Are we missing the point in dementia research?
Authors: None The Lancet Neurology
Journal: The Lancet Neurology (2004)

How do you find out if a treatment is effective? By doing a placebo-controlled clinical trial. How do you find out if one particular drug is more effective than another? By doing a head-to-head clinical trial of the two treatments. Simple questions, simple answers. Or so you might think. The practice of “evidence-based medicine” is a minefield of trial design, statistical tests, secondary-outcome measures, and subgroup analyses. If you're lucky, someone will have done the hard work for you by doing a meta-analysis. But even these supposedly objective analyses have their shortcomings, not least that they can only include results that are in the public domain, thus excluding the vast amounts of data collected by pharmaceutical companies that have not been published. In this month's issue of the journal, David Hogan and coauthors report their analysis of three comparative trials of acetylcholinesterase inhibitors for the treatment of dementia (see page 624). The authors assessed the trial methodology, the validity of the results, and whether the conclusions were valid on the basis of the reported results. Hogan and coauthors' conclude that the design of all three trials was biased towards the drug produced by the trial sponsor and, therefore, that the validity of the conclusions was compromised. Just one of the problems Hogan identified is that the sponsor's drug was more likely to be given at the target maximum daily dose than the competitor drug. This is an old trick: either give the competitor drug at a dose too low to have a clinical effect or, conversely, give it at a dose that is likely to maximise any adverse events. Two of the studies scrutinised by Hogan and coauthors were trials of the same cholinesterase inhibitors—galantamine and donepezil. In the study sponsored by donepezil's manufacturer, 92% of individuals reached the target daily dose compared with 69% in the study sponsored by the manufacturer of galantamine. Such problems are not new. Previous analyses have shown that, although industry-sponsored trials are usually better designed than their non-industry counterparts, industry research is more likely to report positive outcomes than research sponsored by other funding sources. With the ever-increasing influence of industry money in medical research, can we really trust the results of these trials? The results of AD2000—a non-industry sponsored trial of donepezil for treatment of Alzheimer's disease—were recently published (Lancet 2004; 363: 2105–15). This UK trial, in which the National Health Service picked up the costs of drug treatment, was criticised for replicating trials that had already shown that donepezil treatment is of some benefit for patients with Alzheimer's disease. AD2000 undoubtedly had some problems, but nonetheless, there is an important take-home message. The results show that although activities of daily living and cognitive scores improved in the group of patients receiving donepezil, the drug's effect on “more socially relevant outcomes”, such as carer wellbeing, behavioural and psychological symptoms, or on delay of institutionalisation, was not significant. The authors' conclusion was therefore that donepezil treatment is not cost-effective, contrary to previously published studies and guidance. One important feature of the AD2000 was that the only prerequisites for inclusion were a diagnosis of Alzheimer's disease and uncertainty over whether the patient would benefit from the treatment. This approach contrasts to that of industry sponsored trials, many of which have such restrictive inclusion and exclusion criteria that the trial population is not representative of patients in the general population. In a second paper in this issue, Niels Schoenmaker and Willem Van Gool address one feature of population characteristics: age (see page 627). When the authors analysed the age range of patients with Alzheimer's disease participating in clinical trials, they found that these patients were on average 8 years younger than patients in the general population. Older patients can have different underlying disease pathologies, additional vascular pathology, different clinical courses, different genetic predispositions, and other comorbidities, which may all influence trial outcomes. The authors conclude that this age gap is a potential obstacle to the practice of evidence-based medicine in patients with dementia. It is predicted that by 2030 there will be 63 million patients with dementia worldwide. We are still a long way from finding a truly effective treatment for this disease and many questions remain. Issues in trial design—such as comparator bias and the age gap—must be addressed and trial samples must be more representative of patients in the community if we are to make the necessary advances in treatment and care.