Alzheimer’s Association Update

Article Outline

• Research Roundtable explores biomarkers, optimal clinical trial design
• Association awards grant for pilot European Alzheimer’s Disease Neuroimaging Initiative (E-ADNI)

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Research Roundtable explores biomarkers, optimal clinical trial design 

This issue of Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association includes a review article by Siemers et al. on the rapid evolution under way in development of biomarkers for presymptomatic diagnosis and monitoring of Alzheimer’s disease. The article summarizes state-of-the-art information presented and discussed at a November 2004 invited meeting hosted by the Alzheimer’s Association Research Roundtable.

The Research Roundtable is a membership consortium bringing together Association senior science staff and advisors, pharmaceutical and biotechnology companies, and imaging equipment manufacturers. The Roundtable meets several times each year in person and via teleconference to identify common challenges in research and drug discovery and share expertise across member organizations.

The Roundtable also hosts invited meetings on topics of especially high interest, such as progress toward identification of Alzheimer biomarkers. Invited meetings create a forum for spirited, collegial exchange by featuring a combination of structured presentations, panel discussions and open question-and-comment sessions. Typical invited guests include subject matter experts, officials from federal health and regulatory agencies, and policy makers.

The most recent Research Roundtable invited meeting, held Nov. 2-4, 2005, in Washington, D.C., addressed issues in optimal design of a clinical trial to test a next-generation dementia drug with potential to modify underlying disease processes. The fundamental question to be explored was: If the benefit of a disease-modifying drug were not immediate but accrued slowly over time, would this require a different development paradigm? If so, what does this new paradigm look like? The biggest challenge in any chronic disease is that the outcome of primary interest takes too long to reach to be feasible to use as a trial endpoint. As a result, the U.S. Food and Drug Administration (FDA) in 1992 introduced the concept of surrogate endpoints. However, there are currently no validated surrogate endpoints for disease modification in Alzheimer’s disease and related disorders.

Guest experts in multiple sclerosis, rheumatoid arthritis, atherosclerosis and osteoporosis, all chronic diseases in which current standards of care are considered disease-modifying, discussed how evolving understanding of the pathogenesis and natural history of these conditions led gradually to identification of meaningful surrogate endpoints and biomarkers. Speakers described an iterative process in which mechanisms of presumed pathogenesis were proposed, tested, and turned out to be wrong, leading back to the laboratory and generating new theories, therapeutic targets, putative biomarkers and refinements in trial design.

Even where some degree of disease modification has been achieved, the hunt for more and better biomarkers goes on. For example, although low-density lipoprotein (LDL) is an extremely well validated biomarker for cardiovascular disease, recent clinical data suggest there may be a further “first cause” biomarker at work upstream of LDL.

Regulatory officials cautioned that from their perspective, “disease-modifying” is an ill-defined concept. In approving a drug, the FDA does not distinguish between symptomatic treatment and disease modification, and labeling simply describes the effect observed in clinical trials. The agency acknowledges that new outcomes may emerge post-marketing, as happened with recognition of the disease-modifying effects of statins and antihypertensives. Following approval, a “public health multiplier” effect resulting from exposure of thousands of additional individuals to a drug may also uncover problems not seen during clinical trials.

Several speakers noted that third-party payers, clinicians, patients and other stakeholders are increasingly concerned about “real-world” effects in assessing a drug’s value and impact.

One unique feature of the meeting was a Patient and Family Advocacy Panel. Moderated by Stephen McConnell, Ph.D., Alzheimer’s Association senior vice president of public policy, the panel included individuals with Alzheimer’s who have participated in trials; caregivers of participants who had both positive and negative experiences; FDA officials; experts involved in clinical research; and a representative from an institutional review board who also co-directs the newly created California Institute for Regenerative Medicine (“stem cell institute”). Panelists offered differing perspectives on risk tolerance and expressed frustration with the pace of clinical research.

A central theme emerging from the meeting concerned the growing difficulty trial sponsors face in recruiting participants. Strategies proposed to meet this challenge included identifying mechanisms for raising awareness of clinical trial participation opportunities among primary care physicians; enlisting the help of the Alzheimer’s Association in recruitment; and speeding development through open-access databases such as the one that will be developed as part of the federally funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).

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Association awards grant for pilot European Alzheimer’s Disease Neuroimaging Initiative (E-ADNI) 

The Alzheimer’s Disease Neuroimaging Initiative (ADNI), described by Weiner et al. in Vol. 1, Issue 1 of Alzheimer’s & Dementia, is a federally funded $60 million nationwide U.S. effort to develop optimum standardized methods for acquiring and processing brain images; validate data from imaging and biomarkers; and create an open-access database for all ADNI results. The ultimate goal is to determine whether some combination of imaging, laboratory values and psychological tests may provide better ways to identify individuals at high risk for Alzheimer’s, track disease progression and monitor response to treatment.

In recognition of ADNI’s pivotal importance, the Alzheimer’s Association has committed $1 million to the project. In a further step that may greatly amplify ADNI’s impact, the Association has awarded Giovanni B. Frisoni, M.D., of the Laboratory of Epidemiology and Neuroimaging of the National Fatebenefratelli Alzheimer’s Center in Brescia, Italy, a major grant to spearhead a pilot European Alzheimer’s Disease Neuroimaging Initiative (E-ADNI). Pilot E-ADNI is a seven-site feasibility study to gauge whether ADNI methodology and data collection can be coordinated with data currently being gathered through the European Neuroimage Repository. Sites in addition to Brescia will be in Amsterdam, Copenhagen, Göteborg, Munich, Stockholm and Toulouse. If the pilot study determines the two data sets can successfully be combined, it will lay the groundwork for a major proposal to the European Commission to create a centralized data collection system fully compatible with U.S. ADNI protocols.

The Alzheimer’s E-ADNI grant is awarded through the generosity of a donor who wishes to remain anonymous.