Pediatric Drug Development: Optimizing Extrapolation

Drug development in pediatrics continues to be a substrate for the application of innovative tools and techniques. When a new drug is approved in the United States, the European Union, or elsewhere for that matter, there is an expectation of a standard achieved for the evidence of effectiveness of the new molecule in question, as well as acceptable safety. This burden of evidence of effectiveness could depend on a particular disease or therapeutic area and could range from acute interventions to a more chronic nature. Thus, concepts of acute effect, maintenance of the effect and long-term outcomes come to mind. Three main issues emerge that relate to the disease itself, target engagement and pharmacology, and response to treatment. Collectively, they form the basis on which the principle of extrapolation can be assessed.

The concept of extrapolation is deeply embedded in region-specific legislation. These include the Best Pharmaceuticals for Children Act of 2002, and Pediatric Research Equity Act (PREA) of 2003 in the US, and the Paediatric Regulation of 2006 in the EU. Revisions to ICH E11 further deliberated the pediatric extrapolation concept. So, what is this extrapolation concept? In its most basic sense, extrapolation allows sponsors to decide on the level of clinical development that is needed to assess similarity between pediatric and adult populations, and streamline the manner in which pediatric studies are performed.

To enable the assessments underlying extrapolation, one needs to better understand the disease in question, the pharmacology of the drug, as well as the clinical response to treatment. An assessment on the potential sources of differences is also vital, as there might be underlying drug metabolizing enzymes that could affect the way the drug is metabolized as age decreases. Finally, methods to understand similarity between adults and pediatric subjects are often subject to extensive debate.

The case in point story of belimumab (Benlysta) deserves a mention in any blog considering the extrapolation concept. Belimumab was approved by the FDA in adults in 2011. Part of the conditions of approval included a PREA commitment to undertake a pediatric phase 2 study in SLE. Whereas the initial trial needed a sample size of 100 pediatric subjects to be enrolled, due to recruitment challenges, the trial did not meet this sample size. FDA reviewers applied a Bayesian prior post-hoc to justify a lower sample size and released the sponsor from PMR. While considerable debate lingers on in the scientific literature on the FDA’s approach, it does create an opportunity for novel trial designs prospectively within pediatric studies to reduce the burden of patient trial access.

In this blog, we reflect on a few key considerations that are central in the optimal use of the pediatric extrapolation concept.