Harmonizing AP & H Services in Support of Global Oncology
 

Harmonizing AP & H Services in Support of Global Oncology

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- Challenges Inherent in Conducting Oncology Clinical Trials ...

- Challenges Inherent in Conducting Oncology Clinical Trials
- Pre Analytic and Analytic Variability
- Understanding Disease Complexity and the Need for Flexibility in Trial Design
- Testing Methodologies Required to Support Oncology Trials

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  • Overview: DUAL FOCUS – Best practices in diagnostic oncology services and supporting global clinical trials <br /> Objectives: Attendees should leave this event with a clear understanding of where APH fits and how it’s applied, and hopefully take away some new ideas you can incorporate into your clinical trial design and execution. <br />
  • Transition to Brodie – more detailed intro…”he will take us through the role of APH, including a couple of case studies. <br /> Reiterate request for attendees to submit questions <br />
  • Verbalize for framing: This is why central labs exist <br />
  • We currently have more than 700+ pathologists who have utilized our tech-only model (and over 2000 that have simply referred work to us). <br /> Within that group, there are multiple KOLs and SMEs that subspecialize in an area of pathology, hematopathology, uropathology, dermatopathology, GI pathology, etc. <br /> Covance and Neo can control who will provide professional component services based on the nature of any proposed study. <br /> If Pfizer wants a Ewing&apos;s Sarcoma FISH expert to read cases from her office in Helsinki, but all of the samples are in the US and China….the answer is “Yes, we can do that for you.” <br /> (read remaining bullets) <br />
  • Present an opportunity for tailored treatments. <br />
  • NCCN guidelines are recommending EGFR and ALK FISH testing to detect ALK gene rearrangements and then recommending Crizotinib therapy for all ALK positive patients. ROS1 is now a footnote here. <br /> Several testing methodologies are actively being discussed in the literature including PCR, IHC and FISH. An advantage of FISH is that a commercially available ASR for ROS1 and an FDA-approved ALK FISH probe kit are on the market. <br /> The IHC tests utilized to detect ALK gene rearrangements are inadequate for the detection of the majority of ALK-rearranged lung adenocarcinomas primarily due to the low level of ALK expression in rearranged NSCLCs compared to anaplastic large cell lymphomas. There is no ROS1 IHC test or standards yet. <br />

Harmonizing AP & H Services in Support of Global Oncology Harmonizing AP & H Services in Support of Global Oncology Presentation Transcript

