Post on 16-Jan-2017
Integrating Laboratory Services
Richard Scheyer, MDVP, Medical Affairs, Medpace
Abdel Halim, PharmD, PhDVP, Translational Medicine, Biomarkers and Diagnostics, Celldex Therapeutics
Matthew Kelso, PharmD, PhDAssoc Dir, Medpace Reference Laboratories
Managing Biomarker-Driven Clinical TrialsSCOPE Summit 2016
2 Physician Led | Therapeutically Focused
Collaboration of CRO, Laboratory andSponsor to Support Biomarker-Driven Clinical Trialso Ensuring assay quality in face of
extended trial and evolving technologyo Balancing interests and priorities of
diagnostic and therapeutic sponsorso Accelerating assay turnaround in global
trials
What do We Need?
When Do We Need It?
Richard Scheyer, MDVice President Medical Affairs,
Medpace
4 Physician Led | Therapeutically Focused
Selecting Treatment
5 Physician Led | Therapeutically Focused
Regulatory Framework“Ideally, a therapeutic product and its corresponding IVD companion diagnostic device should be developed contemporaneously, with the clinical performance and clinical significance of the IVD companion diagnostic device established using data from the clinical development program of the corresponding therapeutic product.” FDA In Vitro Companion Diagnostic Devices Guidance August 2014
Frueh FW 2007 (FDA)
6 Physician Led | Therapeutically Focused
Biomarker Validation / Qualification
o Assay analytical / pre-analytical validation Need assay sufficiently reliable, reproducible, and
accurate for the intended application (“fit for purpose”)o Biological validation “qualification”
Links BM with clinical outcomeFor a predictive biomarker: Does BM identify which patients will benefit from our
drug? Does BM identify which patients may be harmed by
our drug?
7 Physician Led | Therapeutically Focused
Predictive BM Qualification
o Need: Data for both Drug and reference therapy
o Need: Both BM+ and BM- (<threshold) patients
BM+
?≠
BM-
Outcome on drug
Outcome on reference therapy[ ] Outcome on drug
Outcome on reference therapy[ ]For a BM to qualify as predictive, it must predict effect of treatment. Effect of drug in BM+ patients must differ from effect of drug in BM- patients:
Meier K 2009 (FDA)
8 Physician Led | Therapeutically Focused
Targeted Design: “Enrichment”Treat only BM+ patients
o Pros: Ethics: Only treat patients
likely to benefit Efficiency
• Major savings if BM+ uncommon & BM has high biological importance
» Herceptin, Crizotinibo Cons:
Need rapid tumor sample acquisition, & adequate quality assay with rapid turn-around time
• Issues especially in early development
Tissue Is the Issue
10
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11 Physician Led | Therapeutically Focused
The Tortuous Path
12 Physician Led | Therapeutically Focused
CDx; Efficient Planning and Collaboration are Badly Needed
Abdel Halim, PharmD, PhD, DABCC, FACBVP, Translational Medicine, Biomarkers & DX
SCOPE Summit 2016- Managing Biomarker-Driven Clinical Trials
CDx can help you succeed but can lead to failure too…
1
9
Drug without CDx
Success Fail
11
IVT assay without a drug
Success Fail
1
19
A drug with a CDx
Success Fail
1
4
A drug with a CDx
Success FailGood assay
Bad assay
SPONSOR
Lab
CROIVD
CDx Stakeholders
page 15
Not only inter-party but within-pharma misalignment is challenging too
16
X 2
2Drug Co-development
Here’s the real world!
• PIII pivotal trial: ~1,000 patients at > 260 clinical sites located in > 20 countries in NA, SA, EU and AUS.
