For the purpose of this Reflection Paper extrapolation is defined 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 main focus of the document is to provide a framework for extrapolation as a methodology to generate evidence for regulatory assessment in a target population. Specifically the framework addresses the use of quantitative methods to help assess the relevance of existing information in a source population to one or more target population(s) in respect of the disease, the drug pharmacology and clinical response. Based on this, predictions on the expected effects of treatment in the target population can be formulated. These predictions will be conditional on certain assumptions, and a specific extrapolation plan can be developed to address gaps in knowledge and assumptions, so that the totality of available evidence can address the scientific questions of interest for marketing authorisation in the target population. The principle elements of the framework are:
Extrapolation Concept: Existing information about the disease, the drug pharmacology and the populations should be quantified. Based on the differences between source (e.g. adults and/or children) and target populations (e.g. other paediatric population), important assumptions and uncertainties about the relation between dose, exposure, pharmacodynamic response and clinical efficacy should be identified. From this exercise it can be assessed whether clinical efficacy can be predicted, e.g. via drug exposure (PK), a relationship between drug exposure (PK) and pharmacodynamic (PD) response or, in the absence of a quantified Pharmacokinetic (PK)/ pharmacodynamic (PD) relationship, based on other pharmacological or clinical justification. A structured documentation, including an assessment of the impact of identified assumptions and uncertainties on the predictions should be provided.
Extrapolation Plan: In accordance with the assumptions and uncertainties as identified by the extrapolation concept, specific objectives(s) and methodological approaches should be proposed for the tests and trials that need to be conducted to draw inferences that are relevant for the target population. These tests and trials should primarily aim to generate evidence that strengthens and ultimately, based on success criteria, validates the extrapolation concept. This validation confirms whether regulatory decisions can rely on the initial, or revised, predictions for the expected effects of treatment in the target population or if more data needs to be generated.
Mitigation of uncertainty and risk: As with any regulatory decision, the data generated in the target population may not be sufficient to address all uncertainties related to efficacy and safety by the time of a marketing authorisation in the target population. In some situations it may be important to gather additional data post-authorisation to address residual uncertainties.
An exhaustive list of methodological approaches is not provided. The framework should encourage exploration of potentially suitable methods for specific situations. Different approaches may be taken and the applicant should justify their choice. While the focus is on extrapolation for the development of medicines in children, the underlying principles may be extended to other areas.