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Biomarkers and FDA Regulation of In Vitro Diagnostic Devices


Qualification of a biomarker means developing the correlative ... from Studies Evaluating Diagnostic Tests (March 07) ... Pre-IDEs ... – PowerPoint PPT presentation

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Title: Biomarkers and FDA Regulation of In Vitro Diagnostic Devices

Biomarkers and FDA Regulation of In Vitro
Diagnostic Devices
HUPO 2008 Amsterdam, NL 19 August 2008
Robert L. Becker Jr, MD, PhD Office of In Vitro
Diagnostics CDRH / FDA
Biomarker Qualification
  • Qualification of a biomarker means developing the
    correlative information that lets us understand
    its clinical meaning in a given situation
  • Qualification often must begin with an initial
    stage of standardization of the technology, i.e.,
    need for a reproducible, quantitative test.

Once a biomarker is qualified
  • Development and use of a diagnostic test
  • Validation of biomarker assay

-gt OIVD (Office of In Vitro Diagnostic Device
Evaluation and Safety) clearance or approval
of diagnostic tests that measure biomarkers in a
clinical setting
  • Risk-based classification and submission paths
  • Validation of Biomarker Assay (for an Intended
    Use) submission elements
  • Analytical Validation
  • Clinical Validation
  • Sources for Help

Regulatory Mechanisms for IVD Markers
  • PMA
  • 510(k)
  • De novo
  • IDE
  • HDE

Risk-Based Regulation
Risk-Based Classification of IVDs
  • Class III most complex, high risk
  • e.g. cancer diagnosis or screening
  • Premarket Application PMA
  • Safety, effectiveness
  • Class II more complex, moderate risk
  • e.g. prognosis, monitoring in already diagnosed
    cancer patients
  • Premarket Notification 510(k)
  • Substantial equivalence
  • Special controls
  • Class I common, low risk devices
  • Most exempt from premarket submission
  • General controls

Risk for Intended Use determines type of
  • A CFTR genotyping assay with the indication
  • For carrier screening
  • For fetal screening
  • One multiplex instrument system with two devices
  • Device detecting BCR-ABL for CML diagnosis
  • Device detecting BCR-ABL for monitoring

? 510(k) ? PMA
  • PMA
  • ? 510(k)

In-Vitro Diagnostic Products
Review and Approval Requires
  • Evidence for Safety
  • Are there reasonable assurances, based on valid
    scientific evidence that the probable benefits to
    health from use of the device outweigh any
    probable risks? 860.7(d)(1)
  • Evidence for Effectiveness
  • Is there reasonable assurance based on valid
    scientific evidence that the use of the device in
    the target population will provide clinically
    significant results? 860.7(e)(1)

Ultimately - provide patients access to new and
useful diagnostic tests
Major Elements of IVD Submission
  • Intended use/indications for use
  • Device description
  • Analytical Validation
  • Clinical Validation/Clinical Utility
  • Instrument and software validation, if applicable
  • Labeling (package insert) - truth in labeling
  • For PMA - manufacturing, design controls, quality
    system requirements (QSR/GMP) (21 CFR 820 all
    products must follow)

Intended Use
What assay measures, how to use
results determines FDA classification, risk
Review path, types of studies depend on IU
claims Independent of the technology or assay
format. Example MammaPrint is a qualitative
in vitro diagnostic test service, performed in a
single laboratory, using the gene expression
profile of fresh frozen breast cancer tissue
samples to assess a patients' risk for distant
metastasis. The test is performed for breast
cancer patients who are less than 61 years old,
with Stage I or Stage II disease, with tumor size
lt 5.0 cm and who are lymph node negative. The
MammaPrint result is indicated for use by
physicians as a prognostic marker only, along
with other clinicopathological factors.
Indication For Use
Analytical Validation
  • Analytical performance
  • Precision (repeatability, reproducibility)
  • Accuracy
  • Sensitivity, Limit of Detection
  • Specificity (interference, cross-reactivity)
  • Sample type / matrix
  • Sample preparation / conditions
  • Performance around the cut-off
  • Potential for carryover, cross-hybridization

Analytical Validation Steps
  • Varies with technology
  • Varies with Quantitative or Qualitative
  • Varies with setting of use (e.g., marketed vs.
    single laboratory service)
  • Varies by what is reported (individual markers
    vs. composite score)

For example Precision
  • Intended to capture total test variability
    (should capture all steps from specimen prep to
    final result)
  • Varies with technology, setting of use, and what
    is reported
  • Day to day variation
  • Lot to lot variation
  • Operator to operator variation
  • Lab to lab variation (Depends…)
  • For each marker or the final score (Depends..)

