Integrating Laboratory Services

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


Selecting Treatment


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)


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?


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)


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

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The Tortuous Path

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…

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9

Drug without CDx

Success Fail

11

IVT assay without a drug

Success Fail

1

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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

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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

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

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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%

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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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Heterogeneity

Gerlinger M 2012


Alternative tissues

Maheswaran S 2008

Schwarzenbach H 2011

Circulatingcell-free nucleic acid

Circulating Tumor Cells


Oncology leads in CDx development

Agrawal et al., 2015


What are the key areas of CDx development?

Davis et al., 2009


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.


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.


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?


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


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


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


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


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


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


Courier NetworkStrategically located

Medpace Full Service

Central LabsUSA

Global capabilities can enhance the development of CDx


Central Labs

SINGAPORE


Central LabsCHINA


Central Labs

BELGIUM


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


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


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


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


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

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

Integrating Laboratory Services

Health & Medicine

Transcript of Integrating Laboratory Services