New Guidelines Aim to Advance Pediatric Drug Development

A new framework for extrapolating clinical trial data from adult studies seeks to facilitate the testing and approval of therapies for children more quickly and at less cost. The process for achieving such gains is presented in a draft guideline recently released by the International Council for Harmonization (ICH) that maps out common methods and strategies for identifying how development programs for adult drugs can inform pediatric indications. By establishing common regulatory requirements among regions, the initiative aims to speed the approval of and access to new drugs for young patients around the world, while limiting the number of children needed for testing in clinical trials.

The proposed pediatric extrapolation guideline (ICH E11A) was released by ICH in April to gain broader review and assessment by regulatory authorities and drug development sponsors around the world.^1,2 This harmonization process began in 2017 and now appears on track to adopt a final guideline in 2024. An ICH assembly in Korea in November is slated to discuss this and several other proposed standards moving through the review process, such as quality risk management and analytical validation requirements, and newer projects on structured product quality, stability testing, and model informed drug development. In recent years, ICH has adopted guidelines on estimands and sensitivity analysis in clinical trials and on reproductive toxicology testing to support clinical studies; a newer initiative aims to update the E8 guideline on the conduct and reporting of clinical trials by incorporating quality-by-design principles into clinical research.

ICH also is moving forward with an initial roadmap for developing guidance on model-informed drug development (MIDD), considered a key approach for achieving a more efficient and more predictive clinical research process, with potential for reducing unnecessary patient exposure. The MIDD discussion group released a plan on March 31that lays out general principles, anticipated gains, time frames and options.³ The aim is to develop a general principles guideline in the next three-to-four years and a completed standard in 10 years. That would set the stage for revisions in several basic guidelines, such as on dose response information, population pharmacokinetic-pharmacodynamic studies, and disease progression modeling.

The ICH initiative on pediatric extrapolation was outlined at a public meeting on May 11 organized by FDA and Health Canada to update stakeholders on that and several other ICH projects.⁴ Lynne Yao, director of FDA’s Division of Pediatric and Maternal Health in the Center for Drug Evaluation and Research (CDER), described ICH efforts since 1994 to establish common global regulatory standards designed to provide children with access to medicines appropriately evaluated in adults and to support the inclusion of pediatric patients in product development programs where appropriate and feasible.

These initiatives for advancing pediatric clinical investigations have expanded since publication in 2000 of the initial ICH E11 guideline on pediatric clinical investigations. An addendum, E11 (R1), appeared in 2017 and recognized the need for more detailed standards on pediatric extrapolation. In response, an expert working group was formed to develop a reflection paper on the need and scope of an ICH E11A guideline on pediatric extrapolation. Initial steps involved aligning terminology and developing a systematic approach for considering study design, statistical methodologies, and modeling and simulation strategies in this area, Yao explained.

Now a draft, ICH E11A guideline provides a framework for utilizing pediatric extrapolation methods to meet regulatory standards for approval. It outlines a systematic approach for pediatric extrapolation studies that involves a full assessment and synthesis of existing data; quantitative predictions on the degree of similarity; development of a framework for potential reduction of required evidence; and later revision of uncertainties and assumptions. Pediatric extrapolation plans would consider patient response to treatment and identify gaps in knowledge involving dose selection, types of efficacy studies, and the need for a safety plan. The goal is to achieve more alignment among regulatory authorities on terminology and what study designs, statistical methodologies, and modeling and simulation strategies will advance pediatric extrapolation in drug development.

ICH standards for pediatric extrapolation, moreover, may help address broader concerns about the scope and extent of data extrapolation to support added indications for new drugs in patients not studied in original pivotal trials. While authorities generally agree that such extrapolation is valid and important for extending disease treatment to added patient populations, some experts question whether sponsors over-rely on limited clinical data to support added indications. This issue was highlighted in the recent debate over the extrapolation of limited clinical evidence in approving the Alzheimer’s disease treatment Aduhelm for patients with mild cognitive impairment. While experts agree that FDA and sponsors should have flexibility to expand an indication of an approved drug based on extrapolation of initial clinical data, pressure has increased for requiring post-approval studies to support such actions and to provide clear evidence of appropriate use.