A critique of the GENERATION RCT: What are we willing to accept for preventing Alzheimer's disease?
http://www.sciencedirect.com/science/ar ... 2216300540
On Sept 28, 2015, the GENERATION randomised clinical trial (RCT) was submitted to the ClinicalTrials.gov registry (NCT02565511). The study will test the effectiveness versus placebo of two drugs targeting amyloid (CAD106 and CNP520) on cognition, global clinical status, and underlying pathology in individuals at risk for the onset of clinical symptoms of Alzheimer's disease. The study is funded by Novartis and AMGEN, in collaboration with the Banner Alzheimer's Institute (Phoenix, AZ, USA), the US National Institute on Aging, and the Alzheimer's Association.
We are aware that the registry only provides limited information about GENERATION, but some aspects of the study methodology seem worrisome. Participants will be eligible for randomisation if they are aged 60–75 years, present with a Mini-Mental State Examination score of 24 or higher, and are homozygous for the APOE ɛ4 genotype. It is noteworthy that the presence of brain amyloid will not be considered an eligibility criterion. In other words, the investigators are planning to treat healthy individuals with anti-amyloid drugs only because these participants present with a specific genetic profile. The genotyping of the APOE ɛ4 allele (with all its limitations) is dangerously translated into an exclusive diagnostic biomarker for judging whether a person might be a candidate for a pharmaceutical intervention, regardless of any clinical manifestations (ie, cognitive impairment) or the targeted pathophysiological abnormality (ie, brain amyloid deposition).
In the medical literature, a growing number of statements request early interventions against Alzheimer's disease, with the false assumption that early diagnosis might increase the effect size of available treatments.1 and 2 This approach is arguable because predicting the boundaries between so-called normality and abnormality might simply lead to overdiagnosis and overtreatment.3
We realise that the GENERATION trialists are acting in the context of a research project without necessarily implying a direct implementation of their future findings in clinical practice. Nevertheless, too many times a research concept has been automatically translated into a clinical paradigm. For example, the actual use of the mild cognitive impairment concept in clinics might be questionable, because this concept was originally framed only for research purposes and this occurrence is still surrounded by multiple ambiguities (eg, spontaneous reversibility of this disorder to normality).4
In conclusion, we are worried that GENERATION might pave the dangerous way that assumes that everything can be done in the name of prevention, even treating individuals just on the basis of their genetic profile. We believe that this approach is ethically arguable and hope that more careful arguments will be taken into consideration during the implementation of the study.
We declare no competing interests. The opinions expressed in this Correspondence are those of the authors and do not necessarily reflect the views of their institutions.