critical path for alzheimer’s disease (cpad) · * stephen p. arnerić, phd, cpad executive...
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Critical Path for Alzheimer’s Disease (CPAD)
CPAD IMPACT
Stephen P. Arnerić, Executive DirectorVolker D. Kern, Senior Project Manager
www.c-path.org/cpad2
TRANSITION TO CRITICAL PATH FOR ALZHEIMER’S DISESEASE
Why
▪ To more clearly convey the consortium’s mission to the Alzheimer disease (AD) research andhealthcare communities
Forward Path
▪ Create a forum to be leveraged across the entire AD community with the goal to foster enhanceddata sharing amongst all stakeholders
▪ Develop a quantitative understanding of disease progression across the AD continuum (pre-symptomatic to dementia) with focus on biomarker dynamics, based on acquisition andavailability of data, and the ultimate goal to enable a more-informed pathway to the design ofDrug Development Tools that accelerate the delivery of treatments to effectively treat AD
www.c-path.org/cpad
FDA AD DRAFT GUIDANCE
February 15, 2018
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www.c-path.org/cpad
OVERVIEW OF THE AD DRUG DEVELOPMENT PIPELINE
J. Cummings et al., 2018
112 agents in 135 AD Trials in Phases 1, 2, and 3
[https://clinicaltrials.gov/]
A rich source of data that hasnot yet been made available to improve our understanding of AD progression
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www.c-path.org/cpad5
WHY DEVELOPING BETTER WAYS TO MEASURE PATIENT COGNITION AND FUNCTION IS CRITICAL!
https://www.gbhi.org/about/
CRITICAL REASONS
▪ Unmet need for effective treatments
▪ Economic burden to Healthcare Systems Worldwide
▪ A new therapeutic for AD has not been approved in over a decade!
▪ Any trial in AD is dependent upon the outcome measures used, and must require the necessary sensitivity and specificity -especially true for the “pre-symptomatic” stage of the disease
▪ Need for early detection assessments to detect those “at risk” for cognitive decline
www.c-path.org/cpad
FOCUS
▪ Data standards
▪ Clinical trial simulation tools from actionable data
▪ Disease progression models
▪ Biomarkers
▪ Clinical outcome assessment instruments
CRITICAL PATH INSTITUTE
Fifteen global consortia collaborating with 1,450+ scientists and 84 organizations
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www.c-path.org/cpad
CPAD QUALIFIES DRUG DEVELOPMENT TOOLS FOR CLINICAL DRUG TRIALS TREATING DEMENTIA
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www.c-path.org/cpad
MEMBERS, STAKEHOLDERS & CONTRIBUTORS
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C-Path staff advancing CPAD
Stephen P ArnerićExecutive Director
Volker D KernSenior Project Manager
Klaus RomeroDirector of Clinical Pharmacology and
Quantitative Medicine
Daniela J ConradoAssociate Director of
Quantitative Medicine
Jackson BurtonAssociate Program
Director, Quantitative Medicine
Robert StaffordSenior Data Specialist,
Data Programming Team Lead
All other C-Path support staff…
Pharmaceutical Industry
AbbVie Inc.BiogenBoehringer Ingelheim Pharmaceuticals Inc.EisaiEli Lilly and CompanyF. Hoffman La RocheJohnson & Johnson Pharmaceutical Research & Development LLCMerck, Sharp & Dohme Corp.Novartis Pharmaceuticals CorporationPfizer Inc.Takeda Pharmaceuticals
