Abstract
To date, the external validity of randomized controlled trials (RCTs) on Alzheimer’s disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients’ complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The “RCT sample” and the “real world sample” were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the “real world sample” was found to be significantly frailer compared to the “RCT sample,” as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1); p < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the “RCT sample” (Spearman’s r = 0.01; p = 0.98), while it was statistically significant in the “real world sample” (r = 0.49; p = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the “real world.” The adoption of multidimensional measures capable to capture the individual’s biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena.
Highlights
Randomized controlled trials (RCTs) represent the gold standard for establishing the efficacy and safety/tolerability of medical interventions
The “real world sample” was found to be significantly frailer compared to the “randomized controlled trials (RCTs) sample,” as indicated by higher Frailty Index (FI) scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1); p < 0.001, respectively] (Figure 1A)
The majority (78.3%) of patients in the “real world sample” were frail [i.e., FI ≥0.25 [9]], whereas only 26.1% of frailty prevalence was reported in the “RCT sample”
Summary
Randomized controlled trials (RCTs) represent the gold standard for establishing the efficacy and safety/tolerability of medical interventions. Besides providing information concerning clinical and therapeutic outcomes, RCTs should try to generate messages that are externally valid or generalizable as much as possible. In other words, they should provide information that can be translated. If the RCT eligibility criteria are too selective (in order to maximize the focus on a specific aspect of research), the representativeness of the sampled population and the following generalizability of the results will be challenged. A substantial discrepancy has been shown between patients enrolled in RCTs and the patients’ population which should benefit from the studies results [3, 4]. A good representativeness with regard to sex distribution has been reported for most of available RCTs [6]
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