# Presentation: 828613

## New Draft Guidance for Multiplex Tests

**Elizabeth Mansfield and**
**Michele Schoonmaker**
**Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)**

**CDRH/FDA**

## Notice of Availability was posted in the Federal Register on April 21, 2003.

Draft guidance can be found at:
http://www.fda.gov/cdrh/oivd/guidance/1210.pdf

Draft comment period is 90 days

Draft will be withdrawn and amended

- Draft guidance can be found at:
- _[http://www.fda.gov/cdrh/oivd/guidance/1210.pdf](http://www.fda.gov/cdrh/oivd/guidance/1210.pdf)_
- Draft comment period is 90 days
- Draft will be withdrawn and amended

**Draft Multiplex Guidance**

## Recommendations are non-binding

OIVD has little experience reviewing multiplex tests 

OIVD hopes that industry will step forward with meaningful ideas for good guidance

- OIVD has little experience reviewing multiplex tests
- OIVD hopes that industry will step forward with meaningful ideas for good guidance

**Major Points**

## As with other devices, regulatory path will be determined using a risk-based approach (not technology-based)

FDA does not consider multiplex tests as ASRs

Genomics and genetics have been combined in a single draft

- FDA does not consider multiplex tests as ASRs
- Genomics and genetics have been combined in a single draft

**Major Points**

## Technical Issues in Multiplex Test Validation

## Intended Use

- FDA requires that a device have an intended use, which usually encompasses the indications for use.
- Intended use specifies what the test measures, why, and in what population it should be used.
- FDA generally does not recommend multiple intended uses in a single submission.

## Platform Design and Manufacturing

- Should conform with applicable parts of the Quality System Regulation
- Recommend characterization of design, components, instruments/software, methods/conditions, layout and stability, etc.
- Controls and calibrators: identity and physical location (if applicable), value assignment, span decision points (if applicable), etc.

## Test Design: Pre-analytical

- Describe collection, storage, handling processing of sample (identity, acceptance criteria, etc.)
- Validate purification and/or amplification methods
- Describe acceptance criteria for material used in assay (e.g., 260/280, conc., etc.)

## Specific performance characteristics

- Analytical studies on clinical samples (where appropriate)
- Sensitivity
- Reproducibility/precision
- Cut-off, ref. range, decision point
- Assay range
- Effect of excess/limiting sample
- Specificity and interfering substances

## Array and data processing

- Optimization of multiple simultaneous target detection
- Sample carry-over/signal bleeding
- Computational methods
- Limiting factors, e.g., saturation level of hybridization

## Instrumentation

- Instrumentation can be general purpose or part of a system
- If general purpose, should be characterized and have specifications
- If part of a system, will be reviewed
- Describe calibration of and uncertainties introduced by instrument

## Regulatory Strategies

## 510(k): Class II devices

- Compare to:
- A commercially available predicate device (percent agreement)
- A reference method or “gold standard”
-    (Sensitivity/specificity)
- Standard is substantial equivalence

## PMA: Class III devices

- Comparison to clinical diagnosis
- Define “clinical truth” first
- Sample adequate specimens/populations
- Determine ref. ranges if appropriate
- May verify with second detection system (e.g. RT-PCR, other appropriate system)
- Standard is “safe and effective”

## De novo 510(k)

- A clearance process for certain moderate-risk novel devices that have no predicate
- Compare to reference method or   clinical diagnosis
- Standard is “safe and effective”

## Pre-IDE (protocol review)

- IDE not required
- Sponsor describes proposed intended use and supporting studies
- Interactive process to provide feedback prior to initiating studies.
- Non-binding on either party
- Recommended for novel devices or uses

## Clinical Effectiveness

- New markers, mutations, patterns should meet FDA standard for effectiveness for clinical use (see 21 CFR 860.7)
- Established markers may refer to clinical literature to support the effectiveness of the marker for clinical use.

## Use of Literature

-     For some markers, mutations or patterns, a sufficient literature base may exist to support clinical validity.
- Provide summary of available information pertinent to device.
- Should use same technology as “new” test and similar patient population.

## Problem areas

## Study Design

- How to establish appropriate sample numbers, identities, etc., esp. when available samples are rare
- Archived vs. prospective sampling?
- Multiple intended uses for a single test?

## Statistical Methods

- Depending on type of test, statistical methods may be straight-forward, complex and/or novel. FDA is uncertain what types of methods may be presented.
- Describe statistical methods used for calculations, including measures of precision, confidence intervals

## Quality Control	

- What will be the measure of quality control?
- Will there be universal standards/controls for arrays?
- Importance of controls in inter- and intra-assay reproducibility at manufacturer and user level

## Regulatory Environment

- Least Burdensome
- TPLC principles
- Transparency (truth in labeling)

## Your role

- Review draft guidance carefully
- Make comments to the docket
- On the guidance
- On related issues
- Unvalidated features on clinical diagnostic
- General vs. specific claims
- Combination devices (CDRH and CDER or CBER)
- Understand QSR (formerly GMP)

## Future Directions

- Specific guidance is probably needed for QSR/GMP for microarray and multiplex devices—input from interested parties would be valuable