CAMD and
Critical Path Institute
Introduction:
Accelerating drug development through
regulatory science
Diane Stephenson, Ph.D.
Executive Director, CAMD
Critical Path Institute
Critical Path Institute Consortia
Seven global consortia collaborating with 1,000+ scientists and 41 companies
Coalition Against Major Diseases
UNDERSTANDING DISEASES OF THE BRAIN
Critical Path to TB Drug Regimens
TESTING DRUG COMBINATIONS
Multiple Sclerosis Outcome Assessments Consortium


DRUG EFFECTIVENESS IN MS
Polycystic Kidney Disease Consortium
NEW IMAGING BIOMARKERS
Patient-Reported Outcome Consortium
DRUG EFFECTIVENESS
Electronic Patient-Reported Outcome Consortium
DRUG EFFECTIVENESS


Biomarkers
Clinical
Outcome
Assessment
Instruments
Clinical Trial
Simulation
Tools
Data Standards
Predictive Safety Testing Consortium
DRUG SAFETY
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C-Path Online Data Repository
MSOAC
www.cdisc.org/therapeutic
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Coalition Against Major Diseases:
Tools to Advance Effective Treatments
for Alzheimer’s and Parkinson’s Disease
Government/Regulatory
participants
Industry members
Non-profit
research members
Not listed: Numerous Key opinion leaders/academic experts
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Alzheimer’s Disease: the High Unmet
Need for New Therapies
Problem
High risk and
increasing cost for AD
drug development
Lack of biomarkers
for decision making
No effective therapy
for modifying
disease progression
Gap
Huge uncertainty in
design of clinical trials
Highly variable
subpopulations
recruited into
randomized clinical
trials
Inadequate outcome
measures for assessing
efficacy of drugs in
predementia stages
CAMD Approach
Regulatory endorsed
clinical trial simulation
tool
Regulatory biomarker
qualification for
enrichment in
randomized clinical
trials
Innovative/sensitive
clinical outcome
assessment for efficacy
of novel drug candidates
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CAMD AD clinical trial simulation tool:
First regulatory endorsed disease model
“Model-based drug
development was one of the
goals defined in FDA’s 2004
Critical Path Initiative report,
and this new tool sets the stage
for applying new technologies
to accelerating medical product
development,”
Janet Woodcock, FDA
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Modeling depends on Data!
Nine companies
24 trials
~6500 Patients total
Data first had to be remapped
in order to be pooled
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CAMD Recognizes Teva for Their Data
Contribution to Parkinson’s Disease
.
Teva received an award for being the only member organization
to contribute clinical trial data for Parkinson’s disease to CAMD.
This data is critically enabling for our PD biomarker team and our
PD modeling efforts.
Watch this space!
.
Alzheimer’s Disease: the High Unmet
Need for New Therapies
Problem
High risk and
increasing cost for AD
drug development
Lack of biomarkers
for decision making
No effective therapy
for modifying
disease progression
Gap
Huge uncertainty in
design of clinical trials
Highly variable
subpopulations
recruited into
randomized clinical
trials
Inadequate outcome
measures for assessing
efficacy of drugs in
predementia stages
CAMD Approach
Regulatory endorsed
clinical trial simulation
tool
Regulatory biomarker
qualification for
enrichment in
randomized clinical
trials
Innovative/sensitive
clinical outcome
assessment for efficacy
of novel drug candidates
9
Pre-dementia Clinical Outcome
Assessment (pCOA) Tool Project
Objective:
Advance through a formal regulatory path a
composite clinical outcome assessment tool as a
primary outcome measure for pre-dementia AD
trials
Impact:
Regulatory accepted / qualified clinical outcome
measure to be applied across targets and industry
stakeholders
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Alzheimer’s Disease (AD) Stages
Pre-Dementia
Dementia
Memory complaints
Cognitive Impairment
Cognitive, Functional & Behavioral deficits
Pre-Symptomatic
MCI / Prodromal AD
Mild
No apparent symptoms
Symptoms
• Risk factors; family
history, old age, ApoE4
genotype, TBI, mutations
• No symptoms, or subtle
cognitive deficits
(memory complaints)
• Emerging biomarker
evidence of AD
pathology
Moderate
Severe
Current diagnosis & treatment
• Mild cognitive impairment
(MCI)
• Amnestic Mild Cognitive
Impairment (aMCI) - episodic
memory deficits
• aMCI combined with
biomarker evidence of AD
pathology = Prodromal AD
• AD diagnosis based on clinical
symptoms; cognitive deficits &
dementia of the AD type
• Biomarker evidence of AD
pathology may increase
specificity of diagnosis (?)
