Presentation: FDA’s CLIA Complexity Process Clara A. Sliva, MT(ASCP), MPA Acting CLIA Coordinator FDA IVD Roundtable 510(k) Workshop - April 23, 2002

Expected Outcomes

• What is CLIA ’88
• Key Features
• Who are the players
• FDA and CLIA
• CLIA regulations
• What is categorization
• What requires categorization
• What is not regulated under CLIA
• How FDA categorizes tests
  -CDRH
  -CBER
• "Automatic" categorizations
• Specific requests for categorizations
• Categorization notifications: letter, internet
• Where do you go for help

What is CLIA

• Clinical Laboratory Improvement Amendments of 1988 (CLIA)
• Enacted as result of reports of inaccurate test results from Pap smears
• Questions were raised about how labs functioned and what quality control procedures existed
• Comprehensive plan to improve the quality of labs
• 1987 = 12,000/200,000 labs regulated
• 2002 = 170,000 labs

Who are the Players

• Centers for Medicare and Medicaid Services (formerly HCFA) oversees CLIA
• CLIA self-funded
• User fees from regulated labs
• CMS pays FDA for CLIA categorization commercially marketed tests
• CDC categorizes lab procedures
  --Provider performed microscopy
  --Gram stain

DCLD’s Players

• Lisa King
• Renita Hoard
• Dr. Joe Hackett
• Dr. Steve Gutman
• CLIA team represents all Branches
  

Key Features

• Standards based on complexity of testing, NOT lab site
• How complex it is for the analyst to run the test
  -e.g. training, knowledge, interpretation

FDA and CLIA

• 1992 CLIA regulations
• FDA responsible for complexity categorization
• 1993-94 FDA categorized >900 tests
• 1994 CDC delegated responsibility
• Resources, funding issues
• Impetus for change
• Manufacturers
• Congress
• "Confusion and duplication of effort"
• CDC, HCFA, FDA consensus
• Interagency agreement 2/27/99
• HCFA, CDC, FDA = CLIA partners

What Regulations Govern Categorization

• 42 CFR 493.17, categorization of specific laboratory tests by level of complexity
• Moderate, high
• 7 Criteria

Moderate, High

42 CFR 493.17

• Knowledge
• Training and experience
• Characteristics of operational Steps
• Calibration, QC, PT materials
• Troubleshooting, Maintenance
• Interpretation and judgment
• 7 criteria scored as 1, 2, or 3
• Score of 1 = minimum
• Score of 3 = specialized
• Total scores of 12 or < = moderate
• 13 or > = high
• e.g. PCR = high complexity

Categorization Regulations

• 42 CFR 493.15 (c) 9 generic tests
• Categorized by regulation
• Automatically waived
• But still requires review and notification from FDA
• Requires posting categorization on website

Generic 9

493.15 (c)

• dipstick and tablet reagent urinalysis
• fecal occult blood
• ovulation tests
• urine pregnancy tests
• erythrocyte sedimentation rate
• hemoglobin (copper sulfate)
• blood glucose devices (FDA-cleared for OTC use)
• spun microhematocrit
• hemoglobin single analyte instruments (1993)

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%

Categorization Regulations

• CMS and PHS Sept 13, 1995 Notice of Proposed Rulemaking
• Clarified statutory criteria for obtaining waiver
• Guidelines list the criteria
• Final rule pending

CMS/PHS Waiver Criteria

• Defined simplicity, low risk
• Defined accuracy as comparison to reference materials, methods
• Precision field studies in hands of lay user
• Studies distinct from FDA premarket review

Categorization Regulations

• Food and Drug Modernization Act Nov. 21, 1997
• Clarifies OTC tests automatically waived.
• But still requires categorization notification letter from FDA
• Requires posting categorization on website

OTC

• Growing number OTC tests
  -drugs of abuse
  -cholesterol
  -vaginal ph
  -microalbumin
  -follicle stimulating hormone

Prescription Home Use

• Prescription home use is an Rx device physician instructs patient to use in home
• FDA devices are OTC or Rx
• Any device used in the home that is not OTC
• Examples - prothrombin time, hemoglobin A1c

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

What Requires 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
• Plain Language:
• Commercially marketed tests produce a result

Not Categorized

Produce no test result

• Quality Control
• Calibrators
• Collection kits
  --drugs of abuse
  --hepatitis C

Not currently regulated under CLIA

• Non-invasive (laser hematocrit)
• Breath tests (h. pylori, alcohol)
• Drugs of abuse - Workplace
• Monitoring devices

How FDA Categorizes

• Centers for Devices and Radiological Health
• Centers for Biologics Evaluation and Research

CDRH Categorizes

• Pre-amendment
• 510(k) exempt test systems
• New Premarket Notification 510(k) e.g. special 510(k)s
• New Premarket Approvals (original, supplement)
• New Humanitarian Device Exemptions (original, supplement)
• 510(k) add-to-files
  -Replacement reagents
  -Manufacturer name change
  -Relabel
• Previously uncategorized test systems

Automatic Categorizations

• Manufacturer submits premarket submission to Document Mail Center
• Categorization in conjunction with product review
• CLIA notification accompanies clearance, approval order or follows shortly after

Automatic Categorization, Replacement Reagents

• Well characterized analyzers for use by lab professionals.
• Previously cleared analyzers and reagents
• Claim is made for a new reagent/analyzer combination.
• New analyzer family members of a previously cleared analyzer family.

