
Full genome bp
Whole-genomeBisulphite seq
MSPProbes
(450-27K)
Genetics
Genetics
107 106 105 104 103 102 101 1108109
Full genome bp
GENETIC
Whole-genomesequencing
Enrichment seq(Exome)
PCREnrichment
Targeted Panels
Genetics
107 106 105 104 103 102 101 1108109
Full genome bp
GENETIC
Whole-genomesequencing
Enrichment seq(Exome)
PCREnrichment
Targeted Panels
Instrument and Assay providers
Genetics
107 106 105 104 103 102 101 1108109
Full genome bp
GENETIC
Whole-genomesequencing
Enrichment seq(Exome)
PCREnrichment
Targeted Panels
Instrument and Assay providers
CLIA Lab service providers
ClinicalMDx <-R&D-> PharmacoMDxProstate, 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
Monetize Epigenetic Capabilities in Two Markets
Agenda
MDxHealth– Epigenetics
– Business Model
CLIA– Regulatory Agencies
– Categorization
– CLIA 88: QMS/QC/QA
Howto– MDxHealth, a CLIA lab setup
CLIA ?
Congress established the Clinical Laboratory Improvement Amendments (CLIA) in 1988 to ensure that patients' laboratory tests were being handled by labs qualified to handle them. Every lab in the United States that handles human test samples is required to obtain CLIA certification.
Program administered by CDC,FDA, CMS
Federal Regulatory Agencies
U.S. Department of Health and Human Services (hhs.gov)
Federal Regulatory Agencies
U.S. Department of Health and Human Services (hhs.gov)– Food and Drug Administration (fda.gov)
Federal Regulatory Agencies
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
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
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
Moderate, High
42 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
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%
FDA Databases
FDA Databases
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”
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
31
Total 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
CMS database
CMS database
Agenda
MDxHealth– Epigenetics
– Business Model
CLIA– Regulatory Agencies
– Categorization
– CLIA 88: QMS/QC/QA
Howto– MDxHealth, a CLIA lab setup
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
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, 19912Plebani and Carraro, Clin Chem 43:1348, 1997
Error Source
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 healthcareAdopt insights from Quality Management
QC
Quality Control (QC)
A set of procedures designed to monitor the test method and test results to ensure appropriate test system performance
QC|A
Quality Control (QC)
A set of procedures designed to monitor the test method and test results to ensure appropriate test system performance
Quality Assurance (QA)
The practice that encompasses all procedures and activities directed toward ensuring that a specified quality of product is achieves and maintained
QC|A|MS
Quality Control (QC)
A set of procedures designed to monitor the test method and test results to ensure appropriate test system performance
Quality Assurance (QA)
The practice that encompasses all procedures and activities directed toward ensuring that a specified quality of product is achieves and maintained
Quality management (QMS) is what the organization does to enhance customer satisfaction, and achieve continual improvement of its performance
QMS evolving standards (CLIA-CLSI-ISO)
2003CLIA
Final QC Rule
1988CLIA’88
Quality Management System Essentials
These CLSI and ISO standards apply a core set of 12 quality system essentials basic to any organization across all operations in the health-care path of workflow that defines how a particular product or service is provided.
Quality Management System Essentials
These CLSI and ISO standards apply a core set of 12 quality system essentials basic to any organization across all operations in the health-care path of workflow that defines how 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.
Quality Management System Essentials
These CLSI and ISO standards apply a core set of 12 quality system essentials basic to any organization across all operations in the health-care path of workflow that defines how 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.
Quality Management System Essentials
These CLSI and ISO standards apply a core set of 12 quality system essentials basic to any organization across all operations in the health-care path of workflow that defines how 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.
The process of analysis must be controlled and documented.
Quality Management System Essentials
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.
Quality Management System Essentials
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.
Quality Management System Essentials
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.
Quality Management System Essentials
Quality Control
Quality control is a set of procedures designed to monitor the test method and test results to ensure appropriate test system performance.
CLIA' 67 was the first quality law for clinical laboratories in the United States that mandated the performance of two levels of quality control, at a normal and abnormal concentration of analyte, each day of patient testing. CLIA 88 reinforced this need for two levels of controls at least every 24h of testing Two levels of controls each day of testing have thus become the de facto historical standard for good laboratory practice.
