Alzheimer's disease drug development: old problems require new priorities

Abstract

Alzheimer's disease (AD) clinical drug development and patient care depend on rating instruments, research designs and methods, and translations of clinical trial (CT) results into the clinic without support from standardized protocols able to control (i) random measurement error intrusions into observations, (ii) inaccuracy and bias introduced by clinical evaluators, (iii) conformity of research sites to conditions of research protocols, (iv) the ability of the CT to model for practitioners the most effective use of the drug with individual patients, and (v) other factors able to invalidate research and patient care data. This relaxed attitude with regard to AD methods may be changing now with Alzheimer's Disease Neuroimaging Initiative (ADNI) evidence that carefully standardized protocols are needed to validate biomarkers for use in AD diagnosis, drug development, and patient care. In the fields of psychiatry and AD, recent studies have detected serious inaccuracies, imprecision, biases and compromises of study protocols able to invalidate CT outcome data and conclusions drawn from these data. This limited but troubling evidence reinforces ADNI calls for more detailed methodological protocols. Based on the limits to precision and accuracy associated with rated outcomes in CTs and patient care, we call for priority to be given to the qualification and use of biomarkers as outcome variables in AD drug development and patient care and, to insure effective uses of biomarkers, to development of protocol guided practices being modeled in ADNI research. To meet clinical pharmacology's therapeutic aims we conclude that AD CTs need to set for clinicians the conditions of use of drugs shown efficacious, biomarker surrogate endpoints as drug targets, and not to function merely as tests for efficacy conducted under field conditions determined by current clinical practices.