The European Medicines Agency (EMA) released a reflection paper on Monday with the hope of helping drugmakers avoid unnecessary pediatric research by establishing a framework for extrapolating clinical data from adult patients to support pediatric indications for new drugs.
EMA says the framework will help "optimize" clinical trial participation for pediatric patients by using existing data from other populations, including adults and other pediatric subgroups, to predict how pediatric patients will respond to a drug.
Extrapolation can be vital in cases where there are too few patients or where there are ethical issues that would make it difficult to conduct a study in children.
According to EMA, the framework will guide sponsors in determining "when, to what extent, and how extrapolation can be applied and validated."
The framework is intended to further the goals of the Paediatric Regulation, which "aims to ensure that medicines for use in children are of high quality, are ethically researched and are authorised appropriately."
The Paediatric Regulation also requires sponsors to develop a pediatric investigation plan (PIP), unless they receive a waiver exempting them from completing one.
However, the Paediatric Regulation also seeks to protect children from unnecessary studies. By developing a framework for extrapolating adult clinical trial data, the agency says sponsors can reduce the amount of pediatric data they require, "without reducing evidentiary standards."
Using the framework, EMA says sponsors should be able to determine appropriate doses for different age groups and provide insights on the safety and efficacy of their drugs in children.
However, to do so effectively, EMA says the decision to extrapolate data "can only be justified when it is the result of a careful and explicit scientific process ... rather than an intuitive leap of faith."
Additionally, the agency says extrapolation is not always possible, and instructs sponsors to "follow the relevant therapeutic area [Committee for Medicinal Products for Human Use] CHMP guidelines," unless the sponsor can provide justification otherwise.
The framework is centered around four principle elements: the extrapolation concept; extrapolation plan; confirmation and extrapolation; and mitigating uncertainty and risk.
To develop an extrapolation concept, EMA says that sponsors should look at all available data sources relevant to their product, the condition it treats and the populations affected. These sources include in vitro, preclinical, epidemiological, diagnostic, pharmacokinetic (PK) and pharmacodynamic (PD) studies, as well as biomarkers, surrogate endpoints and data from other clinical trials and observational studies.
Then, the agency says sponsors should synthesize and model the data they have gathered for PK and PD; disease manifestation and progression; and clinical response so they can be assessed for differences between adult and pediatric populations.
EMA says these assessments should be based on hypotheses that explore the similarities and differences between adult and pediatric populations using both mechanistic and empirical approaches.
"The extrapolation concept should result in explicit predictions of differences in PK, PK/PD, the nature of disease (manifestation, severity, progression, etc.), and clinical response to treatment in the target population as compared to the source population," EMA writes, stressing that these predictions "should be quantified to the greatest degree possible."
From there, EMA says that sponsors should develop a plan encompassing the extrapolations they intend to study, taking into account any uncertainties they hope to resolve. The agency also makes recommendations for designing efficacy studies, when necessary, to "optimize trial design" for pediatric populations.
EMA adds that sponsors should use the data observed to validate and confirm their extrapolation concept to determine whether there are any "substantial deviations" from what the sponsor predicted, and make any updates to the concept.
When sponsors are able to confirm their extrapolation concept, EMA says "the data generated can be used to make conclusions for the target population," but warns that the data may not be "self-standing to support any conclusions" and must be taken in context before it can be used to support a pediatric indication.
EMA, Reflection Paper