A Critical Look over the Past 10 years of PREA and Use of Innovative Statistical Methods

We discuss a randomized, double-blind, placebo-controlled trial design for children and adolescents with epilepsy with myoclonic-atonic seizures (EMAS). The primary endpoint is EMAS-associated seizure frequency over the treatment period. Based on the need for therapeutic treatments in the EMAS population, the difficulty of enrollment in this rare population, and the consistent treatment effect across related indications for the investigational therapy, Bayesian methods are used to formally incorporate previous trial results from related populations into the primary analysis of the proposed study in the EMAS population. A Bayesian hierarchical model is specified for the treatment effects across populations that induces dynamic borrowing of the data from the historical studies. In addition, the design incorporates an adaptive sample size via Goldilocks methodology using Bayesian predictive probabilities. We discuss the process of trial design in the context of the FDA Complex and Innovative Design (CID) program, and the key simulations used to explore and evaluate the innovative trial design.
 

Genetic diseases often result from errors in protein or enzyme production which are critical to the functioning of the central nervous system. The consequences of these disorders manifest early in life and have a broad impact, with symptoms include developmental delay, motor impairment, sleep disruption, and seizures. Fortunately, our improved understanding of these diseases' genetic origins has paved the way for promising, targeted treatments such as antisense oligonucleotides, AAV gene therapies, and enzyme replacements.

However, designing clinical trials for these diseases is challenging. They have many manifestations and it may be difficult to choose endpoints which are amenable to treatment when designing a clinical trial. Another issue is identifying treatment related growth, as these children which may demonstrate some natural improvements as they age. Finally, the rarity of these diseases means that clinical trials are necessarily small, often unblinded, and there is limited data available to assist in planning. This talk will share insights into designing clinical trials for neurodevelopmental disorders, highlighting techniques including disease progression modeling and multivariate analyses.
 

Information Bayesian methods have been proposed and are increasingly used in pediatric trials to implement extrapolation approaches that rely to a flexible degree on borrowing the study results in other populations, such as adults and older pediatric patients. This is because Bayesian methods offer a rigorous way to incorporate this prior information to reduce the burden of the efficacy studies in the target population. However, one of the main challenges in implementing such approaches is deciding the appropriate degree of borrowing in a particular situation. In this presentation I will discuss considerations for determining this degree of borrowing from the perspective of a regulator.

*This speech reflects the views of the author and should not be construed to represent FDA's views or policies. 

The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development. A search was performed in September 2022 using two data sources (PubMed and ClinicalTrials.gov) and included studies conducted in the past 10 years. General study information was extracted such as study type, study status, therapeutic area, and clinical trial phase. Study characteristics that are specific to pediatric studies (such as age of the participants and pediatric drug dosing) and important study design elements (such as number of test drug arms and whether randomization and/or concurrent control was used) were also collected. Our results suggest that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. Most of this experience is in oncology and early phase studies. There is a rise in the use starting in 2020, largely in oncology and COVID-19 trials. However, adoption of master protocols in pediatric clinical research is still on a small scale and could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up infrastructure to interpreting study findings.