Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations

Abstract

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

“Unsettling circularity”: Clinical trial enrichment and the evidentiary politics of chronic pain

“…Enrichment had been a focus of IMMPACT since its 2006 meeting on "Randomized Clinical Trials for Chronic Pain Treatments: Placebo Controlled-Designs and their Alternatives" (IMMPACT, 2006), and in 2010 the organization published its recommendations on the value of enriched enrollment specifically for pain trials (Dworkin et al, 2010). While IMMPACT is a private organization and not a public-private partnership, FDA officials such as Bob Rappaport, then director of the CDER's Division of Anesthesia, Analgesia and Addiction Products, sometimes appear as co-authors on IMMPACT publications.…”

“…The GFI is the most coherent articulation of a broader discourse on the value and promise of enrichment (Katz, 2005;Katz et al, 2008;McQuay et al, 2008;Katz, 2009;Dworkin et al, 2010;Riordan and Murphy, 2010;Temple, 2010;Dworkin et al, 2012;Temple, 2012Temple, , 2013. The GFI defines enrichment as "the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population" (FDA, 2012c, p. 2), and divides enrichment strategies into three broad categories: practical, prognostic and predictive.…”

“…For the most part, however, the discourse on EERW that has emerged from the FDA, IMMPACT and related publications focuses on improved assay sensitivity (Katz, 2005;Dworkin et al, 2010;Riordan and Murphy, 2010;Woolf, 2010;Hewitt et al, 2011;Dworkin et al, 2012;FDA, 2012c;Gewandter et al, 2014a). Proponents acknowledge that the design sacrifices external validity for improved internal validity, but tend to treat the loss of external validity as a non-issue, because (in theory at least) the drug tested in an enriched trial is only intended for use in that small subset of the population for which it is effective (McQuay et al, 2008;Katz, 2009).…”

“…We examine a set of rhetorical strategies that situate EERW as continuous with both routinely accepted research practice and the promise of pharmacogenomics and personalized medicine. Both pharmacogenomics and EERW rest upon the assumption that heterogeneity in patients' drug response is caused by the existence of distinct patient subtypes which, once identified and elaborated, will provide the grounds for individualization of diagnosis and therapy (Hedgecoe, 2004;Lakoff, 2008;Dworkin et al, 2010). Although proponents of EERW designs for analgesic trials mobilize this rhetoric of heterogeneity and subtyping, in practice such trials do not actually contribute to the elucidation of this heterogeneity, or to the personalization of treatment.…”

Randomized clinical trial of multimodal physiotherapy treatment compared to overnight lidocaine ointment in women with provoked vestibulodynia: Design and methods

“…Women with moderate or severe pain during intercourse were included as they are representative of the PVD population [30], and their pain may also correspond to a typical level of severity at which many women will seek medical advice [6]. It will also prevent a floor effect and thus ensure that the intervention will have a measurable efficacy [62]. Moreover, a 6-month duration of symptoms was selected based on the DSM-V criteria for genito-pelvic pain/penetration disorders [63].…”