Johan Luthman
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How to Measure Deficits in the
Pre-Dementia Stages of AD?
Pre-Dementia
Dementia
Memory complaints
Cognitive Impairment
Cognitive, Functional & Behavioral deficits
Pre-Symptomatic
MCI / Prodromal AD
Mild
No apparent symptoms
Symptoms
Moderate
Severe
Current diagnosis & treatment
• Established Instruments to measure cognition lack sensitivity
& responsiveness in early stages of the AD disease process
– The regulatory standard Alzheimer’s Disease Assessment Scale Cognitive
Subscale (ADAS-Cog) developed for more advanced stages of disease
– In Mild, Prodromal & Presymptomatic AD, ceiling/floor effects of ADAS-Cog
limit the ability to detect and follow the disease progression
Johan Luthman
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Efforts to Develop Improved Clinical
Outcome Measure Instruments
Individual industry & academic efforts have proposed more
sensitive and responsive instruments in early stage AD
• Some components (“items”) of currently used Instruments, especially cognitive
measures, are more sensitive in earlier stages of AD (e.g., delayed word recall,
orientation, word recognition)
Leading proposals include items from ADAS-Cog, CDR-SB
and MMSE as a Composite Clinical Endpoint emphasizing
cognitive measures of performance
• Proposals are based on selection of key items from existing Instruments to
develop a new composite clinical score
• Two general approaches:
•
Improved weighting of ADAS-Cog items,
•
Additional content to ADAS-Cog with items from other instruments (CDR-SB, MMSE etc.)
Johan Luthman
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Composite Endpoints Presented at
ADNI PPSB Data Mining Session
April 2012
Nandini Raghavan, Janssen
AstraZeneca
ProADAS
Pfizer
X
X
ADAS-Cog
CDR-SB
FAQ
AVLT
MMSE
Subscale Description
Q1
Word Recall
Q2
Commands
Q3
Construction
Q4
Delayed Word Recall X
Q5
Naming
Q6
Ideational Praxis
Q7
Orientation
X
Q8
Word Recognition
Q9
Recall Instructions
Q10
Spoken Language
Q11
Word Finding
X
Q12
Comprehension
Q14
Number Cancellation X
CDRSB
CDR Sum-of-Boxes
CDRSB-Cog
FAQ
AVLT-Immediate
MMSE
MMSE-Orientation
MMSE-Constructional Praxis
Eisai
Janssen
MCIMax/
TriAD, TriAD-G ADCOMS
X
?
X
X
X
?
X
X
X
X
X
X
X
X
X1
X1
X2
X2
X
X
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Pathway for New Composite
and Cognition Instrument
2008-2013
1) Various Composite & Cognition Scores developed by Industry and
Academic Groups
Eisai, AZ, Janssen, ADAS-Cog Plus (Dan Mungas), Merck, etc.
Harmonization of Efforts
2) ADNI PPSB Clinical End Points Working Group
2012-2014
1. Mapping proposals from #1
2. Identifying all available databases (e.g., prior MCI trials) for validation
3. Selecting candidate Instrument(s) for Mild, Prodromal, and presymptomatic AD to move to #3
Regulatory Qualification
2013-2016
3) CAMD (Critical Path Institute): pCOA Project
1. Data analyses on candidates selected in #2
2. Submission Qualification request to FDA and EMA
3. Aim for approved new Instrument (as primary or secondary EP)
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FDA issues draft guidance on
early AD: alignment with pCOA
Feb 2013
“Because many of the assessment tools used to measure functional or
global impairment in patients with dementia have not been validated for
use in these early stage patients, we consider the use of a composite
scale, validated in early stage patients to assess both cognition and
function as a single primary efficacy outcome measure, to be appropriate.”
