[co-author: Alexander Wenzel]

The reflection paper and extrapolation

The European Medicines Agency (EMA) has published a reflection paper regarding the use of extrapolation when developing medicinal products for paediatric use. The main focus of the reflection paper is to provide a framework and guidance for the use of extrapolation in the development of medicinal products in paediatric patients. It is largely addressed to researchers planning a clinical trial. While the focus of the paper lies in extrapolation for the development of paediatric medicinal products, the paper mentions that underlying principles may be extended to other areas.

The term extrapolation is described in the paper as the use of information in one or more source populations (example given adults) being relevant to the target population (minors), in a way that can be quantified and used as a basis for further development. The paper intends to promote the use of available evidence and objective criteria to support extrapolation.

To obtain a marketing authorisation it is necessary to establish therapeutic efficacy and a positive benefit-risk profile for a medicinal product. The sponsor of a clinical trial wishing to obtain a marketing authorisation of the medicinal product must develop research questions. The research can concern, as an example, the appropriate doses of the active substance or the therapeutic efficacy of the medicinal product. The research questions are addressed through a clinical trial or a series of clinical trials. Once the research questions have been formulated, the use of extrapolation in planning the clinical trials, can support the competent authority’s assessment of a marketing authorisation application for a medicinal product. Extrapolation can only be used for those research questions where reliable data already exist.

Minors should only participate in clinical trials when there are no alternatives. The paper highlights the possibilities and advantages that extrapolation can bring. The paper also highlights how the proposed framework could provide the guidance necessary to apply extrapolation for the development of medicinal products in paediatric patients in practice.

The principal elements of the framework

The three main elements of the framework are i) the extrapolation concept, ii) setting up an extrapolation plan, and iii) mitigating uncertainty. The paper provides detailed information concerning how to set up an extrapolation concept. It also provides guidance regarding the “extrapolation plan” to implement the extrapolation concept.

The extrapolation plan should mainly document specific study objectives and designs intended to address gaps in knowledge and assumptions made by the researchers. What those study objectives and designs could entail, is explained in detail in Section 5 of the paper which concerns the proposed framework.

The paper does not provide an exhaustive list of methodological approaches for extrapolation. It does provide that a main principle is the mitigation of uncertainty. The paper encourages the exploration of suitable uncertainty mitigation methods for specific situations. An example given is that, to mitigate an identified uncertainty, the extrapolation plan can continue post-authorisation.

Section 5 of the paper, describes the proposed framework. The Section explains step by step how to construct the extrapolation concept under the proposed framework. Section 5 does this by example, listing factors that could limit extrapolation or referring to EMA guidelines that should be taken into consideration when designing the extrapolation concept. The Section also provides examples of the decision process for extrapolation. The paper further provides a decision process schedule and an extrapolation framework table.

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