PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0285807 PONE-D-23-05719 Research Article Biology and life sciencesBioengineeringBiotechnologyMedical devices and equipment Engineering and technologyBioengineeringBiotechnologyMedical devices and equipment Medicine and health sciencesMedical devices and equipment Medicine and health sciencesMental health and psychiatryDementiaAlzheimer's disease Medicine and health sciencesNeurologyDementiaAlzheimer's disease Medicine and health sciencesMedical conditionsNeurodegenerative diseasesAlzheimer's disease Medicine and health sciencesNeurologyNeurodegenerative diseasesAlzheimer's disease Science policyResearch integrityResearch ethics Computer and information sciencesData management Medicine and health sciencesMental health and psychiatryDementia Medicine and health sciencesNeurologyDementia Engineering and technologyEquipmentOptical equipmentCameras Computer and information sciencesSoftware engineeringComputer softwareApps Engineering and technologySoftware engineeringComputer softwareApps People and placesGeographical locationsEurope Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study Ethical challenges of using remote monitoring technologies for clinical research https://orcid.org/0000-0001-9397-4602 Muurling Marijn Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Visualization Writing – original draft Writing – review & editing 1 2 * Pasmooij Anna M. G. Writing – original draft Writing – review & editing 3 Koychev Ivan Investigation Resources Writing – review & editing 4 Roik Dora Investigation Resources Writing – review & editing 5 Froelich Lutz Investigation Resources Writing – review & editing 5 Schwertner Emilia Investigation Resources Writing – review & editing 6 7 Religa Dorota Investigation Resources Writing – review & editing 6 8 Abdelnour Carla Investigation Resources Writing – review & editing 9 https://orcid.org/0000-0003-2617-3009 Boada Mercè Investigation Resources Writing – review & editing 10 11 Almici Monica Investigation Resources Writing – review & editing 12 Galluzzi Samantha Investigation Resources Writing – review & editing 12 Cardoso Sandra Investigation Resources Writing – review & editing 13 de Mendonça Alexandre Investigation Resources Writing – review & editing 13 Owens Andrew P. Investigation Resources Writing – review & editing 14 Kuruppu Sajini Investigation Resources Writing – review & editing 14 https://orcid.org/0000-0002-8762-3109 Gjestsen Martha Therese Investigation Resources Writing – review & editing 15 Lazarou Ioulietta Investigation Resources Writing – review & editing 16 Gkioka Mara Investigation Resources Writing – review & editing 17 Tsolaki Magda Investigation Resources Writing – review & editing 17 Diaz Ana Writing – review & editing 18 Gove Dianne Writing – review & editing 18 Visser Pieter Jelle Funding acquisition Project administration Supervision Writing – review & editing 1 2 6 19 Aarsland Dag Funding acquisition Project administration Supervision Writing – review & editing 14 15 Lucivero Federica Conceptualization Data curation Formal analysis Investigation Methodology Visualization Writing – original draft Writing – review & editing 20 de Boer Casper Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Supervision Visualization Writing – original draft Writing – review & editing 1 2 the RADAR-AD Consortium Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands Dutch Medicines Evaluation Board, Utrecht, Netherlands Department of Psychiatry, University of Oxford, Oxford, United Kingdom Department of Geriatric Psychiatry, Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany Division of Clinical Geriatrics, Department of Neurobiology, Department of Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Faculty of Psychology, SWPS University of Social Sciences and Humanities, Krakow, Poland Theme Inflammation and Aging, Karolinska University Hospital, Huddinge, Sweden Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States of America Ace Alzheimer Center Barcelona–Universitat Internacional de Catalunya, Barcelona, Spain Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain Laboratory Alzheimer’s Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway Information Technologies Institute, Center for Research and Technology Hellas (CERTH-ITI), Thessaloniki, Greece Laboratory of Neurodegenerative Diseases, Center for Interdisciplinary Research and Innovation (CIRI–AUTh), Balkan Center, Aristotle University of Thessaloniki, Thessaloniki, Greece Alzheimer Europe, Luxembourg, Luxembourg Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Ethox and Welcome Centre for Ethics and Humanities, University of Oxford, Oxford, United Kingdom Chu Dinh-Toi Editor International School, Vietnam National University, VIET NAM

The authors have read the journal’s policy and have the following competing interests: IK is a paid medical advisor for digital healthcare technology companies Five Lives SAS and Cognetivity Ltd., outside the submitted work. CA has received honoraria as speaker from F. Hoffmann-La Roche Ltd, Zambon, Nutricia, Schwabe Farma Ibérica S.A.U, outside of the submitted work. CA is a member of the Board of Directors of the Lewy Body Dementia Association, outside the submitted work. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics, outside the submitted work. MB is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist. There are no patents, products in development or marketed products associated with this research to declare.

¶ Membership of the RADAR-AD Consortium is listed in the Acknowledgments.

 * E-mail: m.muurling@amsterdamumc.nl 7 7 2023 2023 18 7 e0285807 27 2 2023 2 5 2023 2023 Muurling et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction

Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer’s disease, and what gaps remain.

 Methods

Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse–Alzheimer’s Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach.

 Results

Four main themes emerged after analysis: data management, participant’s wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites.

 Discussion

The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.

 http://dx.doi.org/10.13039/501100010767 Innovative Medicines Initiative 806999 Stichting Alzheimer Nederland Stichting VUmc fonds National Institute of Health Research Koychev Ivan Medical Research Council (Dementias Platform UK Grant) Koychev Ivan Susan and Charles Berghoff Foundation Abdelnour Carla The RADAR-AD project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806999. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Software AG. See https://www.imi.europa.eu/ for more details. This communication reflects the views of the RADAR-AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. IK declares support for this work through the National Institute of Health Research (personal award and Oxford Health Biomedical Research Centre) and the Medical Research Council (Dementias Platform UK grant). CA’s postdoctoral fellowship is funded by the Susan and Charles Berghoff Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability The data are confidential documents from the local ethical committees. We can share the data upon reasonable request via radar.ad@amsterdamumc.nl. Introduction

Digital devices, data analytics and artificial intelligence are rapidly changing the way clinical research is conducted, as a variety of aspects of people’s health and lifestyle can be collected in real-time and patterns in large datasets can be identified. Remote monitoring technologies (RMTs), such as wearables, smartphone applications, and fixed sensors at home can capture real-world information about study participants in a continuous and objective manner. RMTs therefore have several potential advantages over in-clinic pen-and-paper tests that are usually assessed periodically, rely on the participant’s or partner’s recall and can only be completed in a controlled environment of the clinic [1]. Such advantages of RMTs are especially helpful in health conditions with a long preclinical phase, such as Alzheimer’s disease (AD) [2, 3], or recurring episodes, such as depression [4]. However, while RMTs open new opportunities for clinical research, the use of digital technologies also raises new questions for research ethics, including obvious concerns regarding privacy and data security [5, 6]. Moreover, although participants consent to participate in the study, it is almost impossible to inform participants completely, simply and clearly about what types of data are being collected, who can access the data and how the data will be analyzed [7, 8]. Another important concern is equality, meaning that people who do not own a smartphone–whether for economic, educational or geographical reasons–will have limited possibilities to participate in RMT research with consequences for reliability and generalizability [9].

While several studies have addressed the issue of governance of big data in clinical research from the legal perspective [10–12] or ethical perspective [13–16], the perspective of institutional research ethics committee (REC) members is underrepresented in the current body of literature [17]. Research ethics committees (RECs) enforce research governance through a review mechanism, reviewing the study design and protocols, inclusion and exclusion criteria for participants, informed consent procedures and data safety, management and monitoring plans. The composition of RECs is diverse, so that a comprehensive set of perspectives is considered. Variation in how research governance practices are enforced across different institutions and countries participating in multi-site studies is a concern. With the introduction of novel technologies for data collection and analysis, such as RMTs, the role of the RECs becomes central in assessing the legitimate, fair, and ethical use of those technologies in research settings. To this end, we must better understand the ‘needs, views and attitudes’ of REC members wherever health-related RMTs are used as a source of ‘big data’ in research [17]. This study addresses this knowledge gap by studying the views of REC members in the context of a large pan-European study on remote monitoring in AD [2], using a qualitative analysis approach. This paper explores the type of issues that are currently highlighted by RECs, how they are addressed within a project, what gaps remain and provide suggestions on how these gaps may be addressed. We describe the specific challenges raised by RECs using examples from the European research project Remote Assessment of Disease and Relapse–Alzheimer’s Disease (RADAR-AD) [2], which aims to validate how RMTs assess functional decline in AD. Since the RADAR-AD study protocol is implemented in 10 European countries, this material gives us an opportunity to compare ethical questions across European countries.

