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Pain. 2014 Sep;155(9):1683-95. doi: 10.1016/j.pain.2014.05.025. Epub 2014 May 24.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.

Author information

1
University of Rochester, Rochester, NY, USA. Electronic address: jennifer_gewandter@urmc.rochester.edu.
2
University of Rochester, Rochester, NY, USA.
3
University of Washington, Seattle, WA, USA.
4
University of Kiel, Kiel, Germany.
5
Metrum Research Group, Tariffville, CT, USA.
6
Queen's University, Kingston, Ontario, Canada.
7
Analgesic Solutions, Natick, MA, USA; Tufts University, Boston, MA, USA.
8
Cytel, Boston, MA, USA.
9
Johns Hopkins University, Baltimore, MD, USA.
10
CRP Santé, Strassen, Luxembourg.
11
CP Taylor Consulting, Ann Arbor, MI, USA.
12
American Chronic Pain Association, Rocklin, CA, USA.
13
Desjardins Associates and Rutgers University, Newark, NJ, USA.
14
Allergan, Irvine, CA, USA.
15
East Carolina University, Greenville, NC, USA.
16
University of Pennsylvania, Philadelphia, PA, USA.
17
Merck, Blue Bell, PA, USA.
18
Eli Lilly, Indianapolis, IN, USA.
19
Virtuous Pharma, Inc., Raleigh-Durham, NC, USA.
20
University of Helsinki, Helsinki, Finland.
21
VA Connecticut Healthcare System, West Haven, CT, USA.
22
Richard L Leff MD LLC, Chadds Ford, PA, USA.
23
Stanford University, Stanford, CA, USA.
24
California Pacific Medical Center, San Francisco, CA, USA.
25
Voyager Therapeutics, Cambridge, MA, USA.
26
Johnson and Johnson, Raritan, NJ, USA.
27
Imperial College, London, UK.
28
Faculdade de Medicina de Lisboa, Lisbon, Portugal.
29
University of Southern Denmark, Odense, Denmark.
30
Alpharma, Piscataway, NJ, USA.
31
Grünenthal GMbH, Aachen, Germany.
32
GlaxoSmithKline, Research Triangle Park, NC, USA.
33
Jazz Pharmaceuticals, Palo Alto, CA, USA.
34
Heidelberg University, Mannheim, Germany.
35
University of California San Diego, San Diego, CA, USA.
36
Endo Pharmaceuticals, Chadds Ford, PA, USA.

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.

KEYWORDS:

Clinical trials; IMMPACT; Methodology; Proof of concept

PMID:
24865794
PMCID:
PMC4500524
DOI:
10.1016/j.pain.2014.05.025
[Indexed for MEDLINE]
Free PMC Article

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