In July, we reported that the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) had announced a joint proposal to promote the use of innovative approaches to paediatric drug development. We noted that the EMA expected to publish a Reflection Paper setting out a systematic approach to extrapolation of paediatric data by the end of the year. This has now been published.
The Reflection Paper defines extrapolation as “extending information and conclusions available from studies in one or more subgroups of the patient population (source population(s)), or in related conditions or with related medicinal products, in order to make inferences for another subgroup of the population (target population), or condition or product, thus reducing the amount of, or general need for, additional information (types of studies, design modifications, number of patients required) needed to reach conclusions”.
The Paper recognises that varying levels of uncertainty exist with each decision to extrapolate data to children, depending on disease and drug characteristics. It also notes that in some cases extrapolation will not be justifiable, such as where the disease is completely different in children compared to adults, or the understanding of the drug’s pharmacology is insufficient. In other cases it would be unethical not to extrapolate, since the understanding of the disease and drug pharmacology is so well established—the Paper gives the example of when a certain exposure leads to the same clinical outcome in adults and children, such as in HIV.
The main focus of the Reflection Paper is to provide a framework for extrapolation, which should be split into three elements:
- Extrapolation concept: Existing information about the disease, the drug pharmacology and the population should be quantified. Based on the differences between source and target populations, important assumptions and uncertainties about the relation between dose, exposure, pharmacodynamics response and clinical efficacy should be identified.
- Extrapolation plan: In accordance with the assumptions and uncertainties identified, specific objectives and methodological approaches should be proposed for tests and trials to draw inferences that are relevant for the target population. The tests and trials should aim to generate evidence that strengthens and validates the extrapolation concept. If the objectives of these studies are met, the extrapolation concept would be considered valid.
- Mitigation of uncertainty and risk: If the data generated in the target population is not sufficient to address all uncertainties related to efficacy and safety by the time of marketing authorisation, it may be important to gather data post-authorisation to address residual uncertainties.
The EMA encourages applicants to discuss extrapolation prospectively with regulatory authorities, considering the potential for future extrapolation exercises, even when designing studies to support initial marketing authorisation applications in a source population. The EMA notes that whilst the current focus for extrapolation is paediatric medicine development, the underlying principles may be extended to other areas.
The deadline for comments on the draft reflection paper is 14 January 2018.