A new approach for extrapolating clinical trial data using adult research aims to speed up and lower the cost of testing and approval of medicines for children. The methodology for attaining such advantages is outlined in a proposed guideline published recently by the International Council for Harmonisation, which outlines standard procedures and tactics for determining how adult drug research programmes can influence paediatric prescriptions. The programme intends to accelerate the approval of and access to novel treatments for young patients worldwide by establishing similar regulatory requirements across areas while decreasing the number of children required for clinical studies.
ICH released the proposed paediatric extrapolation guideline in April 20221 in order for regulatory bodies and drug development sponsors all over the world to study and assess it. This harmonisation process began in 2017, and it now appears that a final guideline will be adopted in 2024. This and many other suggested norms in the evaluation process, like quality risk management and analytical verification requirements, as well as newer initiatives on organised quality of products, stability studies, and prototype-informed drug development, will be discussed at an ICH assembly in Korea in November 2022. To support clinical studies, the ICH has recently adopted regulations on estimands and sensitivity analysis in clinical trials, as well as breeding toxicology testing; a newer action plan aims to review the E8 guideline on the actions and disclosure of clinical trials by integrating quality-by-design principles.
ICH is also moving forward with an early roadmap for generating model-informed drug development guidelines, which is seen as a critical step toward a more effective and predictable clinical research approach, with the ability to reduce unnecessary patient exposure. On March 31, 2022, the MIDD discussion group presented a plan2 that lays out general concepts, expected gains, time frames, and options. In the next three to four years, a comprehensive principles guideline will be created, accompanied by a finalised standard in ten years. This would pave the way for changes to various fundamental guidelines, including dose response data, population pharmacokinetic-pharmacodynamic research, and disease progression modelling.
On May 11, 2022, FDA and Health Canada held a public meeting3 to inform stakeholders on the ICH programme on paediatric extrapolation and numerous other ICH projects. Lynne Yao, director of the FDA’s Center for Drug Evaluation and Research’s Division of Pediatric and Maternal Health, characterised ICH’s attempts since 1994 to build community global regulatory requirements intended to provide children with access to medicines that have been properly evaluated in adults and to endorse the inclusion of paediatric patients in product development programmes where appropriate and feasible.
Since the inaugural ICH E11 guideline on paediatric clinical investigations was published in 2000, many attempts to advance paediatric clinical studies have grown. In 2017, an amendment, E11 (R1), was published, recognising the necessity for more detailed paediatric extrapolation guidelines. In reply, an expert working group was organised to write a reflection paper on the need for and scope of an ICH E11A paediatric extrapolation guideline. According to Yao, the first efforts in this field included unifying terminology and adopting a systematic framework for addressing study design, statistical approaches, and modelling and simulation strategies.
A proposed ICH E11A guideline now exists to provide a framework for using paediatric extrapolation methodologies to meet the regulatory clearance requirements. It lays out a structured approach for paediatric extrapolation research that includes a thorough analysis and synthesis of existing data, quantifiable predictions on the degree of correlation, the development of a framework for potential evidence reduction, and subsequent modification of ambiguity and hypotheses. Pediatric extrapolating strategies would take into account patient response to therapy and identify knowledge gaps in areas such as dose selection, efficacy study types, and the necessity for a safety plan. The goal is to get regulatory agencies to agree on language and study designs, statistical methodology, and modelling and simulation strategies that will help in paediatric extrapolation in medication discovery.
Furthermore, ICH criteria for paediatric extrapolation may assist in addressing broader issues about the definition and scope of data extrapolation to support additional indications for novel medications in patients who were not evaluated in pivotal studies. While most experts believe that extrapolation is legitimate and crucial for expanding disease treatment to new patient populations, other specialists wonder if sponsors are relying too heavily on inadequate clinical data to justify new indications. This problem was raised in the recent discussion over the approval of the Alzheimer’s drug Aduhelm for individuals with mild cognitive impairment based on little clinical evidence. While experts believe that the FDA and sponsors should have the option to expand an approved drug’s indication based on extrapolation of preliminary clinical data, pressure has grown for post-approval studies to back up such changes and offer clear proof of appropriate use.