Automatic Categorization

• Replacement reagent
  -Replacement reagents require a package insert with the new instrument/reagent combination
  -CLIA notification follows shortly after
  -Categorization posted on website

Categorization by Request

• Change in company name (e.g. Now GWB, formerly WJC)
• Relabel
• Not previously categorized
  -defaults to high complexity
• Submit new labeling to FDA
• Document Mail Center, HFZ-401, 9200 Corporate Blvd., Rockville, MD 20850
• "For CLIA Categorization Only"
• Reference original 510(k) number
• CLIA categorization performed
• Notification letter to manufacturer
• Categorization posted on website
• Categorization by Request
• Exempt from 510(k), CLIA required
• Submit new labeling to FDA
• "For CLIA Categorization Only"
• Cite regulation, product code
• DCLD assigns "X" document number
• CLIA categorization performed
• CLIA letter issued
• Categorization posted on CLIA website
• Waiver via CMS/PHS 1995 Criteria
• Test cleared or approved to apply for waiver through process
• FDA approves waiver protocol
• Waiver studies begin

CBER

• Manufacturer submits request for product review to CBER
• When test is cleared, approved, licensed CBER sends test instructions to Clara Sliva
• CBER test logged into CDRH CLIA database using CBER document number: BK, BP, BL, PL
• CBER reviewer consults on categorization
• Notification letter issued by CDRH
• Categorization posted on CLIA website

Categorization Notification Letter

• FDA’s document number is the key
• "k001111" - new 510(k) CDRH
• "BL002222" - new BLA CBER
• "k001111/A1" - new trade name
• complexity
• test system name
• analyte name

FDA’s CLIA Workload

• 1/18/00 - 4/22/02
• 3,642 categorized
• 3,121 - moderate
• 521 -high
• 301 - waived

>3,121 Tests Categorized

(graph showing approximately 70% Moderate, 28% High and 4% Waived)

Benefits

• Streamlined administrative process
• One stop agency for marketing and categorization
• Reviewer familiar with the products
• Categorization, no impediment to clearance or approval
• Improved turn around time, decision

FDA’s CLIA Website

• http://www.fda.gov/cdrh/clia/
• "Government Google" for current CLIA information
• Lists all waived analytes and tests
• Links to CMS, CDC websites
• CLIA database

CLIA Database

• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCLIA/search.cfm
• Contains all commercially marketed tests categorized by CDC and FDA
• Several ways to search

Search CLIA Database

• Search for CLIA records by
  -test system name
  -specialty/subspecialty
  -analyte
  -document number
  -qualifier (reagent application) e.g. SLIVA Analyzer/Dr. Gutman reagent
  -effective date
  -complexity

Tips

• You may enter the entire test name
• But most successful if you enter the first word or two
• Or just the first few letters
• e.g. first few letters of manufacturer name

Mastering the CLIA Database

• Manufacturer Test System
• Qualifier
• Analyte
• Document Number
• Complexity
• Analyte
• Specialty
• Effective Date (mm/dd/yyyy)
• Sort one or a combination of the values and select Search:  

Publication of Categorizations

• Monthly on FDA’s CLIA Home Page
• Federal Register Notice, interval to be determined

What We Have Learned

• Multiple stakeholders
• Labs
• Providers
• Patients
• Manufacturers
• Government

Over 28,600 Categorizations

• Laboratory Inspectors, Laboratories, Manufacturers, and Other Stakeholders Want to Know

CLIA INFORMATION

http://www.fda.gov/cdrh/clia/
clia@cdrh.fda.gov
phone (301) 827-0496
fax (301)827-1401

CLIA waived tests are used abroad in physician's office laboratories and are widely in-demand for occupational health and criminal justice applications. These tests are simple and easy enough to be used by non-laboratory trained personnel. CLIA (Clinical Laboratory Improvement Amendment) was enacted in 1988 to regulate diagnostic testing on human specimens to ensure the reliability of test results. Waived tests, the least regulated category, are simple and accurate and therefore most commonly used in doctor's offices with point of care patients. 100,000 plus doctor's offices in the United States are capable of performing CLIA waived drug tests. The E-Z or Noble split specimen Urine Integrated Drug Testing Cup 3,4, & 5 panel along with the Urine Cassette Pipette 2,3,4,5, & 6 panels as well as QuickTox dip cards 8-11 panel are part of an extensive line of rapid diagnostic products offered by Rapid-Exams, Inc.