When it comes to pediatric analgesic clinical trials, protocols cannot be simply “cut and paste” from adult trials. Likewise, extrapolation of efficacy and risks from adult studies is not always reliable due to developmental and physiological differences. Researchers engaged in pediatric trial design must consider the specific physiology, pharmacology, and normal daily activities for each group being studied.
Determining the Safest Dose
Relevant studies of pharmacokinetic and safety are needed to provide a rationale for dose calculation and patient selection. Sponsors should also consider the drug’s mechanism of action in order to determine the data needed to properly evaluate drug metabolism, dose response, and toxicity.
Drug classes with well-understood mechanisms are likely to have similar efficacy at similar effect-site concentrations in children over two years of age compared with adults. For these drugs, doses can be extrapolated from adult pharmacodynamic study data, and adolescent safety data can be inferred from adult data.
For drugs with less well-understood mechanisms, pediatric pharmacodynamic, safety, and efficacy studies should be performed.
Dosage strengths should be based on body size and organ development. Simply weight-scaling from adult dosages can lead to significant over- or under-dosing. Keep in mind that there is a great deal of pharmacogenomic variability among pediatric patients, especially when it comes to medications that act as prodrugs.
Covering all Therapeutic Uses
In order to gain regulatory approval, studies must address multiple pharmaceutical forms and routes of administration. When thoroughly defining the risks and benefits of a new drug, sponsors are required to conduct studies in all patient populations likely to use the drug, which the FDA issues in the form of Written Requests.
However, sponsors can also apply for full or partial waivers of pediatric assessment under certain criteria. For example, if the FDA makes a Written Request for studies on neonates, sponsors may provide sufficient justification that the studies are not feasible or that the study drug will not have meaningful health benefits in that pediatric population.
The Ideal Patient Population
For pediatric analgesic studies, the preferred population is children who are undergoing elective inpatient surgery. This allows for prospective enrollment in clinical trials. In contrast, in emergent settings, the patient is already in pain. Inpatient surgeries are also preferable to outpatient, as compliance with the study drug can be monitored with easier and more complete data collection.
The Advantage of Two-Phase Trials
To ensure regulatory compliance, patient health, and scientific rigor, sponsors may consider implementing analgesic safety and efficacy studies in two separate phases:
- An open-label, single-dose, dose-selection phase.
- A double-blind, multiple-dose phase that includes an active comparator using immediate opioid rescue design.
For safety studies, sponsors may choose to start enrollment with older age groups with an independent data monitoring committee evaluating safety from the early data collected before proceeding with the enrollment of younger patients.
The 6 Core Outcome Domains for Acute Pain
As with other aspects of trial design, efficacy endpoints used in adult trials may not translate directly to pediatric analgesics. The Pediatric Initiative on Method, Measurements, and Pain Assessment in Clinical Trials (Ped-IMMPACT) recommends these core outcome domains for evaluating acute pain:
- Pain intensity, frequency, duration, and extent.
- Satisfaction with treatment.
- Symptoms and adverse events.
- Physical recovery.
- Emotional recovery.
- Economic factors.
A Special Note on Safety
Safety follow-up for pediatric patients must be longer and more thorough than in adult trials. This is done to detect any adverse effects on development that might occur as children grow. Assessments should include cardiac, respiratory, and neurological function.
Pediatric Pain Measurement Strategies
There are three basic approaches to measuring pain in children: self-report, observational, and behavioral or psychological. Patient self-report in combination with one or more of the other approaches is ideal. Approach selection must take into account the developmental, communication, and cognitive capacities of the pediatric population being studied. For example, behavioral measures are the most useful for research involving infants, as well as both pre-verbal and non-verbal children.
Despite the inherent difficulty pediatric pain researchers face, their efforts are well worth it — child patients need more safe and effective analgesic treatments on the market. Read our full white paper, Designed Especially for Kids, for more information.