The case for RWE is being built by FDA...OK
FROM FDA Guidance doc
The co-primary endpoint approach was used, in part, because the cognitive assessments used in 57 the studies were not considered inherently clinically meaningful. Such assessments typically 58 measure the cognitive deficits of AD through the use of highly sensitive formalized measures of 59 neuropsychological performance that are capable of discriminating small changes of uncertain 60 independent clinical meaningfulness. This historical dichotomy of functional and cognitive 61 assessments has led to common use of the terms cognition and function with respect to outcome 62 assessment in AD clinical trials, with the implication that an effect on cognition is non-63 meaningful unless accompanied by a benefit on an independent endpoint assessing function in a 64 meaningful manner. FDA rejects this dichotomy and finds such usage inappropriate, because it 65 implies that an effect on cognition itself, regardless of the nature of the observed effect and the 66 manner in which it is assessed, cannot be clinically meaningful. This is certainly not the case. 67 68 Cognition, in its entirety, encompassing all its constituent processes and domains, is most 69 certainly meaningful in terms of daily function. Although small changes in various cognitive 70 domains may be detected using sensitive neuropsychological tests that are capable of detecting 71 changes of uncertain clinical meaningfulness, more marked cognitive changes may represent 72 impairment that is clearly clinically meaningful. It follows, in concept, that cognitive changes of 73 particular character, perhaps defined by magnitude or breadth of effect(s), may represent 74 clinically meaningful benefit. The issue of concern with regard to considering the 75 meaningfulness of cognitive measurements is the method of assessment, not the entity of 76 cognition itself, especially for cognition taken as a whole. In short, cognition is meaningful, but 77 when measured using conventional approaches with sensitive tools directed at particular 78 domains, the meaningfulness of measured changes may not be apparent. 79 80 As the scientific understanding of AD has evolved, efforts have been made to incorporate in 81 clinical trials, to varying degrees, the use of biomarkers reflecting underlying AD 82
3
pathophysiological changes and the enrollment of patients with AD at earlier stages of the 83 disease, stages in which there may be no functional impairment or even no detectable clinical 84 abnormality. These efforts are particularly important because of the opportunity to intervene 85 very early in the disease process that AD provides, given the development of characteristic 86 pathophysiological changes that greatly precede the development of clinically evident findings 87 and the slowly progressive course of AD. It is obvious that delaying, or, preferably, halting or 88 reversing, the pathophysiological process that will lead to the initial clinical deficits of AD is the 89 ultimate goal of presymptomatic intervention, and treatment directed at this goal must begin 90 before there are overt clinical symptoms. This opportunity carries with it the need to understand 91 the optimum manner in which to assess treatment benefit in these earlier stages of disease.
