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- 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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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 timesFixative time
Analytical:Technical: Different IHC Antibodies may have different sensitivity to receptorsProfessional: 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 VariabilityCAP/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 MarkersTHE 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 categorizati
on is critical for treatment decisions
Clinical categorizati
on 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:oAdenocarcinomaoSquamous cell carcinomaoLarge 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
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