1. Diane Stephenson, PhD; Executive Director, CAMD
Coalition Against Major Diseases (CAMD) – Advancing Regulatory Science for AD CSF Biomarkers
Diane Stephenson, PhD; Executive Director, CAMD

2. CAMD AD CSF Biomarker Team Members
AbbVie—Devan Devanarayan, Just Genius, Leslie Carter, Jeff Waring
Alzheimer’s Association—Maria Carrillo, Jim Hendrix
Biohaven– Rob Berman
Biomarkable—Hugo Vanderstichele
Boehringer Ingelheim—Mark Gordon
Critical Path Institute—Diane Stephenson, Steve Arneric, Robin Shane, Volker Kern, Klaus Romero
Eisai—June Kaplow, Johan Luthman
Eli Lilly—Peng Yu, Brian Willis, Bob Dean, Janice Hitchcock
FDA—Jim Kaiser
Genentech/Roche—Susan Yule
Janssen—Mahesh Samtani
MSD—Bob Umek
Novartis—Richard Meibach
Pfizer—Kaori Ito
Roche Diagnostics—Richard Batrla-Utermann, Tobias Bittner
University of Antwerp—Sebastiaan Engelborghs
University of California, UC Davis—Laurel Beckett
University of Pennsylvania—Les Shaw
University of Göteborg—Kaj Blennow
AD CSF Team
Co-chairs:
Hugo Vanderstichele
Bob Dean

3. Objective of CAMD CSF Biomarker Team
FDA Biomarker Qualification of CSF analytes (Aβ1-42, tau, p-tau)
for the purpose of enrichment in clinical trials at the
Pre-dementia stage
Out of Scope:
Regulatory approval/clearance of CSF biomarkers as In Vitro Diagnostics
Approval of CSF biomarkers as companion diagnostics (IVD)
Use of CSF biomarkers as pharmacodynamic biomarkers
Use of CSF biomarkers as clinical outcomes or surrogates of efficacy

4. Progress since last GBSC
FDA issues letter of support to CAMD CSF biomarker team
FDA qualifies first clinical biomarker for prognostic use in COPD
FDA requests novel candidate biomarkers and posts results
Overall increased Transparency
Evidentiary standards for qualification is being highlighted in multiple workshops
FDA posts Biomarker qualifications under review
CAMD receives first ever case of biomarker data contributed from AD clinical trial
Draft manuscript from CSF team nearly ready for submission

5. Pathways to integrate biomarkers in drug development
Amur et al., Clin Pharm & Ther Vol 98(1) July 2015

6. CAMD Biomarkers aiming for FDA Qualification Prognostic Application, AD & PD
Low Hippocampal
volume at baseline
for enrichment in
pre-dementia trials
Baseline measures of
β-amyloid protein, tau, and
phosphotau levels in CSF
as biofluid biomarkers for
enrichment in pre-dementia
AD trials
Dopamine transporter neuroimaging as a prognostic biomarker to exclude those subjects termed as SWEDDs (scans without evidence of dopamine deficiency) for clinical trials in early motor PD subjects
SPECT imaging of DAT in healthy and PD

7. FDA issues letters of support to CAMD biomarkers teams March 26, 2015

8. FDA Letter of Support (LoS)
What is a Letter of Support? A LoS describes CDER’s thoughts on the potential value of a biomarker and encourages further evaluation to enhance visibility of the biomarker, encourage data sharing, and stimulate additional studies.
Why issue a Letter of Support? To encourage identification, development, and qualification of new drug development tools to overcome hurdles in drug development programs and to enhance drug safety and efficacy.
What is it not: a fully qualified biomarker or approved IVD

9. CAMD AD CSF Biomarker FDA Letter of Support
The need for data sharing
&
Consensus data standards

10. CSF Biomarker Letter of Support (contd)
Biomarker Validation comments:
Analytical performance
expectations

11. Assay manufacturers highlight FDA and EMA LoS
C-Path’s Predictive Safety Testing Consortia (PSTC) consortia achieves Letter of Support for kidney safety biomarkers, including NGAL

