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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

Updated 4/29/2002

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