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

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Development of Molecular In Vitro Diagnostics
for the Early Detection of Cancer Sudhir
Srivastava, Ph.D., MPH Chief, Cancer Biomarkers
Research Group
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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
  structures"
• authentication, certification - validating the
  authenticity of something or someone

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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
  specificity?

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Outline

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

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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

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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
  included
• User training should be the same for studies and
  for marketed assay

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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

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Clinical Validation /Clinical Utility

• May be based on
• New clinical trial data
• Prospectively collected data in a longitudinal
  study
• 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

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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
  validation
• 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

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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
  planned.

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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
  technology
• platforms.

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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
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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
  format.
• 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.

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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
  disease
• Prognostic Markers outcome survival
• Predictive markers outcome response to
  therapy

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Regulatory Aspects of Validation
Source Kesslers Presentation
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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

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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?

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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

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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
  preparation

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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
  presentation
• Expected values
• Specific performance characteristics
• Bibliography
• Name and place of business
• Date of the package insert

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Public Perspectives of Validation
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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

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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

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Summary

• 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