  • HARMONIZING AP & H SERVICES IN SUPPORT OF GLOBAL ONCOLOGY CLINICAL TRIALS Paul Kirchgraber, MD, FCAP Covance Central Laboratory Services Steven Brodie, Ph.D. FACMG NeoGenomics Laboratories, Inc. May 21, 2014
  • SESSION AGENDA / INTRODUCTION • Challenges Inherent in Conducting Oncology Clinical Trials • Pre Analytic and Analytic Variability • Understanding Disease Complexity and the Need for Flexibility in Trial Design • Testing Methodologies Required to Support Oncology Trials
  • Importance of Oncology Clinical Trials ONCOLOGY IS NEARLY A $100 BILLION SEGMENT Harmonizing APH May 21, 20143 Already highest # of clinical trials, oncology increased 4.9% (2013 vs ‘14)
  • But Hold the Lowest FDA Approval Rate (approval from Phase1 = 6.7%) Harmonizing APH May 21, 20144 SOURCEs: Citeline Pharma R&D Annual Review 2014 (Trialtrove) Nature Biotechnology volume 32 NUMBER 1 Jan 2014 Fierce Pharma May 2014
  • Covance Existing Histology Network & Experience Harmonizing APH May 21, 20145 Our oncology protocols, 2009-13  1000+ protocols  75+ countries  24,000+ investigator sites  141,000+ patients 47 of the 50 best selling oncology drugs were developed in partnership with Covance
  • Complexity of Anatomic Pathology for Global Oncology Trials EXAMPLE: THROUGH LENS OF BREAST CANCER Harmonizing APH May 21, 20146 ER / PR and HER2 testing Pre-analytical: Differences in pre-fixation cold ischemic times Fixative time Analytical: Technical: Different IHC Antibodies may have different sensitivity to receptors Professional: Subjectivity/variability in interpretation  ALTTO trial – central review pre-randomization confirmation of receptor status at the European Institute of Oncology (EIO) N > 1000; 4.3 % false positive for ER on central review, and 20 % false negative JNCI 2006;98(21):1571  In ECOG 2197, 11 percent of local ER-negative tests were scored positive upon central testing; concordance rate for ER of approximately 90 percent J Clin Oncol. 2008;26(15):2473.
  • Recent Guidelines address ER/PR/HER2 IHC Variability CAP/ASCO 2010 Harmonizing APH May 21, 20147 Standards: Defined cut point for positivity of ER/PR as >/= 1% Use of and interpretation of controls Standardized specimen rejection criteria (controls, crush artifact, lack of normal epithelium in negative)
  • Guidelines address IHC Variability (cont.)  Validation and Repeat criteria  Laboratory Accreditation (CAP or equivalent); n.b. IHC validation and PT not required by CLIA  Guidelines for other IHC/other clinical indications receive less attention  Recent CAP IHC validation guidelines- generalized to other TA’s outside Breast CA CAP/ASCO 2010 Harmonizing APH May 21, 20148 Arch Path Lab Med 2010 134:907
  • Harmonizing APH May 21, 20149 One Approach to Combining Technical and Professional Expertise in AP & H Services New Covance Lab co-located with NeoGenomics facility in Fort Myers, Florida ► Covance performs technical component services globally ► Images digitalized ► NeoGenomics performs professional component services centrally Technical Component Professional Component
  • Mitigating the Variability In Oncology Trials with Tissue Markers THE KEY IS COMBINABILITY Harmonizing APH May 21, 201410 • Pre-fixation cold ischemia time and fixation time remains with sites, usually prior to any consideration for clinical trial; • More education needed. ER/PR/HER2 guidelines help • Analytical controls very important. • Same Ventana Benchmark instrumentation in Ft Myers, Shanghai, soon in GVA, Singapore • Sequestered lot numbers of antibodies for trials • Same SOPs globally • Training in IHC/FISH by Neo staff • Digital pathology utilized for centralized IHC reading by small number of experts • Bioview FISH TC by Covance; PC by NeoGenomics • Central reading more consistent than numerous sites • LIMs and digital images allow for 3rd party adjudication in near real time
  • Steven G. Brodie, Ph.D., FACMG Director of Molecular Genetics and Cytogenetics NeoGenomics Laboratories Harmonizing AP & H Services in Support of Global Oncology Clinical Trials
  • Benefits of Harmonizing AP + Histology Services 12 • Complete integration of cancer diagnostic testing methodologies • Cytogenetics • Flow cytometry • Fluorescence in-situ hybridization (FISH) • Immunohistochemistry (IHC) • Molecular genetics • Specialization in AP enables confident diagnosis of cancer • Macroscopic, microscopic, biochemical, immunologic and/or molecular examination of organs and tissues • Flexible LIS system + extensive network of pathologists • Reduced sample and data variability via localization of testing services
  • Access to Professional Network Tap expertise of 700+ Pathologists KOL professional services • Broad array of pathology subspecialties, global locations • Sponsor can control / direct who performs professional component services on all trials • Seamless delivery of clinical data Flexible, global and high quality reviews w/o compromising consistency Flexible, global and high quality reviews w/o compromising consistency
  • Genetics Neighborhood - Testing “resolution” • IHC -picture of a neighborhood like Google Maps analogous to human tissue architecture. • Cytogenetics -picture of a neighborhood with 46 houses from 1000 feet up. Each house is analogous to a human chromosome. • Flow Cytometry –picture walkways and trim around a single house from 500 feet. The trim around the house is analogous to the cell surface markers. • FISH gives you a close-up view of the doors and windows of one house. The doors and windows are analogous to a gene located on a chromosome. • Molecular testing gives you a close-up view of the serial number on the door lock. The serial number is analogous to a DNA sequence. CytogeneticsCytogenetics IHCIHC Flow CytometryFlow Cytometry FISHFISH MolecularMolecular
  • HER2 FISH and 2013 Guidelines Normal Amplified
  • Positive Reported as positive Negative Reported as negative FISH Antibody test Equivocal Reported as negative Not amplified Reported as positive Amplified >10% moderate/strong, complete membrane staining No staining HER2 Testing Algorithm Clinical categorization is critical for treatment decisions Clinical categorization is critical for treatment decisions
  • HER2 FISH Testing Algorithm Protocol design should include flexibility to reflex to additional markers Protocol design should include flexibility to reflex to additional markers
  • HER2 Equivocal Testing 18
  • • Diagnoses: Lung Cancer >220,000 cases in USA anticipated in 2011; 2nd most common type of cancer • Deaths: ~157,000 anticipated. More common than colon, breast & prostate combined • 85% of all lung cancers are non-small cell lung cancer (NSCLC) which includes: oAdenocarcinoma oSquamous cell carcinoma oLarge cell carcinoma Source: Nurses’ Health Study Non-Small Cell Lung Cancer (NSCLC)
  • Heterogeneity in NSCLC Normal lung tissue Abnormal Lung tissue Complexity of disease requires an informed and precise approach Complexity of disease requires an informed and precise approach
  • ALK (EML4) EGFR HER2 K-Ras Raf Erlotinib/ gefitinib Inhibitors Prevention of cell deathCell proliferation EGFR (HER1) & HER2 Cell Signaling Pathway
  • Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical Trial. Participation in clinical trials is especially encouraged. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical Trial. Participation in clinical trials is especially encouraged.
  • Complexity of mutations drive therapy •EGFR mutations : Increased or reduced sensitivity to erlotinib, gefitinib •HER2: 4-5%; mutation not amplification: Herceptin benefit unknown •KRAS mutations: Reduced sensitivity to erlotinib, gefitinib •BRAF V600E: <2%; potential for future therapy NCCN Guidelines for NSCLC
  • Navigating Global Clinical Trials • Successful oncology clinical trials require the right diagnostic tools, flexible protocol design and seamless execution • Anatomic Pathology specialization • Global network of investigator site support and central labs • Complexity of disease requires an informed and precise approach • Clinical categorization is critical for treatment decisions Reducing sample and data variability in clinical trials begins with standardized testing, smart logistics and quality data management Reducing sample and data variability in clinical trials begins with standardized testing, smart logistics and quality data management
  • • Challenges Inherent in Conducting Oncology Clinical Trials • Pre Analytic and Analytic Variability • Understanding Disease Complexity and the Need for Flexibility in Trial Design • Testing Methodologies Required to Support Oncology Trials Session Goals