Alzheimer disease (AD), the most common form of dementia, affects about
four million Americans and has been estimated to cost US society $100 billion
per year, exceeded only by the costs of heart disease and cancer.1,2 The prevalence of AD has been
predicted to reach 14 million by 2050 unless a treatment is found, and overall
costs may increase four-fold.1,2 While
considerable debate remains about the pathogenesis, nosology, and treatment
of AD,3 there is no doubt that this research
has the potential for enormous financial and professional gains. Thus, there
is a need to balance the interests of both researchers and society in conducting
Although the financial interests of clinical investigators have not
necessarily affected the validity of trial results, experiences with some
AD drug trials have prompted the development of organizational guidelines
to limit the appearance or reality of financial conflicts of interest. Based
on a trial of tacrine4 and other drugs,
a multidisciplinary panel was convened to study the financial relationship
between academia and industry.5 Its recommendations
included proactive disclosure of both personal and organizational conflicts
in all clinical trials, particularly as a way to build public trust in the
drug development process.6 The Parkinson
Study Group, a not-for-profit physicians' group that coordinates research
at 85 sites across the United States and Canada, has adopted similar principles
and has published the results of some 25 multicenter trials for diagnostic
methods and experimental interventions in Parkinson disease.7 This
group further mandates review of all research by outside health care providers
and the release of both positive and negative results to the public.
Guided in part by the approach of the Parkinson Study Group, a large
multisite study—the National Institute on Aging (NIA) Cooperative Study—has
developed and internally disseminated conflict-of-interest guidelines. These
include a $10 000 annual cap on consulting fees for investigators and
stringent limitations on ownership of equity in companies involved in the
studies. Those leading the studies are subject to stricter guidelines. However,
the blanket exclusion of experts with some industry ties from the design of
trials might make drug development less efficient. Therefore, the Cooperative
Study's guidelines reflect a need to balance access to scientific expertise
with the goal of mitigating conflicts of interest. The group is currently
studying the impact of its guidelines on the conduct of clinical trials.
Novel targets of AD pathogenesis, however, would present a new set of
challenges even if all appearances of conflict were to be addressed. A recent
trial of a vaccine-based treatment for AD8 was
viewed by many as a critical test of the amyloid hypothesis, a popular model
of AD pathogenesis. Vaccination of transgenic mice against components of human
amyloid, a protein at the core of senile plaques in AD, led to clearance of
this protein from the brain.9 However, in
phase II human trials with this same vaccine, some subjects developed autoimmune
encephalitis, an adverse effect that prompted termination of the trial.10 As others have suggested, the public health can
best be served in this case by a full disclosure of the disease course and
clinical response of all trial participants,11 rather
than analyses of single cases8 or subsets
of subjects.12 Equipped with as complete
a set of positive and negative findings as possible, clinical investigators
would be better able to anticipate potential problems with mechanistically
novel agents in future trials.
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