Predictive drug safety
Thursday, August 11, 2011
Biomarker Qualification Consortia: The ADNI Success Story
Over the past decade, the rate of biomarker discovery has accelerated considerably thanks to the development of new methods such as advanced mass spectrometry techniques. However, the effort dedicated to the qualification of these newly discovered biomarkers (i.e. the process of confirming the predictive value of a biomarker candidate) has remained insufficient. Disease biomarker qualification most often requires access to a large population of patients representing the full spectrum of disease stages encountered in every day medical practice. While a few large organizations can muster the resources necessary to assemble such large patient samples, most biomarker qualification efforts require close collaboration between multiple stakeholders. Similarly, the qualification of safety biomarkers, intended to be broadly applicable across the industry, presents an investment that few companies are willing to take on their own. Hence, the gap in biomarker qualification can only be eliminated by promoting the collaboration between all drug development stakeholders.
The past ten years have seen the emergence of a series of non-competitive biomarker qualification efforts driven by consortia of academic, industrial, and non-profit organizations (see table 1 for examples)
Among these examples, one effort stands out due its ground-breaking impact on the field of biomarker development. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a vast longitudinal study focused on monitoring the evolution of Alzheimer’s disease (AD) patients, Mild Cognitive Impairment (MCI; a common precursor of AD) patients, and age-matched healthy volunteers (see also the article in Lancet of March 2011 about ADNI). Since its inception in 2004, ADNI enrolled 200 AD patients, 400 MCI patients, and 200 age-matched controls who were followed every 6 months for 2, 4, and 4 years, respectively. At the onset of the project, the consortium established a set of standardized procedures aimed at monitoring cognition, cerebrospinal fluid (CSF) biomarkers, and brain structure biomarkers. These standardized procedures have been used uniformly across 57 North-American clinical sites who committed to sharing their results through a common data repository (see also the public presentation by Dr. Michael W. Weiner for more detail about the science). Over the years, these procedures have been adopted by additional ADNI participants in Europe, Japan, Australia, China, and Korea.
This treasure trove of inter-connected standardized data has resulted in an amazing number of publications (212 accepted publications as of August 2011; source ADNI.org) which have already have fundamental impact in the field of AD science. For example, the National Institute on Aging and the Alzheimer’s Association proposed in July 2010 to amend the official diagnosis criteria for AD to reflect the advances in biomarkers of AD. Also, the work on CSF biomarkers has revealed that the level of amyloid-beta fragment Ab42 is a reliable predictor of conversion from MCI to AD. Finally, the work on brain structure biomarkers using standardized MRI has demonstrated that changes in key structures of the brain (cortex, ventricles, hippocampus) are much more sensitive than conventional cognitive assessment tools, potentially enabling clinical studies requiring significantly fewer patients. In 2010, ADNI received additional funding to extend the monitoring of patients already enrolled in the program and to enroll additional volunteers to explore more advanced biomarkers such as high resolution MRI, functional imaging, and amyloid aggregate imaging.
Beyond these remarkable scientific achievements, ADNI has demonstrated beyond doubt that academia, the industry, and non-profit organizations can collaborate efficiently in a non-competitive environment. Convincing all stakeholders that sharing their data with each other was not an easy task but this proved to be one of the key elements to the success of this project.