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IMMPACT 2008 “Early Clinical Study Designs, Emphasizing … Proof-of-Concept Trials …” An industry* perspective

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. Talking Points. Industry general perspective Putting it into global perspective

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IMMPACT 2008 “Early Clinical Study Designs, Emphasizing … Proof-of-Concept Trials …” An industry* perspective

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  1. 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 Christine Rauschkolb

  2. Talking Points Industry general perspective Putting it into global perspective Some critical questions Some existing answers Example Imaging Example QST More questions Answers??? Christine Rauschkolb

  3. 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 Christine Rauschkolb

  4. 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 Christine Rauschkolb

  5. “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 Christine Rauschkolb

  6. “More Innovation ” Boeing Dreamliner – 787 Collaboration of ~200 different companies = Boeing themselves don’t ‘produce’ the aircraft Photo from official Boing website Christine Rauschkolb

  7. 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) Christine Rauschkolb

  8. 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 … Christine Rauschkolb

  9. 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 Christine Rauschkolb

  10. 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 • … Christine Rauschkolb

  11. 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 Christine Rauschkolb

  12. Imaging Examples how a new technology can “innovate” a new approach Christine Rauschkolb

  13. Imaging Targets in the Brain Blood flow Blood volume Brain metabolites Brain volume Cerebral metabolism Cytoarchitecture Neurotransmitters Receptors Synthetic pathways Gene expression Christine Rauschkolb

  14. Imaging & Development Continuum Wise RG, Tracey I: Neuropsychopharmacology 2004 Mar, 29(3), 826-876 Christine Rauschkolb

  15. 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 Christine Rauschkolb

  16. 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 Christine Rauschkolb

  17. 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 Christine Rauschkolb

  18. 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 Christine Rauschkolb

  19. Case Study Remifentanil Time-course of fMRI and perceived pain intensity Wise RG, Williams P, Tracey I. Neuropsychopharmacology. 2004 Mar;29(3):626-35 Christine Rauschkolb

  20. 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. Christine Rauschkolb

  21. QST (and Questionnaires) NTE-2 Thermal Sensitivity Tester Somedic Thermotest & Aesthesiometer Christine Rauschkolb

  22. Neuropathic Pain Symptom Inventory (NPSI) Based on earlier work from the same group: Bouhassira D et al, Pain 2004 April 108(3) 248-57 Christine Rauschkolb

  23. 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 Christine Rauschkolb

  24. 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 Christine Rauschkolb

  25. 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/ Christine Rauschkolb

  26. Answers??? http://www.phenomics.ucla.edu/phenomics/ Christine Rauschkolb

  27. 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/tc20080610_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/tc20080610_151383.htm?campaign_id=yhoo> Christine Rauschkolb

  28. 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_medical_researchers_to_pool_work/> Christine Rauschkolb

  29. 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 Christine Rauschkolb

  30. 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 Christine Rauschkolb

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