P3‐377: Apathy in dementia methylphenidate trial (ADMET): Recruiting for apathy in Alzheimer's disease

Abstract

private partnerships. The Coalition Against Major Diseases (CAMD) was formed by Critical Path Institute in September of 2008 in response to FDA’s Critical Path Initiative (CPI). CPI identified quantitative disease models as an innovative way to accelerate drug development, also recognized by EMA. CAMD developed the first regulatory submission of a drug-disease-trial model for AD.Methods: CAMD is based on the value of sharing non-competitive data, to generate generalizable and applicable knowledge for Alzheimer’s and Parkinson’s diseases. A coalition of sponsors, regulatory agencies, academic experts and patient groups developed an analysis plan for a drug-disease-trial model in mild and moderate AD patients with the ADAS-Cog cognition measure as the outcome. Data standardization and database development resulted in the creation of C-Path Online Data Repository (CODR) comprised of patient-level data from control arms of AD trials. Existing standards from the Clinical Data Interchange Standards Consortium (CDISC) were used, and new ones developed as needed. CAMD analyzed data from published literature, ADNI, and the CAMD-CODR database to develop the model. FDA and EMA input was critical to prepare the regulatory submission. Results: The drug-diseasetrial model comprises functions for disease progression, placebo and drug effects, which can be combined to simulate clinical trials in mild and moderate AD. The final regulatory submission included a detailed analysis plan, with input from FDA, EMA, CAMD members, and external experts. It also included a detailed context of use for drug development, a description of the data used, analyses results, model development, covariate testing, predictive checks, external validation, and example applications for use in comparing trial designs. Key opinion leaders representing clinicians, statisticians, and pharmacometricians provided advisory input as to the context of use and suitability of the tool. Conclusions: The successful development of the current AD drug-disease-trial model was made possible by the consortium approach, and accelerated by continuous regulatory engagement. The model will be made publically available and represents a milestone to the pharmacometrics community as a way to encourage the advancement of drug-disease-trial models for a variety of diseases.