Biomarkers: Not just another bioanalytical challenge

Biomarkers: Not just another Biomarkers: Not just another bioanalytical challenge

Patrick BennettPPD Biomarker Laboratorieso a abo a o

November 2015

European Bioanalysis ForumEuropean Bioanalysis Forum

European Bioanalysis Forum 20151

Biomarker Life Cycle

Discovery … Preclinical ... Clinical Testing … Commercialization

FDA Filing/Approval & Launch

PreclinicalDevelopment

Clinical

Phase 1 Phase 2 Phase 3

Prototype Design or Discovery

Basic Research

Target ID and Biomarker

Di

Clinical Validity/Utility of Post-market

Di tiand Validation Discovery y/ y

Screening/Dgx Diagnostics

Analytical Validation

Clinical Validation and Utility

Bridging


Agenda

2

Intended Use of Data

C li

1

2

3

Compliance

Analytical Platforms3

4

Analytical Platforms

Assay Challenges4

5

Assay Challenges

Industry Challengesy g


Comparing Intended Use

Bioanalytical Biomarker

● Dosed ● Endogenous analyte response to drug

oa a yt ca o a e

● Quantitative, Qualitative or bothD t i d t ti

drug● Quantitative, Qualitative or both● Measurement or characterization

in a biological matrix related to ● Determine drug concentration in biological matrix− ADME

in a biological matrix related to intended use− Up/down-regulated

Activity− Toxicology− Safety & Efficacy

− Activity− Predictive, diagnostic,

prognostic, theragnostic, pharmacodynamic

− Pharmacokinetics− Drug-Drug Interactions

● Drug metabolites

p y− Patient selection or stratification− Exposure− Safety/efficacy● Drug metabolites

● Immunogenicity

Safety/efficacy− Mechanism of action− Specific vs pathway

Actual or surrogate endpoint− Actual or surrogate endpoint


Use of Biomarker Data

● Biomarkers may have a change as a response to a o a e s ay a e a c a ge as a espo se to adrug or disease.

● Biomarker response does not have to be a change ● Biomarker response does not have to be a change in concentration. It can be a change in activity or function. function.

● There may be normal ranges of the biomarker, but the response observed may be an increase or but the response observed may be an increase or decrease and the % change may be great or very slight.slight.

● The normal range can vary both within patient and between patientand between patient.

● How normal range is established is variable.


Use of Biomarker Data

● Patient selection: rapid turnaround time, at e t se ect o ap d tu a ou d t e,global implementation

● Safety & medical diagnostic related: rapid ● Safety & medical diagnostic related: rapid turnaround time, global implementation, different compliance regulationscompliance regulations

● Method validation/compliance/sample analysis and reporting varies based on use of the dataand reporting varies based on use of the data

● May be poor standardization of sample collection, processing or curationprocessing or curation


Compliance Comparison


● Unregulated ● Unregulated

oa a yt ca o a e

g− Screening/discovery

● Tiered fit-for-purpose

g− Biomarker discovery− Research

● Tiered fit for purpose● Regulated

FDA

− Exploratory● Pharma Regulated

− FDA− EMEA

ICH

− FDA, EMEA, ICH, ANVISA, BARQA, OECDCAP & CLIA− ICH

− ANVISABARQA

− CAP & CLIA● Medical Regulated

LDT− BARQA− OECD

− LDT− CLIA− Diagnostic/DeviceDiagnostic/Device


Biomarker Compliance Challenges

● UnregulatedUnregulated● Pharma Regulated

Medical Regulated● Medical Regulated● Fit for purpose = bad term for biomarkers● Quality Vs. Compliance● Qualifications & ValidationsQualifications & Validations


