This initial qualification is part of the Mobilise-D’s wider objective to establish acceptable DMOs (derived from suitable mobile wearable devices and associated algorithms) as biomarkers for clinical benefit (i.e., as surrogate, primary or key secondary endpoints) in pivotal clinical trials for treatment of diseases or health conditions that impact upon mobility. An incremental approach is being taken, with qualification of monitoring biomarkers in Parkinson’s Disease (PD), as the initial stage.
During two seperate meetings held in March, first the the Scientific Advice Working Party agreed on the advice to be given to the Applicant which was then adopted by the Committee for Medicinal Products for Human Use.
The overall purpose of this application is to obtain qualification advice on the steps required for the outcomes derived from suitable mobile wearable devices and their associated algorithms to be accepted as biomarkers of clinical benefit (i.e., as surrogate, primary or key secondary endpoints) in
pivotal clinical trials for diseases or health conditions where mobility is a concern.
Due to the complexity of this request for qualification advice, the Mobilise-D consortium is pursuing an incremental approach. In this first submission, the consortium seeks qualification advice on the use of DMOs as monitoring biomarkers of disease status (show relationship with changes in the degree or extent of the disease) in patients affected by PD. In a subsequent submission the consortium plans to seek qualification advice on the use of DMO’s as monitoring biomarkers of disease status in multiple diseases, including Parkinson’s Disease (PD), Chronic Obstructive Pulmonary Disease (COPD), Multiple Sclerosis (MS), and outcome of a Proximal Femur Fracture (PFF).
Mobilise-D intends to pursue regulatory qualification for a new methodology to quantify mobility performance continuously over a week in real world settings, using a multi-sensor wearable device and associated algorithms that compute the various DMOs by analysing the raw signals recorded by the device.
The Consortium intends to use this measurement as an additional monitoring biomarker to account for mobility performance in assessing the efficacy of new treatments for Parkinson’s Disease (PD) patients. This approach is complementary to those already in use, that account only for patient’s
perception of mobility (patient reported outcomes, PRO’s) and mobility capacity (performance related outcomes, PerfO’s, such as 6-minute walk distance).
Mobilise-D proposes that Digital Mobility Outcomes can be used as biomarkers in PD in addition to the movement disorders society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) components II and III. The MDS-UPDRS-II provides a measure of the patient’s perception of mobility, and the MDSUPDRS III provides a clinician rated measure of mobility capacity during brief tests performed during the visit. The Mobilise-D DMOs will quantify in addition mobility performance measured continuously in the real-world. To demonstrate the validity of the DMOs, the applicant will evaluate their construct validity, predictive capacity, and ability to detect change. The applicant intention is to qualify DMOs as secondary endpoints, complementary to the MDS-UPDRS II and III.
In order to demonstrate the validity of this biomarkers, the consortium plans to perform an extensive technical validation, and a large scale observational clinical trial. The technical validation will verify the accuracy of the device and algorithm to measure a range of different DMOs. The design of the study is based on a metrology approach where state of the art human movement analysis lab is used to quantify the accuracy and precision of a multisensory wearable instrumentation, expected to be one order of magnitude more accurate than the wearable sensors. This instrumentation is then used to quantify the accuracy and precision of the wearable sensors in real world conditions, on small cohort of healthy volunteers and of patients affected by PD.
In a second stage, clinical validation will be obtained in an observational multicentre clinical trial involves a longitudinal 24 months cohort study (with 6 monthly follow-up) in patient cohorts for each disease of interest, where disease progression is monitored from a clinician’s and patient’s perspective using the accepted gold standards in each disease. The Mobilise-D consortium also plans to use the Later-Life Function & Disability Instrument (LLFDI) as a disease-independent outcome of mobility disability, to validate the use of DMO’s across all the target diseases. At each six-month assessment each patient will be asked to wear the device continuously for seven days. The raw data from the device will be collected through a secure digital infrastructure, and analysed with the Mobilise-D analytical software, that calculates a number of DMOs for each patient. The clinical and patient-reported outcomes will be used to assess construct validity, predictive capacity, and ability to detect change for each DMO.
Summary of the Qualification Advice
The European Medicines Agency supports the general objective of the Mobilise-D consortium to pursue the qualification of DMOs as biomarkers of mobility performance in regulatory drug trials.