Early Clinical Study Designs, Emphasizing Proof-of-Concept Trials

Ian Gilron, MD, MSc, FRCPCDirector of Clinical Pain Research,

Associate ProfessorDepts. of Anesthesiology

& Pharmacology, Queen’s University,Kingston, CANADA

TREATMENT EFFICACYDivergent 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 responsivenessCan experimental- predict clinical treatment responses?

A case study of gabapentinModel/condition Efficacy? 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 2004.

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 butNOT sensory intensity of pain following toothpulp electrical stimulation (Gracely et. al., 1982)

• Benzodiazepines also shown to beineffective for neuropathic pain (Max et. al., 1988; Dellemijn et. al., 1997)

• Benzodiazepines subsequently used as an“active placebo” to improve blinding in severalanalgesic 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 studytreatment?

Q: How to interpret POCT results in light of blinding questionnaire data?

Innovative designs to improve analgesic evaluationCan RCTs deal with heterogeneous populations?

Byas-Smith et. al., Pain 1995

Innovative designs to improve analgesic evaluationCan 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. 1990 Aug;42(2):135-44.

truepositive

falsepositive

falsenegative

truenegative

POCTs as a “diagnostic test” of efficacy phase 3 RCT outcome

+ -

POCT

out

com

e

-

+ 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 treatmentFalse 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.