A Call for Objective Dose Selection to Increase Success in Pediatric Clinical Trials: A Perspective From NICHD and NIMH Program Staff

Abstract

As we heard at the “Pediatric Dose Selection” workshop,1 held on October 22 to 23, 2020, and is summarized in this journal issue, the field of quantitative dose selection as it applies to the pediatric population has come a long way in the last decade. The computational pharmacometrics models and the underlying knowledge base are now able to go beyond allometric scaling and include physiologicalbased parameters as well as population covariates to enhance pharmacokinetic prediction. Regulatory agencies now accept and encourage these approaches to select initial doses for pediatric studies in regulatory filings. The pharmaceutical sector has embraced these approaches, and many companies specializing in pharmacometric modeling have incorporated models addressing pediatric development. The increased role of these quantitative and physiological-based models in pediatric dose selection has enabled the identification of safer initial doses and reduced the number of failed pediatric clinical trials through selection of dose ranges most likely to be efficacious at particular development stages. Although quantitative dose selection (Figure 1) has made technical strides, become accepted and encouraged by regulatory agencies, and is being increasingly used by large and midsized pharmaceutical companies, these techniques are not as broadly used in pediatric trials, and that lack of use is likely a contributor to their failure.2 Recent attention has been brought to the need to enhance trust, transparency, and increase the likelihood of success in National Institutes of Health (NIH)-funded clinical trials through several initiatives to strengthen the NIH clinical trial enterprise.3,4 Given this recent precedent, we have asked ourselves why quantitative approaches to dose selection do not appear to be more common in NIH-funded pediatric clinical trials. Several possibilities exist: (1) there may be a lack of awareness of these approaches and their utility and power in improving safety and success in pediatric clinical trials; (2) the expertise to conduct such modeling is specialized, and there are a few number of trained pediatric pharmacometricians and limited resources available to many academic institutions and small businesses, compared with the pharmaceutical industry; and (3) the NIH does not always require specific information on how pediatric doses have been selected for use in proposed clinical studies in NIH grant applications. To obtain data to generate a more informed view of approaches to pediatric dose selection in NIH-funded applications, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has initiated a pilot effort to