  • Real clinical samples
  • Compare to a reference method, e.g.,
    bi-directional DNA sequencing for genotyping
  • Certain assays comparison of assay results to a
    clinical outcome

Analytical validitydoes my test measure the
analyte I think it does? Correctly? Reliably?
Clinical validitydoes my test result correlate
with the expected clinical presentation? How
Limit of Detection
  • Index derived from microarray
  • …assess specimen integrity and minimum
    amount of RNA to run assay
  • Combines results of multiple assays
  • …May need to establish LOD for each assay to
    determine if it is reasonable
  • FDA refers to several CLSI guidance documents
    (EP5, EP6, EP9, EP12, EP17…)

  • Performance characteristics described in the
    Special Controls Guidance document
    Instrumentation for clinical multiplex test
  • http//

  • Software documentation for a software controlled
    medical device of moderate level of concern per
    FDAs Guidance for the Content of Premarket
    Submissions for Software Contained in Medical
    Devices http//
  • Software Risk assessment Ensuring that all
    potential hazards are identified, e.g., incorrect
    results/interpretation. Documenting how these
    hazards are reduced or mitigated by the test

Clinical Validation Steps
  • Training Set(s)
  • Develop classifier and/or cut-offs
  • Fully specified device
  • Test Set (s)
  • Independent Validation on intended use population

Statistical challenges
  • Prospective studies are not always feasible
  • Retrospective and / or banked samples are a
  • Need to be representative of intended use
  • Consecutive cases meeting a set of inclusion /
    exclusion criteria
  • Storage conditions dont impact assay

Appropriate Statistical Methods
  • Well planned studies
  • Confirmatory studies w/Protocols
  • Fully specified device, hypotheses, success
    criteria, statistical methods
  • Statistical Guidance on Reporting Results from
    Studies Evaluating Diagnostic Tests (March 07)

Labeling of In Vitro Devices
  • 21 CFR 809.10
  • Clear instructions for use
  • Need to capture expected analytical and clinical
    performance of device
  • Prospective performance in intended use

Some tips
  • Study plan for an in vitro diagnostic product
    depends on the intended use
  • Type of data required depends on the intended
    use, indications for use, technological
    characteristics of the device, and on other
    claims made by the manufacturer

Device Advice
  • See the Center for Devices and Radiological
    Health website at http//, and
    especially its Device Advice link at
    http//, for useful
    information about the regulation and review of
    medical devices, including in vitro diagnostic

Additional Guidance Documents
  • Pharmacogenetic tests and genetic tests for
    heritable markers
  • http//
  • Quality Control Material for Cystic Fibrosis
    Nucleic Acid Assays - Class II Special Controls
    Guidance Document http//
  • Drug-Diagnostic Co-Development Concept Paper
  • Guidance on Informed Consent for In Vitro
    Diagnostics Device Studies Using Leftover Human
    Specimens that are Not Individually Identifiable

  • Not an IDE (just a misnomer)
  • It is a protocol review and regulatory guidance
  • No charge to the sponsor
  • Non-binding on either party
  • Recommended for novel devices / uses
  • http//

  • Allow us the opportunity to become familiar with
    the technology before seeing the formal
    pre-market submission.
  • Provide manufacturers with advice on types of
    submission and types of data appropriate in order
    to maximize the likelihood of rapid premarket
    review with a successful outcome.

  • Special Thanks to
  • Dr. Reena Philip
  • Dr. Maria Chan
  • Dr. Estelle Russek-Cohen
  • Dr. Zivana Tezak

Thank You !
  • General information http//
  • OIVD website http//