Innovations In Clinical Neuroscience

JAN-FEB 2017

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

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Innovations in CLINICAL NEUROSCIENCE [ 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 ] 24 dementia, they suggest that trials with i ndividuals with early AD or late mild cognitive impairment (MCI) can theoretically use a single primary outcome measure if it can substantiate a treatment effect on both cognition and function, t hough no drug has been approved on such an outcome. The draft guidance newly acknowledges that the co-primary endpoint approach is impractical for predementia trials because of limited or relatively absent functional deficits. An effect solely on cognition may also be insufficient in preclinical cohorts, as detecting changes from no cognitive impairment or a relatively weak signal remains challenging. Nevertheless, in the case where functional deficits are essentially absent (e.g., early MCI or preclinical AD), an improvement on a cognitive measure may be sufficient for possible accelerated approval under Subpart H (i.e., an effect on an intermediate clinical endpoint that is reasonably likely to predict ultimate clinical benefit 48 [i.e., an effect on function]). This route would then require confirmatory post-marketing studies to establish clinical benefit. The European Medical Agency (EMA) has also considered new guidance for trials in AD with concept papers, entitled "Need" and "No need" issued at the end of 2013. 49,50 The "No need" paper made the case that it is premature to rewrite the current, broadly worded guidance that accepts data-driven discussions and agreements with the EMA on a program by program basis. The "Need" paper holds that some clinical trials already focus on "prodromal" populations, and highlights the increasing emphasis on strategies aimed at earliest diagnosis, prognostication, and enrichment of clinical trials. The "Need" concept paper (as in the preceding 2009 guidance) explicitly acknowledges the "asymptomatic" disease stage. Version 2 of the "Discussion Paper on the Clinical Investigation of Medicines for the Treatment of Alzheimer's Disease and Other Dementias," released in October 2014, moved this discussion forward, and a new version of the EU draft AD guidance was released in January 2016. 51 The 2016 draft of the EMA guidance recognizes potential challenges with a cognition-function co-primary requirement for pAD/MCI due to AD, including ceiling e ffects with existing tools and impact of compensation strategies. It also notes that creation of more sensitive and specific tools or novel cognition-function composites may be possible solutions, w hile stressing the need to assess both cognition and function in a comprehensive manner and demonstrate clinical relevance of effects. For preclinical AD, multiple approaches are described, such as diagnosis of dementia, significant cognitive decline, and change in cognitive function, including the use of more sensitive novel tools. Issues of a lack of tool validation, use of responder definitions and time-to- event analyses to support relevance, feasibility issues around trial duration and drop-out, and lack of reliable surrogates/need for lengthy follow-up to confirm relevant cognitive changes, are also discussed. There is no doubt that regulatory conversations are moving the field in a much needed direction. Evolving therapeutic strategies that sequentially move from established regulatory paths for AD dementia to novel strategies for MCI due to AD/prodromal AD, and now to early MCI, take more direct aim at targeting the disease at its various stages. Building on this progress, consensus discussions focused around new principles for accepting the earliest predictive features of the AD in its preclinical state become crucial. HEALTH ECONOMICS AND PAYERS Consideration should also be given to the evidentiary needs of payers (i.e., coverage bodies and health technology assessment bodies) to support reimbursement. Currently, this includes using endpoint and statistical analyses to address the following questions: Is a new product better or safer than an existing product? How does its value compare to existing products? These considerations will continue to apply to therapeutic strategies aimed at AD. However, the next phase of AD drug development has prevention as its goal, and there are no precedents for judging value. In this context, what constitutes "meaningful benefit" is being debated across the research field and has yet to be resolved. Issues include determining the potential impacts on patient-reported outcomes, i ncluding quality of life, and on ethical, legal, and social issues. 52 Finally, the field needs to be prepared to address the likely question from third party payers of "How do we value therapeutics that prevent the s lide from 'normal function' to clinical decline?" It is likely that some clarity will ensue with regard to health economic criteria once there are new successful clinical trials for the prevention of Alzheimer's disease and the totality of the evidence base can be evaluated. COGNITIVE OUTCOMES: HISTORY AND PSYCHOMETRICS The most frequently used cognitive outcome measure in clinical drug trials for mild to moderate AD is the Alzheimer's Disease Assessment Scale-Cognitive, which was designed in 1984 to assess deficiencies in episodic memory and a number of other cognitive domains (e.g., language, orientation, praxis) that are universally affected by AD disease. 5 3,54 While the ADAS-Cog has proven utility in clinical trials of cholinesterase inhibitors in demented patients and has become standard in the field, there is concern that the test is not particularly sensitive to cognitive changes in very mild AD, MCI, or preclinical AD, and will not be appropriate for trials in these cohorts. 55–59 Indeed, in several recent clinical trials of cholinesterase inhibitors and other novel interventions in patients with MCI, the ADAS-Cog did not differentiate between treatment and placebo effects, 15–20 despite the introduction of supplementary items and use of 11-, 12-, 13- and 14-item versions. Psychometric evaluation has shown that total scores on the ADAS-Cog are very low in MCI, often in the range of 11 to 12 (standard deviation [SD]=~4.0) out of a potential range 0 to 70 or 0 to 80 (potential range 0–70, 11-item; 0–80, 12- item including Delayed Word Recall). 60–62 This contrasts with average scores of 25 to 28 in mild-to-moderate AD cohorts entering treatment trials. 62,63 Although the ADAS-Cog performs adequately in terms of scaling assumptions, reliability, and validity, in the mild AD and MCI cohorts, the presence of large floor effects in mild AD and MCI cohorts imposes serious limitations on the instrument's ability to

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