Diagnostic Assays to Plan Specific Drug Treatment

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Diagnostic Assays to Plan Specific Drug Treatment

• Elizabeth Hammond MD

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Criteria for Development of Diagnostic assays

• Defined assay characteristics for total test
• Standardized procedures for assay, reference
  materials and training plan to assure initial
  and ongoing competence
• Acceptable interlaboratory variability evaluated
  in standard manner, possibly using TMAs
• Plan for new laboratory validation
• Plan for ongoing laboratory competence assessment

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Assay Characteristics

• Specimen adequacy definition of unacceptable
  samples
• Specimen handling time from surgery to
  processing, time in fixative, temperature
• Standardized Reference Materials
• Assay conditions precise, clearly reported
• Interpretation and reporting criteria precise,
  including how reference material is used in the
  evaluation and acceptable limits of interobserver
  variation

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CAP FISH Survey Results

• FISH amplified
• 2000 35 participants
• 35/35 amplified
• 2001 63 participants
• 58/63 amplified
• (others no response)

• FISH non amplified
• 2000 35 participants
• 35/35 non amplified
• 2001 63 participants
• 49/63 non amplified
• (others no response)

CAP CYH survey results, 2000-2001
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CAP IHC (MK) Survey

• FISH amplified case
• 357 participants
• IHC scores
• 0 19 (3.7)
• 1 4
• 2 52
• 3 296

• FISH unamplified case
• 380 participants
• IHC scores
• 0 275
• 1 69
• 2 27 (7)
• 3 10 (3)

Source 2000 CYH 01, 02 and MK Surveys, CAP
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CAP MK B Survey Image Scoring
Score not provided for all images by all
participants
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FISH vs IHC

• Specimen handling, adequacy not specified for
  either assay type DNA less affected than protein
• FISH for Her2 has internal standard (Chr 17)
• Standard procedures and training are mandatory
  for laboratories performing FISH, but not
  required for all IHC assays
• Interpretation criteria are quantitative and
  clearly specified for FISH, ambiguous for IHC

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Conclusions

• Use of central laboratory during pivotal trial is
  necessary if there is not assay method
  standardization, standardized reference materials
  and training plans for assay and interpretation
• Interlaboratory comparison of assay and
  interpretation criteria should be conducted
  concurrently with pivotal trial
• Validated assay with standardized reference
  materials, training plan, and interpretation
  criteria is required prior to Phase III trial

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Treatment Guidelines for Patients with Negative
Assay Results

• Assay should not be used to assign treatment if
• Relationship between analyte and drug efficacy is
  unclear
• Interpretation guidelines of assay do not clearly
  specify cut point of positive and negative
• Assay method is non validated
• Standardized reference materials are not available

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Package Insert Information

• Specific information about specimen adequacy and
  handling parameters
• Assay performance characteristics with assay
  comparisons, where appropriate
• Assay interpretation guidelines
• Acceptable methods of assay validation in a lab
• Acceptable levels of interlaboratory variability
• Requirement of laboratory participation in
  ongoing competency assessment

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Assay Utility Assessment

• Phase III clinical trials should be used to
  assess assay utility
• Tissue banking on such trials should be mandatory
  so that new assays can be validated on the same
  specimens
• TMAs can be created to promote new assay utility
  assessment while optimizing tissue bank specimen
  use.

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TMA Concordance with Slides
RTOG Study, presented USCAP, 2001 N 150 tumors