Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing

Nicky Best, Robert G Price, Isabelle J Pouliquen, Oliver N Keene, Nicky Best, Robert G Price, Isabelle J Pouliquen, Oliver N Keene

Abstract

Assessment of efficacy in important subgroups - such as those defined by sex, age, race and region - in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non-informative prior.

Trial registration: ClinicalTrials.gov NCT01691521.

Keywords: Bayesian; borrowing; confirmatory; exacerbation; paediatric; subgroup.

© 2021 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Prior distributions for the adolescent efficacy response: (A) informative (adult) and weak priors, (B) robust mixture prior representing mixture of adult and weak priors, for differing choices of prior weight w on adult component
FIGURE 2
FIGURE 2
Analysis of rate of clinically significant exacerbations by age group
FIGURE 3
FIGURE 3
Posterior median and 95% credible interval (CrI) for the estimated rate ratio in adolescents against prior weight given to the adult prior component
FIGURE 4
FIGURE 4
Prior versus posterior weight on adult component of the robust mixture prior
FIGURE 5
FIGURE 5
Hypothetical examples with different levels of conflict between subgroups

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