The Role of the Laboratory Director
The laboratory director plays a central leadership role in laboratory management. The laboratory director holds a CLIA' 88 certificate that allows the laboratory to perform testing under the director's supervision. The laboratory director must ensure compliance with all legal and regulatory aspects of CLIA88.
The laboratory director has ultimate responsibility for the quality of laboratory results reported under his or her direction. Although the laboratory director can delegate some functions within the laboratory, he or she is ultimately responsible for ensuring compliance.
The federal government takes laboratory directorship seriously and wants directors to play an active role in laboratory management rather than just apply their name to licensing paperwork.
Laboratory inspectors look for documentation of active participation by the laboratory director, through meeting minutes, signatures on policies and procedures, review of control and proficiency test results, and participation in performance improvement or other laboratory committees and activities.
For this reason, a laboratory director can only hold a maximum of five CLIA 88 certificates.
The Role of the Laboratory Director
Quality assurance (QA)
Quality assurance (QA) is an objective assessment of a laboratory's capability and commitment to produce repeatable, defendable, and accurate data. QA includes regulation of the quality of raw materials, assemblies, products, and components; services related to production; and management, production, and inspection processes. Two key principles characterize QA: "fit for purpose" and "right at the first time." It is important 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) procedures
Participating in proficiency testing schemes• Becoming accredited to an International Standard
Definition Phase
Verification Phase
Validation Phase
Accuracy (final clinical studies)
Regulatory / Product
Sequence areaChoose regionsInitial DesignsDesign VerificationFinal designTransfer to CLIA as service
Development Phase
Biomarker Fit-for-Purpose Validation
Definition Phase
Verification Phase
Validation Phase
Accuracy (final clinical studies)
Regulatory / 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
Development Phase
Biomarker Fit-for-Purpose Validation
Definition Phase
Verification Phase
Validation Phase
Accuracy (final clinical studies)
Regulatory / 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
Development Phase
Biomarker Fit-for-Purpose Validation
“right at the first time” –> Method Validation
Validation of methods is an integral part of QA to demonstrate the applicability for the intended use. According to IUPAC technical report, typical performance characteristics of analytical methods are applicability, selectivity, calibration, trueness, precision, recovery, operating range, limit of quantification, limit of detection, sensitivity, and ruggedness. Additional parameters may be relevant for particular analytical purpose. For quantitative bioanalytical procedures, at least the following validation parameters should be evaluated : selectivity, calibration model, precision, bias, limit of detection, the lower limit of quantification (LLOQ), statistical process control, and measurement uncertainty.
Precision
Precision can be the "within-laboratory reproducibility, where operator and/ or equipment and/or time and/or calibration can be varied, but in the same laboratory." It is usually specified as standard deviation (SD).
Method: Analysis of five to six replicates per level under repeatability conditions. Control samples at low and high concentrations relative to calibration range.
Acceptance criteria: Relative standard deviation (RSD) within ±15% (±20% near LLOQ).
Limit of Detection
The limit of detection (LOD) is the smallest amount or concentration of an analyte that can be reliably distinguished from zero. Depending on the intended use, it must not be part of the validation procedure. For practical use, the LOD can be determined 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 with decreasing concentrations of the analyte.
Acceptance criteria: Checking for compliance with identification criteria or a signal-to-noise ratio (SNR) >= 3.
The Lower Limit of Quantification
The LLOQ defines the concentration below which the analytical method cannot operate with an acceptable precision.
Method: Control samples with an analyte concentration near the LOQ. Alternatively, analysis ofspiked samples with decreasing concentrations of the analyte.
Acceptance criteria: Compliance with accuracy and precision data of control samples near LLOQ or a SNR >= 10.
LODLOQSelectivityPrecisionLinearityAccuracy
LOD, LOQ, LLOQ, LLODPrecisionReproducibilityRobustnessLinearityCutoff determinationAccuracy
Manufactured ComponentsNo
Definition Phase
Verification Phase
Validation Phase
Accuracy (final clinical studies)
Regulatory / Product
Development Phase
CDx: Fit-for-Purpose / Minimizing Error
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
Agenda
MDxHealth– Epigenetics
– Business Model
CLIA– Regulatory Agencies
– Categorization
– CLIA 88: QMS/QC/QA
Howto– MDxHealth, a CLIA lab setup
to CLIA or to CLIA(there no question)
Prof. Wim Van Criekinge, CSO9th of march 2013