• Trial planned start date Dec 2010
• CDx discussions: Started July 2010
• Biomarkers EGFR and KRAS genotyping as CDx Biomarker A (Drug target) by FISH as a secondary endpoint
page 17
Qualification of a technology for EGFR & KRAS
page 18
Whole gene /exon sequencing
Targeted mutation detection
RFLP + Sequence
HRMA + Sequence
ARMS ASP + TaqMan
Efficiency Gold standard; can detect all mutations
Detect prevalent known mutations; 95% of EGFR, and 98.5% of KRAS mutations
LOD (M/WT) 25-30% <1% 5 1-2% 10%
Sensitivity 70-75% > 99% 95% 98-99% 90%
% indetermin. Expected > ARMS due to longer amplicon and subjectivity ~5% due to poor sample quality
Complexity High; needs skills High, needs confirmation by sequencing
Low; can be run by a reasonably-trained tech
TAT 4 days to 2 weeks from sample receipt 3-5 days from sample receipt
Result output Highly subjective Less subjective than sequencing alone
Objective
Candidacy for automation
No Yes
Approval LDT-candidate IVD kit-candidate
Amplification Refractory Mutation System (ARMS)
Qualification of an IVD manufacturer- The world two leaders in molecular DX
page 19
IVD I IVD IICapability as IVD manufacturer + ++++
Capability related to molecular testing in general
+ +++
Capability in oncology/FFPE +++ +
Years in market in oncology testing kits
2.5 0
Readiness of EGFR and KRAS testing platform for CDx (Lockable assay)
EGFR in Sep 2010, and KRAS Feb-May 2011
KRAS in Sep 2010, and EGFR Mar-Jun 2011
Mutation coverage 95% of known EGFR and 98.5% of known KRAS
~0.7-1% more coverage than IVD I is possible but could not be guaranteed or disclosed
EGFR and KRAS Testing Scenarios
Typical CDx prospective strategy No lockable test kits for both from either IVD I or II with a possible IDE by Dec
2010
Mid-trial bridging Start with a LDT (if acceptable to FDA), convert to an IVD when ready with
bridging (reanalysis of all previous samples)
Post-trial bridging Complete the trial with LDT, bridge to IVD after the trial ends
• Even 2nd and 3rd options were close-to-impossible to attain in the time window!
page 20
Pros and Cons of Different Scenarios
Scenario Pros ConsProspective Optimal regulatory path Does not meet study timelines; ~
a year delayMid-trial bridging
Meet study timelines • Regulatory & contractual limitations
• Availability of lockable IVD could not be guaranteed
• Tissue availability and concordance of bridging
Post-trial Meet study timelines • Regulatory & contractual limitations
• Reanalysis of all samples• 18 – 30 months after trial
ends
Risk of bridging• Probability of discordance; Final IVD version might not
perform like “prototype” or “LDT” versions.
• Potential reasons for discordance;
• Intra-sample heterogeneity
• Biomarker stability
• Analytical factors
• Wrong decision on enrollment;
• Bias data/clinical outcome
• Medical/legal liability
• Samples may not be enough to test at enrollment and bridging
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LDT vs IVD as a provider for a CDxo Pros
Less expensive ~1/3 of the IVD Less parties easier for pharma to manage Can be a solution for low-number tests (orphan)
o Cons While any regulated lab (CLIA/CAP) can perform analysis for a pivotal
clinical trial under IDE, for post-approval launch, the lab should have the capabilities to mange patients
Less regulatory experience Inferior quality- Less traceability; No to low GMP capabilities Post-approval limitations
• One testing location vs worldwide accessibility logistics• Risk to close the testing site including disastrous situations, license
suspension or abandoning the test, e.g. PT failure• Low probability to approve same test from a competitor (exclusivity!!)• Less experience in reimbursement approaches• Reimbursement problem in some countries
More realty of the real world!
