title: Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.
abstract: 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.
authors.affiliation: University of Rochester, Rochester, NY, USA University of Washington, Seattle, WA, USA University of Kiel, Kiel, Germany Metrum Research Group, Tariffville, CT, USA Queen's University, Kingston, Ontario, Canada Analgesic Solutions, Natick, MA, USA Tufts University, Boston, MA, USA Cytel, Boston, MA, USA Johns Hopkins University, Baltimore, MD, USA CRP Santé, Strassen, Luxembourg CP Taylor Consulting, Ann Arbor, MI, USA American Chronic Pain Association, Rocklin, CA, USA Desjardins Associates and Rutgers University, Newark, NJ, USA Allergan, Irvine, CA, USA East Carolina University, Greenville, NC, USA University of Pennsylvania, Philadelphia, PA, USA Merck, Blue Bell, PA, USA Eli Lilly, Indianapolis, IN, USA Virtuous Pharma, Inc., Raleigh-Durham, NC, USA University of Helsinki, Helsinki, Finland VA Connecticut Healthcare System, West Haven, CT, USA Richard L Leff MD LLC, Chadds Ford, PA, USA Stanford University, Stanford, CA, USA California Pacific Medical Center, San Francisco, CA, USA Voyager Therapeutics, Cambridge, MA, USA Johnson and Johnson, Raritan, NJ, USA Imperial College, London, UK Faculdade de Medicina de Lisboa, Lisbon, Portugal University of Southern Denmark, Odense, Denmark Alpharma, Piscataway, NJ, USA Grünenthal GMbH, Aachen, Germany GlaxoSmithKline, Research Triangle Park, NC, USA Jazz Pharmaceuticals, Palo Alto, CA, USA Heidelberg University, Mannheim, Germany University of California San Diego, San Diego, CA, USA Endo Pharmaceuticals, Chadds Ford, PA, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Gewandter
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dworkin
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authors.lastname: Turk
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authors.lastname: Baron
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authors.initials: MR
authors.lastname: Gastonguay
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authors.lastname: Katz
authors.forename: Cyrus
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authors.lastname: Mehta
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authors.lastname: Raja
authors.forename: Stephen
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authors.lastname: Senn
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authors.initials: C
authors.lastname: Taylor
authors.forename: Penney
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authors.lastname: Desjardins
authors.forename: Rozalina
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authors.lastname: Dimitrova
authors.forename: Raymond
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authors.lastname: Dionne
authors.forename: John T
authors.initials: JT
authors.lastname: Farrar
authors.forename: David J
authors.initials: DJ
authors.lastname: Hewitt
authors.forename: Smriti
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authors.lastname: Iyengar
authors.forename: Gary W
authors.initials: GW
authors.lastname: Jay
authors.forename: Eija
authors.initials: E
authors.lastname: Kalso
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kerns
authors.forename: Richard
authors.initials: R
authors.lastname: Leff
authors.forename: Michael
authors.initials: M
authors.lastname: Leong
authors.forename: Karin L
authors.initials: KL
authors.lastname: Petersen
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Ravina
authors.forename: Christine
authors.initials: C
authors.lastname: Rauschkolb
authors.forename: Andrew S C
authors.initials: ASC
authors.lastname: Rice
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
authors.forename: Cristina
authors.initials: C
authors.lastname: Sampaio
authors.forename: Sren H
authors.initials: SH
authors.lastname: Sindrup
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Stauffer
authors.forename: Ilona
authors.initials: I
authors.lastname: Steigerwald
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stewart
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tobias
authors.forename: Rolf-Detlef
authors.initials: RD
authors.lastname: Treede
authors.forename: Mark
authors.initials: M
authors.lastname: Wallace
authors.forename: Richard E
authors.initials: RE
authors.lastname: White
mesh_terms: D059350:Chronic Pain / Q000188:drug therapy / Q000628:therapy*; D002986:Clinical Trials as Topic; D006801:Humans; D012107:Research Design; D018401:Sample Size
keywords: Clinical trials; IMMPACT; Methodology; Proof of concept