IMMPACT 2008
“Early Clinical Study Designs,
Emphasizing …
Proof-of-Concept Trials …”
An industry* perspective
Christine Rauschkolb, MD, PhD
* Disclaimer – this is not an official J&J presentation
June 13, 2008
Christine Rauschkolb
1
Talking Points
Industry general perspective
Putting it into global perspective
Some critical questions
Some existing answers
Example Imaging
Example QST
More questions
Answers???
June 13, 2008
Christine Rauschkolb
2
How Bad is It?
 Productivity per R&D dollar is declining
 The average new drug now costs $802m to develop, or
$897m if the costs of post-approval R&D are also
considered
 The pharmaceutical industry is suffering from a lack of
genuine innovation
 To overcome declining productivity, pharmaceutical
companies have continued to invest heavily in R&D
without compensatory improvements in pipeline value
Winning Pharmaceutical R&D Strategies: Reuters Business Insight
(HealthCare) Jun 2004
June 13, 2008
Christine Rauschkolb
3
Current Situation
• Highly regulated field
• Huge safety concerns
• Potential life threatening situation if
products unsafe
• Massive cost burden and pressure
• Patent limitations/constraints
• … it is not Pharma …
Aircraft Industry
June 13, 2008
Christine Rauschkolb
4
“Innovate” a New Approach
Airbus A380
>120 partners & suppliers
New way of working together in the industry
Extensive customer input
Catalyst for innovative technologies
Spread environmental best practice as requirements down supply chain
Design philosophy based on entire life cycle of aircraft
Provide double digit increase in operator’s (airlines) return
Photo from official Airbus Industry website
June 13, 2008
Christine Rauschkolb
5
“More Innovation ”
Boeing Dreamliner – 787
Collaboration of ~200 different companies =
Boeing themselves don’t ‘produce’ the aircraft
Photo from official Boing website
June 13, 2008
Christine Rauschkolb
6
Learnings for / in the Pain Area
“This is beyond the capacity of any pain researcher.”
needs
“joint planning among research sectors”
(Woolf and Max, Anesthesiology 2001)
“The proceedings of the workshop support the need to
enhance the scientific basis for analgesic drug
development and the regulatory process.”
(Dionne and Witter, Clin J Pain, 2003, NIH/FDA
Analgesic Drug Development Workshop Special
Report)
“… investment in knowledge….develop more scientists
with the quantitative skills to implement MBDD on a
broader scale … more training programs …
Partnerships … will be important …”
(Lalonde et al, Clin Pharmacol Ther 2007)
June 13, 2008
Christine Rauschkolb
7
What is in the Tool Box?
Signal detection or traditional
Human pain models or pain studies
Study design / statistical methods
Identify placebo responders
Objective testing
New imaging techniques
Electrophysiologic testing (e.g., QST, LSEP)
Questionnaires / PROs / assessments
PK-PD modeling and simulation
Pharmacogenomics
…
June 13, 2008
Christine Rauschkolb
8
Critical Early Study Issues?
• What and when is POC
• Often POC studies still are smaller Phase 2b
or 3
too expensive
• Not always generalizable
• Not enough early differentiation
• Placebo response not addressed
• Too many compounds killed too early (or too
late)
• Still too little sharing across silos
Ultimately not enough new / alternative
treatments for patients
June 13, 2008
Christine Rauschkolb
9
A Good POC Model …?
• Quick to recruit relatively healthy subjects
• Allow a supervized setting with intense monitoring for
efficacy and safety (AEs)
• Specific to a subtype of pain and be generalizable to
the entire population with that pain
• Specific to clinical symptoms rather than disease type
• Sensitive to show dose response in efficacy
• Sensitive enough to pick up side effects
• Objective enough to rule out placebo response
• Simple enough to allow for multiple different sites
without unduly increasing variability
• Include comparator for assay sensitivity
• …
June 13, 2008
Christine Rauschkolb
10
How to Customize?
“…a careful sequential plan involving only a few
key studies can provide sufficient basis for
embarking on phase 3.” (Sheiner, Clin
Pharmacolog Ther 1997)
“Why Math Will Rock Your World” (S. Baker,
Business Week, Jan 3, 2006 coverstory)
describing new ways math will be used in all
sectors, including research
June 13, 2008
Christine Rauschkolb
11
Imaging
Examples how a new technology can
“innovate” a new approach
June 13, 2008
Christine Rauschkolb
12
Imaging Targets in the Brain
Blood flow
Blood volume
Brain metabolites
Brain volume
Cerebral metabolism
Cytoarchitecture
Neurotransmitters
Receptors
Synthetic pathways
Gene expression
June 13, 2008
Christine Rauschkolb
13
Imaging & Development Continuum
Wise RG, Tracey I: Neuropsychopharmacology 2004 Mar, 29(3), 826-876
June 13, 2008
Christine Rauschkolb
14
Molecular Imaging Impact
• Dynamic/longitudinal in vivo (non-invasive)
measurements of molecular and cellular events in real time
• Follow trafficking and targeting of cells
• Biodistribution, uptake, clearance, compartment kinetics
• Mode of Action
• Receptor occupancy, target validation/engagement,
dosing
• Pharmacodynamic, including downstream effects
• PK/PD relationship
• Biomarkers for diagnosis, disease risk, progression
treatment response, relapse
June 13, 2008
Christine Rauschkolb
15
Added Value despite
Bottlenecks
 Cross species differences, not always translatable to humans
 Patient heterogeneity
 Need for qualified and validated imaging makers
 Development/validation
 State of the art imaging analysis tools
Go/No Go decisions, eliminate compounds
likely to fail and support development
Guidance for dose selection, resulting in
fewer dose levels and arms
Biomarkers for efficacy (surrogate marker)
and patient selection
