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Department of
Health and Human
Services
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
Department of
Health and Human
Services
Setting
• Coordinated, interdependent development and
use of diagnostic devices and therapeutics is
both needed and happening now.
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Preclinical drug development
Focusing drug trials
Shaping drug indications (test, then treat)
Measuring drug effect (treat, then test…)
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Department of
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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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What’s 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
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Sensitivity
Specificity
Accuracy
Precision
Cut-off
Linearity
• Clinical
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Cut-off
Sensitivity
Specificity
Dose response
• Clinical Utility
- Population
- Individual
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Department of
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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. Tumorassociated 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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Department of
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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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Department of
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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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Department of
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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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Department of
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Immunohistochemical Applications
“Class I IHC’s provide the pathologist with adjunctive diagnostic
information that may be incorporated into the pathologist’s report, but that
is not ordinarily reported to the clinician as an independent finding.”
“Class II IHC’s 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 IHC’s
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 IHC’s] are IHC’s that do not meet the criteria for class I or class
II, or are IHC’s 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.
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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 BMpatients?
- 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 patient’s 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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Department of
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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.
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