IVD Validation and Regulation in Rx/Dx Combinations

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IVD Validation and Regulation in Rx/Dx
Combinations
FDA/Industry Statistics Workshop Classifiers in
Combination Rx/Dx Submissions
Robert L. Becker, Jr, MD, PhD U.S. Food and Drug
Administration Center for Devices and
Radiological Health Office of In Vitro Diagnostic
Device Evaluation and Safety
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Setting

• Coordinated, interdependent development and use
  of diagnostic devices and therapeutics is both
  needed and happening now.
• Preclinical drug development
• Focusing drug trials
• Shaping drug indications (test, then treat)
• Measuring drug effect (treat, then test)

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Practical Constraints

• Diagnostic devices measuring biomarkers have
  technical characteristics and limitations,
  demonstrated from experience, that inform their
  use.
• Biomarker measurement is a messy affair, with
  challenges that affect the ease of Rx/Dx
  application.
• Study designs for biomarker/IVD validation, and
  clearance or approval, present trade-offs.
• Regulatory approach must accommodate all of the
  above.

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Whats coming

• Serological tumor markers
• Histological tumor markers
• Recent Applications
• CD 117
• Her2/neu
• EGFR

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Serological Markers

• CA 19-9, CA 125, CA 15-3, CEA, AFP
• Monitoring (510(k))
• PSA
• Monitoring, total (510(k))
• Diagnosis, free and total (PMA)

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Practical Challenges in Validation

• Analytical
• Sensitivity
• Specificity
• Accuracy
• Precision
• Cut-off
• Linearity

• Clinical
• Cut-off
• Sensitivity
• Specificity
• Dose response
• Clinical Utility
• Population
• Individual

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Tumor Associated Antigen Immunological Test System
Measurement of tumor-associated antigen levels
may aid in the monitoring of patients for disease
progression or response to therapy or for the
detection of recurrent or residual disease.
Tumor-associated antigen immunoassay systems
intended for use in screening for the early
detection or diagnosis of cancer in either the
general population or in a high risk population,
or in disease staging, are not included.
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TAA Uses and Impacts

• Diagnosis
• Screening
• Confirmatory initial diagnosis
• Residual or recurrent disease
• Monitoring
• Change in tumor burden over time
• Prognosis
• Likely outcome (e.g. natural history), given a
  set of features
• Prediction
• Marker-dependent change in outcome, given a new
  or changed therapy

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Histological Tumor-Associated Markers

• Reviewed (history)
• Immunohistochemistry
• Gene amplification (FISH)
• Not yet reviewed (future)
• Gene expression (mRNA)
• Gene imbalance (CGH)
• Somatic mutations

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Immunohistochemistry Methods
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A Few IHC Complications

• Non-linear amplification, signal development
• Antigen recovery, variation
• Antibody specificity, affinity, avidity
• Readout variates (distribution, intensity,
  prevalence)
• As a result, analytical (and hence clinical)
  sensitivity and specificity are highly dependent
  on technique.

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FISH vs IHC Techniques

• FISH probes and ligands usually better defined
• FISH uses less layering or amplification
• FISH cytologic features more discrete possibly
  easier readout
• Multiple (e.g. two) markers readily accomodated
• Technique aside, what is clinical import? Less
  widely studied, but this is changing.

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Immunohistological Markers

• Long and wide (TNTC) experience with markers of
  tumor histogenesis generally Class 1 exempt
• Long but narrower (e.g. down-classified ER/PR)
  experience with markers for prognosis or
  prediction
• Recent experience with a few markers intended to
  help guide chemotherapy selection.

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Immunohistochemical Applications
Class I IHCs provide the pathologist with
adjunctive diagnostic information that may be
incorporated into the pathologists report, but
that is not ordinarily reported to the clinician
as an independent finding. Class II IHCs are
intended for the detection and/or measurement of
certain target analytes by immunological
techniques in order to provide prognostic and
predictive data that are not directly confirmed
by routine histopathologic internal and external
congtrol specimens. These IHCs provide the
pathologist with diagnostic information that is
ordinarily reported as independent diagnostic
information to the ordering clinician, and the
claims associated with these data are widely
accepted and supported by valid scientific
evidence. Class III IHCs are IHCs that do
not meet the criteria for class I or class II, or
are IHCs that meet those criteria but raise new
issues of safety and effectiveness.
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Three Recent PMA IHC Applications

• CD 117 (c-kit) for imatinib (Gleevec) treatment
  of gastrointestinal stromal tumor
• Her2/neu for trastuzumab (Herceptin) treatment of
  metastatic breast cancer
• EGFR for cetuximab (Erbitux) or panitumumab
  (Vectibix) treatment of metastatic colorectal
  cancer
• None of these applications included a prospective
  trial of the device for its ability to predict
  drug response.

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Absent a BM/BM- Drug Trial

• Biomarker predictive value for drug effect is
  incompletely evaluated at best.
• Rely on BM-dependent drug effect within BM
  patients.
• Risk exclusion of potentially responsive
  patients.
• Cannot dissect BM predictive power from
  prognostic power.
• How much confidence in the BM IVD cut-off? In the
  assay to meet it?
• Post-approval study commitments? Fulfillable?
• What non-trial evidence suffices to conclude
  non-response for BM- patients?
• Larger problem when BM fraction is small.
• Some combination of practical benefits to trial
  execution.
• Lower cost?
• More power?
• Fewer adverse events?

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CD 117 and Gleevec for GIST

• indicated as an aid in the diagnosis of GIST
  within the context of the patients clinical
  history, tumor morphology, and other diagnostic
  tests may be used after the diagnosis of GIST
  as an aid in the selection of GIST patients who
  may qualify for imatinib mesylate (Gleevec)
  therapy.
• Any specific staining is a positive result.
• Main utility is in helping to identify GIST, not
  in selecting the drug.

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Her-2/neu IHC and Herceptin for Breast Ca

• indicated as an aid in the assessment of
  patients for whom HERCEPTIN (Trastuzumab)
  treatment is being considered
• Graded staining result (2 vs 3 makes a
  difference)
• Technique and read-out variations, in deployed
  performance, may decrease effectiveness FISH
  back-up for IHC 2 cases.

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EGFR and Erbitux for Colorectal CA

• indicated as an aid in identifying colorectal
  cancer patients eligible for treatment with
  ERBITUX
• No sign of clinical response dependence on IHC
  signal strength
• Post-market suggestions that IHC negative
  patients respond similar to positives
• Ambiguity as to what is a negative result

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Some Issues to Address

• Analytical validation of IHC tests, the earlier
  the better, especially wrt definition and
  performance near cut-off points.
• Trial designs such that clinical validity is
  assessed across the full range of test results
  (i.e. including negative patients).
• Retention and access to clinical trial samples so
  that later tests (either same or different
  technique) can be properly evaluated.

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Why worry?

• Multiple modalities for tumor assessment aimed at
  drug selection are emerging EGFR for NSCLC as
  an example.
• Other markers further complicate the picture.
• Numerous non-comparable, low-power studies.
• Risk that biomarkers will be unfairly dismissed,
  or relied on without justification.

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Why hope?

• Issues, though complex and controversial, can at
  least be defined.
• Continually improving coordination between
  stakeholders.
• With large stakes, continuing interest seems
  assured.