Cerreta F, Eichler HG, Rasi G.
Drug policy for an aging population--the European Medicines Agency's geriatric medicines strategy.
N Engl J Med. 2012 Nov 22;367(21):1972-4.
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The data presented in the Perspective article by Cerreta et al. show a clear disjuncture between the ages of those who are prescribed cardiovascular drugs and participants enrolled in clinical trials to test such candidate drugs. The authors rightly argue for a better match in age distributions, among other considerations, between people who are evaluated in trials and those who are prescribed medicines in the clinic. What does this have to do with Alzheimer’s disease (AD) clinical trials?
Currently, there is no known disease-modifying therapy for AD. This partly arises from a lack of understanding of AD etiology. Thus, AD trials test compounds whose targeting mechanisms might, or might not, prove to be disease modifying to some degree. A risk is that efficacy of a truly disease-modifying therapy might be missed if the trial was underpowered. Even if the drug’s effect was not large, it could have a large impact globally, and would likely be invaluable in further elucidating AD etiology.
There is a very pressing need to find disease-modifying AD therapies. In longitudinal clinical trials, the greater the disease effect (i.e., the treatable effect), the greater the likelihood of finding any efficacy in a candidate therapy. In AD, the disease effect is larger in younger elderly than in older elderly (younger elderly decline faster). Thus, in terms of the single goal of finding disease-modifying efficacy, a longitudinal clinical trial will have greater statistical power with younger elderly as compared with older elderly. With a successful trial, and therefore a known mechanism in hand, further research could be expected to improve on this critical advancement in mechanistically understanding AD. Furthermore, if stratifying enrollees with respect to some disease biomarkers allows for subgroups with larger disease effects, or for subgroups that are more appropriate for a specific targeting mechanism, then this should be embraced. If any efficacy at all can be found in AD therapeutics research, this would be a boon for everyone, moving us from the dark ages of no efficacy whatsoever into relative enlightenment.
Cerreta and coauthors’ points are, nevertheless, critically important. In particular, therapies need to be tested across the age spectrum in a manner that reflects the age distribution of those patients who are likely to be prescribed the medication. At a minimum, for example, safety and tolerability extension studies across a wide age range can be carried out following intervention studies.
Holland D, Desikan RS, Dale AM, McEvoy LK, .
Rates of decline in Alzheimer disease decrease with age.
PLoS One. 2012;7(8):e42325.
Holland D, McEvoy LK, Desikan RS, Dale AM, .
Enrichment and stratification for predementia Alzheimer disease clinical trials.
PLoS One. 2012;7(10):e47739.
It is true that most of the patients included in drug trials do not reflect the general elderly population. In the Gerontopole (Gillette-Guyonnet and Vellas, 2012), we have to screen almost 50 Alzheimer's patients in order to have one included in current AD drug trials. We have to select those with few comorbidities with a caregiver, living at home, in generally good conditions, without severe behavior disorders, and the patient as well as the family need to accept to be part of the trial.
New drug trials in Alzheimer's exclude any vascular lesions, because of the use of anti-amyloid treatments. Now, some trials exclude those aged more than 80 years old. However, a majority of AD appears after age 80. Moreover, all trials based on biomarkers and imaging are probably difficult to replicate in the older olds. The majority of biomarkers and imaging studies including amyloid PET scans have targeted a 70-year-old population. However, we know that with increasing age, the risk for AD rises, with a maximum of around 85 years old. Most likely, drugs for AD after 80 will not be the same as before 80.
Gillette-Guyonnet S, Vellas B.
The Toulouse Gérontopôle Research Center: report of activities, 2007-2011.
J Alzheimers Dis. 2012;28(3):721-32.
This regulatory perspective paper points out that trials are frequently done in younger populations than they are prescribed to. It advises against increasing stratification, "confounder cleansing," and the general trend to test drugs in more narrowly defined participant groups. In the Alzheimer’s field, sponsors are moving toward evaluating potential medicines in enriched, i.e., more tightly defined subgroups rather than in broadly representative geriatric populations that may disproportionately end up taking those drugs.
The figure in Cerreta et al. relating to cardiovascular medications in Italy would look the same for acetylcholinesterase inhibitor medications (AChI). There are several population-based or registry examples for this. For example, data from a drugs claim database show that 52 percent of persons prescribed AChIs were over 80 (Pariente et al., 2012). In contrast, the mean ages for the trials represented in the Cochrane systematic reviews were 72-75.
So the "average" person actually on AChIs is likely to be five to 10 years older than those included in the trials. Extrapolating from the current research on specific targets is likely to feed into polypharmacy in the oldest old. While polypharmacy in itself is associated with several adverse outcomes, there are few population data on the efficacy of dementia drugs and their interactions, especially as regards procholinergic side effects of other drugs (e.g., see Johnell and Fastbom, 2008), and in the context of comorbidity.
Others will argue that "enriched" samples will give a clearer "signal" to demonstrate first efficacy. The population-based answer would be: "Yes, but in whom?"
Pariente A, Fourrier-Réglat A, Bazin F, Ducruet T, Dartigues JF, Dragomir A, Perreault S, Moore N, Moride Y.
Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors.
Neurology. 2012 Mar 27;78(13):957-63.
Johnell K, Fastbom J.
Concurrent use of anticholinergic drugs and cholinesterase inhibitors: register-based study of over 700,000 elderly patients.
Drugs Aging. 2008;25(10):871-7.