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      On the use of wearable sensors as mobility biomarkers in the marketing authorization of new drugs: A regulatory perspective


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          The loss of mobility is a common trait in multiple health conditions (e.g., Parkinson's disease) and is associated with reduced quality of life. In this context, being able to monitor mobility in the real world, is important. Until recently, the technology was not mature enough for this; but today, miniaturized sensors and novel algorithms promise to monitor mobility accurately and continuously in the real world, also in pathological populations. However, before any such methodology can be employed to support the development and testing of new drugs in clinical trials, they need to be qualified by the competent regulatory agencies (e.g., European Medicines Agency). Nonetheless, to date, only very narrow scoped requests for regulatory qualification were successful. In this work, the Mobilise-D Consortium shares its positive experience with the European regulator, summarizing the two requests for Qualification Advice for the Mobilise-D methodologies submitted in October 2019 and June 2020, as well as the feedback received, which resulted in two Letters of Support publicly available for consultation on the website of the European Medicines Agency. Leveraging on this experience, we hereby propose a refined qualification strategy for the use of digital mobility outcome (DMO) measures as monitoring biomarkers for mobility in drug trials.

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          Most cited references15

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          Osteoporosis in the European Union: medical management, epidemiology and economic burden

          Summary This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). Introduction Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. Methods The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. Results Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Incident fractures represented 66 % of this cost, long-term fracture care 29 % and pharmacological prevention 5 %. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. Conclusions In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted.
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            Gait impairments in Parkinson's disease

            Gait impairments are among the most common and disabling symptoms of Parkinson's disease. Nonetheless, gait is not routinely assessed quantitatively but is described in general terms that are not sensitive to changes ensuing with disease progression. Quantifying multiple gait features (eg, speed, variability, and asymmetry) under natural and more challenging conditions (eg, dual-tasking, turning, and daily living) enhanced sensitivity of gait quantification. Studies of neural connectivity and structural network topology have provided information on the mechanisms of gait impairment. Advances in the understanding of the multifactorial origins of gait changes in patients with Parkinson's disease promoted the development of new intervention strategies, such as neurostimulation and virtual reality, aimed at alleviating gait impairments and enhancing functional mobility. For clinical applicability, it is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.
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              Integration of balance and strength training into daily life activity to reduce rate of falls in older people (the LiFE study): randomised parallel trial

              Objectives To determine whether a lifestyle integrated approach to balance and strength training is effective in reducing the rate of falls in older, high risk people living at home. Design Three arm, randomised parallel trial; assessments at baseline and after six and 12 months. Randomisation done by computer generated random blocks, stratified by sex and fall history and concealed by an independent secure website. Setting Residents in metropolitan Sydney, Australia. Participants Participants aged 70 years or older who had two or more falls or one injurious fall in past 12 months, recruited from Veteran’s Affairs databases and general practice databases. Exclusion criteria were moderate to severe cognitive problems, inability to ambulate independently, neurological conditions that severely influenced gait and mobility, resident in a nursing home or hostel, or any unstable or terminal illness that would affect ability to do exercises. Interventions Three home based interventions: Lifestyle integrated Functional Exercise (LiFE) approach (n=107; taught principles of balance and strength training and integrated selected activities into everyday routines), structured programme (n=105; exercises for balance and lower limb strength, done three times a week), sham control programme (n=105; gentle exercise). LiFE and structured groups received five sessions with two booster visits and two phone calls; controls received three home visits and six phone calls. Assessments made at baseline and after six and 12 months. Main outcome measures Primary measure: rate of falls over 12 months, collected by self report. Secondary measures: static and dynamic balance; ankle, knee and hip strength; balance self efficacy; daily living activities; participation; habitual physical activity; quality of life; energy expenditure; body mass index; and fat free mass. Results After 12 months’ follow-up, we recorded 172, 193, and 224 falls in the LiFE, structured exercise, and control groups, respectively. The overall incidence of falls in the LiFE programme was 1.66 per person years, compared with 1.90 in the structured programme and 2.28 in the control group. We saw a significant reduction of 31% in the rate of falls for the LiFE programme compared with controls (incidence rate ratio 0.69 (95% confidence interval 0.48 to 0.99)); the corresponding difference between the structured group and controls was non-significant (0.81 (0.56 to 1.17)). Static balance on an eight level hierarchy scale, ankle strength, function, and participation were significantly better in the LiFE group than in controls. LiFE and structured groups had a significant and moderate improvement in dynamic balance, compared with controls. Conclusions The LiFE programme provides an alternative to traditional exercise to consider for fall prevention. Functional based exercise should be a focus for interventions to protect older, high risk people from falling and to improve and maintain functional capacity. Trial registration Australia and New Zealand Clinical Trials Registry 12606000025538.

                Author and article information

                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                21 September 2022
                : 9
                : 996903
                [1] 1Department of Industrial Engineering, Alma Mater Studiorum - University of Bologna , Bologna, Italy
                [2] 2Medical Technology Lab, IRCCS Istituto Ortopedico Rizzoli , Bologna, Italy
                [3] 3European Medicine Agency , Amsterdam, Netherlands
                [4] 4Regulatory Affairs, Novartis Pharma AG , Basel, Switzerland
                [5] 5R&D, Regulatory Affairs, Bayer AG, Wuppertal, Germany
                [6] 6Department of Mechanical Engineering and Insigneo Institute for in Silico Medicine, University of Sheffield , Sheffield, United Kingdom
                [7] 7Insight Centre for Data Analytics, School of Public Health Physiotherapy and Sport Science, University College Dublin , Dublin, Ireland
                [8] 8ISGlobal , Barcelona, Spain
                [9] 9Departament de Ciéncies Experimentals i de la Salut, Universitat Pompeu Fabra , Barcelona, Spain
                [10] 10CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
                [11] 11Department of Geriatric Medicine, Robert Bosch Gesellschaft für Medizinische Forschung mbH , Stuttgart, Germany
                [12] 12Department of Neurology, University-Hospital Schleswig-Holstein, Kiel University , Kiel, Germany
                [13] 13Department of Rehabilitation Sciences, KU Leuven, Leuven and Pulmonary Rehabilitation, University Hospital Leuven , Leuven, Belgium
                [14] 14Pulmonary Rehabilitation, University Hospital Leuven , Leuven, Belgium
                [15] 15Department of Neuroscience and Sheffield NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals NHS Foundation Trust and University of Sheffield , Sheffield, United Kingdom
                [16] 16AstraZeneca R&D, Global Regulatory Excellence , Paris, France
                [17] 17Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne, United Kingdom
                Author notes

                Edited by: Lise Aagaard, Independent Researcher, Copenhagen, Denmark

                Reviewed by: Jiawei Chen, Air Force Hospital of Eastern Theater Command, China; Arunanshu Mahapatro, National Institute of Science and Technology, India

                *Correspondence: Marco Viceconti marco.viceconti@ 123456unibo.it

                This article was submitted to Regulatory Science, a section of the journal Frontiers in Medicine

                Copyright © 2022 Viceconti, Tome, Dartee, Knezevic, Hernandez Penna, Mazzà, Caulfield, Garcia-Aymerich, Becker, Maetzler, Troosters, Sharrack, Davico, Corriol-Rohou, Rochester and the Mobilise-D Consortium.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 18 July 2022
                : 01 September 2022
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 15, Pages: 8, Words: 5681
                Funded by: Horizon 2020 Framework Programme, doi 10.13039/100010661;
                Original Research

                digital mobility outcomes,regulatory qualification,mobility biomarkers,wearable sensors,mobility disability


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