Our ability to develop new antiviral agents has flourished in the last few decades with impressive successes in the treatment of complex diseases like HIV and hepatitis C. This gives us significant hope for development of antiviral drugs to treat patients with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infections. With the report that an National Institutes of Health–sponsored trial demonstrated adult patients with advanced coronavirus disease 2019 (COVID-19) treated with remdesivir had 31% faster time to recovery compared with placebo recipients, it seems that this hope is being realized.1 Although more detailed information from the trial are yet to be released, these findings have resulted in Food and Drug Administration (FDA) issuing Emergency Use Authorization (EUA) for remdesivir2 and will likely mean that this drug will be used routinely to treat patients with SARS CoV-2 infections as our understanding of this infectious disease and its treatment continue to evolve.
One important feature of the National Institute of Allergy and Infectious Diseases trial that is serving as the basis for the EUA is that it excluded children. Clinical trials results assessing treatment effects of remdesivir in children await the completion of 2 ongoing trials (NCT04292730 and NCT04292899C) that involve adolescents (children >12 years of age). Nevertheless, the EUA for remdesivir does include use in children. The inclusion of children in the EUA at the time it was issued for adults with serious COVID-19 is an important milestone that deserves recognition. At the same time, it highlights challenges pediatricians undoubtedly will face as we continue to develop new treatments for children with this infection.
Although the risk of children with COVID-19 developing serious disease appears to be lower compared with adults, children with disease can require hospitalization, including ICU care.3,4 Preliminary information suggests that remdesivir treatment of adult patients with serious COVID-19 shortens time to recovery. Because remdesivir’s mode of action is specific interference with SARS-CoV-2 replication, these results suggest that reducing viral replication is associated with clinical improvement. Once this relationship is established in adults, it would be reasonable to expect that all patients, including infants and children, would benefit from antiviral treatment of symptomatic SARS-CoV-2 infections. This type of extrapolation has been used in other viral illnesses, including HIV infection, with great success and is likely the rationale behind inclusion of children in the EUA for remdesivir.
Although children may be similar to adults when it comes to the effects of antivirals, they often require different doses or dosing regimens to achieve the same exposure to drug that is associated with the antiviral effect in adults. Dosing for children can be approximated using the innovative method of physiologically based pharmacokinetic modeling combined with simulation of pharmacokinetic data obtained from studies in healthy adults. Using our understanding of the developmental characteristics of drug metabolism in children can be combined with data about how the drug is handled in adults to approximate the dose and dosing schedule for children.
The inclusion of children in the EUA for remdesivir is important given the urgency of a pandemic, but it should not make us complacent with using preliminary data in making decisions about using new therapies for children. Nor does it obviate the need for conducting rigorous studies involving children as the development of remdesivir and other investigational agents move forward. The EUA is not the same as drug approval. It provides guidance for use of the drug in urgent, serious and life-threatening situations. For infants and children, the EUA for remdesivir demonstrates that innovative methodology can be used to improve children’s treatment in a rapidly moving field. This also demonstrates that the FDA is continuing to put its commitment to advance pediatric drug development into practice.
As our understanding of COVID-19 disease advances, it is important to keep the medical needs of children in focus. With rapid advances in this field, the observation that children appear to have lower risk of severe disease from COVID-19 compared with adults should not result in their exclusion from clinical research on new investigational treatments and vaccines.5 Children still develop serious and life-threatening COVID-19 infections. For COVID-19 studies, the default should be inclusion of adolescents (>12 years of age) into adult trials or the conduct of parallel studies in adolescents, given their physiologic similarity to adults and the potential benefit these new drugs have in treating life-threatening infection. Studies of new investigational agents should advance to include younger children as soon as appropriate based on assessment of risk and potential benefit. As we go forward, it is essential to consider children’s needs early in the drug development processes, use innovative methods of study and launch studies in children as soon as ethically justified.
1. NIAID Office of Communications. NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.Available at: https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
2. U.S. Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA of remdesivir (GS-5734™).Available at: https://www.fda.gov/media/137566/download
3. Zimmermann P, Curtis N. Coronavirus infections in children including COVID-19. An overview of the epidemiology, clinical features, diagnosis, treatment, and prevention options in children. Pediatric Infect Dis J. 2020;39:355–368.
4. Centers for Disease Control and Prevention COVID19 Response Team. COVID-19 in Children in the United States - February 12-April 2, 2020. MMWR. 2020;69:422–426.
5. Hwang TJ, Randolph AG, Bourgeois FT. Inclusion of children in clinical trials of treatments for coronavirus disease 2019 (COVID-19). JAMA Pediatr. 2020. doi:10.1001/jamapediatrics.2020.188.