ABSTRACT
The average time between regulatory approval and labeling of an innovative medicine for adults and children is nearly a decade.1 Often this is the result of poorly integrated adult and pediatric studies within medicines development programs, which consequently leads to prolonged off-label pediatric use. Furthermore, the conduct of studies in children after adult market approval becomes difficult if not impossible. Experiences during the SARS-CoV-2 pandemic have heightened awareness of this disparity. The fact that most children have been less severely affected by COVID-19 combined with reluctance to include children in early phases of investigational research has contributed to delays in evaluation of potential treatments for those children who present with more severe forms of the disease.2 Our study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance since such documents set critical expectations for trial design and regulatory decision-making for innovative medicines. The authors conducted multiple sequential PubMed searches in November 2019 (and repeated in August 2021) utilizing a variety of grouped search terms-including ''pediatric,'' ''paediatric,'' ''adolescent,'' ''adolescence,'' ''regulatory guidance,'' ''guidance,'' ''FDA guidance,'' ''regulatory guideline,'' ''guideline,'' ''EMA guideline,'' and/or ''meta-analysis.'' The searches failed to return any results showing that an analysis of regional regulatory guidance specific to age-inclusive research has been published. It is our understanding that this study represents the first comprehensive analysis of age-inclusive language within regulatory guidance for two globally important health agencies, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The study utilized a qualitative analysis approach to review FDA and EMA regulatory guidance documents assessing their recommendations about adolescent inclusion in clinical trials. The study found that regulatory guidance contained recommendations supporting adolescent inclusion in 32% of FDA and 15% of EMA documents, while 14% and 21%, respectively, were found to be exclusionary. In both regions, more than half of all guidance documents were silent regarding the applicability of adolescentinclusive trial methodologies. Analysis by therapeutic area revealed FDA guidance for infectious diseases and EMA guidance for conditions requiring blood products was the most permissive. A more inclusive approach was identified to disease guidance published by the FDA Oncology Center of Excellence. Our study has identified important opportunities for enhancement of regulatory guidance which, if addressed, can facilitate inclusion of adolescent patients in adult trials to accelerate adolescent access to life-changing medicines. Regulatory guidance plays a critical role in improving the type and the quality of data generated in clinical trials which inform medicines use in diverse patient populations. As pediatric policy reforms have led to significant experience with pediatric medicines development, this should be leveraged to update existing regulatory guidance, fostering scientifically justified inclusion of adolescents in adult clinical trials.