Module232025

5/7/2025

Efficacy generating designs : choice of control*

primary efficacy objective evaluated should be defined using a pre-specified threshold - sample size calculated to meet this threshold or to ensure an estimate of sufficient precision is obtained

from the comparator arm in the reference population, relevant control arms from other RCTs, or RWE sources in the target population.

P>0.05, Non Inferiority margin choice, Bayesian

29 * when the aim is not to demonstrate efficacy per se but to demonstrate that efficacy is in line with prior expectations based on the extrapolation concept

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Extrapolation of safety • Same principles of the appropriate use of efficacy data from a reference population(s) to in a target population can also apply to the generation of safety data • Evaluation of the extent to which safety will be extrapolated should be included in the extrapolation concept early in drug development planning. • Aim : increase certainty about the expected safety profile + determine additional gaps in knowledge to be addressed in the CTs • Extrapolation of safety data depends :  on the available knowledge of the known and/or potential safety issues in the reference population that are relevant to the target paediatric population.  data from children and/or adults exposed to the same drug or class of drugs  populations who have been treated with different dosing regimens and/or for different diseases/indications • Other information (e.g., nonclinical, mechanistic) should be considered. • Inclusion of adolescents in the adult trials for earlier evaluation of safety for the adolescents + provide important information to support the safe use of a drug in younger patients. 30

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