CAMD GBSC UPDATE Diane Stephenson

Executive Director, CAMD Critical Path Institute Tucson, AZ

July 11, 2014

Overall Goal of CAMD CSF

AD Biomarker Team

2

FDA Biomarker Qualification of CSF analytes (Aβ42, tau, p-tau)

for the purpose of enrichment in AD clinical trials at the

pre-dementia stage

Out of Scope:

• Regulatory approval/clearance of CSF biomarkers as diagnostic agents

• Approval of CSF biomarkers as companion diagnostics (IVD)

• Use of CSF biomarkers as pharmacodynamic biomarkers

• Use of CSF biomarkers as surrogates of efficacy

CAMD AD CSF Biomarker Team Members

3

AbbVie-- Devan (Viswanath) Devanarayan, Bradford Navia

Alzheimer’s Association—Maria Carrillo, Jim Hendrix

Biomarkable—Hugo Vanderstichele

Boerhinger Ingelheim– Mark Gordon

Cerora– Adam Simon

Critical Path Institute—Diane Stephenson, Klaus Romero, Hemaka Rajapakse, Robin Shane

Eisai—June Kaplow

Eli Lilly & Company—Peng Yu, Bob Dean, Janice Hitchcock, Brian Willis

FDA—Marc Walton, Jim Kaiser

Innogenetics—John Lawson

Janssen—Jerry Novak, Mahesh Samtani

Merck—Omar Laterza

Meso Scale Discovery—Bob Umek

Novartis–Richard Meibach

Orion-Kristiina Haasio

Pfizer-Kaori Ito

Quanterix—Andreas Jeromin

ICON—David Raunig

University of California, UC Davis—Laurel Beckett, Huanli Wang

University of Pennsylvania—Les Shaw

Boehringer Ingelheim--Mark Gordon

Maastricht University—Pieter Jelle Visser

University of Göteborg, Henrik Zetterberg, Kaj Blennow

Washington University—Anne Fagan, Betsy Grant

University of Antwerp—Sebastiaan Engelborghs

Biomarker Qualification Process

- Consultation phase is iterative 4

Woodcock et al.,

Expert Opin. Med. Diagn.

(2011) 5(5):369-374

FDA feedback: what is the path to biomarker qualification?

CSF Assays Performance and Biomarker Performance

• Precision-based vs accuracy-based assays

• Cutoff values and how to define

• Variability: Intra- & inter-lab, lot-to-lot, reference standards

• Assay analytic performance features defined

Data Analysis and Interpretation

• Define and describe confirmatory datasets

• Concern for bias

• Detailed statistical analysis plan with learn and confirm phases

Guidelines/SOPs to help sponsors effectively use

biomarkers for enrichment

Current challenges: Need for more data especially clinical trial data

CSF Assay Design, Characterization & Standardization: the impact of consortia

ASSAY

LAB SAMPLE

accuracy

External QC Programs (Alzheimer Association)

Proficiency panels

Regulatory guidance(s)

Operator training

Reference

methods/materials

(GBSC, IFCC)

Lab SOPS

(Customer)

Robustness

Lot consistency

Raw Materials Qualified

Stability Run Validation

Modified according to Vanderstichele et al. Alzheimer & Dementia 2012

SOP for collection & storage

(ADNI, JPND, AIBL, ...)

No matrix interference

Improved precision

Selective & specific

(Vendor)

Harmonization The needs for the future

biotin

SV Biomarker Qualification

Clinical Data Standards

Enable pooling of data that can generate new insights and reveal subtle signals

Value Proposition 2010 C-Path CAMD –AD database

April 2012 FDA presentation at CDISC International Interchange

Improve the efficiency and effectiveness of regulatory reviews (Standards will be required by 2017)

7

Regulatory Landscape Embraces Data Standards

8

NEJM feature on big data highlights data standards

9

CAMD recognized

10

Therapeutic Area Data Standards Development Experience

www.cdisc.org/therapeutic

What is CDISC?

11

• Nonprofit standards development organization, founded 1997

• Publishes global open standards for clinical and non-clinical data

• Accepted and soon to be required by regulatory agencies

for new submissions

• CDISC offers a system of standards that addresses end to end

need for data researchers

Concepts covered by the Alzheimer's CDISC User Guide (v2.0) ApoE Genotype Family History of AD Volumetric MRI PET, PET/CT (FDG, Florbetapir, PiB) CSF Biomarkers and Sampling Outcome Assessment Scales ADAS-COG MMSE CDR AVLT FAQ Modified Hachinski DAD ADCS-ADL MCI NPI CGI GDS

AD CDISC standards

CSF Biomarker Concept Map

CSF

COLLECTION

AND

BIOMARKER

TESTING

COMPLEX

but . . .

possible to

standardize in

the near future

Summary

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• CAMD’s AD CSF team is aiming for qualification of CSF biomarkers

with FDA for the purposes of enrichment in pre-dementia trials. More

data and resources are needed for success.

• CAMD and CDISC have developed globally accepted therapeutic

area specific CDISC standards for AD, including biomarkers

• Adoption of CDISC data standards in clinical trials will enable

efficient regulatory review and is the format that will be required

in the future

• CDISC standards enable pooling of diverse sources of clinical data

to address research questions and look for subtle signals in large

data

• Proactive agreement to adopt biomarker standards in planning

clinical trials in the future will facilitate learnings and enable

harmonization of ongoing and prospective data

Acknowledgements

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C-Path Staff • Martha Brumfield, CEO

• Lynn Hudson, CSO

• Steve Broadbent, COO

• Klaus Romero, Director, Clinical Pharmacology

• Data Team

Jon Neville, Bob Stafford, Emily Hartley, Bess LeRoy, Marty Cisneroz

C-Path gratefully acknowledges the support of

The Tucson Community

• Robin Shane, CAMD Project Coordinator

• Hemaka Rajapakse, CAMD Senior PM

Experts contributing to CDISC standards development NINDS, Andreas Jeromin, Hugo Vanderstichele, Jerry Novak, Mark Gordon,

Patricia Cole, Mark Austin, Steve Kopko, Susan De Santi, Ken Marek,

Jessica Langbaum, Kewei Chen and Adam Fleisher