June 13, 2008
Christine Rauschkolb
16
Case Study Remifentanil
Using fMRI to quantify the time dependence of
remifentanil analgesia in the human brain
• Time of onset and the half-life of action of a clinically relevant dose
• By temporal variation of amplitude of blood oxygen level-dependent
(BOLD) response in insular cortex contralateral to painful hot thermal
stimuli
• First time successful measurement of temporal pharmacological
parameters for a CNS-active drug
• Comparison of time course of regional brain activity with pain
perception could reveal the regions engaged in drug-induced analgesia
Wise RG, Williams P, Tracey I. Neuropsychopharmacology. 2004 Mar;29(3):626-35
June 13, 2008
Christine Rauschkolb
17
Case Study Remifentanil
One imaging session lasting approximately 30 min
Intravenous infusion either remifentanil or saline
Painful thermal stimuli were of a constant temperature within
one session
Wise RG, Williams P, Tracey I. Neuropsychopharmacology. 2004 Mar;29(3):626-35
June 13, 2008
Christine Rauschkolb
18
Case Study Remifentanil
Time-course of fMRI and perceived pain intensity
Wise RG, Williams P, Tracey I. Neuropsychopharmacology. 2004 Mar;29(3):626-35
June 13, 2008
Christine Rauschkolb
19
fMRI – HPM - PK Modeling
•
•
•
•
The signal changes identified occurred over periods of minutes and where therefore
likely to represent drug induced changes in neuronal activity
Evaluation of a continuous range of remifentanil effect site concentrations is new,
previously only steady state, before/after
The value of this continuous setting is to reduce intersession variability which can
be substantial in a study that uses multiple discrete drug doses
Regional modulation of pain-related activity in the bilateral insular cortices &
anterior cingulate cortex is consistent with the distribution of mu-opioid receptors
Novel information gained within the drug discovery process - in vivo
drug induced effects on brain function
Neuroimage. 2002 Aug;16(4):999-1014
Wise RG, Rogers R, Painter D, Bantick S, Ploghaus A, Williams P, Rapeport G, Tracey I.
June 13, 2008
Christine Rauschkolb
20
QST (and Questionnaires)
NTE-2 Thermal Sensitivity Tester
Somedic
Thermotest &
Aesthesiometer
June 13, 2008
Christine Rauschkolb
21
Neuropathic Pain Symptom
Inventory (NPSI)
Based on earlier work from the same group:
Bouhassira D et al, Pain 2004 April 108(3) 248-57
June 13, 2008
Christine Rauschkolb
22
NPSI linked to QST
A: p < 0.0001
Rho = 0.83
B: p < 0.0001
Rho = 0.79
C: p < 0.0001
Rho = 0.75
Similar relationship pressure/cold when
expressed as  painful/control side
Lower suprathreshold mechanical/cold
Attal et al, in press PAIN 2008 see previous slide
June 13, 2008
Christine Rauschkolb
23
Translational Strategy
• We need a seamless integration and translation of
early learnings in subsequent steps
• Pre-clinical – PD markers – Phase 1 – Clinical POC –
PRO measures – Registration studies – Post
approval studies
• Integration not only vertical, but horizontal,
inclusive of various pain “areas” like nociceptive,
neuropathic, acute and chronic
June 13, 2008
Christine Rauschkolb
24
Answers???
Center for Cognitive Phenomics (CCP)
with chair Robert Bilder accelerate identification and efficient
measurement of cognitive phenotypes across syndromes and across
species to advance interdisciplinary research on neuropsychiatric
therapeutics.
http://www.phenomics.ucla.edu/phenomics/
June 13, 2008
Christine Rauschkolb
25
Answers???
http://www.phenomics.ucla.edu/phenomics/
June 13, 2008
Christine Rauschkolb
26
Answers???
Western pharmaceutical companies are increasingly teaming up
with companies in China and India. Virtually every big
pharmaceutical company is hiring contractors such as Wuxi
PharmaTech, Shanghai ChemPartners, and ShanghaiBio to do
everything from synthesizing and analyzing new compounds
to testing drugs on tissue samples and animals. Full-fledged
discovery collaborations such as those in India are starting to
appear.
<http://www.businessweek.com/technology/content/jun2008/t
c20080610_071365_page_2.htm>
A new Duke and Harvard study shows that research in China and
India is getting more sophisticated much faster than the
numbers let on. As a result, scientists from Indian and Chinese
companies are rapidly developing the ability to innovate and
create their own intellectual property resulting in a change in
the global technology landscape.
<http://www.businessweek.com/technology/content/jun2008/t
c20080610_151383.htm?campaign_id=yhoo>
June 13, 2008
Christine Rauschkolb
27
Answers???
Harvard medical researchers to pool work
Under a program announced Thursday, Harvard teaching hospitals
have agreed to pool some of their research efforts to shorten the time it
takes to turn discoveries into treatments. A massive, centralized
database will give Harvard's researchers instant access to one
another's work. The National Institutes of Health grant of $117.7 million
over the next five years, will go to Harvard Medical School, which will
award the money to teams of researchers spread among its various
affiliated hospitals.
<http://www.boston.com/news/local/articles/2008/05/30/harvard_medic
al_researchers_to_pool_work/>
June 13, 2008
Christine Rauschkolb
28
Conclusion
We are on the right track but there is a long way
to go …
Translational medicine tools must be rigorously
applied to enable efficient decision-making in
small, rapid clinical studies
June 13, 2008
Christine Rauschkolb
29
Acknowledgements
• Co-workers and industry colleagues have contributed
ideas to the general question, but these in particular
• Gary Romano, MD, PhD
• Magali Haas, MD, PhD
• David Upmalis, MD
• Bradford Navia, MD, PhD
June 13, 2008
Christine Rauschkolb
30