A linearization approach for the model-based analysis of combined aggregate and individual patient data

The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between-trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data.