Analytical Platform Comparison


● Technology ● Technology

oa a yt ca o a e

gy− LC/MS− Ligand Binding

gy− LC/MS− Ligand Bindingg g

● Method Development− Custom developed

− Flow Cytometry− Molecular Genomics

Custom developed− Proprietary− Very rare for commercial

− Imaging− Other – activity basedMethod De elopmentVery rare for commercial

kit● Method Development− Custom developed

Proprietary− Proprietary− Kit based− HybridHybrid


Assay Challenges Comparison


● Pre-analytical Factors ● Pre-analytical Factors

oa a yt ca o a e

y− Study Design− Compliance

− Study Design− Test selections

Laboratory selectionsp● Analytical Factors− Compliance

− Laboratory selections− Geography− ComplianceCompliance

− Method Development & Validation

● Analytical Factors− Compliance decisions per

analyte● Data Processing &

Reporting

analyte− Method Development &

Qualification/Validation p g− Study based ● Data Processing &

Reporting− Study & sample/patient basedStudy & sample/patient based


Biomarker Assay Challenges: Study Design

● Range of samples/time point possible for each a ge o sa p es/t e po t poss b e o eacstudy

● Shared samples for many biomarkers● Shared samples for many biomarkers● Healthy vs Diseased performance differences

Potentiall diffe ent locations labs companies ● Potentially different locations, labs, companies, instrumentation, methodology and SOPsS l ll ti i d hi i ● Sample collection, processing and shipping inconsistencies

● Matrix selection & volumes


Biomarker Assay Challenges: Methodology

● Sample preparation, linearity, precision, Sample preparation, linearity, precision, selectivity, sensitivity, sample and reagent stability, reagent specificity and availability, stability, reagent specificity and availability, parallelism

● Surrogate matrix● Surrogate matrix● Reagents

N COA h k − No COA, heterogenous, source unknown − Often no lot to lot continuity

● Trueness● Within and between study – multiple methods, y p

technologies, matrices possible● Clinical performanceClinical performance


Industry Structure Comparison


● Pharma/Biopharma: ● Pharma/Biopharma

oa a yt ca o a e

/ p− Discovery− DMPK/Bioanalytical

/ p● CRO− Bioanalytical

− Outsourcing & Procurement

● CRO:

Bioanalytical− Central Labs− Specialty Labs

− Bioanalytical group● LC/MS

Specialty Labs● University

Medical/Clinical ● LBA

● University:

● Medical/Clinical DiagnosticsCompanion Diagnostics

− Research− Clinical

● Companion Diagnostics● Vendors


Industry Challenges for Biomarkers

Pharma/Biopharma CRO

● Bioanalytical ● Bioanalytical group

a a/ op a a C O

y● Translational Sciences● Biomarker

y g p− LC/MS− LBA● Biomarker

● ClinicalO t i &

● Central Lab− LC/MS

● Outsourcing & Procurement

LC/MS− LBA− Flow CytometryFlow Cytometry− Molecular genomics− IHCIHC− Anatomical Pathology− Clinical ChemistryClinical Chemistry


Industry Challenges for Biomarkers

CRO

● Clinical Diagnostic &

C O

gHospital− Medical

● University− ResearchResearch− Medical

● Specialty Lab● Specialty Lab− Molecular genomics− Proteomics− Proteomics− Metabolomics− Other ‘omics− Other omics


Summary

● Bioanalysis of drugs can be challengingBioanalysis of drugs can be challenging● Bioanalysis/characterization of biomarkers can

be extremely challenging from an analytical be extremely challenging from an analytical, logistical and compliance standpointThe challenges between these are often not the ● The challenges between these are often not the same

f● The intended use of biomarkers dictates many decisions


Insightful Papers

● Pragmatic issues in biomarker evaluation for targeted therapies in cancer. Armand de Gramont Sarah Watson Lee M Ellis Jordi Rodón Josep Tabernero Aimery de Gramont, Sarah Watson, Lee M. Ellis, Jordi Rodón, Josep Tabernero, Aimery de Gramont & Stanley R. Hamilton. Nature Reviews Clinical Oncology 12, 197–212 (2015) doi:10.1038/nrclinonc.2014.202, Published online 25 November 2014.

● Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease Christine M ● Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Christine M. Micheel, Christine M., Committee on Qualifications of Biomarkers and Surrogate Endpoints in Chronic Disease, Institute of Medicine. 06/25/2010.

● Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and p pp gchallenges. Anna K Füzéry, Joshua Levin, Maria M Chan and Daniel W Chan. Clinical Proteomics 2013 10:13.

