New Draft Guidance for Multiplex Tests

1
New Draft Guidance for Multiplex Tests
CDRH/FDA

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

2
Draft Multiplex Guidance

• 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• Draft guidance can be found at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• Draft will be withdrawn and amended

3
Major Points

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

4
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

5
Technical Issues in Multiplex Test Validation
6
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.

7
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.

8
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.)

9
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

10
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

11
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

12
Regulatory Strategies
13
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

14
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

15
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

16
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

17
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.

18
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.

19
Problem areas
20
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?

21
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

22
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

23
Regulatory Environment

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

24
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)

25
Future Directions

• Specific guidance is probably needed for QSR/GMP
  for microarray and multiplex devicesinput from
  interested parties would be valuable