New Draft Guidance New Draft Guidance for Multiplex Testsfor Multiplex Tests

Elizabeth Mansfield andElizabeth Mansfield andMichele SchoonmakerMichele Schoonmaker

Office of In Vitro Diagnostic Office of In Vitro Diagnostic Device Evaluation and Safety Device Evaluation and Safety

(OIVD)(OIVD)

CDRH/FDA

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

Draft guidance can be found at:Draft guidance can be found at:http://www.fda.gov/cdrh/oivd/guidance/1210.pdhttp://www.fda.gov/cdrh/oivd/guidance/1210.pdff

Draft comment period is 90 daysDraft comment period is 90 days

Draft will be withdrawn and amendedDraft will be withdrawn and amended

Draft Multiplex Guidance

Recommendations are non-bindingRecommendations are non-binding

OIVD has little experience OIVD has little experience reviewing multiplex tests reviewing multiplex tests

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

Major Points

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

FDA does not consider multiplex FDA does not consider multiplex tests as ASRstests as ASRs

Genomics and genetics have been Genomics and genetics have been combined in a single draftcombined in a single draft

Major Points

Technical Issues in Technical Issues in Multiplex Test Multiplex Test

ValidationValidation

Intended UseIntended Use

FDA requires that a device have an FDA requires that a device have an intended use, which usually intended use, which usually encompasses the indications for use. encompasses the indications for use.

Intended use specifies what the test Intended use specifies what the test measures, why, and in what population measures, why, and in what population it should be used.it should be used.

FDA generally does not recommend FDA generally does not recommend multiple intended uses in a single multiple intended uses in a single submission.submission.

Platform Design and Platform Design and ManufacturingManufacturing

Should conform with applicable parts of Should conform with applicable parts of the Quality System Regulationthe Quality System Regulation

Recommend characterization of design, Recommend characterization of design, components, instruments/software, components, instruments/software, methods/conditions, layout and methods/conditions, layout and stability, etc.stability, etc.

Controls and calibrators: identity and Controls and calibrators: identity and physical location (if applicable), value physical location (if applicable), value assignment, span decision points (if assignment, span decision points (if applicable), etc.applicable), etc.

Test Design: Pre-Test Design: Pre-analyticalanalytical

Describe collection, storage, handling Describe collection, storage, handling processing of sample (identity, processing of sample (identity, acceptance criteria, etc.)acceptance criteria, etc.)

Validate purification and/or Validate purification and/or

amplification methodsamplification methods

Describe acceptance criteria for Describe acceptance criteria for material used in assay (e.g., 260/280, material used in assay (e.g., 260/280, conc., etc.)conc., etc.)

Specific performance Specific performance characteristicscharacteristics

Analytical studies on clinical samples Analytical studies on clinical samples (where appropriate)(where appropriate)

SensitivitySensitivity Reproducibility/precisionReproducibility/precision Cut-off, ref. range, decision pointCut-off, ref. range, decision point Assay rangeAssay range Effect of excess/limiting sampleEffect of excess/limiting sample Specificity and interfering substancesSpecificity and interfering substances

Array and data Array and data processingprocessing Optimization of multiple Optimization of multiple

simultaneous target detectionsimultaneous target detection Sample carry-over/signal bleedingSample carry-over/signal bleeding Computational methodsComputational methods Limiting factors, e.g., saturation Limiting factors, e.g., saturation

level of hybridizationlevel of hybridization

InstrumentationInstrumentation

Instrumentation can be general Instrumentation can be general purpose or part of a systempurpose or part of a system

If general purpose, should be If general purpose, should be characterized and have specificationscharacterized and have specifications

If part of a system, will be reviewed If part of a system, will be reviewed Describe calibration of and Describe calibration of and

uncertainties introduced by instrumentuncertainties introduced by instrument

Regulatory Regulatory StrategiesStrategies

510(k): Class II 510(k): Class II devicesdevices

Compare to:Compare to:

A commercially available predicate A commercially available predicate device (percent agreement)device (percent agreement)

