setting up a clia lab

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