Office of In Vitro Diagnostic Devices: Organizational Structure and Function

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Office of In Vitro Diagnostic Devices
Organizational Structure and Function
Don St.Pierre, Deputy Director Office of In Vitro
Diagnostic Device Evaluation and Safety Center
for Devices and Radiological Health
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IVD Definition

• reagents, instruments, and systems intended
  for use in the diagnosis of disease or other
  conditions, including a determination of the
  state of health, in order to cure, mitigate,
  treat, or prevent disease or its sequelae. for
  use in the collection, preparation, and
  examination of specimens from the human body.
• 21 CFR 809.3

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What Does OIVD Regulate?

• IVDs
• Tests for analytes found in human specimens
• proteins
• nucleic aids
• Pathogens
• Immunoglobulins
• Metabolites
• Drugs
• any other type of substances
• Instrumentation used in testing
• Materials and supplies used in testing
• Algorithms using IVD test results

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What is an IVD?
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World of IVDs

• 10-15 Billion industry for raw materials
• 30-50 Billion for testing
• 10 Billion lab tests in gt 200,000 labs

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Our Vision

• integrated regulatory oversight throughout the
  Total Product Life Cycle

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Multi-tasking Workforce

• 120 dedicated scientists, managers support
  staff doing TPLC regulation to promote and
  protect public health
• Premarket Applications (1,000/yr)
• Compliance Actions (150/yr)
• MDR Surveillance (10,000/yr)
• CLIA Determinations (2,000/yr)

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OIVD Organizational Chart
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Office of the Director

• Bob Becker - Chief Medical Officer
• Liz Mansfield Director, Personalized Medicine
• Jean Cooper Associate Director, Outreach
• Duffy Warren Director, Program Management
• Scott McFarland - Regulatory Council
• Pat Beverly Program operations

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Division of Chemistry and Toxicology Devices

• General/Special Chemistry tests
• Cardiac Markers (i.e. Lipids/Cholesterol, CRP)
• Pregnancy tests
• Osteoporosis Markers
• Glucose tests
• Drugs of Abuse tests
• Therapeutic Drug Monitoring

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Division of Immunology and Hematology Devices

• Allergy tests
• Autoimmune Assays
• Tumor Markers
• Hematology tests
• Cytology tests
• Coagulation tests

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Division ofMicrobiology Devices

• Antimicrobial Susceptibility
• Bioterrorism Preparedness
• Sexually Transmitted Diseases
• Bacterial Identification
• Hepatitis
• Herpes
• Rubella
• Influenza

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Premarket Programs

• Classification Information Request - 513(g)
• Investigational Device Exemption (IDE)
• Pre-IDE
• Premarket Notification (510(k))
• Including denovo classification
• Premarket Approval (PMA)
• Humanitarian Device Exemption (HDE)

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Postmarket Programs

• Post-Market Studies
• Medical Device Adverse Event Reporting
• MedWatch
• LabNet
• Other signals

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Compliance Programs

• Registration and Listing
• GMP Inspections
• Bioresearch Monitoring Audits
• Enforcement Actions
• Import/Export

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CLIA Categorizations

• High Complexity/Moderate Complexity and Waived
• Determination made based on expertise needed to
  perform the test
• Many High, Most Moderate, Few Waived

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Program Implementation

• Premarket Industry provides the evidence,
  FDA reviews and
  clears or approves
• Postmarket Industrys responsibility, FDA
  monitors and provides guidance
• Compliance FDA acts as policemen
• CLIA Categorization performed after
  
  approval or clearance

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Classification of tests

• OIVD classifies and regulates tests according to
  their intended use
• Regulations related to intended use for
  particular analyte measurement
• Different intended uses of the same test may have
  different questions of safety and effectiveness,
  and thus different classification
• Technology used for testing may influence risk if
  it introduces new questions of safety and
  effectiveness
• Technology generally not the primary risk

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Elements of IVD review

• Intended Use
• Preanalytical
• Specimen, matrix
• Analytical
• Performance of IVD in terms of measurement
  ability
• Clinical
• Performance of IVD in terms of clinical
  significance
• (Manufacturing)
• Ability to manufacture quality device with
  sustained performance characteristics

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Intended Use

• What analyte is measured?
• For what purpose?
• Quantitative, qualitative, other?
• In what matrix?
• In what population?
• In what setting?
• Who performs measurement?

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Preanalytical Questions

• How is the specimen collected?
• Does it use special (regulated) collection
  devices?
• How must the specimen be treated to
  stabilize/prepare for testing?
• Which matrices are appropriate?
• How are specimens selected to reduce bias?
• Are patient characteristics important, e.g.,
  under treatment with chemo, etc.?

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Analytical Questions

• Safety
• Precision
• Accuracy
• Comparison to reference/predicate
• Sensitivity
• Linearity
• Specificity (interference, cross-reactivity)
• Reproducibility (repeatability, robustness)
• Cut-offs

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Other issues

• Instrument performance
• Software validation
• Stability of calibration
• Drift
• Uniformity (instrument-to-instrument)
• Sources of variability
• Reagent performance
• Stability
• Uniformity (lot-to-lot)

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Substantial Equivalence

• For IVDs, often a comparison of analytical
  performance of new test to existing (predicate)
  test
• Similar analytical performance characteristics
• Sometimes comparison to reference method
• Bidirectional sequencing for DNA
• YSI for glucometers
• Cannot establish superiority

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Clinical Questions

• Effectiveness
• Does test identify intended clinical condition?
• Sensitivity
• Specificity
• Predictive value
• Odds ratio
• Population/setting
• Tested in correct population?
• Using correct statistical approach?
• Diagnosis, prognosis, prediction, adjunctive,
  screening, risk, monitoring, response, etc

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Clinical Study Required?

• Analytical comparison in clinical samples not
  adequate to assess performance characteristics
• Novel analytes/intended uses
• Screening
• Prediction/response to specific therapeutics
• Others
• Some 510(k)s, nearly all PMAs
• Use of peer-reviewed literature sometimes

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Instructions for Use

• Unique regulation for IVDs
• Adequate instructions for use
• Intended use
• Supplied/required materials
• Explicit instructions
• Warnings
• Limitations
• Mfr/lot/expiry, etc.
• For in vitro diagnostic use
• Not For research use only
• For investigational use if investigational

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Manufacturing

• Document review and premarket inspection for PMAs
• All aspects of IVD under control
• Instrument
• Reagents
• Equipment
• Instructions for use
• Other labeling
• Can be complex mix of suppliers, components,
  control mechanisms

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Information on cleared/approved IVDs-510(k)

• OIVD Review Decision Summary
• Standard template w/ 510(k) review data
• 510(k) database http//www.fda.gov/cdrh/oivd/decis
  ionsummaries.html
• For de novo 510(k)s, Special Controls Guidance
  Documents available
• Describes 510(k) submission requirements for
  devices of same type with same/similar intended
  use
• http//www.fda.gov/cdrh/oivd/index.html

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IVD Hot Topics

• Laboratory developed tests (home brew), and
  Multivariate index assays
• Personalized medicine, drug/device
  co-development, companion diagnostics, critical
  path, biomarkers, and combination products
• Direct to Consumer Genetic Testing
• Biothreat diagnostics/inter-agency
  activities/pandemic flu
• CLIA Waiver