 Materials and methods

The RADAR-AD study (www.radar-ad.org) is a European multi-center observational study, aiming to find and validate remote monitoring technologies that measure functional and cognitive decline in AD [2]. This study included over 220 participants, equally distributed in four study groups: healthy controls, preclinical AD, prodromal AD, and mild-to-moderate AD participants. Participants visited the clinic at the start of the data collection period and were thereafter monitored in the real-world for eight weeks, using the RMTs presented in Table 1. RADAR-AD identified these RMTs based on an elaborate literature study and asking patients [18] and only used RMTs that were already publicly available. No data safety monitoring board (DSMB) was installed during the study, as the risk assessment of the sponsor (Amsterdam UMC) showed that overall risks were low.

10.1371/journal.pone.0285807.t001 Remote monitoring technologies in the RADAR-AD protocol.
RMT Description Usage Assesses
Fitbit charge 3 A wrist-worn activity tracker At home, measures continuously for 8 weeks Heart rate, step count and sleep patterns
Axivity AX3 A wrist-worn activity tracker [19] At home, measures continuously for 8 weeks Activity and sleep patterns
RADAR passive RMT app An Android-based smartphone application that passively collects data on phone usage [20] At home, measures continuously for 8 weeks Phone usage, surroundings, location
Autographer wearable camera A camera which is worn around the neck and takes a photo every 20 seconds. The use of the camera is optional [21] At home, three times 2 consecutive days (self-chosen by the participant) Activities of daily living
Mezurio app A smartphone application presenting daily cognitive tasks and short questionnaires [22, 23] At home, twice per day for 8 weeks Planning skills, memory, keyboard dynamics, language sleep quality and mood
Altoida app A smartphone and tablet based application that simulates a complex activity of daily living using augmented reality [24] Once at the clinic and weekly at home Spatial navigation, memory, functional impairment, and motor functions
Gait up Physilog sensors Three body-worn sensors containing accelerometers and gyroscopes during three short walk tests [25] Once in the clinic Gait
Banking app An application simulating a bank withdrawal [26] Once in the clinic Functional abilities of managing finances
Data collection

Documents describing the REC review process at ten RADAR-AD study sites were collected for analysis. These sites included clinical academic sites specializing in brain health and dementia in Amsterdam (The Netherlands), Barcelona (Spain), Brescia (Italy), Lisbon (Portugal), London and Oxford (United Kingdom), Mannheim (Germany), Stavanger (Norway), Stockholm (Sweden) and Thessaloniki (Greece) (Table 2). RECs operated either on a site-specific, region-specific, or country-specific level (Table 2), meaning that that particular REC reviews studies from that site only, from several sites in that region, or from sites in the entire country, respectively. Amsterdam UMC (Amsterdam site) was the sponsor of the study and therefore coordinated the clinical study. The other RADAR-AD sites (see Muurling, de Boer [2]) had not yet obtained ethical approval yet by the time of writing, mainly due to legal contract issues, and were therefore excluded from the current study. The REC process for King’s College London and University of Oxford was centralized and was therefore analyzed as one. These documents included, but were not limited to, primary REC submission documents, feedback on the submission from RECs, response letters to feedback from RECs, and correspondence between local study teams and RECs, Data Protection Officers (DPO’s), and scientific review boards (More detailed information in S1 Table). Documents were anonymized and translated into English by local study teams. At each RADAR-AD study site, written permission was obtained from the REC to use direct anonymized quotes for publication.

10.1371/journal.pone.0285807.t002 The participating sites and the REC that approved the study.
Country City Institution REC Level
Germany Mannheim Zentralinstitut für Seelische Gesundheit Mannheim Ethics Committee II of the Ruprecht-Karls-University of Heidelberg (Medical Faculty Mannheim) Site-specific
Greece Thessaloniki Aristotle University of Thessaloniki Ethics Committee of Medical Faculty of Aristotle University of Thessaloniki and Ethics Committee of Alzheimer Hellas Site-specific
Italy Brescia IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Comitato Etico IRCCS Centro San Giovanni di Dio–Fatebenefratelli di Brescia Site-specific
Norway Stavanger Centre for Age-Related Medicine Regionale komiteer for medisinsk og helsefaglig forskningsetikk Region-specific
Portugal Lisbon Faculdade de Medicina da Universidade de Lisboa Comissão de Ética do Centro Académico de Medicina de Lisboa Site-specific
Spain Barcelona Ace Alzheimer Center Barcelona Drug Research Ethics Committee (CEIm) of Universitat International de Catalunya Site-specific
Sweden Stockholm Karolinska Institutet Swedish Ethical Review Authority Country-specific
The Netherlands Amsterdam Amsterdam UMC Medisch Ethische Toetsingscommissie VUmc Site-specific
United Kingdom Oxford University of Oxford London–West London & GTAC (Gene Therapy Advisory Committee) Research Ethics Committee Region-specific (REC gets randomly allocated across the country)
London King’s College London

Note. Last column: RECs operated either on a site-specific, region-specific, or country-specific level, meaning that that particular REC reviews studies from that site only, from several sites in that region, or from sites in the entire country, respectively.

 Data analysis and paper drafting

The translated REC documents were imported into Atlas.ti version 9 [27], a software package for qualitative analysis of research documents. Following thematic analysis methods [28], main authors FL, CdB and MM read a predefined subset of the documents independently and formulated a deductive codebook based on an internal discussion on emerging issues in the study documents and issues highlighted in existing literature. FL, CdB, and MM independently coded a subset of the study documents using the agreed codebook, while adding codes inductively when necessary [29]. New codes and emerging themes were discussed in subsequent meetings. At last, MM reviewed all coded documents to harmonize the coding.

The main findings were drafted based on the primary analysis by FL, CdB, and MM and submitted to all co-authors together with several discussion points. A larger meeting was organized to discuss the findings and a first draft of the discussion was drafted by FL, CdB and MM. This draft was circulated among co-authors who further contributed to it. All co-authors agreed to the final version of the manuscript.

 Results

The analysis of the documents highlighted the diversity of the REC review process as well as four emerging types of issues that we clustered in four categories: data management, participant’s wellbeing, methodological issues, and definition of the devices. Code frequencies are available in Table 3, while code descriptions and exemplary quotes are listed in Tables 4–7.

10.1371/journal.pone.0285807.t003 Code frequencies per site.
Totals Centre for Age-Related Medicine (Stavanger) IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia) Zentralinstitut für Seelische Gesundheit Mannheim (Mannheim) King’s College London (London) / University of Oxford (Oxford) Karolinska Institutet (Stockholm) Ace Alzheimer Center Barcelona (Barcelona) Faculdade de Medicina da Universidade de Lisboa (Lisbon) Amsterdam UMC (Amsterdam) Aristotle University of Thessaloniki (Thessaloniki)
N N % N % N % N % N % N % N % N % N %
Data management
Data access 3 1 14.3% 0 0.0% 0 0.0% 1 7.7% 0 0.0% 0 0.0% 0 0.0% 1 2.9% 0 0.0%
Data protection 16 0 0.0% 2 50.0% 9 39.1% 0 0.0% 0 0.0% 1 20.0% 0 0.0% 4 11.4% 0 0.0%
Data security 10 1 14.3% 1 25.0% 1 4.3% 1 7.7% 3 12.5% 0 0.0% 0 0.0% 3 8.6% 0 0.0%
Data sharing 6 1 14.3% 0 0.0% 2 8.7% 3 23.1% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Data storage 6 3 42.9% 0 0.0% 1 4.3% 1 7.7% 1 4.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Participant’s wellbeing
Comfort 3 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 8.3% 1 20.0% 0 0.0% 0 0.0% 0 0.0%
Competence 4 0 0.0% 0 0.0% 1 4.3% 1 7.7% 0 0.0% 1 20.0% 0 0.0% 1 2.9% 0 0.0%
Incidental findings 4 0 0.0% 0 0.0% 0 0.0% 2 15.4% 1 4.2% 0 0.0% 0 0.0% 1 2.9% 0 0.0%
Privacy 14 1 14.3% 1 25.0% 4 17.4% 1 7.7% 5 20.8% 0 0.0% 0 0.0% 2 5.7% 0 0.0%
Proportionality 7 0 0.0% 0 0.0% 0 0.0% 0 0.0% 4 16.7% 0 0.0% 1 20.0% 2 5.7% 0 0.0%
Resistance 1 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 2.9% 0 0.0%
Safety 5 0 0.0% 0 0.0% 1 4.3% 0 0.0% 4 16.7% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Stigmatisation 0 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Methodological issues
Liability 4 0 0.0% 0 0.0% 1 4.3% 0 0.0% 0 0.0% 0 0.0% 1 20.0% 2 5.7% 0 0.0%
Methodological concerns 21 0 0.0% 0 0.0% 1 4.3% 2 15.4% 3 12.5% 1 20.0% 2 40.0% 12 34.3% 0 0.0%
Recruitment 5 0 0.0% 0 0.0% 0 0.0% 1 7.7% 1 4.2% 0 0.0% 1 20.0% 2 5.7% 0 0.0%
Definition of the devices
Medical devices 7 0 0.0% 0 0.0% 2 8.7% 0 0.0% 0 0.0% 1 20.0% 0 0.0% 4 11.4% 0 0.0%
Totals 116 7 100% 4 100% 23 100% 13 100% 24 100% 5 100% 5 100% 35 100% 0 100%

Number of times a theme was mentioned in the ethics review documents from that particular REC, as absolute number (n) and percentage per site (%), clustered on themes. Darker green indicates higher percentages.