12. FDA Speaks Out: What is Needed
Enhanced data sharing and collaborative efforts among consortia
Qualification packages that don’t try to “boil the ocean”
Limited versus expanded context of use
Data/specimen repositories which can support expanded contexts of use for biomarkers once additional data is aggregated
Upfront conversations around context of use—which drives the level of evidence needed
More communication about the value and progress made by consortia efforts
Greater clarity around levels of evidence for qualification. This takes the entire scientific community – not just FDA
Patience…we are learning as we go…..
Dr ShaAvrhee Buckman, Director,
Office of Translational Sciences , FDA

13. Evidentiary Considerations for Integration of
Biomarkers in Drug Development Symposium
Aug 21st, 2015
Univ Maryland
The objective of the symposium is to begin to define and ultimately codify the scientific and regulatory expectations for the qualification of biomarkers 
Two biomarker classes will be discussed
Safety biomarkers
Biomarkers used for trial enrichment 
The symposium format is designed to elicit participant feedback on defining evidentiary standards based on hypothetical biomarker qualification projects with varying complexities of COUs.
Website:

14. Paving the way for the future - promising biomarkers
CAMD biomarker teams submitted two candidate biomarkers:
CSF Neurogranin (Kaj Blennow, Erik Portelius, Hugo Vanderstichele)
Tau PET imaging (Mike Weiner, Pat Cole, Susan DeSanti, Dawn Matthews, Jeff Sevigny)
CONFIDENTIAL

15. CSF Team…….What is needed for success?
Context of Use
Level of Evidence
Qualification
CSF analytes as
Prognostic biomarkers for Enrichment in AD
Pre-dementia trials
Assay analytical performance
Reliability & Reproducibility
Clinical validation:
Possible Supportive Studies -
ADNI
DESCRIPA
Wash Univ ADRC
BMS Avagacestat
MORE

16. ADNI and CAMD Synergies
ADNI goals align with CAMD goals
ADNI Scientific Questions
Validate Biomarkers for Clinical Trials
Standardize Biomarkers for use in Clinical Trials
Optimize Biomarkers for Clinical trials
Provide a platform for simulated clinical trial platform
All CAMD regulatory Achievements were enabled by ADNI
AD CDISC consensus Clinical Data Standards
AD EMA qualification opinion - hippocampal volume
AD FDA and EMA regulatory endorsement of AD disease model
FDA letters of support, AD biomarkers

17. How can you help?
Sharing of analytical performance data similar to what was shared with ADNI3 biofluid core group
Patience with the process and awareness of challenges in data and sample sharing
Employ CDISC AD standards (CSF biomarkers) in ongoing and future studies.
Patient informed consent to enable data sharing of clinical data and samples
Contribute to CAMD CSF biomarker team to achieve goal that will improve efficiency and cost of CSF biomarker implementation in trials

18. Acknowledgements Critical Path Institute Staff FDA colleagues:
John-Michael Sauer, PSTC Executive Director
FDA colleagues:
James Kaiser, ShaAvhree Buckman, Billy Dunn, Nick Kozauer, Shashi Amur, Chris Leptak
CAMD Members
CSF Team Co-chairs Bob Dean, Hugo Vanderstichele
Johan Luthman
CAMD Co-Director, Mark Gordon
Alzheimer’s Association
C-Path acknowledges the generous support of FDA and our CAMD members

19. BACK UPS

20. Progress in ADNI could help us now
Johan Luthman, biofluid BM WG
ADNI PPSB, April 2015

21. F FDA Qualifies the First Clinical Biomarker for Prognostic Use, July 2nd

22. Lessons Learned, plasma fibrinogen qualification
Consortia driven
5 clinical data sets (each with >1000 patients)….all observational, no RCTs
Only one of the datasets fits COU and was analyzed to support qualification
Assay specific cutpoints was OK
Bridging between assays was considered but it looks like not required in advance
OK to qualify biomarker based on multiple assays and platforms
All encouraging news for our team

23. CSF Biomarkers predict MCI progression to AD