Government and Regulatory Agencies
European Medicines Agency (EMA)National Institute on Aging (NIA)National Institutes of Health (NIH)National Institute of Neurological Disorders and Stroke (NINDS)U.S. Food and Drug Administration (FDA)
Non-profit Research Organizations
Alzheimer’s AssociationAlzheimer’s Drug Discovery FoundationAlzheimer’s Research UKCHDI FoundationUsAgainstAlzheimer’s
www.c-path.org/cpad
CPAD’S GOVERNANCE STRUCTURE
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* Stephen P. Arnerić, PhD, CPAD Executive Director, Critical Path Institute** Michael Gold, MS MD, AbbVie, Vice President Neuroscience Development
COORDINATING COMMITTEE
C-Path*
Executive
Director
Industry**
Co-Director
Government Agencies
Regulatory Agencies
Academic Experts
Patient Advocacy Organizations
Philanthropies
Pharmaceutical Industry
Research Foundations
Advisors
CPAD WORKING GROUPS
www.c-path.org/cpad
CPAD TEAMS/WORKING GROUPS
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▪ Imaging Biomarker Team
▪ Modeling & Simulation Team
▪ Fluid Biomarker Team
▪ Digital Drug Development Tools Team
▪ Ad-hoc/limited-duration Teams
Create Drug Development Tools for Alzheimer disease and related dementias
Common Data Standards
Integrated, actionable Databases
Quantitative Modeling
Aims for Regulatory Acceptance of Biomarkers/Endpoints
Advancing regulatory science through cross-disciplinary collaboration
www.c-path.org/cpad11
2008
2010
2011
2012
2013
2015
2018
……. Coalition Against Major Diseases launched on August 13, 2008
……. First integrated database of anonymized, patent-level clinical data for AD
……. First AD CDISC standards (v1.0); v2.0 published in 2013
……. AD biomarker qualified by EMA
……. AD Clinical Trial Simulation Tool endorsed by EMA and FDA
……. FDA Letters of Support for AD biomarkers
……. Consortium name change to Critical Path for Alzheimer’s Disease
……. Funding received to curate & expand the database with up to 10 prioritized Clinical Trials
KEY CONSORTIUM ACHIEVEMENTS
The Consortium was rebranded in January 2018 to convey the current Focus and Mission
On August 13, 2018, the consortium celebrated its 10th Anniversary
Leveraging CPAD’s core strengths for the future
……. EMA Letter of Support for aMCI Model
……. 4 AD trials from Servier integrated into database
2017 ……. Concise Informed Consent Form published
……. Joined GAAIN
www.c-path.org/cpad
RECENT CONSORTIUM-LED PUBLICATIONS
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26 Publications Neville et al., Alz. Res., 2015
www.c-path.org/cpad
569 Total Applicants
350 Distinct Institutions
from
Industry
Abbvie; Allergan; AstraZeneca; Biogen; Biomarkable; CoreLab; Daewong; Eisai; GE Healthcare; IBM; Johnson & Johnson; Lundbeck; Merck; NeuroCog; Novartis; Pentara; Pfizer; Siemens; SAS
Academia & Foundations
Amherst College; Arizona State Univ.; Bill & Melinda Gates Foundation; CHDI Foundation; Duke Univ.; Fraunhofer Institute; Goethe Univ.; Harvard Univ.; Karolinska Institute; King’s College London; Michael J Fox Foundation; Rockefeller Univ.; Seoul National Univ.; Univ. of Oxford; Yale Univ.
