|FEASIBILITY1||SCOPING2||RESEARCH3||SUBMITTED4||ENDORSED/ FIT FOR PURPOSE5|
U.S. Food & Drug Administration (FDA)
European Medicines Agency (EMA)
★ Letter of Support
The CPAD team has developed a non-linear mixed effects model for the longitudinal trajectory of Clinical Dementia Rating – Sum of Boxes (CDR-SB), based on patient-level data from the ADNI-1 and ADNI-2 trials. The Investigation Into Delay to Diagnosis of Alzheimer’s Disease With Exelon (InDDEx) trial was used as an external validation dataset. The model accounts for baseline intra-cranial volume-corrected hippocampal volume (ICV-HV), apolipoprotein E4 (APOE-ɛ4) carrier status, baseline MMSE scores, baseline age and CDR-SB, as well as sex as other relevant covariates. This model allows the user to perform simulations to inform sample size estimation and power calculations, as well as evaluating enrichment strategies, over a varied range of assumptions and trial design options. Current approaches for sample size estimation, based on literature metadata of the estimated standard deviation for the clinical endpoint and the expected effect size, do not account for differences in clinical and demographic characteristics of the enrolled trial population, disease worsening profile over time, and the different levels of variability (e.g., between-study, between-subject, and residual variability). The current version of the model accounts for the contribution of the aforementioned aspects and is being used to develop a web-based aMCI clinical trial simulator with a user-friendly graphical interface. This tool will simulate clinical trials based on user-defined trial and subject characteristics at study entry. The EMA supports the primary objectives of the applicant and has decided to issue a Letter of Support to the CPAD Consortium to encourage industry sponsors to share the patient-level data from completed phase II and III clinical trials in the intended target population as defined in the COU statement, including active and control arms, with CPAD. This will allow the CPAD team to complete the development and validation of the proposed quantitative novel methodology in drug development, while also encouraging the CPAD team to disseminate and provide access to the current version of the model for implementation by sponsors actively designing clinical trials in aMCI.