Development of Molecular In Vitro Diagnostics for the Early Detection of Cancer - PowerPoint PPT Presentation


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Development of Molecular In Vitro Diagnostics for the Early Detection of Cancer


FDA device classification and review is driven by ... Determine potential risks of device. If positive more diagnostic tests or surgery? ... – PowerPoint PPT presentation

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Title: Development of Molecular In Vitro Diagnostics for the Early Detection of Cancer

Development of Molecular In Vitro Diagnostics
for the Early Detection of Cancer Sudhir
Srivastava, Ph.D., MPH Chief, Cancer Biomarkers
Research Group
Definition of Validation
  • validation - the act of validating finding or
    testing the truth of something
  • determination, finding - the act of determining
    the properties of something, usually by research
    or calculation "the determination of molecular
  • authentication, certification - validating the
    authenticity of something or someone

Meaning of Diagnostic Validation
  • Fletcher
  • Is the test clearly described?
  • Is the true presence or absence of disease
    established for all individuals?
  • Is the spectrum of patients with and without
    disease adequate?
  • Is assessment of test and disease status
    conducted in an unbiased manner?
  • Is the performance summarized by sensitivity and

  • Disease-Context Validation
  • - Analytical Validation
  • - Clinical validation
  • Regulatory Perspectives of Validation Background
  • Tools and Solutions
  • Public Perspective of Validation
  • A Hypothetical Example
  • Summary

Analytical Validation
  • Precision (reproducibility)
  • Accuracy (clinical samples compare to cleared or
    gold standard method )
  • Limit of Detection
  • Potential Interferences
  • Software
  • Sample preparation / conditions
  • Performance around the cut-off
  • Potential for carryover or cross-hybridization
  • Assay Limitations
  • Confidence Intervals

Analytical Validation
  • Precision (Reproducibility)
  • Studies should demonstrate that the intended
    users can get reliable results
  • Studies should evaluate reproducibility of assay
    at external sites
  • Should use clinical samples where possible
  • All analytical steps of the assay should be
  • User training should be the same for studies and
    for marketed assay

Analytical Validation
  • Accuracy
  • Real clinical samples
  • Compare to a reference method, e.g.,
    bi-directional DNA sequencing
  • In limited cases (i.e., very rare alleles) may
    use contrived samples
  • Samples should mimic the molecular composition
    and concentration of real clinical samples

Clinical Validation /Clinical Utility
  • May be based on
  • New clinical trial data
  • Prospectively collected data in a longitudinal
  • Retrospective studies
  • Must have appropriate IRB, informed consent
  • Sample control well characterized
  • Tests standardized across laboratories
  • Review of Information in the literature
  • e.g., Cytochrome P450 2D6 genotyping assay

Clinical Validation
  • Clinical studies are needed to show clinical
    utility in
  • Prospective clinical studies
  • Retrospective validation
  • Banked samples from prior clinical studies
    (optimal storage)
  • Bridging studies may be done if a platform change
    or device change is necessary after clinical
  • Clinical Cut-Offs
  • Clinical and analytical cut-off points should be
    described and
  • independently validated
  • Identify clinical cut-off points in a training
    set and validate them in
  • a test set
  • When applicable, literature references may
    support clinical cut-offs

Clinical Validation Go or No-Go Decision
  • Clinical validation studies are expensive.
  • Only few biomarkers may succeed.
  • There is a need for triage system that allows a
    Go or No-Go decision.
  • EDRN has developed a mechanism through which
    biomarkers are first tested in Standard Reference
    Samples for the intended use.
  • If successful, then a large validation study is

Standard Reference Samples
  • Standard Reference Samples are sets of samples
    with cases and controls statistically powered to
    allow rapid assessment of technologies and
    biomarkers discovered through a wide variety of
  • platforms.

Pipeline Concept From discovery to prevalidation
to validation
Prevalidation Reference Set
Validation Set
Convenience Set
Anything Theoretically Interesting or
identified Via profile
Screening or Diagnostic Sensitivity
gt40 Specificity 80 Analytical scale up
possible Potentially marketable Any stage cancer
Screening Sensitivity 60 Specificity
90 Diagnostic Has to match colonoscopy (gt95
sensitivity 99 specificity
Entry Fee
Higher cost for frozen tissue samples, they
are rarer
Regulatory Review Intended Use
FDA device classification and review is driven
by the intended use of the device and the
associated risk
  • The claims made in the intended use will
    determine the type of review and the types of
    studies that are necessary.
  • This is independent of the technology or assay
  • Example
  • The Roche AmpliChip CYP450 test is intended to
    identify a patient's CYP2D6 and CYP2C19 genotype
    from genomic DNA extracted from a whole blood
    sample. Information about CYP2D6 and CYP2C19
    genotype may be used as an aid to clinicians in
    determining therapeutic strategy and treatment
    dose for therapeutics that are metabolized by the
    CYP2D6 and CYP2C19 gene products.

Types of Intended Use
  • Risk Markers probability less than 100,
    outcome incidence
  • Early Detection Markers probability close to
    100, outcome
  • incidence
  • Diagnostic Markers probability 100, outcome
  • Prognostic Markers outcome survival
  • Predictive markers outcome response to

Regulatory Aspects of Validation
Source Kesslers Presentation
Regulatory Mechanisms forDiscussing IVD Markers
  • Determine potential risks of device
  • If positive more diagnostic tests or surgery?
  • And, hence, the class I, II, III
  • N.B. 510(k) vs. de novo 510(k)
  • If applicable
  • Pre-IDE (Investigational Device Exemption)
  • IDE

Device Description
  • The Biomarker
  • CA125, Mesothelin and HE4
  • Linear combination of standardized values
  • Focus on change over time in serum
  • Sample requirements
  • Platform description
  • Algorithm description complex software involved?

Quality System Regulations
  • Design controls
  • Design quality in
  • Define inputs
  • Define outputs
  • Controlled environment and processes
  • Modern approach toward quality
  • Harmonized approach toward quality, ISO, GHTF

Labeling of in vitro diagnostic devices 809.10(b)
  • Proprietary and established names
  • Intended Use(s)
  • The Access OV Monitor assay is indicated for
    use in the measurement of CA 125 antigen to aid
    in the management of ovarian cancer patients.
  • Summary and explanation of test
  • Principle of procedures
  • Information on reagents
  • Information on instruments
  • Information on specimen collection and

Labeling 809.10(b)(continued)
  • Procedures
  • Results
  • Limitations of the procedure
  • 4. The Access OV Monitor results should be
    interpreted in light of the total clinical
  • Expected values
  • Specific performance characteristics
  • Bibliography
  • Name and place of business
  • Date of the package insert

Public Perspectives of Validation
Biomarker (Device) In Health Care
  • Definitive Technology, e.g. Vaccine, X-ray
  • Competing Technology, e.g., Sputum Cytology
  • and other biomarkers
  • Half-Way Technology (Add On),
  • e.g., biomarkers
  • Cost Saving Technology

Biomarkers in Health Care
  • Considerations for Technology Assessment
  • Degree to which technology supports the needs of
    cancer patients and physicians
  • Throughput and cost-effectiveness
  • Standardization and quality control

(No Transcript)
  • Diagnostic testing is becoming more complex
  • Suggests early interaction with FDA is desirable
  • Biomarker Test Development
  • Prime Time for FDA Approval of a Suite of Tests
    Multimarker Strategy for same indication?
  • The de novo process brings new technologies,
    whose safety and effectiveness have been
    established, to market faster
  • Increased dialogue between Regulatory Agencies
    and developers as science develops