# Presentation: 036330

## FDA Overview of Molecular Diagnostics and the Critical Path Initiative

- Steven Gutman, MD, MBA
- Director, Office of In Vitro Diagnostics

## Medical Device Amendments of 1976

- General controls
- Registration and listing
- Good manufacturing practices
- Post market reporting

## Premarket Review

- 510(k)s
- PMA
- Administrative differences
- Common scientific base

## Analytical Performance

- Accuracy
- Precision
- Analytical specificity
- Analytical sensitivity

## Clinical Performance

- Signals can be turned in to clinical action
- Diagnostic sensitivity
- Diagnostic specificity
- Predictive value or positive or negative results

## Labeling -- 809.10(b)

- Intended use
- Performance characteristics
- Limitations

## Analytical performance
Feasibility *
Clinical performance 
FDA approval – market access
---------------------
Real world use

- Analytical performance
- Feasibility *
- Clinical performance
- FDA approval – market access
- ---------------------
- Real world use

## FDA 
CMS (CLIA)
CMS and others (third party pay)

- FDA
- CMS (CLIA)
- CMS and others (third party pay)

## Slide 9

## Slide 10

## Critical Path Initiative

- Biomarkers appear in two contexts
- Diagnosis
- Drug discovery
- Concept of personalized medicine grounded in genomic map but not bounded by this

## Critical Path Initiative

- Infrastructure
- Opportunities list
- Pilot programs

## Cutting edge new technology -- multiplex, bioinformatics, nanotechnology
Paucity of material or method standards
Biological and clinical nuances
Financial uncertainties

- Cutting edge new technology -- multiplex, bioinformatics, nanotechnology
- Paucity of material or method standards
- Biological and clinical nuances
- Financial uncertainties

## Scientific limitations are clear 
Spectrum bias
Verification bias
Impact of missing data points
Discrepancy

- Scientific limitations are clear
- Spectrum bias
- Verification bias
- Impact of missing data points
- Discrepancy

## Regulatory trail is well lit
Literature
Standards
Guidances

- Regulatory trail is well lit
- Literature
- Standards
- Guidances

## Principle Road Maps

- STARD Initiative
- ReMARK Initiative

## Growing Literature on Co-Development

- Simon and Wang, 2006
- Pennello and Vishnuvajjala, 2005
- Sargent et al, 2005
- Pustzai and Hess, 2004

## Growing FDA Guidance

- Voluntary Genomic Data Submissions guidance
- Concept paper on co-development
- Statistical guidance on IVD labeling
- Guidance on pharmacogenetic and heritable genetic tests
- Bayesian statistics

## Broad menu of regulatory tools
Mandate to be least burdensome
New scientific resources -- MDUFMA
New regulatory programs -- FDA data template, critical path

- Broad menu of regulatory tools
- Mandate to be least burdensome
- New scientific resources -- MDUFMA
- New regulatory programs -- FDA data template, critical path

## Flexible Regulatory Tools

- Pre-IDE
- Expedited reviews
- Real time reviews
- De novo classification

## Cystic Fibrosis test – 109 days
Avian flu – 14 days
UGT1A1 – 9 days

- Cystic Fibrosis test – 109 days
- Avian flu – 14 days
- UGT1A1 – 9 days

## Co-Development

- If predictive diagnostic determines drug choice
- Safety and effectiveness of drug becomes hostage to diagnostic
- Need to understand system as a whole

## Predictive Marker

- Identify patients by biomarker status; randomize therapy across all patients
- Identify patients by biomarker status; randomize therapy in subsets
- Randomize by treatment; look back at biomarkers

## Predictive Marker

|  | Positive test | Positive test | Neg test | Neg test |
| --- | --- | --- | --- | --- |
| Therapy | A 
(response) | B (non-response) | C
(response) | D (non-response) |
| Placebo | E
 (response)  | F (non-response) | G (response) | H (non-response) |

## Predictive Marker

|  | Positive test | Positive test |  |  |
| --- | --- | --- | --- | --- |
| Therapy | A 
(response) | B (non-response) |  |  |
| Placebo | E
 (response)  | F (non-response) |  |  |

## FDA Mission

- Promote public health
- Protect public health
- Tension in objectives

## Good Science