Transcript Crosstalk_Cripe_v3 - Cincinnati Children's Hospital

Promises and Perils of
Translational Research at
Academic Health Centers:
The CCHMC Model
Timothy P. Cripe, MD, PhD
Faculty Cross-Talk
October 5, 2006
Public Mandate
It is no longer good enough
to cure a mouse.
Promises
Translational research is…
“...moving a basic discovery
into early clinical trials.”
-J Kaiser, in
“Translational Research: A Cure for Medicine’s Ailments?”
Science 311:1852, 31 Mar 2006
Discovery
Development
Delivery
Discovery
Delivery
Development
Is it safe? Does it work? Can we make it better?
Translational Research
is a Two-Way Bridge
Laboratory
Clinic
Bench
Bedside
Petri Dish
Patient
Analogy compliments of S. Davies
Peril #1: Time and Money
Time and Money
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•
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Preclinical: 3-5 yrs, $3-5 million
Manufacturing: 1-2 yrs, $1-2 million
IND: 3-6 months, $0.5-1 million
Phase I: 1-2 yrs, $1-3 million
Phase II: 2-3 yrs, $3-6 million
Phase III: 3-4 yrs, $10-20 million
FDA: 1-3 yrs, $2-4 million
Source: http://www.wistechnology.com/article.php?id=377
Pharmaceutical Drug
Development: Saganesque
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“…billions and billions…”
15-20 years
Direct costs: $403 million
Add in marketing: $802 million
Some estimates up to $1.7 billion
From: DeMasi et al., J Health Economics 22:151, 2003
“…does anybody truly believe that academic
translational research centers will be as
efficient, let alone competitive, at developing
drugs as pharma?”
“…investing in translational research is akin
to building a bridge to nowhere.”
-J Erickson, in
Commentary: “Translational Research and Drug Development”
Science 312:997, 19 May 2006
Is AHC Translational Research Successful?
Nature, Cell, Science,
JBC, JCI, J Exp Med
From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003
20 Year Follow-up of Promising
Basic Science Technology
Of those identified over 5 year period:
• 1 in 4 led to published randomized trial
• 1 in 6 validated in positive trial
• <1 in 10 entered routine clinical use
• Only 1 deemed to have major impact
(ACE inhibitors)
From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003
From: Contopoulos-Ioannidis et al., Am J Med 114:477, 2003
Peril #2: Regulatory Hurdles
Human Subject Research
• Extensive pre-clinical (laboratory) research precedes
clinical trials
• History has shown that safeguards are necessary to
protect people in clinical trials
• Safeguards are extensive
• Enormous effort, time, costs underlie trials
Regulatory Steps in
Translational Research
IRB
Laboratory
cGMP
TOX
RAC
IND
Clinic
IRB
SAC
IBC
Levels of Burden: Sponsor vs. Investigator
• No IND
– Fulfill PI level obligations (GCP)
• Company-held IND
– Fulfill PI level obligations (GCP)
• Investigator-held, cross-referenced IND
– Fulfill PI and Sponsor obligations (GCP)
• Investigator-held IND
– Manufacture product (GMP)
– Conduct non-clinical studies (GLP)
– Fulfill PI and Sponsor obligations (GCP)
(Be the pharmaceutical company)
Peril #3: Academic Metrics
Hurdles for Patient-Oriented
Translational Clinical Researchers
• Training
– Extended
– Requires scientist-clinician mentoring
– Typically has been “on the job”
• Funding
– Especially for orphan diseases, childhood diseases!
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Slow results (may take years for 1 trial)
Regulatory burdens
Fragmented infrastructure
Traditional metrics of success inadequate
– Publications
– Grants
– Patient revenues
From: Nathan DG, J Clin Invest 115:795, 2005
Example
HSV Oncolysis for Cancer
• 2001: Initial preclinical data
UV-Mutant HSV
Mutant HSV
Example
HSV Oncolysis for Cancer
• 2001: Clinical trial concept proposed
• 2001-2004: More animal efficacy/safety
• 2004-2006: Regulatory/funding hurdles
– Local
• GCRC SAC, IBC, Radiation, IRB
– National
• NGVL, NIH RAC, FDA IND
My IND: 1 year and counting
Why should AHCs Conduct Translational Research?
• AHCs are birthplaces of ideas
– Lionshare of basic science research
– Unburdened by company constraints
• Tantalizing translational data needed to engage
industry
• AHCs can promote agendas with low market value
– Orphan diseases
– Pediatric diseases
What’s an Institution to do?
•Enhance scientific and clinical interactions
•Build scientific infrastructure through grants program
•Build clinical operations to facilitate complex and
multidisciplinary translational and clinical trials
•Provide support for complex regulatory help/oversight
CCHMC TRI
NIH CTSA
CCHMC
Translational Research Initiative (TRI):
• Founded in 2001
• Supported by clinical revenues
• Two-tiered mission
– To stimulate translational research via grants (financial support)
• Pre-clinical and early phase clinical trials
• Includes collection/analysis of biological samples
– To create infrastructure (regulatory support)
• New cores
• Workshops for clinical/research interactions
• Education
– Annual symposium
– Faculty scholar
– Masters program for fellows
• Translational Research Trials Office
Cripe et al. Acad Med 80:1012, 2005
TRI Projects Funded 2001-2004
• Translational research projects
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31 projects
30 investigators
21 divisions/departments
$2.475 million
• Cores
– 3 cores
• Fanconi anemia cell repository
• Human milk bank
• Mouse genotoxicity
– $250,000
• Workshops/symposia/retreats
– 13
– $39,000
Results: First Four Years
(30 Investigators given $2,475,000)
• 44 manuscripts
• 18 extramural grants
– Total direct costs: $27,691,304
• 7 patents
• 12 clinical trials launched
TRTO Office: First Five Years
• 11 INDs (plus 2 in development)
• 48 IRB-approved protocols
– 15 Therapeutic
– 33 Biologic/specimen collection
• Utilized by 8 CCHMC divisions
• Normal donor program for lab research
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–
–
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Blood (124)
G-CSF mobilized peripheral blood stem cells (86)
Bone marrow (173)
Umbilical cord blood (380)
2001 TRTO Human Resources
Personnel Funding
Associate Chair for Translational Research
David W illiams, MD
Director, TRTO
Blythe Thomson, MD
100%
Administrative Assistant
Carol Johnson
Institutional
Biostatistical Support (10%)
Mekibib Ataye
Clinical Research Coordinator
Susan Radtke, RN
Grants
Clinical Research Coordinator
Jen Garrett, PA
2 staff
2006 TRTO Human Resources
Associate Chair for Translational Research
David W illiams, MD
Personnel Funding
Director, TRTO
Timothy P. Cripe, MD, PhD
46% 54%
Administrative Assistant
Carol Johnson
Institutional
Clinical Research Manager
Peg Kaiser (interim)
Grants
Rare Lung Disease Network
Clinical Coordinators
QA Coodinator
Elva Turner
Data Manager
(open)
Normal Donor Program
Carrie Stevens
Fanconi Anemia Program
Vivian Arnold
General/IND Studies
Clinical Research Coordinator
Jeanie Bailey
Research Nurse
Ruth Spencer
Biostatistical Support (25%)
Mi-ok Kim
Clinical Research Coordinator
Susan Radtke
8 staff
Clinical Research Coordinator
Rubina Dosani
In conclusion…
Translational
Research:
Mission
Impossible?
Proceed cautiously, hang in there
Pre-clinical testing is essential
Usually testing in multiple
species is required
Other ideas may also work
When it comes to getting water to the fire…