An extensive literature search was undertaken using MEDLINE, Current Contents and PubMed using the search terms “Alzheimer and clinical trial”, “Alzheimer and disease modifying”, “Alzheimer and therapeutic trials”, “Alzheimer and study design”, “MCI and treatment”, “dementia and therapeutic trials”, “Alzheimer and biomarkers”, “Alzheimer and diagnosis”, “Alzheimer and economic aspects”. Articles were also identified through searches of the experts' own files. No language restrictions were
ReviewDisease-modifying trials in Alzheimer's disease: a European task force consensus
Introduction
After the introduction of symptomatic treatment, the next target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs.1 The aim of these drugs should not only be to have symptomatic effects but, more importantly, to delay progression of the disease by acting on pathophysiological processes—for example, many current drugs use strategies that are intended to reduce the load of amyloid β in the brain. This is a crucial time in the fight against Alzheimer's disease because many of these new potential anti-amyloid treatments (eg, γ-secretase inhibitors,2 amyloid-β immunotherapy,3 and amyloid-β antagonists4) are now undergoing or are about to enter clinical trials. The design of these trials raises many questions. Which populations should be studied? For how long? How should treatment effects be measured in terms of principal and secondary endpoints? Are surrogate markers available to assess disease-modifying outcomes?
Any flaws in the methodology of these trials will be costly, render them ineffective, and will delay the introduction of more effective treatments for clinical practice. Potential problems that can compromise a trial include a high dropout rate due to trial duration and inadequate sensitivity or specificity of the outcome measures. For these reasons, under the auspices of the European Alzheimer's Disease Consortium, we decided to organise a task force to propose a European consensus paper in this new area. Task force members were chosen because of their academic, regulatory, or pharmaceutical experience in the area.
Section snippets
Methods
The experts selected by the organising committee (BV, CS, GW) were asked to write a comprehensive review of methodological aspects—ie, biological, neuroimaging, cognitive, and non-cognitive assessment methods for use in trials of potential disease-modifying treatments for Alzheimer's disease. Papers were circulated to all task force members at the end of November—3 weeks before the task force meeting, held in Toulouse, France, on December 15, 2005. At the same time each task force member was
The concept of disease-modifying treatment
Disease modification is difficult to define and is the subject of much debate. For a neurodegenerative disorder, such as Alzheimer's disease, a disease-modifying intervention is typically considered to be one that can reduce progression rate. To some extent, this intuitively implies an effect on the pathophysiological mechanism of the disease. However, from the patient's perspective, a disease-modifying treatment should result in long-lasting changes in disability, regardless of the drug's
Definition of the population to be studied
Even though disease-modifying drugs would be most useful in the very early stages of the disease, we agreed that patients with mild cognitive impairment are not good targets for disease-modifying trials because of the lack of diagnostic consensus, the difficulties in defining the population, and the poor efficacy of recent trials in this area.5 Also, mild cognitive impairment is a heterogeneous disorder in which only a subset of patients will have Alzheimer's disease,6, 7 and usually the
Role of biomarkers
The term biomarker is usually applied loosely in the context of assessing outcomes of clinical trials in Alzheimer's disease, but is best defined in accordance with the definitions from the US National Institutes of Health—the result of a working group report published in 2001.24 This group created a standard reference base for terminology that we can now use in trials of disease-modifying drugs. Thus a biomarker is defined as a characteristic that is objectively measured and assessed as an
Ethical and risk–benefit issues
Inherent within the design of any clinical trial is an acceptance of a particular level of risk–benefit ratio. This raises important questions for trials as well as for ethics committees and regulators. Significant issues include who decides what levels of risk are acceptable: should it be the professional or should it be the patient and their carers? Is there a role for patient and carer organisations? How can one obtain informed consent from a patient with more than mild dementia?
In general
Pharmacoeconomic issues
Alzheimer's disease puts a heavy economic burden on western societies. Assuming societies are willing to pay to alleviate that burden, the price paid for each intervention must be commensurate to the mitigation that is produced. There are different ways to approach these calculations. Whichever cost-effectiveness model is used it must include actual data. Furthermore, apparently small benefits in impairments and disabilities might have a substantial effect on handicap. Thus, there are two good
Conclusion
In conclusion, there was much agreement on the approach to designing trials to assess putative disease-modifying drugs, despite the breadth of European countries that participated in the discussion. The main points are summarised in panel 3. This is encouraging because such treatments are increasingly coming to clinical assessment, and this consensus may help to inform the response of regulatory and funding bodies as the results of trials become available.
Search strategy and selection criteria
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