Continuous changing of priority/plan1. EGFR & KRAS as CDx, Biomarker A by FISH secondary2. No, BM A by FISH as a CDx and EGFR & KRAS for
randomization using LDT3. No, just BM A by IHC as a secondary endpoint (retrospective
analysis) + EGFR & KRAS by LDT4. No, BM A by IHC as a CDx- retrospective approach
page 24
Qualification of a wet lab
Main attributes CLIA-accredited Capability to report EGFR and KRAS genotyping results within a
reasonable TAT Has or willing to have the preferred technology As global reach as possible, with the assays validated/transferred at/to
different sites, is preferred Has good record for sample tracking/management
page 25
Recommendations for wet lab(s): EGFR & KRAS genotyping
page 26
Candidates Top Reasons for recommendations7 Laboratories 2 (A
&B)*• No one of all these candidates have the assay validated to
meet our expectations but A is already working on, and B promised to finish before study start
• CDx companies stated that they could work with both• Both have been using current our preferred technology• Large companies, presumably more stable• Both give reasonable turn-around-time; 5-6 working days• Both can report regular histopathology from the same set
of slides• Prior experience• A and, probably, B can manage sample shipping from site
to testing lab which could streamline logistics.
*Not including the lab used in the PII
page 27
A B
Previous experience
+++ +
Platform One of the preferred technology for EGFR and KRAS
One of the preferred technology for EGFR and the other for KRAS
Testing locations Two testing sites (US & EU); sample transit time to 24-72 hr & reduce shipping cost
One testing site (US)
Status of assay validation for EGFR and KRAS
A great part of assay validation is complete. Need 6-8 weeks
12-14 weeks for assay validation
Turn around time (from sample receipt)
5 working days 6 working days
Cost $2.2M $1.8M
Final selection of a wet lab
Assay validation parameters
• Optimization; set up the most appropriate conditions for the reactions
• Sensitivity; % of cell lines and/or tumor tissues known positive that can be detected by the technique
• Specificity; % of cell lines and/or tumor tissues known negative that give negative results by the technique
• Limit of detection (LOD); The lowest concentration of mutant DNA that can be detected by the technique in terms of % mutant in WT background
• Repeatability ; within-run precision by repeating a reasonable number of mutant specimens within the same run
• Reproducibility; between-runs/days precision by repeating a reasonable number of mutant specimens on a reasonable number of days
• Stability???
page 28
Garbage-in Garbage-out
Pre-analytical variables- Examples of tissue samples
Samples can severely impact enrollment
30
1st 6 months% Last 12 months0
10
20
30
40
50
60
50.0
30.027
5.6
Total
Tissue-related
% s
cree
n fa
ilure
KRAS kit change
Time Was expected Feb/May 2011 It happened in Jul
What was changed? Some reagents, likely, polymerase which was in-licensed from a
competitor
Supply in-hand ~3 weeks
Cross-validation All cell lines, synthetic DNA used initially ~ 20 split from previously tested human samples covering the assay
dynamic range Overall concordance; ~98%
31
How poor quality samples can put pivotal PIII trials at risk?
Geographical trend- Racial??
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E EU W EU US S AM0%
10%
20%
30%
40%
50%
60%
70%
34%
56%60% 63%
Chart Title
% p
ositi
ve s
ampl
es
% IHC-positive samples from different clinical sites in global PIII trial ( 4 samples/site)
0
10
20
30
40
50
60
70
80
90
100
0.0
100.0
47.2% posAver % +Linear (Aver % +)
% p
ositi
ve
Impact of time between sectioning to analysis
1-12 13-24 25-36 37-48 >4825
30
35
40
45
50
55
60
65
70
75
66.7
53.3
41.237.8
30.8
52.0
Time in weeks
% p
ositi
ve
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Recipe for a CDx success
Pharma Early cross-department consensus, planning and alignment is critical Good projection for the need for a universal kit or if a LDT can be enough Rigorous assessment and qualification of partners
Lab Transparency; only promise what you can deliver Highlight expected challenges but not just attractive selling points Good assay validation with sample stability included Good QC program including assessment of sample quality
CRO Setting up logistics and good sample reconciliation plan Efficient result reporting link for real-time analysis Lab manual to specify sample acquisition, processing, storage and handling Training sessions to sites
IVD Do not make timelines and cost too prohibitive
Copyright: <a href='http://www.123rf.com/profile_shsphotography'>shsphotography / 123RF Stock Photo</a>
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38 Physician Led | Therapeutically Focused
Heterogeneity
Gerlinger M 2012
39 Physician Led | Therapeutically Focused
Alternative tissues
Maheswaran S 2008
Schwarzenbach H 2011
Circulatingcell-free nucleic acid
Circulating Tumor Cells
40 Physician Led | Therapeutically Focused
Oncology leads in CDx development
Agrawal et al., 2015
41 Physician Led | Therapeutically Focused
What are the key areas of CDx development?