 10.1371/journal.pone.0285807.t004 Issues raised about data management.
Code Description Example quote Number of sites
Data access Describes issues related to who has access to the data during and within the study ‘How is privacy guaranteed? Support of IT personnel is possibly needed to install the app, downloading data from the RMTs and/or prevent malfunction, so that there is a chance that IT personnel sees sensitive information. Is a confidentially and/or processing agreement formalized?’ 3
Data protection Is used when explicit reference to General Data Protection Regulation (GDPR) or other data protection regulations is made ‘Provide an assessment of impact on the protection of data, which guarantees compliance with the GDPR and the additional provision XVII of the Organic Law 3/2018 of December 5, of personal data protection and guarantee of the digital rights that are collected from the smartphone application ‘Mezurio’, the photographs captured by the camera ‘Autograph’, the application ‘RADAR-base’ and the devices ‘Fitbit charge 3’ and ‘Axivity AX3.’ 4
Data security Is used when there is an explicit reference to data security, in contrast to the code ‘safety’, which is used for participant’s safety only. ‘Banking app: how is data secured? How is abuse and accusation of abuse prevented?’ and ‘It should be informed that participants agree to the data being stored at Fitbit. The information sheets should address what this entails. Here you should seek advice from the data protection officer.’ 6
Data sharing Describes issues regarding third parties using the data, i.e., parties that are not related to the project. ‘Make it clearer in the participant information sheets […] that only anonymized data will be made available to RADAR-AD sites/organizations outside the confines of the study itself.’ and ‘If the planned data recipients were persons and companies based outside the EU (in particular the USA), the data transfer would only be permissible under the conditions of the EU GDPR.’ 3
Data storage Describes issues regarding storing data, for example sufficient storing capacity, storage duration and the storage place. ‘It must be stated that data will only be analyzed until the end of the project. After the end of the project, it is allowed to store data for 5 years, but only for follow-up.’ and ‘In the event of revocation, all data must be deleted if they are not anonymized.’ 4
10.1371/journal.pone.0285807.t005 Issues raised about participant’s wellbeing.
Code Description Example quote Number of sites
Comfort Refers to the concern that participants could experience mental or physical discomfort during the study. ‘Neuropsychological tests can be tiring. The remote measurement techniques must be used every day, which can lead to discomfort […].’ 2
Competence Describes issues regarding participant’s (mental and physical) ability to participate in the study. ‘In this study, can all study participants be considered mentally competent?’ 5
Incidental findings Refers to issues related to finding unexpected (medical) outcomes during the study procedures. This code applies both to unexpected cognitive or medical findings and illegal activities. ‘What happens when a healthy control subject has similar scores on the study tests as an Alzheimer subject?’, and ‘if the images [of the wearable camera] show illegal activities, according to national law, the researcher may have a legal and professional obligation to breach confidentiality and pass on image data to appropriate authorities.’ 4
Privacy Describes concerns regarding the privacy of the participant and their environment during data collection, including privacy of partners or bystanders. ‘How are the researchers planning to deal with the privacy of bystanders whose images are being recorded while the study subject wears the camera?’, ‘How is the privacy and data-protection of study subjects safeguarded on the RADAR-base platform?’, or ‘Statements made by the caregiver about the patient may not be used and processed without the patient’s consent.’ 6
Proportionality Is used to describe concerns about asking participants too much. ‘The study protocol states that study partners also have to install the RADAR-base app on their smartphone. Please justify why this is necessary.’ 3
Resistance Describes references to participants being suspicious or resisting the study. ‘How is patient confusion/suspicion prevented; how is resistance of the patient handled?’ 1
Safety Is used when there are concerns that a device or participation in the study could jeopardize participant’s safety. This does not include data safety, but a participant’s physical and mental wellbeing only. ‘[…] wearing cameras in everyday situations can potentially be associated with a certain risk. […] Possible scenarios include the following: the participant is questioned by (potentially hostile or suspicious) third parties objecting to unwanted image recording, thus posing a threat to the participant’s safety.’ 2
10.1371/journal.pone.0285807.t006 Issues raised about methodology.
Code Description Example quote Number of sites
Methodological concerns Concerns related to study objectives, study design, outcome measures, data analyses (statistical analysis) or the choice of a certain RMT, without explicit reference to a specific ethical issue. ‘There is a high chance of incorrect or missing data. How will be dealt with this statistically?’, ‘Do control subjects also need a study partner? If yes, please explain why.’, or ‘Please provide a clear study objective, describing what is being sought in respect of each participant group in respect of assessing the feasibility of the remote technologies in each group.’. 6
Recruitment Describes issues related to recruitment of participants in the study. ‘Please provide a clear recruitment process of the three groups of participants, explaining how they will be identified, approached and consented into the study.’ 4
Liability Refers to issues of responsibility or liability, related to the use of medical devices, data management, patient safety, or other. ‘Who has liability when a device gets lost or suffers damage while in the possession of a study subject?’ 4
10.1371/journal.pone.0285807.t007 Issues raised about definition of the devices.
Code Description Example quote Number of sites
Medical devices Refers to issues regarding the question if the remote monitoring technologies used in the study should be defined as medical devices. ‘The researchers indicate that this study does not include medical devices because the technological devices in this study are not used for diagnosis, treatment, or alleviation of disease symptoms. However, the committee needs to be further convinced of this and therefore the committee has some questions about the technological devices.’ 3

Fig 1 describes the duration of the REC review process at 10 different RADAR-AD study locations. More detailed information on the review processes can be found in the S1 Table. At all study locations, the same research protocol was submitted to the REC. The duration of the REC process, i.e., from primary submission to obtaining approval, differed significantly across the consortium. The fastest approval was obtained in Faculdade de Medicina da Universidade de Lisboa (Lisbon site, 71 days), while the longest approval process took place in Karolinska Institutet (Stockholm site, 423 days). The average duration of the REC process was 232 (SD 145) days. Most study sites (5 out of 9) received one round of comments before REC approval was obtained. One study site (Aristotle University of Thessaloniki, Thessaloniki site) obtained direct approval after the primary submission, while Amsterdam UMC (Amsterdam site) and Karolinska Institutet (Stockholm site) had to go through 4 rounds to obtain approval. In 5 out of 9 study locations, the protocol also required approval from a Data Protection Officer (DPO) (S1 Table). In Amsterdam UMC (Amsterdam site), additional approval had to be obtained from an independent scientific board and the institution’s Information Technology (IT) department. Also, in the Centre for Age-Related Medicine (Stavanger site), the study could not start until the institution’s IT-department had approved the RMTs used.

10.1371/journal.pone.0285807.g001 Duration in days of the REC process per site.

Blue blocks indicate the REC review, while orange blocks indicate the preparation of the response. The long preparation of response time in Amsterdam (second orange block) was because the REC requested approval from the IT department after the second REC review round, which resulted in several months waiting time. More detailed information can be found in the S1 Table.

All RECs were concerned about several issues related to data management, such as data access, data security, data sharing, data storage, and data protection (Table 4), except for the sites in Lisbon and Thessaloniki. These issues represented most of the expressed concerns. In Amsterdam UMC (Amsterdam site), and the Centre for Age-Related Medicine (Stavanger site), the security of the apps, devices and data platform had to be checked by a specialized IT security department. Data security was often intertwined with data sharing, data storage and data protection issues, for example: ‘The REC requests that [Sites name]’s routines will be followed for secure data collection, data transfer and data storage, and that one contacts the data protection officer at [Sites name] for guidance.’ Regarding data protection, the REC suggested that most sites seek the advice of a DPO to check data protection. The use of the wearable camera during the RADAR-AD study was often mentioned in relation to the data protection issues. Faculdade de Medicina da Universidade de Lisboa (Lisbon site), and IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia site) decided to submit the protocol without the wearable camera in the first place. The other sites submitted the protocol with the wearable camera, but based on the REC comments, Zentralinstitut für Seelische Gesundheit Mannheim (Mannheim site), Ace Alzheimer Center Barcelona (Barcelona site), and Karolinska Institutet (Stockholm site) decided to omit the wearable camera from the protocol: ‘Uninvolved passers-by/shop visitors/staff etc. are permanently recorded every 30 seconds in public space, without them being able to be informed in time about the circumstance of the recording, e.g. in order to avoid it. After all, the people concerned are not simply photographed, but stored in a database for a research project. […] In any case, the personal rights of those concerned […] are considerably affected by recordings.’ In the other sites, the use of the wearable camera was allowed.