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EMA recognizes need for
improvements in AD
Three major issues have been important for assessment of recent and future clinical
trial protocols in AD and other dementias:
1. New research diagnostic criteria are used in clinical trials for different stages of AD,
2. The potential use of several biomarkers in the different stages of drug
development,
3. The use of appropriate outcome measures with adequate clinical relevance to be
used at any stage of the disease continuum.
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CAMD pCOA Project
Progress to Date
Aug 2, 2013
Oct 23, 2013
Mar 26, 2013
Project
Concept
Proposal
ADNI PPSB
data mining
session
April, 2012
CAMD Launch
meeting
April 16-17, 2013
Project
Concept
Proposal
Letter of Intent
to FDA
Letter of Intent
to EMA
Response from
FDA
Response from
EMA
Mar 26, 2013
Aug 5, 2013
Oct 28, 2013
FDA and EMA are collaborating in qualification across all stages
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What is Clinically Meaningful Effect?
• Graded



evaluation of a clinical outcome measure
Statistically significant effect
Effect size
Clinically meaningful effect
• No
clear consensus on a single definition for clinically
meaningful difference in randomized controlled trials
Multiple perspectives:
 Patient (Patient reported outcome – PRO)
 Caregiver
 Clinician
 Statistician
 Payer
 Healthcare economist
 Investor
 Regulator
 Etc.
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Critical for Success:
Aligning across consortia
Improved
outcome
measure
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CAMD sharing learnings from
AD across CNS diseases
• Parkinson’s disease
• Multiple Sclerosis (MSOAC)
• Traumatic Brain Injury
• ALS
• Neuropsychiatric conditions
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Acknowledgements:
CAMD pCOA team (stage 1)
Alzheimer’s Association—Maria Carrillo, Dean Hartley
AFA—Eric Sokol
AstraZeneca—Kristin Hannesdöttir, Tina Olsson
Boehringer Ingelheim—Mark Gordon, David Brill, Jana Podhorna
Bristol-Myers Squibb—Jesse Cedarbaum, Rob Berman
Critical Path Institute—Diane Stephenson, Ann Robbins, Stephen Joel Coons
CROnos—Pamela Keenan
Eisai—Veronika Logovinsky, Andy Satlin, Ira Do, Martin Rabe, Jinping Wang,
Johan Luthman
Eli Lilly—Richard Mohs, Alette Wessels, Robin Pitts Wojcieszek, Janice Hitchcock
Eric Siemers
FDA—Ashley Slagle, Marc Walton
Janssen—Gary Romano, Nandini Raghavan, Michael Ropacki, Jerry Novak
Medical Care Corp—Dennis Fortier, Rod Shankle
Merck—David Hewitt, Bach Yen Nguyen, Tamra Goodrow
Novartis—Richard Meibach, J Michael Ryan
Pfizer—Rachel Schindler, Brian Harvey
Ad hoc: Suzanne Hendrix, Pete Snyder, Paul Maruff, Bob Stern
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Acknowledgements
C-Path Staff
•
•
•
•
•
•
• Robin Shane, CAMD Project Coordinator
Martha Brumfield, CEO
• Hemaka Rajapaske, CAMD Senior PM
Lynn Hudson, CSO
• Ann Robbins, regulatory consultant
Steve Broadbent, COO
Klaus Romero, Director, Clinical Pharmacology
Stephen Joel Coons, Executive Director, PRO Consortium
Data Team
• Jon Neville, Marty Cisneroz, Bob Stafford
CAMD Industry Co-director: Mark Gordon, Boerhinger Ingelheim
C-Path gratefully acknowledges the support of
the Tucson Community
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