A reference method or “gold A reference method or “gold standard”standard”

(Sensitivity/specificity)(Sensitivity/specificity)

Standard is substantial equivalenceStandard is substantial equivalence

PMA: Class III devicesPMA: Class III devices

Comparison to clinical diagnosisComparison to clinical diagnosis Define “clinical truth” firstDefine “clinical truth” first Sample adequate specimens/populationsSample adequate specimens/populations Determine ref. ranges if appropriateDetermine ref. ranges if appropriate May verify with second detection system May verify with second detection system

(e.g. RT-PCR, other appropriate system)(e.g. RT-PCR, other appropriate system) Standard is “safe and effective”Standard is “safe and effective”

De novo 510(k)De novo 510(k)

A clearance process for certain A clearance process for certain moderate-risk novel devices that moderate-risk novel devices that have no predicatehave no predicate

Compare to reference method or Compare to reference method or clinical diagnosisclinical diagnosis

Standard is “safe and effective”Standard is “safe and effective”

Pre-IDE (protocol Pre-IDE (protocol review)review)

IDE not requiredIDE not required Sponsor describes proposed Sponsor describes proposed

intended use and supporting intended use and supporting studiesstudies

Interactive process to provide Interactive process to provide feedback prior to initiating studies.feedback prior to initiating studies.

Non-binding on either partyNon-binding on either party Recommended for novel devices or Recommended for novel devices or

usesuses

Clinical EffectivenessClinical Effectiveness

New markers, mutations, patterns New markers, mutations, patterns should meet FDA standard for should meet FDA standard for effectiveness for clinical use (see 21 effectiveness for clinical use (see 21 CFR 860.7)CFR 860.7)

Established markers may refer to Established markers may refer to clinical literature to support the clinical literature to support the effectiveness of the marker for clinical effectiveness of the marker for clinical use.use.

Use of LiteratureUse of Literature

For some markers, mutations or For some markers, mutations or patterns, a sufficient literature base patterns, a sufficient literature base may exist to support clinical validity.may exist to support clinical validity.

Provide summary of available Provide summary of available information pertinent to device.information pertinent to device.

Should use same technology as Should use same technology as “new” test and similar patient “new” test and similar patient population.population.

Problem areasProblem areas

Study DesignStudy Design

How to establish appropriate How to establish appropriate sample numbers, identities, etc., sample numbers, identities, etc., esp. when available samples are esp. when available samples are rarerare

Archived vs. prospective sampling?Archived vs. prospective sampling?

Multiple intended uses for a single Multiple intended uses for a single test?test?

Statistical MethodsStatistical Methods

Depending on type of test, statistical Depending on type of test, statistical methods may be straight-forward, methods may be straight-forward, complex and/or novel. FDA is uncertain complex and/or novel. FDA is uncertain what types of methods may be what types of methods may be presented. presented.

Describe statistical methods used for Describe statistical methods used for calculations, including measures of calculations, including measures of precision, confidence intervalsprecision, confidence intervals

Quality ControlQuality Control

What will be the measure of quality What will be the measure of quality control?control?

Will there be universal Will there be universal standards/controls for arrays?standards/controls for arrays?

Importance of controls in inter- and Importance of controls in inter- and intra-assay reproducibility at intra-assay reproducibility at manufacturer and user levelmanufacturer and user level

Regulatory Regulatory EnvironmentEnvironment

Least BurdensomeLeast Burdensome

TPLC principlesTPLC principles

Transparency (truth in labeling)Transparency (truth in labeling)

Your roleYour role

Review draft guidance carefullyReview draft guidance carefully

Make comments to the docketMake comments to the docket– On the guidanceOn the guidance– On related issuesOn related issues

Unvalidated features on clinical diagnosticUnvalidated features on clinical diagnostic General vs. specific claimsGeneral vs. specific claims Combination devices (CDRH and CDER or CBER)Combination devices (CDRH and CDER or CBER)

Understand QSR (formerly GMP)Understand QSR (formerly GMP)

Future DirectionsFuture Directions

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