Another set of issues raised by RECs focused on the participant’s wellbeing (Table 5). As research participants were actively involved in the study for 56 days, RECs raised concerns about several issues related to ensuring that they were comfortable and safe and that their privacy was preserved. Another concern was participant’s competence and capacity: most of the comments were related to participants being mentally capable providing informed consent, considering that the study was carried out in a population of dementia patients, for example: ‘The Ethics Committee points out that the study may only be carried out in patients who are capable of giving consent. As soon as there are doubts about the capacity to consent, care must be suggested if necessary.’ The REC of Karolinska Institutet (Stockholm site) initially rejected the study protocol because of proportionality: ‘The potential benefits for future individuals with early dementia appear unclear. As the risks (significant breach of privacy) for the participants are thus not outweighed by the benefit, the application is rejected’. To obtain approval, major changes were made to the protocol, i.e., the wearable camera and several questionnaires and clinical tests were omitted from the protocol.

Methodological issues concerning the design of the study and the responsibilities of each partner were also frequently addressed. Three sub-themes were found: methodological concerns, recruitment, and liability (Table 6). Particularly on recruitment, major differences between study sites were identified, for example: ‘Please provide a clear recruitment process of the three groups of participants, explaining how they will be identified, approached and consented into the study.’ These differences backtracked mainly to the discussion of biological versus clinical definition of AD, i.e., the use of the pathology marker assessments in symptom free individuals. As a result of these discussions, Faculdade de Medicina da Universidade de Lisboa (Lisbon site), and Zentralinstitut für Seelische Gesundheit Mannheim (Mannheim site) decided not to recruit pre-symptomatic individuals into the study.

Finally, RECs raised concerns regarding the definition of the devices used in the study. Initially, the protocol was submitted to each REC with the conviction that the RMTs were no medical devices. However, whether the used RMTs should be classified as medical devices (Table 7) was a major issue in Amsterdam UMC (Amsterdam). Medical devices are products or equipment intended for a medical purpose, for example for diagnosis, prevention, monitoring, prediction, prognosis, treatment or allevation of a disease (European Union Medical Device Regulation (EU no 2017/745), MDR). If devices are classified as medical devices, researchers need to follow specific rules for the submission, assessment and conduct of clinical research using the devices, which are described in the MDR. In the end, the Amsterdam REC was convinced that the RMTs were medical devices: ‘The committee is of the opinion that these devices are medical devices, because the devices are used for scientific research with patients with or suspected of having AD, in order to determine the clinical and technical performances and the acceptance of the various devices and thereby the association of the outcome measures with clinical measures for AD.’. All other sites did not mention the MDR or considered the RMTs as no medical devices after review.

 Discussion

The main goal of this study was to identify the views and concerns of multiple local RECs across Europe and what gaps remain regarding the use of RMTs in clinical research on Alzheimer’s disease through a case study of the RADAR-AD project. The main findings were that on one hand generic concerns were raised around data, participants, methodology, and medical devices, while on the other hand the specific focus of concerns differed significantly across study sites. These differences have led to major variance regarding the duration of the approval process, as well as the way the study protocol was implemented. Below, we highlight the major differences and discuss practical considerations regarding the REC approval process on RMT related study protocols.

Themes

The issues that emerged in the RADAR-AD research ethics process were as expected based on previous literature [30] and can be categorized according to the distinction made by Ienca, Vayena [30] referring to the governance of big data health research. In fact, issues around data fall in their description of “technical” issues, issues about participant’s wellbeing are “social issues”, issues about study set up are “methodological”, and concerns around definition of the devices are “regulatory” in nature. We did not single out ethical issues as each one of these categories were imbued by ethical principles, but privacy was a frequent concern, together with a worry about proportionality of the benefits of the study against the burden imposed on participants.

 Lack of harmonization

More interestingly were the issues that emerged in the comparison of the different processes and the differences between the RECs. As our data was gathered from RECs in different institutions and different European countries, some of the diversity in the responses is due to the lack of harmonization around ethical standards to assess studies in this remit.

The lack of harmonization around evaluative standards can be highly dysfunctional for an international multi-site project. A point in this case is the original rejection of the project by the REC of the Karolinska Institutet (Stockholm site), that resulted in a 1.5 years long approval process when the protocol was finally approved with major changes to the original one. This meant that the data collected by this site was less comparable to the data collected by other sites.

The issue of harmonization is key in health research fields, such as AD, where international multi-site projects are prioritized by funders. Although there are good reasons why some local differences are kept to address cultural differences, harmonizing the process is an important requirement as it saves resources for large research consortia and assures protocol consistency and a sharing of best practices. This lack of harmonization was already found in 2005 in a study involving dementia patients [31], and appears to be unchanged since then.

For example, we saw that in some cases (e.g., Amsterdam UMC), the REC was not the only governance body in charge of assessing the study, and the DPO was also involved in the process. Considering the importance of harmonized interpretation of the General Data Protection Regulation (GDPR), a key area of expertise of a DPO, we found that the involvement of DPO in the approval process of study protocols that involve RMT measurements was highly beneficial. DPOs are key in assessing the data vulnerability of remote assessments, and can provide researchers with important insights on this topic which may not necessarily be provided by an REC. Based on this experience, we suggest that DPOs are involved early in the design of RMT based projects, preferably before the submission of the protocol to the REC, which might even shorten approval duration. Interesting to notify though, was that the interpretation of the DPOs consulted for this study was not similar for all sites. For example, the wearable camera was not approved in the site in Mannheim, after consultation of the DPO, while the camera was approved in the site in Amsterdam, after consultation of the DPO, although both sites are in the European Union and should therefore both adhere to the GDPR.

Another example of lack of harmonization, within the context of AD, is an important difference between countries and institutions concerning the use of biomarker data in asymptomatic individuals. This point concerns rather the view of Alzheimer’s disease in general instead of issues with RMTs, but it is still an important example of how the view of RECs differs between countries. Within RADAR-AD, several RECs raised serious concerns regarding the inclusion of a so-called ‘preclinical AD’ group, i.e., individuals without cognitive complaints but with positive AD biomarkers. The preclinical AD group raises the issue of defining healthy and cognitively normal participants as ‘having AD’, while there is no treatment or certainty that these participants will develop cognitive impairment in the future. Preclinical AD is a widely accepted study group in research [32], but is not used in clinical practice, due to this lack of treatment and uncertainty of progression. In our view, RECs refusing to include preclinical AD in a clinical study are therefore withholding from an important step forward in clinical trials for AD. This issue is not likely to be reconciled easily, as this relates to epistemic and normative differences in the biological versus clinical view of AD as a disease entity [32]. We do recommend that these scientific differences are acknowledged and discussed by researchers in their applications to enable RECs to understand the rationale behind the study design.

The last issue that would benefit from harmonization is the interpretation of the definition of the used RMTs. If RMTs are classified as medical devices, they should apply to the European MDR, which requires more paperwork and rules to adhere to. Although all participating sites in this study are in the European Union (except the site in Geneva, Switzerland), and thus should adhere to the same rules and regulations regarding GDPR and MDR, the RECs decided differently on the definition of the RMTs: in the Amsterdam site, the RMTs were considered medical devices, while the other sites considered the RMTs as no medical devices. On the one hand, the RMTs are used to monitor disease symptoms, and can therefore be considered medical devices, but on the other hand, the RMTs in RADAR-AD are used for research purposes only and will not be used to diagnose, treat, or alleviate disease symptoms. The Clinical Trial Information System (CTIS), starting January 31st, 2023, is a central portal from the European Medicines Agency (EMA) to coordinate the submission of drug trials on a European level, which might help in the harmonization of REC decisions within a multi-site study, at least within a study.