● http://bcn2014.europeanbioanalysisforum.eu/site/ebf_bcn2014/assets/slides/pdf/Marianne_Scheel_Fjording.pdf

● Abdel-Baset Halim (2011). Biomarkers in Drug Development: A Useful Tool but Discrepant Results May Have a Major Impact, Drug Discovery and Development -P t d F t D I t K t ić (Ed ) ISBN 978 953 307 615 7 I T h Present and Future, Dr. Izet Kapetanović (Ed.), ISBN: 978-953-307-615-7, InTech, Available from: http://www.intechopen.com


Insightful Papers

● Lee, J. W., W. Devanarayan, Y. C. Barrett, R. Weiner, J. Allinson, S. Fountain, S. Keller, I Weinryb M Green L Duan J A Rogers R Millham P J O’Brien J Salistad M I. Weinryb, M. Green, L. Duan, J. A. Rogers, R. Millham, P. J. O Brien, J. Salistad, M. Khan, C. Ray, and J. A. Wagner. 2006. Fit-for-purpose method development and validation for successful biomarker measurement. Pharmaceutical Research 23(2):312–328.( )

● Evaluation of biomarkers and surrogate endpoints in chronic disease / Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease, Board on Health Care Services, Board on Health Sciences Policy, Food and Nutrition Board,

f d h h l d h ll d l dInstitute of Medicine ; Christine M. Micheel and John R. Ball, editors. p. ; cm. Includes bibliographical references. ISBN 978-0-309-15129-0 (pbk.) — ISBN 978-0-309-15130-6 (pdf)


Thank you…


Abstract

EBF Abstract: The term biomarker immediately t f i h ti d ithi th k f creates confusion when mentioned within the ranks of

bioanalytical scientists. This is a result of many inputs – industry perspectives and trends on what pu du y p p a d d o abiomarkers are and how they are used in discovering, developing, commercializing and administering pharmaceuticals the specific therapeutic area(s) that pharmaceuticals, the specific therapeutic area(s) that the biomarker is used in, and the preferred platform of the organization/department requesting the biomarker vs the preferred platform of the biomarker vs. the preferred platform of the organization/department being tasked with developing or outsourcing the biomarker. There are p g galso details regarding the analytical matrix type, volume, number and type of sample collections per timepoint, concentration range, number of samples, timepoint, concentration range, number of samples, how the data will be used, compliance decisions, business decisions and technical/scientific decisions.


Abstract

The primary platforms used for biomarker analysis include ligand binding assays flow cytometry molecular genomics LC/MS and binding assays, flow cytometry, molecular genomics, LC/MS and immunohistochemistry/imaging technology. The issue that faces many organizations is that these technologies are typically not all placed in a single organization or management structure Ligand placed in a single organization or management structure. Ligand binding and LC/MS are often combined within a bioanalytical organization, but even these can be located in different geographic locations and management. This makes the planning g g p g p gand execution of biomarker strategies challenging. Some organizations have created formal biomarker departments that guide the strategy or even the technological approaches. Others h i d “Bi k W ki G ” th t i t i have organized “Biomarker Working Groups” that assist in guiding the organizations biomarker strategy as well as assisting in the biomarker strategy of individual studies. However, there are still many disconnects with resulting inefficiencies that can are still many disconnects with resulting inefficiencies that can occur even within or between any organization. For both pharma and CRO’s, these are problematic and are further complicated by the Central Lab and Bioanalytical Lab interfaces, their operational the Central Lab and Bioanalytical Lab interfaces, their operational structure and the regulatory compliance applied – ie, CAP, CLIA, GCLP, GLP and the ubiquitous fit for purpose.


Abstract

Because the best way to optimize issues is to identify them, this talk will highlight the inefficiencies in the current “business model” surrounding the analysis of biomarkers as well as highlight and discuss the drivers that should be of well as highlight and discuss the drivers that should be of paramount importance in deciding how to approach biomarker decisions surrounding platform, compliance and general g p p gapproach to the analysis of biomarkers.


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Biomarkers: Not just another bioanalytical challenge