Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop

Abstract

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

Conflict of interest statement

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Figures

FIGURE 1

Typical time course of pain scores for a double-blind, parallel-group, placebo-controlled, active-comparator analgesic trial. Note that in general, requirement for rescue analgesia results in termination of pain scoring for that subject. VAS, visual analog scale.

FIGURE 2

Idealized immediate rescue analgesic trial for a single-dose analgesic study. A, The time course of hourly rescue dosing of a short-acting opioid. B, The cumulative rescue opioid dosing over time. C, The time course of pain scores. Note that, depending on the dosing schedule for rescue analgesics, in some trials of this design, pain scores remain lower in the active drug group than for the placebo group.