 Involvement of patient advisory board

RECs and DPOs should not be the only bodies assessing research using mobile sensors on vulnerable populations. As suggested by Breslin et al. [15], the specific groups and communities who are part of the research should be involved in discussing and addressing the ethical issues and concerns. This is of particular importance in the case of vulnerable groups and for some conditions, such as dementia, where preconceptions and stereotypes about people living with the disease still prevail. The RADAR-AD project set up a Patient Advisory Board (PAB), composed of people with mild cognitive impairment, people with dementia and caregivers, which was operational from the very start of the project and provided valuable input throughout the whole research process. For example, the PAB provided input on the study protocol, participant-facing documents, device selection [33], recruitment, challenges encountered during the COVID pandemic and various ethical issues. The new clinical trials regulation (Regulation (EU) No 536/2014), requires RECs to include a patient representative, which is a start, but remains difficult with dementia patients. Although the PAB was not directly involved in the process of obtaining ethical approval from the RECs, some of the concerns and issues raised by members of the PAB resonated with those raised by the RECs. However, many of these issues and concerns were discussed in a more nuanced way, often seeking a balance between respect for autonomy and non-maleficence, and reflecting on issues such as personhood, stigma, trust, and equity, though it is noteworthy that concerns about aptitude and capacity to use RMTs was not of concern. This led to ideas to address specific concerns and thereby support future participants. In relation to the consent of participants with dementia, for example, the PAB emphasized the importance of supported decision making and a dynamic ongoing consent process as opposed to a more rigid, one-stop consent procedure. Similarly, they proposed the wearable camera being optional, and to provide participants with a card explaining how people’s images would be protected and with details of the study in case anyone being photographed asked. With regard to study partners, they also questioned the need for healthy control participants to have them. In addition, they challenged the assumption that all participants with mild cognitive impairment or dementia would need one, accepting nevertheless a principle of equality but with concerns about discrimination against people who live alone, further suggesting the need to consider alternatives such as volunteer study partners.

The differences between the PAB and REC perspectives and concerns are not surprising given that RECs are almost entirely composed of professionals who tend to have a more precautionary approach. These differences raise questions about how to balance the enthusiasm, dedication and problem-solving approach of people with the condition (i.e., to make research better by sharing their experience and perspectives with researchers, focusing on what is still possible and exercising their right to voice) with the more protection/liability-based approach of many RECs. The differences also emphasize the need for greater exchange and communication between lay- and expert governance structures in medical research, particularly in research using remote monitoring technologies where the active involvement of people affected by the condition in the study design is central. How such exchange and communication can be implemented in context where patients’ expertise is valued alongside professional assessment of potential vulnerabilities and risks for participants should be the focus of further research.

 Internal ethics during the study

Another aspect to consider is that although the study methodology at large has been questioned by some REC reviews (e.g. Amsterdam UMC), none of the REC reviews received by RADAR-AD sites questioned the ethics support within the project. Research projects often have a dedicated space for ethics research that is expected to strengthen the legitimacy and social desirability of the project, however the internal ethics structure is not considered as compulsory information for REC applications and, in the case of the RADAR-AD project was not questioned. However, experience has shown that ethics support should be an integral part throughout a project rather than a one-off consideration when seeking ethical approval [34]. The medical ethics model, where ethics committees are called upon to discuss complex cases is relevant here. There have been many studies and experiments in these areas [35], but this is not a requirement by funding organizations or by research governance bodies. Especially in a context where innovative technologies are used that disrupt the traditional way of conducting research, it is important to further develop feasible and sustainable ways of building ethical support into the project.

 Limitations

An important limitation for the current study is that the data used, i.e., communications with RECs and DPOs on the RADAR-AD study protocol, was not originally collected as such. Neither did the consortium plan to use these communications for study purposes. We therefore did not collect additional data such as interviews with REC members to better understand their points and considerations. Future research should include interviews or focus groups with REC members to better understand their views on the topics discussed in this discussion, i.e., the involvement of the DPO and PAB, interpretation of the MDR, and internal ethics. At the same time, the material already offered an interesting insight into REC procedures and concerns towards these types of projects.

 Conclusion

To conclude, this study highlights the generic concerns raised by RECs regarding data, participants, methodology, and governance of clinical research protocols using RMTs, while important differences in the view of RECs remain present. As these differences may have important practical consequences, which could lead to significant delays in the approval process, we highly recommend a further harmonization on and further research to specific elements of the approval process. This includes, but is not limited to, the involvement of data protection officers, patient advisory boards, and ethics support. As these are complicated matters, routes towards harmonization should be initiated on a national or even European level.

 Supporting information Details of the documents reviewed for this study and review processes in each site.

(DOCX)

We would like to acknowledge and thank the members of the RADAR-AD Patient Advisory Board for their input to the work described in this article. We thank all past and present RADAR-AD consortium members for their contribution to the project (in alphabetical order): Dag Aarsland, Halil Agin, Vasilis Alepopoulos, Alankar Atreya, Sudipta Bhattacharya, Virginie Biou, Joris Borgdorff, Anna-Katharine Brem, Neva Coello, Pauline Conde, Nick Cummins, Jelena Curcic, Casper de Boer, Yoanna de Geus, Paul de Vries, Ana Diaz, Richard Dobson, Aidan Doherty, Andre Durudas, Gul Erdemli, Amos Folarin, Suzanne Foy, Holger Froehlich, Jean Georges, Dianne Gove, Margarita Grammatikopoulou, Kristin Hannesdottir, Robbert Harms, Mohammad Hattab, Keyvan Hedayati, Chris Hinds, Adam Huffman, Dzmitry Kaliukhovich, Irene Kanter-Schlifke, Ivan Koychev, Rouba Kozak, Julia Kurps, Sajini Kuruppu, Claire Lancaster, Robert Latzman, Ioulietta Lazarou, Manuel Lentzen, Federica Lucivero, Florencia Lulita, Nivethika Mahasivam, Nikolay Manyakov, Emilio Merlo Pich, Peyman Mohtashami, Marijn Muurling, Vaibhav Narayan, Vera Nies, Spiros Nikolopoulos, Andrew Owens, Marjon Pasmooij, Dorota Religa, Gaetano Scebba, Emilia Schwertner, Rohini Sen, Niraj Shanbhag, Laura Smith, Meemansa Sood, Thanos Stavropoulos, Pieter Stolk, Ioannis Tarnanas, Srinivasan Vairavan, Nick van Damme, Natasja van Velthogen, Herman Verheij, Pieter Jelle Visser, Bert Wagner, Gayle Wittenberg, and Yuhao Wu.

https://www.radar-ad.org/

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27 Mar 2023

PONE-D-23-05719Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD studyPLOS ONE

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Review Comments to the Author

Reviewer #1: The study employs qualitative analysis to discover commonalities and differences in how research ethics committees (RECs) evaluated a large-scale multinational research project on the use of remote monitoring technologies (RMTs) for people suffering from Alzheimer’s disease. It compares ethics reviews from RECs in 9 European countries in terms of issues raised, process duration, and the involvement of a data protection officer.

This is an excellent manuscript. Particularly impressive is the authors’ ability to compare the evaluation of the same project across 9 countries. While the perspective of RECs on RMTs is interesting, the value of the manuscript is elevated by the discussion of the lack of harmonization of REC processes. This topic will only gain greater prominence as the harmonization of research processes across the EU picks up and the study will add a valuable contribution to coming debates.

Aims and scope of the study are well-described and motivated. The study context is explained well. The background information provided on remote monitoring technologies and the role of RECs is clear and sufficient; connected ethical issues are described succinctly.

The description of the qualitative methodology misses a reference to the coding approach used and could be slightly more detailed. It is unclear to what degree, if any, peer-coding was used and whether all authors involved in coding were coding all of the material or shared the workload between them. I also missed an overview over which REC provided which types of documents for the analysis (this is not crucial for the manuscript and could be included as supplementary material).

A more detailed overview table over the differing review processes at each site with additional information on intermediary steps might also be helpful and would help strengthen the study’s contribution to REC harmonization efforts (Fig. 1 currently only shows process duration in a coarse manner). I would also be interested in learning about the level of harmonization of REC processes in each country: i.e. to what degree is the process site-specific or country-specific?

It might also help, but is probably out of scope for this study, to relate the findings to country-specific cultural attitudes, e.g. relating to data privacy.

The policy recommendations of the authors are sound and well-argued, but the structure of the discussion section is currently somewhat unclear and could benefit from either being broken up into smaller sections or from additional signposting at the beginning of the section. “Experts by learning” (326) is missing a reference if this is intended to be a quote.

Reviewer #2: The manuscript under review describes the challenges of ethical approval for a large European Study on remote monitoring for Alzheimer’s disease. The research ethics review process at 10 sites in 9 European countries were reported and compared. It is a relevant study that illustrates that ethics review remains a human activity where evaluation of risks between research ethics committees might differ, and the consequences this might have for research.