Davis et al., 2009
42 Physician Led | Therapeutically Focused
Medpace Central Labs Biomarker Trends
o Strong biomarker growth over the past 5 years.
o From 2010 to 2015, more than 1.9 million biomarker results were released.
2010-2015
2010 2011 2012 2013 2014 20150
20
40
60
80
100
120
140
160
Number of Trials Utilizing Biomarker Test-ing
Lipid/CV Other Areas
Num
ber o
f Tria
ls
Cardiovascular and lipid metabolism trials are large-scale and highly dependent upon biomarkers for primary, secondary and exploratory endpoints.
43 Physician Led | Therapeutically Focused
Biomarker Growth Outside CV/Lipid Metabolism Trials
Nearly doubled the number of biomarker results reported in therapeutic areas other than lipid metabolism and cardiovascular disease.
44 Physician Led | Therapeutically Focused
Biomarker Therapeutic Areas 2010 – 2015
We have translated our biomarker experience in lipid metabolism and cardiovascular trials into a wide range of therapeutic areas.
Lipid Metabolism
Endocrinology
Cardiovascular
Oncology
Autoimmune Disease
Nephrology
GastroenterologyCNS
Infectious DiseaseMusculoskeletal
ObesityReproductive
Hematology Lysosomal Storage Disorder
Coagulation
How can a Central Laboratory Partner in Clinical Trial Conduct?
46 Physician Led | Therapeutically Focused
Full Service Central Labo Scientific consulting o Analytical serviceso Project managemento Logistics managemento Biorepository services and sample managemento Data managemento Clintrak® Lab portal for study progress and result
viewingo Quality assurance
47 Physician Led | Therapeutically Focused
Operating Accreditations and Governanceo Same level of accreditation and certification at all
locations CAP (College of American Pathologists) certified Global participation in CDC Lipid Standardization
Program is unique in the industry NGSP (National Glycohemoglobin Standardization
Program) Level 1 certification NIST (National Institute of Standards and
Technology) participation in the Micronutrients Measurement QA Program for Vitamins A (Retinol) and E (tocopherols)
o Operate under the principles of GCLP
48 Physician Led | Therapeutically Focused
Comprehensive Testing Capabilitieso Safety
Hematology, Chemistry, Urinalysis, Coagulation, Serology
o Biomarker Testing Methodology
• Chemiluminescence, ELISA, multiplexing, flow cytometry, Molecular Biology (PCR), HPLC/UPLC
o DNA/RNA extractiono PBMC isolation
49 Physician Led | Therapeutically Focused
Networking with other Laboratories
o Contracting Services Confidentiality Disclosure Agreements Master Service Agreements Study Task Orders
o Quality Oversight – QA team performs a risk assessment/audit
o Integration of the 3PL (Third Party Lab) 3PL samples included in collection kits 3PL collection instructions included in lab manuals 3PL results integrated into database
o Invoicing Medpace manages invoicing of 3PLs
A seamless experience for Sponsor
50 Physician Led | Therapeutically Focused
Personnel Staff Qualifications
– Adequate level of training/education to conduct lab testing
– Dedicated Lab Operators for the clinical trial– All technical personnel are medical technologists with
ASCP or equivalent certification– Technologists dedicated to clinical trials
51 Physician Led | Therapeutically Focused
Project Managemento PM is Sponsor’s primary point of contact o Responsible for overall delivery of the study
including: Triage of scientific inquiries to Medpace Central
Labs scientific staff Development of Laboratory Services Agreement in
collaboration with Sponsor Preparation of protocol-specific materials
• Supply Specifications• Requisitions• Laboratory Manual
52 Physician Led | Therapeutically Focused
Courier NetworkStrategically located
Medpace Full Service
Central LabsUSA
Global capabilities can enhance the development of CDx
Medpace Full Service
Central Labs
SINGAPORE
