Gewandter, Jennifer S2; Dworkin, Robert H3; Turk, Dennis C4; McDermott, Michael P3; Baron, Ralf5; Gastonguay, Marc R6; Gilron, Ian7; Katz, Nathaniel P8; Mehta, Cyrus9; Raja, Srinivasa N10; Senn, Stephen11; Taylor, Charles12; Cowan, Penney13; Desjardins, Paul14; Dimitrova, Rozalina15; Dionne, Raymond16; Farrar, John T17; Hewitt, David J18; Iyengar, Smriti19; Jay, Gary W20; Kalso, Eija21; Kerns, Robert D22; Leff, Richard23; Leong, Michael24; Petersen, Karin25; Ravina, Bernard M26; Rauschkolb, Christine27; Rice, Andrew S C28; Rowbotham, Michael C29; Sampaio, Cristina30; Sindrup, Søren H38; Stauffer, Joseph W31; Steigerwald, Ilona32; Stewart, Jonathan33; Tobias, Jeffrey34; Treede, Rolf-Detlef35; Wallace, Mark36; White, Richard E37
1 Neurology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 University of Rochester, Rochester, NY, USA. Electronic address: email@example.com University of Rochester4 University of Washington5 University of Kiel6 Metrum Research Group, Tariffville, CT, USA.7 Queen's University, Kingston, Ontario, Canada.8 Analgesic Solutions, Natick, MA, USA; Tufts University, Boston, MA, USA.9 Cytel, Boston, MA, USA.10 Johns Hopkins University, Baltimore, MD, USA.11 CRP Santé, Strassen, Luxembourg.12 CP Taylor Consulting, Ann Arbor, MI, USA.13 American Chronic Pain Association, Rocklin, CA, USA.14 Desjardins Associates and Rutgers University, Newark, NJ, USA.15 Allergan, Irvine, CA, USA.16 East Carolina University, Greenville, NC, USA.17 University of Pennsylvania18 Merck, Blue Bell, PA, USA.19 Eli Lilly, Indianapolis, IN, USA.20 Virtuous Pharma, Inc., Raleigh-Durham, NC, USA.21 University of Helsinki22 VA Connecticut Healthcare System, West Haven, CT, USA.23 Richard L Leff MD LLC, Chadds Ford, PA, USA.24 Stanford University25 Institut for Æstetik og Kommunikation - Æstetik og Kultur26 Voyager Therapeutics, Cambridge, MA, USA.27 Janssen Pharmaceuticals28 Imperial College London29 California Pacific Medical Center, San Francisco, CA, USA.30 Faculdade de Medicina de Lisboa, Lisbon, Portugal.31 Alpharma, Piscataway, NJ, USA.32 Grünenthal GMbH, Aachen, Germany.33 GlaxoSmithKline, Research Triangle Park, NC, USA.34 Jazz Pharmaceuticals, Palo Alto, CA, USA.35 Heidelberg University, Mannheim, Germany.36 University of California37 Endo Pharmaceuticals, Chadds Ford, PA, USA.38 Neurology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
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.