Although the authors write that written permission was obtained from the REC to use direct anonymized quotes for publication, I question whether RECs have given their permission that they are named in the article and that specific information about their RECs evaluation (e.g. duration, position on medical device, code frequencies) is being provided. In my view, illustrating the challenges of the current governance structures is possible without naming these committees.

With regard to the duration of the process of ethics approval, the current figures are not sufficiently correct to provide a clear representation of the process. A process of an ethics approval consists of a process between two parties, with questions and answers. So, in order to provide an honest representation it is necessary to detail how long the REC delayed an answer and how long the researchers delayed their answer to the questions of the REC. This is necessary in order to provide a fair representation. If this is not possible, this should be removed.

Although the current analysis is clear with regard to several ethical aspects of research, I was wondering whether interpretations of DPOs with regard to data processing (e.g. legal grounds for processing data) were similar in all sites.

On lines 300-302, the authors refer to the specific groups and communities that should be part of the discussion. The clinical trial regulations obliges now the presence of patient representatives. It might be a relevant addition, even if not every patient group can be represented in an ethics committee.

On line 301, please add the authors’ name.

On line 330, please explain anachronistic.

Reviewer #3: This is an interesting paper that lends support to a new era of digitizing medical research, namely the inclusion of "wearables" and remote monitoring technologies (RMTs). However, there is a significant disconnect between what the authors propose to study and then what is discussed after reporting the results. The results demonstrate a series of thematic analyses that present terms most frequently appearing in the research ethics committee review of the RADAR-AD study across the different study sites. Yet, this qualitative study discussed very few themes qualitatively in the discussion, instead beginning new threads of discussion about the RADAR-AD patient advisory board and specific definitions of RADAR-AD study population, a critique that undermines the authors' central thesis. Lastly, there is no promising conclusion or direction for future research with these qualitative findings in mind. Another discussion point that stood out to me was labeling the Swedish REC as "too strict" when earlier in the paper the themes identified from the initial rejection of the study protocol were legitimate concerns. The IT, data management and several other data and research governance safeguards the Sweden REC requested could be argued in the opposing direction. For instance, maybe the other countries were too quick to approve a study with a novel RMT and ill-defined data privacy and safety, putting vulnerable study participants at risk for a study that the authors critiqued as presenting epistemological flaws (e.g., preclinical AD participants recruited without concrete value to the study).

To help get started on the major revision, I will present the following revisions:

*Lines 95 - 96: RECs ENFORCE research governance through a review mechanism, reviewing study protocol, methods, informed consent forms and data safety, management and monitoring plans. I see the idea of research governance used in different contexts in the paper - RECs enforce research governance, which is an all encompassing term applicable to everything and everyone involved in clinical research.

*Line 97-98: Not usually. For an REC to have quorum, stakeholders who bring a diverse set of perspectives MUST be present (e.g., patient advocates, legal experts, medical professionals, ethicists, community, etc.)

*Lines 98-99: "An issue affecting multi-site studies is that research governance processes vary substantially across institutions and countries". This is the heart of the paper, which studies the multi-site RADAR-AD trial and the variation in how research governance is enforced through respective RECs. This sentence should be more clearly worded. Try: "Variation in how research governance practices are enforced across different institutions and countries participating in multi-site studies is a concern".

*Check line 100-101 for concise + grammar. logical cohesion in writing

*Line 102: Reword to "We must better understand the "needs, views and attitudes" of REC members wherever health-related RMTs are used as a source of "big data" in research."

*Line 103: delete "aims to"

*Line 105: This paper also explores...remove "intends to"

*Line 106: REC, committees -- repetitive

@Editorial Team - Table headings vary in formatting, e.g., Table 2 is italicized but Table 1 is not.

*Line 181-182: This does not hold true according to data presented in Table 3. Lisbon and Thessaloniki sites report 0% code frequencies for data-related terms.

*Line 285-286: My understanding of this paper is that the RADAR-AD study is used as a case study of how RMTs are viewed and handled by different RECs within the same multisite study - the structures that enforce research governance. Diving into an a critique of how RADAR-AD defines its study population is a counter example to your argument - it instead supports the idea that the RADAR-AD study was conceptually flawed to begin with and because of a methodologically-weak study design, the risks of data privacy posed by RMTs greatly outweighed any benefit of the research. This is a separate concern from how different RECs handle RMTs embedded in clinical trials, even the same clinical trial.

*Line 291 and beyond: Please expand on this discussion and make this more clear in the results section for emphasis. How exactly were RMTs classified in the study overall, at each study site, and then how is an RMT supposed to be classified according to the European MDR and for each country's regulations. Is there a certain feature / quality that makes an RMT a medical device? For instance, this is not intuitive. a contact lens worn in place of glasses is a medical device although we use it daily and it seems low risk. Is there a feature of a Fitbit or wrist-worn tracker that makes it a medical device or is the tracking of data (e.g., heartrate, pulse, respiratory rate) in a research study, is what implies that it should be treated as a medical device?

*Line 297 - if CTIS will help coordinate the submission of drug trials - how will this help harmonize how medical devices are defined by RECs and trial investigators? Drug and device trials differ very much, especially since device trials often present far more lenient regulatory and ethical oversight compared to drug trials as they are viewed as less invasive.

*Line 301, please identify the groups or authors instead of adding the citation

*Line 326: Please cite the quotation or advise why this is quoted.

*Line 362: Study results are reported in the discussion as "the material was very rich". This does not add value and should not be included.

Please also include a description of the type of study the RADAR-AD study was. Was this a pragmatic, late phase trial? Did this study aim to collect real world information? What was the purpose of the study and what benefit to society redeemed the risks of data privacy, safety and well-being posed to participants? Lastly, there is no discussion of DSMB (data safety monitoring boards) that can continue to evaluate the safety of the data and report any risks perceived during the study and then ask the study sites to intervene for the safety of participants. This is also an additional safeguard that can reinforce shorter review times at the REC stage.

A final note is a lack of connection to existing literature. There are many studies on data governance, data privacy, big data, health records and the participation/consent of vulnerable communities like those living with AD and dementia. Please see the work of Largent et al like the paper "Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living With Dementia" and Clinical News: Patient Data Safety for Dementia Patients Using Apps by Lisa Rosenfeld, MD, MPH, and Ipsit Vahia, MD (https://www.todaysgeriatricmedicine.com/archive/JF18p8.shtml).

Thank you for your work on this VERY interesting and complex topic.

**********

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 10.1371/journal.pone.0285807.r002 Author response to Decision Letter 0 Submission Version 1

4 Apr 2023

Dear editor,

We would like to thank reviewer 1, 2 and 3 for their constructive comments on our manuscript entitled ‘Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD study’. The comments were relevant and enabled us to improve the quality of our manuscript. Below, please find a point by point response to the provided comments:

Reviewer #1: The study employs qualitative analysis to discover commonalities and differences in how research ethics committees (RECs) evaluated a large-scale multinational research project on the use of remote monitoring technologies (RMTs) for people suffering from Alzheimer’s disease. It compares ethics reviews from RECs in 9 European countries in terms of issues raised, process duration, and the involvement of a data protection officer.

This is an excellent manuscript. Particularly impressive is the authors’ ability to compare the evaluation of the same project across 9 countries. While the perspective of RECs on RMTs is interesting, the value of the manuscript is elevated by the discussion of the lack of harmonization of REC processes. This topic will only gain greater prominence as the harmonization of research processes across the EU picks up and the study will add a valuable contribution to coming debates.

Aims and scope of the study are well-described and motivated. The study context is explained well. The background information provided on remote monitoring technologies and the role of RECs is clear and sufficient; connected ethical issues are described succinctly.

1. The description of the qualitative methodology misses a reference to the coding approach used and could be slightly more detailed. It is unclear to what degree, if any, peer-coding was used and whether all authors involved in coding were coding all of the material or shared the workload between them.

References to the coding approach are added in lines 146-150. The authors shared the workload between them for the first coding round, but after that, MM reviewed all coded documents again to harmonize the coding. This is added in lines 151-152 of the manuscript.

2. I also missed an overview over which REC provided which types of documents for the analysis (this is not crucial for the manuscript and could be included as supplementary material).

An overview over which documents were reviewed for this study is added in a table in the supplementary material.

3. A more detailed overview table over the differing review processes at each site with additional information on intermediary steps might also be helpful and would help strengthen the study’s contribution to REC harmonization efforts (Fig. 1 currently only shows process duration in a coarse manner).

A more detailed overview of the review process at each site is added to as an additional column to the table in the supplementary material. Please see the last column of the table as discussed in the previous question.

4. I would also be interested in learning about the level of harmonization of REC processes in each country: i.e. to what degree is the process site-specific or country-specific?

