Case Study on the Use of Real-World Evidence in a Feasibility Assessment of a Randomized Controlled Trial Design to Support the Fulfillment of Pediatric Requirements with the FDA and EMA.

introductionRegulatory agencies may require industry sponsors of new drugs or biologics to conduct clinical trials that assess the benefits versus the risks of these new medicines in pediatric patients as a means of facilitating their development and availability for children when there is a medical need. Amgen Inc. (henceforth "the company") agreed to conduct a randomized, controlled trial (RCT) in pediatric subjects with Glucocorticoid-induced Osteoporosis (GiOP) under a Paediatric Investigation Plan (PIP) and Pediatric Study Plan (PSP) with the European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA), respectively, as one of the pediatric studies that were a condition of registration for Prolia (denosumab). Enrollment of pediatric subjects with GiOP into the agreed clinical study was exceedingly low despite the implementation of multiple mitigation measures. As a result, the company explored the use of real-world epidemiological analyses of the disease in children with GiOP for further insight into the clinical feasibility challenges with the RCT design. MATERIALS AND

methodsWe initiated a phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of denosumab in pediatric subjects with GiOP (Study 20140444). Following difficulties in recruiting we re-assessed the enrollment potential and overall clinical trial feasibility of Study 20140444 using real-world epidemiological analyses evaluating the size of the pediatric GiOP population using real-world data (RWD) from 3 different databases: (1) the US MarketScan, (2) the United Kingdom (UK) Clinical Practice Research Datalink (CPRD), and (3) the IQVIA Disease Analyzer (Germany).

resultsThe results from the RWD show that very few pediatric patients met the clinical diagnosis of GiOP, irrespective of the database used. In sum, approximately 1 eligible subject per 1,000,000 people per year was estimated to be available for Study 20140444. CONCLUSIONS AND RECOMMENDATIONS: The results suggest a lack of feasibility of conducting an adequate and well-controlled randomized trial in a population of pediatric patients with GiOP. The results also called into question the feasibility of other types of clinical trial designs, including potential single-arm or hybrid study designs, to fulfill the regulatory requirements. Recommendations include considering the use of RWD-based epidemiological analyses prior to agreeing with health authorities to conduct postmarketing required pediatric studies or studies in other rare diseases. This approach to clinical trial feasibility using RWD helps ensure research goals are balanced with the needs of the individual patient, further ensuring the ethical conduct of clinical trials. CLINICAL TRIAL REGISTRATION (STUDY 20140444): ClinicalTrials.gov / NCT03164928 / URL: https://clinicaltrials.gov/search? term=NCT03164928 . EudraCT / 2016-003083-39 / URL: https://www.clinicaltrialsregister.eu/ctr-search/search? query=2016-003083-39 .