Pediatric Extrapolation: The Next Stage in International Guidance on Trials

ICH draft guideline advocating a more comprehensive framework in optimizing pediatric drug development reaches next step.

New international guidance on incorporating pediatric extrapolation into overall drug development plans was published this week, aimed at improving the speed of access to new drugs for pediatric patients while limiting the number of children required for enrolment in clinical trials.

On Monday, the International Conference on Harmonization's draft guideline on pediatric extrapolation reached step 2—the public consultation phase—of the ICH process.1 It is still a draft and an opportunity to comment on its content has now opened up to all comers.

The guideline addresses and aligns terminology related to pediatric extrapolation and provides information on approaches to using it, as well as on study designs and statistical analysis methods for incorporating pediatric extrapolation into a pediatric drug development plan. And it comes with an impressive pedigree: the rapporteur on the project is Lynne Yao, MD, of the FDA.

The justification for this latest in a long line of ICH guidance, dating back to the organization's inception in the 1980s, is that it could reduce the likelihood of substantial differences between regions, and reduce exposure of pediatric populations to unnecessarytrials.

Pediatric extrapolation is already defined by ICH as “an approach to providing evidence in support of effective and safe use of drugs in the pediatric population when it can be assumed that the course of the disease and the expected response to a medicinal product would be sufficiently similar in the pediatric [target] and reference (adult or other pediatric) population.” The move reflects the evolution of thinking on extrapolation—which historically was considered generally unacceptable for safety. Better understanding has emerged of similarities and differences between reference and target populations in this respect. The principle of using data generated in a reference population to define the scope and extent of data that should be collected in a target population can also apply to the generation of safety data.

What the new draft offers is a complement, providing a more comprehensive framework for the use of pediatric extrapolation in optimizing pediatric drug development. It is in effect a roadmap to aid drug developers and regulators on the degree to which pediatric extrapolation can be applied, and the information that should be collected to address gaps in knowledge supporting the safe and effective use of medicines in the pediatric population. It describes a process for understanding the existing information available, the gaps, and ways to generate additional information when needed to support extrapolation. In addition, it discusses how the characteristics of the disease, drug pharmacology, and the response to treatment may influence this determination. It also discusses how the use of statistical and other quantitative tools such as modeling and simulation may be leveraged to fill in gaps in knowledge.

It does not discuss other types of extrapolation, such as bridging studies to leverage foreign clinical data from one region for extrapolation to another region’s population as a basis for registration of a medicine. Nor, it says, is it meant to be a comprehensive instruction guide. "Some basic understanding of the role of quantitative approaches used in clinical trial development is expected," it observes drily.