We added a new column in Table 2 to describe if the RECs operate on a site-specific, region-specific, or country-specific level.

5. It might also help, but is probably out of scope for this study, to relate the findings to country-specific cultural attitudes, e.g. relating to data privacy.

We agree with the reviewer that country specific cultural attitudes of our interest. However, to our opinion, this topic in itself it too large to be included in this study. Cultural attitudes towards dementia and use of technology are highly dependent on many factors including regional/institutional attitudes, state of digital development of a country/region, and types of medical professions included in the clinical center involved. To this end, we decided not to include a discussion of this topic in order to do justice to the breath of this potential discussion.

6. The policy recommendations of the authors are sound and well-argued, but the structure of the discussion section is currently somewhat unclear and could benefit from either being broken up into smaller sections or from additional signposting at the beginning of the section.

We have added sub-headers and added signposting at the beginning of each section in the discussion section.

7. “Experts by learning” (326) is missing a reference if this is intended to be a quote.

These words were not intended to be quoted. We have changed it to ‘professionals’ to avoid confusion (line 359).

Reviewer #2: The manuscript under review describes the challenges of ethical approval for a large European Study on remote monitoring for Alzheimer’s disease. The research ethics review process at 10 sites in 9 European countries were reported and compared. It is a relevant study that illustrates that ethics review remains a human activity where evaluation of risks between research ethics committees might differ, and the consequences this might have for research.

1. Although the authors write that written permission was obtained from the REC to use direct anonymized quotes for publication, I question whether RECs have given their permission that they are named in the article and that specific information about their RECs evaluation (e.g. duration, position on medical device, code frequencies) is being provided. In my view, illustrating the challenges of the current governance structures is possible without naming these committees.

We specifically asked each REC if their name could be included in the publication as well. To our opinion, it is of additional value to name the specific RECs, as the challenges in governance structure could be dependent on regional or institutional attitudes. Also, the RECs involved in the RADAR-AD study are also named in other public documents, such as project deliverables.

2. With regard to the duration of the process of ethics approval, the current figures are not sufficiently correct to provide a clear representation of the process. A process of an ethics approval consists of a process between two parties, with questions and answers. So, in order to provide an honest representation it is necessary to detail how long the REC delayed an answer and how long the researchers delayed their answer to the questions of the REC. This is necessary in order to provide a fair representation. If this is not possible, this should be removed.

We have added a table in the supplementary material which elaborates more on the review process per site and which bodies were involved in each round.

3. Although the current analysis is clear with regard to several ethical aspects of research, I was wondering whether interpretations of DPOs with regard to data processing (e.g. legal grounds for processing data) were similar in all sites.

The interpretations of DPOs were not similar for all sites. For example, the use of the wearable camera was not approved in Germany after a consult with a DPO, while the camera was approved in the Netherlands after a consult with a DPO. This was added in the discussion (lines 301-305).

4. On lines 300-302, the authors refer to the specific groups and communities that should be part of the discussion. The clinical trial regulations obliges now the presence of patient representatives. It might be a relevant addition, even if not every patient group can be represented in an ethics committee.

A sentence about the clinical trial regulation has been added in lines 340-342.

5. On line 301, please add the authors’ name.

The authors’ name is added.

6. On line 330, please explain anachronistic.

We have removed the word anachronistic and simplified the sentence (line 362-363).

Reviewer #3: This is an interesting paper that lends support to a new era of digitizing medical research, namely the inclusion of "wearables" and remote monitoring technologies (RMTs).

1. However, there is a significant disconnect between what the authors propose to study and then what is discussed after reporting the results. The results demonstrate a series of thematic analyses that present terms most frequently appearing in the research ethics committee review of the RADAR-AD study across the different study sites. Yet, this qualitative study discussed very few themes qualitatively in the discussion, instead beginning new threads of discussion about the RADAR-AD patient advisory board and specific definitions of RADAR-AD study population, a critique that undermines the authors' central thesis.

We agree that the issued found in the results section were not discussed elaborately in the discussion. The rationale for this was that the results were expected and did not report new discoveries. The gaps, or themes that were not mentioned were more interesting, and were therefore discussed. To identify the gaps that remain after the REC review was one of the aims of the study. We have added the sentences in lines 259, 268-269 and 278-279 to clarify this more.

2. Lastly, there is no promising conclusion or direction for future research with these qualitative findings in mind.

We have added suggestions for future research including interviews and focus groups with REC members to better understand their views (lines 390-393 and 401), and future research how to involve patients (lines 366-369).

3. Another discussion point that stood out to me was labeling the Swedish REC as "too strict" when earlier in the paper the themes identified from the initial rejection of the study protocol were legitimate concerns. The IT, data management and several other data and research governance safeguards the Sweden REC requested could be argued in the opposing direction. For instance, maybe the other countries were too quick to approve a study with a novel RMT and ill-defined data privacy and safety, putting vulnerable study participants at risk for a study that the authors critiqued as presenting epistemological flaws (e.g., preclinical AD participants recruited without concrete value to the study).

We acknowledge that the reasoning could be argued in the opposing way. The exact (translated) words of the Swedish REC to reject the study were:

The Ethics Review Authority notes that the research project concerns a group which, due to its disease symptoms (memory disorder due to Alzheimer's disease), may be considered a particularly vulnerable group who may be expected to have difficulty taking an active part in participating in the study. The participants are exposed to a significant invasion of privacy and have no personal benefit from participating in the study. The potential benefits for future individuals with early dementia appear unclear. As the risks (significant breach of privacy) for the participants are thus not outweighed by the benefit, the application is rejected.

This shows that their concern was specifically focused on the dementia group, and not on the preclinical AD group. Including a preclinical AD group in research is widely accepted in the AD field (1), especially when the

biomarker status is not disclosed to participants. The argument ‘may be expected to have difficulty’, is not very strong, as RADAR-AD was specifically designed to discover if this dementia group was able to use these kinds of RMTs. Moreover, we would like to point out that the RMTs used in this study are not novel devices or apps. We used RMTs that were already developed, either for research purposes or commercially available. We have added this clarification in lines 118-120. At last, the data privacy and safety of our RMTs was well defined, as we had two work packages within the project specifically appointed to build a secure data platform and focus on research ethics and safety. Moreover, the data platform and RMTs were checked on safety and privacy by a specialized IT department and data privacy officer in Amsterdam (the sponsor of the study). We, however, acknowledge that the wording of being ‘too strict’ might be not appropriate, and we have therefore changed the wording (lines 283-286).

To help get started on the major revision, I will present the following revisions:

4. Lines 95 - 96: RECs ENFORCE research governance through a review mechanism, reviewing study protocol, methods, informed consent forms and data safety, management and monitoring plans. I see the idea of research governance used in different contexts in the paper - RECs enforce research governance, which is an all-encompassing term applicable to everything and everyone involved in clinical research.

We have changed the sentence in lines 94-97, so that it is clear that RECs enforce research governance.

5. Line 97-98: Not usually. For an REC to have quorum, stakeholders who bring a diverse set of perspectives MUST be present (e.g., patient advocates, legal experts, medical professionals, ethicists, community, etc.)

The word usually is removed from the sentence in lines 97-98.

6. Lines 98-99: "An issue affecting multi-site studies is that research governance processes vary substantially across institutions and countries". This is the heart of the paper, which studies the multi-site RADAR-AD trial and the variation in how research governance is enforced through respective RECs. This sentence should be more clearly worded. Try: "Variation in how research governance practices are enforced across different institutions and countries participating in multi-site studies is a concern".

The sentence is changed to the proposed sentence.

7. Check line 100-101 for concise + grammar. logical cohesion in writing

The sentence has been changed to improve the grammar and cohesion.

8. Line 102: Reword to "We must better understand the "needs, views and attitudes" of REC members wherever health-related RMTs are used as a source of "big data" in research."

The sentence is reworded to the proposed sentence.

9. Line 103: delete "aims to"

‘Aims to’ is deleted.

10. Line 105: This paper also explores...remove "intends to"

‘Intends to’ is removed.

11. Line 106: REC, committees – repetitive

Changed to RECs.

12. @Editorial Team - Table headings vary in formatting, e.g., Table 2 is italicized but Table 1 is not.

All table headings are now italicized.

13. Line 181-182: This does not hold true according to data presented in Table 3. Lisbon and Thessaloniki sites report 0% code frequencies for data-related terms.

We added ‘except for the sites in Lisbon and Thessaloniki’.

14. Line 285-286: My understanding of this paper is that the RADAR-AD study is used as a case study of how RMTs are viewed and handled by different RECs within the same multisite study - the structures that enforce research governance. Diving into an a critique of how RADAR-AD defines its study population is a counter example to your argument - it instead supports the idea that the RADAR-AD study was conceptually flawed to begin with and because of a methodologically-weak study design, the risks of data privacy posed by RMTs greatly outweighed any benefit of the research. This is a separate concern from how different RECs handle RMTs embedded in clinical trials, even the same clinical trial.

