Authors Jeffrey I. Campbell, Karen E. Ocwieja, and Mari M. Nakamura are calling for pediatric COVID-19 clinical trials. According to them, “We need pediatric clinical trials to establish the efficacy, safety, and pharmacokinetics of the most promising experimental and repurposed coronavirus disease 2019 (COVID-19) therapies proposed to date.” Researchers of early reports show that pediatric SARS-CoV-2 infection tends to be mild but that some children develop severe disease.
The Proposal of Antiviral Agents
In absence of a vaccine, antiviral agents have been proposed as a strategy to prevent SARS-CoV-2 infection. Because most children experience mild infection, pediatric prophylaxis theoretically would serve to reduce viral reservoirs and mitigate spread from children to individuals at higher risk for severe COVID-19.
Trials studying prophylaxis in children face a number of hurdles, such as challenges with measurement of secondary public health benefits of treating asymptomatic children. However, if antiviral agents do show promise in preventing SARS-CoV-2 infection, use in children should be predicated on robust pediatric trials.
Admittedly, there may be several impediments to antiviral clinical trials in SARS-CoV-2–infected children. These include uncertainty over which outcomes to use (such as improvements in oxygenation, inflammation, or virological clearance) and concerns about low recruitment, given the typically mild course of pediatric infection and public misconceptions of antiviral agents’ efficacy.
To address these concerns and others, and to promote development of trial protocols, authors Campbell et al. offer 6 recommendations:
- Trials should be conducted with central coordination. The multiplicity of studies in China ultimately prompted the government to issue guidelines to harmonize new trials. In the United States, government or professional organizations like the National Institutes of Health, American Academy of Pediatrics, or Pediatric Infectious Diseases Society could issue such guidance proactively. Central coordination could reduce redundant research efforts and promote synergistic trials. Adherence to standardized endpoints would enable effective comparisons between trials and ultimately produce speedier, more robust conclusions.
- Multicenter trials should be prioritized. These would support sufficiently powered studies to test therapies for sicker, hospitalized children and facilitate analyses among subgroups with specific predisposing conditions. Existing trial networks like the Pediatric Trial Network could be enlisted.
- Some therapeutics trials in adults could be extended to include children, as a small number of studies are already doing. Although divergent clinical courses of COVID-19 in adults and children may make many joint studies untenable, some research questions, such as efficacy of preventive antiviral agents, may be answerable by studies that include both adults and children. Joint studies also would enable resource sharing, alleviating pragmatic barriers to pediatric trials.
- Although randomized controlled trials should be conducted whenever possible, children receiving drugs for COVID-19 should at least be offered the opportunity to participate in prospective observational studies. Although these studies are limited in their ability to establish efficacy, they would allow prospective data collection on clinical and virological trajectories and drug-associated adverse effects. It would also permit comparative subgroup analyses between groups of children with varying risks for adverse outcomes.
- Endpoints should be used that consider both the pediatric COVID-19 clinical trajectory and the role of children in the pandemic at large. For example, trials in children could assess both symptom resolution and reduction of viral shedding, which may have implications for transmission. Jin et al6 published a clinical outcomes set for COVID-19 using Core Outcome Measures in Effectiveness Trials Initiative methods. These measures capture virological clearance, outcomes, and endpoints that reflect clinical trajectory and resource use.
- Researchers in pediatric clinical trials should be sensitive to the unique ethical challenges associated with conducting trials during a pandemic. Guidance developed during previous epidemics proposes ways to ensure ethical trial conduct while facilitating rapid results.7 Examples include use of adaptive trials, prioritizing investigation of the most promising agents, and ensuring provision of standard care.
In a parting message to readers, Jeffrey I. Campbell, Karen E. Ocwieja, and Mari M. Nakamura leave this:
“As pediatric researchers and health care providers, we must decide if we will rigorously study drug efficacy for children with COVID-19, or administer these agents on the unproven hope that giving anything at all is better than giving supportive care alone. We know that COVID-19 follows a different course in children than adults, so we cannot rely on results that trickle down from adult trials. Conducting controlled, coordinated pediatric trials is the only way to learn whether the potential benefits of these drugs outweigh their risks. The urgency with which we pursue robust studies now will determine if we know what to do, or if we will continue to guess, should this pandemic persist.”