This article presents general considerations discussed at an IMMPACT consensus meeting regarding proof-of-concept (POC) clinical trials and major POC trial designs as well as their advantages and limitations when used to evaluate chronic pain treatments.
Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic–pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
aUniversity of Rochester, Rochester, NY, USA
bUniversity of Washington, Seattle, WA, USA
cUniversity of Kiel, Kiel, Germany
dMetrum Research Group, Tariffville, CT, USA
eQueen’s University, Kingston, Ontario, Canada
fAnalgesic Solutions, Natick, MA, USA
gTufts University, Boston, MA, USA
hCytel, Boston, MA, USA
iJohns Hopkins University, Baltimore, MD, USA
jCRP Santé, Strassen, Luxembourg
kCP Taylor Consulting, Ann Arbor, MI, USA
lAmerican Chronic Pain Association, Rocklin, CA, USA
mDesjardins Associates and Rutgers University, Newark, NJ, USA
nAllergan, Irvine, CA, USA
oEast Carolina University, Greenville, NC, USA
pUniversity of Pennsylvania, Philadelphia, PA, USA
qMerck, Blue Bell, PA, USA
rEli Lilly, Indianapolis, IN, USA
sVirtuous Pharma, Inc., Raleigh-Durham, NC, USA
tUniversity of Helsinki, Helsinki, Finland
uVA Connecticut Healthcare System, West Haven, CT, USA
vRichard L Leff MD LLC, Chadds Ford, PA, USA
wStanford University, Stanford, CA, USA
xCalifornia Pacific Medical Center, San Francisco, CA, USA
yVoyager Therapeutics, Cambridge, MA, USA
zJohnson and Johnson, Raritan, NJ, USA
aaImperial College, London, UK
abFaculdade de Medicina de Lisboa, Lisbon, Portugal
acUniversity of Southern Denmark, Odense, Denmark
adAlpharma, Piscataway, NJ, USA
aeGrünenthal GMbH, Aachen, Germany
afGlaxoSmithKline, Research Triangle Park, NC, USA
agJazz Pharmaceuticals, Palo Alto, CA, USA
ahHeidelberg University, Mannheim, Germany
aiUniversity of California San Diego, San Diego, CA, USA
ajEndo Pharmaceuticals, Chadds Ford, PA, USA
*Corresponding author. Address: Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 604, Rochester, NY 14642, USA. Tel.: +1 585 276 5661; fax: +1 585 244 7271.
Submitted February 25, 2014; revised May 15, 2014; accepted May 21, 2014.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.