推进中枢神经系统临床试验的数字健康技术（DHT）（第一部分）

PART 1: Advancing Digital Health Technologies(DHTs) for CNS Clinical Trials Measurement advances and use cases for digital endpointsand biomarkers Table of contents Introduction1How are DHTs currently being used as measurement tools in CNS trials?2Coming soon: Navigating challenges and charting the future of DHT use in CNSclinical trials4References5 Introduction Development of new and novel therapies in psychiatry and neurology, togetherCentral Nervous System (CNS)disorders, has historically lagged other therapeuticareas.Limitations in sensitivity to change and reliability of the Clinical OutcomeAssessments (COAs) used as primary endpoints has directly contributed toCNS clinical trials increasing in complexity and cost. Measuring change in CNS within CNS clinical trials. An analysis of neurologytrials by Masanneck and colleagues noted a >2 foldincrease in the number of studies leveraging DHTslisted on ClinicalTrials.gov between 2015 and 2021.2Organizations such as the Digital Medicine Society (DiME) Enhancing CNS trials with DHTsOne of the most significant measurement developments of thepast decade has been the emergence of DigitalHealth Technologies (DHTs) and their associated digitalmeasures. DHTs have been developed with a specifichealth use case. This can include hardware with sensor Hallmark characteristics of DHTs include their high-frequency sampling and ability to passively capture datalongitudinally in real world settings. This positions them There are numerous digital measures being investigatedwithin CNS (see Table 1), though few have beencomprehensively validated for a specific context ofuse of a clinical trial. To date, there have only been twoprominent examples of digital measures displacing Table 1: List of DHT modalities relevant to CNS disorders and their associated developmental stage Mature modalities have multiple qualified vendors and established precedence as exploratory endpoints in CNS clinical trials.Emerging modalities have some qualified vendors and implementations as exploratory endpoints while nascent modalities Within neuromuscular disease, app delivered virtualmotor assessments show promise in enabling higher How are DHTs currently beingused as measurement tools in One of the most advanced of these efforts, the RochePDapp, has shown good to excellent test-retest reliabilityof individual tests, and meaningful associations withhistorically used COAs including the Movement DisorderSociety–Unified Parkinson’s Disease Rating Scale (MDS- Case examples: Enhancing measurementwith DHT endpoints Designing a measurement strategy from a patientfocused perspective requires starting from a conceptualmodel of a disease and mapping COAs to relevantConcepts of Interest (COI). Within CNS, these mappingexercises often illuminate gaps in the coverage of the Speech and language measures are also being leveragedas exploratory endpoints in both psychiatric andneurodegenerative conditions to capture changes in With respect to function, there is broad interest inhow dedicated smartphone apps and actigraphy canbe used to capture physical functioning, and through effects of KarXT. When examining the full studypopulation, no significant differences were observed.However, when the sample was split into impairedvs unimpaired groups by baseline level of cognitiveimpairment (defined as >1 standard deviation belownormative values), treatment with KarXT produced day-to-day function and quality of life. Speech-basedcomposite measures have been shown to capture clinicalprogression in AD with similar effect sizes to established DHTs are also enhancing measurement of negativesymptoms within schizophrenia. These symptoms,which include impairments in sleep, cognition,mood and social functioning, are not well capturedby existing COA measures. Nonetheless, they arehighly relevant to a patient’s day-to-day life.12In Another prominent stratification example leveragesvoice and speech analytics technologies in patients withbipolar disorder. Siegel and colleagues investigatedwhether speech latency (i.e., how many millisecondsit took for a patient to verbally respond to a promptin a clinical interview) could be leveraged to stratifya trial population. Retrospectively analyzing a trial of Case examples: Leveraging DHTs forpopulation stratification The focus on stratification of clinical trial populations inCNS can be seen as an application of a more “precisionpsychiatry” approach to drug development.15DHTs canbe used as behavioral phenotyping tools, and thus have Cognitive Impairment Associated with Schizophrenia(CIAS) is often reported by patients as a persistent andbothersome set of symptoms that are not addressed Coming soon: Navigating challenges and charting the future ofDHT use in CNS clinical trials DHTs are rapidly transforming the landscape of measurement strategies in CNS clinical trials, addressing longstandinggaps in capturing functional outcomes and health-related quality of life. Thr