Pediatric Analgesia: Facilitating Clinical Trials

AUSTIN, TX—A multicenter pediatric pain clinical trials consortium will facilitate better study design and ensure children experience no additional burden for participation in research, including enduring even slightly undertreated pain, a panel of pediatric pain experts said during the American Pain Society’s 30th Annual Scientific Meeting.

Jacqueline A. Spaulding, MD, MPH, of the U.S. Food and Drug Administration, Rockville, MD, said most drugs in children are used off-label and based on age, not the recommended body surface area and weight. For that reason, pediatric trials are needed to provide information on dosing, safety, and to settle issues of efficacy, which have been extrapolated from studies in adults.

Recent U.S. Food and Drug Administration amendments have allowed pharmaceutical companies to submit efficacy data extrapolated from clinical trials in adults. “Extrapolation of efficacy is beneficial, as it requires fewer patients and may expedite information on pediatric use,” said Dr. Spaulding. However, safety and tolerability data must still be provided, including determining pharmacokinetic “ADME + T”: absorption, distribution, metabolism, elimination—and toxicity. Pharmacokinetics can be quite variable: in one study, approximately one-third of children produced no detectable morphine following administration of 1.5 mg/kg codeine, while cases of overdose have been detected in those who were subsequently determined to be CYP450 2D6 ultra-rapid metabolizers of codeine.

Pharmaceuticals companies were provided an incentive to conduct pediatric trials under the Best Pharmaceuticals for Children Act, passed in 2007 as part of the FDA Modernization Act; an additional 6 months of patent exclusivity is granted for trials conducted on products in children. However, challenges to pediatric drug trials remain, including the limited number of patients available for enrollment, ethical concerns of institutional review boards and investigators, and parents unwilling to provide informed consent.

According to Charles Berde, MD, PhD, Harvard Medical School, Boston, MA, studies of acetaminophen, nonsteroidal antiinflammatory drugs, and opioids suggest use of these agents are safe for children as young as 3 months of age. However, evidence from studies of antidepressants and anticonvulsants for neuropathic pain in adults does not support extrapolation of efficacy of these drug classes to children.

Approximately 7% to 10% of otherwise healthy children have recurrent pain problems and one key concern is the potential long-term consequences of chronic pain medication usage among infants and young children when their bodies and internal organs are still developing, said Gary Walco, PhD, Seattle Children’s Hospital and University of Washington, Seattle, WA. “Extrapolating from adult clinical data has been the norm, but that doesn’t provide assurances that opioids and other potent pain drugs are safe or effective, especially in young children,” he said.

Clinical trials based on “immediate rescue” should be considered more widely in pediatrics instead of the traditional placebo or active controlled design, in which patients who receive placebo would remain in pain, Berde said. Using nurse-controlled or patient-controlled anesthesia allows the patient to have immediate pain relief and is clinically relevant, for example, for postoperative care.

In 2009, a consensus conference involving FDA officials and pediatric pain experts examined issues and limitations that should be addressed to remove obstacles to performing more clinical trials in pediatric populations. Recommendations from the conference have been provisionally accepted for publication. Also, earlier in May, the Pediatric Ethics Subcommittee of the FDA’s Pediatric Advisory Committee concluded that in most cases, it is ethical to administer smaller than normal doses of investigational drugs.