# Presentation: 775854

## FDA’s Role in the Regulation of In Vitro Diagnostic Steven I. Gutman, MD

## MEDICAL DEVICE AMENDMENTS OF 1976

## General Controls

- Register and List
- Follow good manufacturing practices
- Report device failures

## General Controls

- Inventory of  tests on the market
- Tools to require good manufacturing practices
- System for remedying device failures

## Premarket Review

- Division of Clinical Laboratory Devices (DCLC)
- 60 scientists

## Submissions Reviewed

- Premarket Notification 510(k)s
- Premarket Approvals (PMAs)

## Semantic Framework

- Old vs. New
- In vitro diagnostic devices

## 510(k)s

- ~ 650 submissions/year
- Substantially equivalent
- Comparisons to predicate device

## 510(k) Reviews

- Accuracy
- Precision
- Analytical sensitivity
- Analytical specificity

## Limitations in Review

- Paper review
- Lack of performance standards

## PMA Review

- ~ 6 - 12 applications/year
- Safety and Effectiveness

## SAFE MEDICAL DEVICES ACT of 1990

- Broader scope to FDA’s regulation
- Safety and effectiveness _summary_
- Safety and effectiveness _statement_

## Clinical Performance Characteristics

- Clinical sensitivity
- Clinical specificity
- Predictive values

## Limitations of Review

- Lack of “gold standards”
- Overt and latent bias
- Lack of performance standards

## Labeling of in vitro diagnostic devices 809.10(b)

- Proprietary and established names
- Intended Use(s)
- Summary and explanation of test
- Principle of procedures

## Labeling 809.10(b)(continued)

- Information on reagents
- Information  on instruments
- Information on specimen collection and preparation

## Labeling 809.10(b)(continued)

- Procedures
- Results
- Limitations of the procedure

## Labeling 809.10(b)(continued)

- Expected values
- Specific performance characteristics
- Bibliography
- Name and place of business
- Date of the package insert

## Intended Use

- Type of  review
- Questions raised
- Data required

## Scientific Model

- Literature
- Voluntary Standards
- FDA guidances

## Development of a Scientific Model

- Upfront design of  the study
- Careful and meticulous collection of data
- Sound interpretation of results

## Quantitative Tests

- Bias or inaccuracy
- Precision
- Experiments for sensitivity and specificity

## Quantitative Tests

- Regression analysis
- ANOVA analysis
- Adequate scope and stress in specificity testing

## Qualitative Tests

- Cut-off points
- Equivocal zones
- Less certain statistical techniques

## FDA Review

- Not outcome oriented
- Usually concurrent not prospective
- Good science

## In-House Laboratory Tests

- Wide variety of tests
- Common practice in laboratories

## In-House Laboratory Tests

- Medical devices
- FDA enforcement discretion
- Recognition of CLIA’s role

## Analyte Specific Reagents (ASRs)

- Rule effective November 24, 1998

## Analyte Specific Reagents

- Antibodies, specific receptor proteins, nucleic acid sequences, and similar biological reagents which through chemical binding or reaction with substances in specimen are intended for identification and quantification of an individual chemical substance or ligand in biological specimens

## ASR: Impact on Manufacturers

- Required to register and list
- Required to meet good manufacturing practices
- Required to report adverse events
- Restricted distribution, use, and labeling

## ASR: Impact on Laboratories

- Restricted to high complexity laboratories
- CLIA requirements
- Report disclaimers

## Labeling of ASRs

- Mandatory language, restricted labeling
- Discretionary explanation

## Postmarket Controls

- Compliance -- production safety
- Surveillance -- problem identification and correction

## Postmarket Controls

- Office of Compliance
- Office of Surveillance and Biometrics
- Dichotomized support -- program vs technical

## Good Manufacturing Practices

- Codified in 1980s
- IVD GMP guidance in 1992
- Moral equivalent to CLIA

## Good Manufacturing Practices

- Clear production requirements
- Field inspections
- Mandatory reports to central office
- Selected premarket reviews

## Quality System Regulations

- GMP regulations revised in 1994
- Based on European ISO model
- Administrative program unchanged
- Administrative program more rigorous

## Quality System Regulations	

- Independent quality assurance function
- Controlled environment
- Controlled processes
- Trained personnel

## Quality System Regulations	

- Design Controls
- Design quality in
- Define inputs
- Define outputs

## Quality System Regulations	

- Verify match
- Validate match

## Quality System Regulations

- Modern approach toward quality
- Harmonized approach toward quality
- Nidus of new inspectional systems

## Medical Device Reporting

- Mandatory reporting manufacturers
- Mandatory reporting user facilities
- Voluntary reporting

## MedWatch Program

- Web based reporting system
- Fax, phone or e-mail
- 3000 reports per year -- glucose meters

## MedWatch Program

- Data quality
- Denominator data
- Arcane nature of lab error
- Poorly promoted
- Underfed and focused

## FDA Regulation

- Multifaceted
- Complex
- Nuanced

## FDA Dual Mission	

- Allow rapid access to good new technology
- Prevent bad products from being marketed
- Obvious inherent tension

## GOOD SCIENCE