Government & Other
NIH; Neurology Today; Gigatrust
CPAD DATABASE UTILIZATION (as of September 30, 2018)
303
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131
84USE BY SECTORSAcademia: 259Pharmaceutical: 167Other: 70Non-profit: 32Government: 11
USE BY REGIONNorth America: 56%South America: 1%Europe: 24%Africa: 1%Asia: 16%Australia: 2%
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28 Clinical Trials6,995 Anonymized Patients
www.c-path.org/cpad
AD CLINICAL TRIAL SIMULATION (CTS) TOOL FOR MILD-TO-MODERATE AD – REGULATORY PATH
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▪ On June 12, 2013 the FDA determined the CTS tool was “Fit for Purpose”
▪ On September 19, 2013 the EMA determined the CTS tool was “Qualified for Use”
www.c-path.org/cpad15
DEMONSTRATED UTILITY OF THE CLINICAL TRIAL SIMULATION TOOL IN MILD-TO-MODERATE AD
Crossover Parallel
91 weeks 78 weeks
• Better power
• ~50% cost savings• 13 weeks less time
Balancing power, sample size, and duration, given varying effect magnitudes
www.c-path.org/cpad
97 Total Applicants
72 Distinct Institutions
from
Industry
AbbVie; Astellas; Biogen; Boehringer Ingelheim; Denali Therapeutics; Eisai; Eli Lilly; Genentech; GlaxoSmithKine; H. Lundbeck; Hoffmann-La Roche; Merck; Pfizer; Regeneron; Trigemina
Academia
Emerson College; Imperial College London; Karolinska Institute; London School of Economics; McGill University; PondicherruUniversity; Universidad Nacional del Litoral; University of Alabama; University of Arizona; University of Bordeaux; University of Manchester; University of Rochester; University of Texas; USC; Washington University
Government, Non-Profit, & Other
FDA; HHS; Medical Genetics Center; RTI; Certara; dMed Biopharmaceuticals; ETHOS Health Communications; IBM; PentaraCorp.; Pleroo Research
CPAD CTS TOOL UTILIZATION (as of September 30, 2018)
USE BY SECTORSAcademia: 42Pharmaceutical: 34Other: 14Non-profit: 3Government: 4
USE BY REGIONNorth America: 64%South America: 1%Europe: 18%Africa: 3%Asia: 14%Australia: 1%
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www.c-path.org/cpad
MCI PROGRESSION MODEL – EMA
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Letter of Support
October 30, 2018
LINK
www.c-path.org/cpad
DIGITAL DRUG DEVELOPMENT TOOLS
WHAT
• Data (signal output) collected from a biosensor that measures a biological response
HOW
• Continuous physiological monitoring with devices (wearables/smart phones, clothing, implants/ ingestibles, remote biosensors)
WHY
• Improve our understanding of real-time changes in FUNCTION during the progression of life in health and disease
• Improve the efficiency of AD clinical trials to accelerate the delivery of novel treatments
• Deliver precision care
Biometric Monitoring Devices (BMDs) as Regulatory-Accepted DDTsFor Specific Contexts-of-Use
KEY CONTEXTS-OF-USE
• Patient Selection
• Understand disease progression
• Measure treatment responses
• Deliver precision care
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www.c-path.org/cpad
THE VISION: DEVELOP AN END-TO-END ALZHEIMER DISEASE MODEL ACROSS THE DISEASE CONTINUUM
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How and when do these factors interact to influence disease progression?
…and treatment response?
www.c-path.org/cpad20
PATIENT SELECTION AND EVALUATION FOR CLINICAL TRIALSRequires a Comprehensive Assessment =
Patient & Physician Reported Outcomes• Cognition (MMSE, CDR-SB, etc.)
• Behavior (sleep/mood scales – QOL-AD, GDS)
• Motor function (UDPRS)
• Sensation (NRS, etc.)
• Balance & Coordination
• Autonomic
SymptomsSigns
Observer/Performance OutcomesGenetics Examination Temperature
Vision Forgetfulness Infection Mobility
GI/Lung/ Kidney EKG EEG/
Glucose tests function HR/BP Sleep/ Fatigue
Imaging Modalities
Real World Data
Wearable & Remote BMDs
www.c-path.org/cpad
CONTINOUS MEASUREMENT IS RELEVANT AND CRITICAL!
Which patient is rapidly declining?
Courtesy of Dr. Jeff Kaye
baseline 12 months 24 months
• These data highlight the challenge of infrequent cross-sectional assessments
• Understanding vector trends (the relevant 90+%)in individual continuous performance would be more reflective of true long-term trends in performance/health maintenance, i.e., Aligned with Precision Medicine Objectives!
• GOAL: Validate BMD Assessments as DDTs to identify the “right patients”, enhance Clinical Trial efficiencies, and enable tailored treatment approaches
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www.c-path.org/cpad
GOAL: A GLOBAL INTEROPERABLE AD DATA REPOSITORY OF SHARED DATA
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