Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] Innovations in CLINICAL NEUROSCIENCE 23 otherwise positively intervene in the d isease course is an international research priority. 3–5 It has been over 10 years since the last of five drugs was approved for the treatment of AD. 6–13 All five approved t herapies target neurotransmitter systems and enhance the function of surviving neuronal circuitry. Although worthwhile, their effectiveness has provided modest symptomatic improvement but has not reversed prior decline or slowed the progression of the underlying disease processes. Efforts have turned toward identifying a disease-modifying therapy for AD, but these efforts have yet to yield a successful intervention. 14–21 The lack of success in developing a disease-modifying therapy for AD may arise, in part, from methodological imprecision in the conduct of clinical trials. Recent advances have occurred to reduce this imprecision by 1) improving the diagnostic accuracy of subjects enrolled into trials, especially through the incorporation of biomarkers; 2) moving to secondary prevention trials to evaluate therapies; and 3) developing more sensitive clinical instruments, including composite, computerized, and performance-based measures to assess disease progression and treatment effects. In past clinical trials, the diagnosis of AD was based largely on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria 22 that relied on clinical assessments of cognitive and functional deficits and the concurrent exclusion of other etiologies of dementia. These criteria had important utility in helping to identify a relatively homogeneous cohort of patients to be studied, but were susceptible to imprecision since up to 20 percent of those with a clinical diagnosis of AD did not have evidence of AD neuropathology (by current criteria) on post-mortem examination 23–25 or on positron emission tomography (PET) imaging of brain amyloid burden during life. 26–29 Furthermore, the criteria did not allow AD to be diagnosed until symptoms were well established, presumably at a point when disease pathology was advanced. It is now widely accepted that pathologic changes in AD begin decades before the emergence of the constellation o f clinical symptoms that define dementia onset. 3,30–32 There is also an emerging consensus that intervention at the earliest stages of AD, prior to dementia onset and widespread irreversible neuronal damage, w ill be the most feasible scientifically and socioeconomically, and will have the most impact. Technical advances in imaging and fluid biomarkers have furthered our understanding of the underlying disease processes, and now allow AD to be identified with some certainty before the onset of obvious clinical symptoms. These advances have been incorporated into new diagnostic criteria proposed by the National Institute on Aging-Alzheimer's Association (NIA-AA) 33–36 and by the International Working Group (IWG). 3 7–39 Both sets of criteria hold that AD encompasses a continuum from preclinical to dementia, and they both aim to improve diagnostic specificity early in the continuum through the use of AD biomarkers. The criteria differ in that those proposed by the IWG capture both the prodromal and the more advanced stages of dementia within the same diagnostic framework, whereas those proposed by the NIA-AA classify three phases of disease: the first identified by the presence of biomarker abnormalities before the emergence of clinical symptoms, 36 the second by the presence of both mild clinical symptoms and biomarker abnormalities, 35 and the third by the presence of AD dementia. 22 Application of either of these new criteria in therapeutic trials 40,41 opens up the possibility for more accurate identification of patients for treatment. In the interim and since the initial IWG criteria, further research in biomarkers associated with stages of AD (i.e., markers of progression vs. diagnosis) has prompted recent publication of the IWG-2 criteria. 42 As aspects of current practices in trial design and conduct improve, as outlined above, the regulatory framework around approval of new AD therapies with different mechanisms of action than the currently approved neurotransmitter-based therapies requires re-thinking. Additional work needs to be done in anticipation of a novel AD therapy that shows clear clinical benefit, including, whenever possible, performance-based assessments that u nderscore real-world functional benefit. Our companion paper 43 considers the state of the art regarding potential performance- based measures of functional capacity. REGULATORY FRAMEWORK Regulators, recognizing the pressing need for a shift in paradigm(s) when evaluating interventions for preclinical and predementia disease, have drafted guidance for AD drug approval. Historically, approval for drugs to treat AD has depended on dual primary endpoints assessing cognition and functioning; however, given the increasing emphasis on preclinical and prodromal AD trials, new definitions of what constitutes "functionally meaningful benefit" and "global decline" must be reexamined. Furthermore, as studies move into earlier intervention, the current divide between clinical trial design and registration requirements for "symptomatic" and "disease-modifying" therapies are likely to close. By United States law, a clinical trial must establish clinical benefit to be the basis for an approval. Customarily, a clinically meaningful benefit is defined as a favorable, statistically robust effect on how a patient feels, functions, and/or survives. 44–46 This "clinical meaningfulness" could be reflected, for example, in an established "minimally important difference" between groups on a measure of functional ability/disability and/or a "responder" definition that is based on prior evidence that a certain degree of improvement on the selected scale represents a meaningful improvement for an individual. When the primary outcome does not directly measure daily function, additional evidence for a relationship between the impact of the drug on the treatment target and how the patient feels or functions is needed. Alternatively, a co- primary functional (e.g. ADCS-ADL) or global endpoint (e.g. ADCS-CGIC) could be used in addition to a cognitive outcome measure as is historically the case for AD trials. Draft guidance was recently issued in the United States offering the US Food and Drug Administration's (FDA) current thinking on the development of drugs for early-stage disease. 47 While their view on trial endpoints remains unchanged for

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