Medpace Full Service
Central LabsCHINA
Medpace Full Service
Central Labs
BELGIUM
53 Physician Led | Therapeutically Focused
Biorepository & Sample Management Serviceso Over 7,000 sq ft of archive storage space onsite
and the capacity to store 2M+ specimens-expandable capacity
o Global presence US, Leuven, Belgium, Beijing, China and Singapore
o Completely secure and continuously monitored environment-multiple, redundant systems backup
o Capable of storing all types of specimens Serum, plasma, urine, DNA, RNA, biopsies and slides, PBMC, and PK
o Variety of controlled temperatures down to –180°C o Flexibility to manage study-specific handling
Aliquoting, buffering, relabeling, de-identifications
o Sample archive management is fully-integrated into our Laboratory Information Management System (LIMS), ClinTrak Lab®
Allows for rapid high-volume and cost-effective specimen storage allocation and retrieval
54 Physician Led | Therapeutically Focused
Data Management
o Customized to meet Sponsor’s format, frequency, and mode of transfer as defined in a Data Transfer Agreement (DTA) Transfers in all major formats: SAS, ascii, CDISC
(SDTM) Experience with many different CRO and Pharma
company data management systems and teams Daily transfers to IXRS systems for the purpose of
screening, randomizing, stratifying or titrating subjects
Experience & Execution – Data Transfer Metrics
Transfers to Client/CRO with Different Formats and Specifications Average Monthly Transfers Average Yearly Transfers
> 90 150 1500
55 Physician Led | Therapeutically Focused
ClinTrak® Lab Web Portalo 24/7/365 web access, views from the global database
Sponsor and investigative site access – tiered permissionso Medpace Labs study team contact informationo Central document repository
Laboratory manual, Quick Reference Chart, Reference Ranges, Accreditations
o Report views include: Daily and Cumulative Lab Reports Study Progress Reports Exclusion Summaries Trend Analysis and Graphing Query Builder Issue Management
56 Physician Led | Therapeutically Focused
Maintaining Global Consistencyo Extensive delta check and recheck procedures prior to result release
Acceptance criteria for all parameters based on method imprecision and biological variation
o Extensive inter-laboratory comparison program Medpace Labs takes extraordinary measures to ensure that all results
generated globally are as identical as possible Ensures lab data reflects impact of your compound and not differences
in testing practiceso Internal QC Programs
Internal QC every 40 samples on automated platforms• More comprehensive than industry standard (beginning and end of
run/shift) In-house QC pools (multi-level) with appropriate matrix for lipid
parameters and biomarkers• CDC-certified Serum Pools for Calibration and Quality Control of Lipid
Testing with target value assigned directly by CDC
57 Physician Led | Therapeutically Focused
Quality Assuranceo QA team is independent of operations
Reports directly to the President of the companyo The QA department is responsible for:
Oversight of company operations & quality systems Monitoring & audit activities per the QA Oversight
Plan• External / Internal / Referral Lab • Risk based approach – effectiveness of quality
control• Administration of Quality Events
Policy and Procedure Management • Administer QMS documents via the EDMS
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BM Lab
Courier
Study Site
Pathogy Lab
Study Lead
Trial Manager
Data Manager
CRA
Patient
59
Right Medicine for Right Patient at Right Dose at Right Time
Thank you
The Right Analysis of the Right Sample at the Right Time
Roundtable
o Accelerating assay turnaround in global trials
o Ensuring assay quality in face of extended trial and evolving technology
o Balancing interests and priorities of diagnostic and therapeutic sponsors