Early Clinical Study Designs, Emphasizing Proof-of-Concept Trials Ian Gilron, MD, MSc, FRCPC Director of Clinical Pain Research, Associate Professor Depts. of Anesthesiology & Pharmacology, Queen’s University, Kingston, CANADA

TREATMENT EFFICACY Divergent dilemmas in the development of new therapies: 1) Falsely negative POCT - could be missing out on a potentially promising and effective treatment 2) Falsely positive POCT - could be "fished in" to devoting substantial resources on an ultimately unmarketable therapy Q: What investigative approaches can minimize risk of the above two problems?

Questions - old & new - for POC trials 1. Do human experimental pain studies reliably predict clinical treatment responses? 2. What is the value of surrogate outcomes for POCTs? 3. Which trial methods optimize “predictive value”? 4. Do active comparators improve “predictive value”? 5. When & how do PK measures need to be incorporated into early efficacy studies?

Pre clinical RCTs to predict disease responsiveness Can experimental- predict clinical treatment responses? A case study of gabapentin Model/conditionEfficacy?Reference 1stº burn+Werner et.al., 2001 UV-B injury-Gustorff et.al., 2004 capsaicin-hyperalgesia+Gottrup et.al., 2004 capsaicin-hyperalgesia-Iannetti et.al., 2005 IM hypertonic saline+Arendt-Nielsen et.al., 2007 IM hypertonic saline-Segerdahl, 2006 electrical stimulation+Arendt-Nielsen et.al., 2007 electrical stimulation+Segerdahl, 2006

RCTs to understand treatment mechanisms in humans Iannetti et. al., PNAS 2005 activation deactivation

Comparing to the moving placebo target: Which is the true result? p<0.01, Pgb 300mg/d vs. placebo Rosenstock et al., Pain NS, Pgb 300mg/d vs. placebo Tolle et al., Eur. J. Pain 2008.

Does more stringent blinding improve “predictive value”? Gracely et. al., Anesth Analg 1982 Diazepam reduced unpleasantness of but NOT sensory intensity of pain following tooth pulp electrical stimulation (Gracely et. al., 1982) Benzodiazepines also shown to be ineffective for neuropathic pain (Max et. al., 1988; Dellemijn et. al., 1997) Benzodiazepines subsequently used as an “active placebo” to improve blinding in several analgesic trials (Gilron et. al., 2000; Sang et. al., 2002; Rorarius et. al., 2004; Gilron et. al., 2005) Q: How to best match active placebo to study treatment? Q: How to interpret POCT results in light of blinding questionnaire data?

Innovative designs to improve analgesic evaluation Can RCTs deal with heterogeneous populations? Byas-Smith et. al., Pain 1995

Innovative designs to improve analgesic evaluation Can RCTs deal with heterogeneous populations? Byas-Smith et. al., Pain 1995 See also review by McQuay et al., Pain 2008

Is enriched enrollment good? or bad? for the “predictive value” of POCTs? exclude placebo responders? exclude treatment non-responders? exclude extremes of pain intensity upon study entry? exclude subjects with psychopathology?

Do active comparators improve “predictive value”? Dionne et. al., ’98. clinically relevant validates trial methods requires available Tx’s

PK for early efficacy studies? Sindrup et. al., Pain Aug;42(2):

true positive false positive false negative true negative POCTs as a “diagnostic test” of efficacy phase 3 RCT outcome + - POCT outcome - + Sensitivity = a/(a + c) Specificity = d/(b + d) +ve pred. value = a/(a + b) -ve pred. value = d/(c + d) False negative - could be missing out on a promising treatment False positive - "fished in" to +++ spending on a failed therapy Q: Can retrospective analysis of studies on recently marketed drugs identify methods with high predictive value? a b c d

DISCUSSION Previous research on pain therapies has nurtured the development of diverse investigative methods & tools. The optimally predictive, safe, inexpensive and efficient approach to a proof-of-concept trial program likely needs to be individualized to the treatment and target condition. Given the prospective nature of development programs (i.e. phase I, then II, then III) it may be impossible to identify the “perfect POC trial design”. Inclusion of at least one active comparator with known efficacy (in addition to placebo), multiple outcome measures, and concurrent PK measures could greatly aid in interpretation of POCT results. Retrospective analysis of POCTs of currently licensed treatments could provide useful information about POCTs with optimal predictive value.