1. 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

2. 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…)

3. 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.

4. What’s coming… Serological tumor markers Histological tumor markers
Recent Applications
CD 117
Her2/neu
EGFR

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

6. Practical Challenges in Validation
Analytical
Sensitivity
Specificity
Accuracy
Precision
Cut-off
Linearity
Clinical
Cut-off
Sensitivity
Specificity
Dose response
Clinical Utility
Population
Individual

8. 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.”

9. TAA Uses and Impacts Diagnosis Monitoring Prognosis Prediction
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

10. Histological Tumor-Associated Markers
Reviewed (history)
Immunohistochemistry
Gene amplification (FISH)
Not yet reviewed (future)
Gene expression (mRNA)
Gene imbalance (CGH)
Somatic mutations

11. Immunohistochemistry Methods

12. 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.

13. 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.

14. 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.

16. 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.”

17. 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.

18. 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?

19. 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.

20. 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.

21. 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

22. 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.

23. 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.

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