We agree that the point discussed in this paragraph does not concern an issue with RMTs, but with the view of Alzheimer’s disease in general. It is however an example of how the view of RECs differs between countries. Importantly, the issues raised by several REC’s did concern the inclusion of a preclinical AD group within the context of RMT measurements, which does link to the goals of this study. Preclinical AD is a widely accepted study group in research, but is not used in clinical practice, as there is no treatment yet. In our view, RECs refusing to include preclinical AD in a clinical study are therefore withholding from an important step forwards in clinical trials for AD, and is therefore an important point to mention in the discussion of this manuscript.

15. Line 291 and beyond: Please expand on this discussion and make this more clear in the results section for emphasis. How exactly were RMTs classified in the study overall, at each study site, and then how is an RMT supposed to be classified according to the European MDR and for each country's regulations. Is there a certain feature / quality that makes an RMT a medical device? For instance, this is not intuitive. a contact lens worn in place of glasses is a medical device although we use it daily and it seems low risk. Is there a feature of a Fitbit or wrist-worn tracker that makes it a medical device or is the tracking of data (e.g., heartrate, pulse, respiratory rate) in a research study, is what implies that it should be treated as a medical device?

The RMTs were classified as medical devices in Amsterdam, but as no medical device (or not mentioned at all) in the other sites. A quote on the rationale for this decision of the REC in Amsterdam was already included in the results section (lines 248-252). We have added a more elaborate explanation in the results section (lines 240-245 and 252-253) and more elaborate discussion in the discussion section (lines 320-324).

16. Line 297 - if CTIS will help coordinate the submission of drug trials - how will this help harmonize how medical devices are defined by RECs and trial investigators? Drug and device trials differ very much, especially since device trials often present far more lenient regulatory and ethical oversight compared to drug trials as they are viewed as less invasive.

The CTIS will help in harmonizing the decision of different RECs within one multi-site study, rather than the harmonization of medical devices across studies. We have added a clarification in lines 327-328.

17. Line 301, please identify the groups or authors instead of adding the citation

The authors are added.

18. Line 326: Please cite the quotation or advise why this is quoted.

We have changed the quoted words for professionals.

19. Line 362: Study results are reported in the discussion as "the material was very rich". This does not add value and should not be included.

The sentence is reworded.

20. Please also include a description of the type of study the RADAR-AD study was. Was this a pragmatic, late phase trial? Did this study aim to collect real world information? What was the purpose of the study and what benefit to society redeemed the risks of data privacy, safety and well-being posed to participants? Lastly, there is no discussion of DSMB (data safety monitoring boards) that can continue to evaluate the safety of the data and report any risks perceived during the study and then ask the study sites to intervene for the safety of participants. This is also an additional safeguard that can reinforce shorter review times at the REC stage.

The type of study and aims of RADAR-AD are discussed in the materials and methods section (lines 113-121). We added a reference to the project website to get a clearer idea about the project (line 113). The study is already finished and collected real-world data from more than 220 participants, as discussed in lines 115 and 117. There was no DSMB during the study, we added a sentence (lines 120-121) to explain this.

21. A final note is a lack of connection to existing literature. There are many studies on data governance, data privacy, big data, health records and the participation/consent of vulnerable communities like those living with AD and dementia. Please see the work of Largent et al like the paper "Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living With Dementia" and Clinical News: Patient Data Safety for Dementia Patients Using Apps by Lisa Rosenfeld, MD, MPH, and Ipsit Vahia, MD (https://www.todaysgeriatricmedicine.com/archive/JF18p8.shtml).

We have added new references to the introduction, in lines 84 and 87 to connect more to existing literature.

References

1. Jack CR, Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.

Submitted filename: PLOSONE_Rebuttal_RADARAD_REC_20230330.docx

 10.1371/journal.pone.0285807.r003 Decision Letter 1 Chu Dinh-Toi Academic Editor 2023 Dinh-Toi Chu This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

19 Apr 2023

PONE-D-23-05719R1Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD studyPLOS ONE

Dear Dr. Muurling,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 03 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Academic Editor

PLOS ONE

 **********

Review Comments to the Author:

Reviewer #1: I thank the authors for addressing my previous concerns and suggestions. I have noticed 2 minor issues that should be addressed before the manuscript is ready for publication:

1) The table in the supplementary material (line 514) is currently missing the content for the column entitled “documents reviewed”.

2) Table 2 (line 141) needs a brief in-text explanation of what is meant by site-specific, region-specific, and country-specific.

Reviewer #2: (No Response)

Reviewer #3: The revision has now addressed the comments of reviewers and provided explanations for the comments they disagreed with. In the responses, the authors gave a good explanation of the study design's inclusion of pre-clinical AD. They agreed that the study design "does not concern an issue with RMTs, but with the view of Alzheimer’s disease in general. It is however an example of how the view of RECs differs between countries. Importantly, the issues raised by several REC’s did concern the inclusion of a preclinical AD group within the context of RMT measurements, which does link to the goals of this study. Preclinical AD is a widely accepted study group in research, but is not used in clinical practice, as there is no treatment yet. In our view, RECs refusing to include preclinical AD in a clinical study are therefore withholding from an important step forwards in clinical trials for AD, and is therefore an important point to mention in the discussion of this manuscript." I believe this is a great point to include in the actual manuscript, particularly in the study description (lines 115-116) or in more detail in the discussion (308-312).

The list of citations includes a #61 that is blank.

There are slight grammatical and spelling errors throughout. Please proofread. E.g., 'publically' line 119-120.

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

 10.1371/journal.pone.0285807.r004 Author response to Decision Letter 1 Submission Version 2

21 Apr 2023

Dear editor,

We would like to thank reviewer 1 and 3 for their additional comments on our manuscript entitled ‘Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD study’. The comments were relevant and enabled us to improve the quality of our manuscript. Below, please find a point by point response to the provided comments:

Reviewer #1: I thank the authors for addressing my previous concerns and suggestions. I have noticed 2 minor issues that should be addressed before the manuscript is ready for publication:

1. The table in the supplementary material (line 514) is currently missing the content for the column entitled “documents reviewed”.

We have changed the header of the table and the title of the column to make it more clear what the column content entails.

2. Table 2 (line 141) needs a brief in-text explanation of what is meant by site-specific, region-specific, and country-specific.

We have added an in-text sentence (line 130-132), and also added a footnote to Table 2 (lines 145-147) to clarify what is meant by site-specific, region-specific, and country-specific.

Reviewer #2: (No Response)

Reviewer #3: The revision has now addressed the comments of reviewers and provided explanations for the comments they disagreed with.

1. In the responses, the authors gave a good explanation of the study design's inclusion of pre-clinical AD. They agreed that the study design "does not concern an issue with RMTs, but with the view of Alzheimer’s disease in general. It is however an example of how the view of RECs differs between countries. Importantly, the issues raised by several REC’s did concern the inclusion of a preclinical AD group within the context of RMT measurements, which does link to the goals of this study. Preclinical AD is a widely accepted study group in research, but is not used in clinical practice, as there is no treatment yet. In our view, RECs refusing to include preclinical AD in a clinical study are therefore withholding from an important step forwards in clinical trials for AD, and is therefore an important point to mention in the discussion of this manuscript." I believe this is a great point to include in the actual manuscript, particularly in the study description (lines 115-116) or in more detail in the discussion (308-312).

Thank you for this suggestion, we have added the explanation in the discussion (lines 313-314 and lines 319-322).

2. The list of citations includes a #61 that is blank.

Thank you for noticing, this 61 belongs however to the previous citation (#35) as part of the page numbers.

3. There are slight grammatical and spelling errors throughout. Please proofread. E.g., 'publically' line 119-120.

We have changed ‘publically’ to ‘publicly’ in line 119. We have proofread the manuscript and corrected grammatical and spelling errors.

Submitted filename: PLOSONE_Rebuttal2_RADARAD_REC_20230421.docx

 10.1371/journal.pone.0285807.r005 Decision Letter 2 Chu Dinh-Toi Academic Editor 2023 Dinh-Toi Chu This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

2 May 2023

Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD study

PONE-D-23-05719R2

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 10.1371/journal.pone.0285807.r006 Acceptance letter Chu Dinh-Toi Academic Editor 2023 Dinh-Toi Chu This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

26 Jun 2023

PONE-D-23-05719R2

Ethical challenges of using remote monitoring technologies for clinical research: a case study of the role of local Research Ethics Committees in the RADAR-AD study

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