Children aren’t little adults: Pediatric populations have needs and physiological factors that set them apart from adults. However, it’s taken time for that philosophy to catch on within the clinical research community at large. When writing protocols for trials of acute pain in pediatric populations, researchers must take these unique needs of children into account to meet regulatory and ethical standards.
While there are major scientific, ethical, and practical challenges in conducting clinical trials among children in general, things are further complicated in analgesia studies by the need to protect these patients from exposure to untreated pain. To do this, all aspects of the protocol — from early study design to endpoints — must be specifically customized for children.
Unfortunately, pediatric analgesia trials are further complicated by three major factors:
- A lack of consensus on pediatric analgesia study designs and outcome measures.
- Limitations in pain assessment by surrogates.
- Unreliability of extrapolated efficacy and risks from adult studies due to developmental and physiological differences.
Take a look at the considerations study designers take into account to address these issues.
The Subjective Nature of Pain Measurement
While the subjective nature of pain measurement is also a problem for adult studies, it is magnified in pediatric trials. Additionally, pediatric pain measurements are inconsistently used across clinical trials, making it difficult to compare results. This can become an issue even within a single trial. For example, different pediatric pain measures are designed for different age groups. As a result, studies involving a broad range of age groups may require multiple pain measures that cannot be directly compared.
Pediatric physiologies have a high degree of variability, both between age groups and individuals. These differences in the way in which drugs are processed result in a wide range of differences in pain perception and analgesic responsiveness. Pharmacogenomic variability plays a major role, especially when it comes to medications that act as prodrugs, raising the question of genetic testing in clinical trials.
Ethical and Legal Considerations
Pediatric analgesia studies present something of an ethical catch-22: Researchers are discouraged from working with pediatric patients to prevent unnecessary harm, but a lack of data on this population can lead to unnecessary harm down the road. This is partly why only 70 percent of medicines regularly used to treat children have only been tested in adults, giving clinicians limited pediatric-specific analgesic prescribing information.
Children may not be able to represent their own best interests, and some are too young to legally give informed consent. For those patients, consent must be given by an appropriate surrogate, though informed assent by the child is also necessary. This factor contributes to just why pediatric participation in trials with more than minimal risk must be justified with potential direct benefit.
To minimize the amount of pain experienced by pediatric study participants, the frequency and intensity of study procedures should be minimized. Likewise, invasive techniques should only be used when clinically necessary. Sponsors should also consider local anesthesia before needle-based procedures or catheterization.
Researchers should keep in mind special regulatory aspects of these principles, including the limited allowable blood draw volume and frequency for clinical trials, which varies between age groups.
While parallel-group, placebo-controlled trials using pain scores as the primary efficacy outcome are standard in adult trials, their application to pediatric populations becomes problematic if children are to be exposed to more than minor pain and effective, approved treatments for the condition already exist.
Understanding the Unique Needs of Pediatric Patients
Differences between adult and minor study participants aren’t just anatomical and physiological. Researchers must also take into account communication barriers and emotional considerations. The significant developmental differences between children of varying age groups must also be considered. Researchers should invest in understanding pediatric trials thoroughly, as a well-designed protocol that has been written to account for the specific needs of children can facilitate regulatory approval, study enrollment, patient retention, and data quality.
Working Around Busy Schedules
All study designs must be realistic to execute while also being rigorous enough to support efficacy, safety, and dosing in children. Designs that don’t take the busy schedules of today’s children and their families into account lead to slow enrollment and low patient retention, which translate into higher costs and approval delays.
Study Drug Formulations Right for Children
Sponsors may need to reformulate their drug for children. Pediatric oral formulations must be:
- Easy to administer and swallow.
- Acceptable in taste, volume, and frequency of administration.
- Appropriate in dosage and strength with adequate bioavailability.
Sponsors have a responsibility to ensure that investigators are educated in the conducting of pediatric clinical trials, especially those sites that are participating in pediatric trials for the first time. Protecting this vulnerable population from untreated pain is of utmost importance.
Learn more about pediatric analgesia study design considerations in our white paper,