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Trials@Home: Center of Excellence – Remote Decentralised Clinical Trials

Deliverables

First version of Data management plan (task 6.4)

Task 6.4: Development and updating of data management plan - Months 1-60 Lygature, UMCU, SARD In order to ensure the implementation of FAIR principles on all levels, Trials@Home will develop and further update a data management plan (in collaboration with WP2 TECH which, under Task 2.4, will develop the pilot data management plan, to be integrated into the overall data management plan). The Data Management Plan describes the data management life cycle for all data sets that will be collected, processed or generated by the research project. Trials@Home’s data management plan will detail: the handling of research data during and after the end of the project; what data will be collected, processed and/or generated; which methodology and standards will be applied; whether and which data will be shared/made open access, accessible for verification and re-use; how data will be curated and preserved. The first version of the data management plan will be delivered in month 6, but the plan will evolve and gain more precision and substance during the lifespan of the project. The consortium will comply with national legislation, the general data protection act (EU), and GCP/ICH guidelines throughout the project. The data management plan will include a description of the anonymisation/pseudonymisation techniques that will be implemented and the possible handling of personal data transfer from a non-EU country to the EU (or another third state), and the consortium will provide confirmation that such transfers comply with the laws of the country in which the data was collected where applicable. The approval package for the pan-EU pilot study will contain detailed information on the informed consent procedures, the informed consent forms and information sheets for the processing of personal data. These approvals will be submitted to the IMI prior to the commencement of the research (D3.5) and retained in the WP3 PILOT trial master file. In case of further processing of previously collected personal data, an explicit confirmation that the consortium has lawful basis for the data processing and that the appropriate technical and organisational measures are in place to safeguard the rights of the data subjects will be provided. Relevant authorisations will be obtained and kept on file. A Data Protection Officer (DPO) will be appointed for the project and the contact details of the DPO will be made available to all data subjects involved in the research (D6.11 Ethical D4). At M22 the updated data management plan, including the pilot data management plan, will be reviewed by the Independent External Expert Panel (D6.12 Ethical D1c)

Criteria for selection of appropriate trials

Task 1.6 Analysing protocol suitability for RDCT including how to establish criteria for selecting trials for the RDCT model UNIVDUN, UMCU, UOXF, MRN, eClinicalHealth, SDU, FISABIO, DREEM, SARD, Allergan, AZ, Bayer, Janssen, Covance, UCB, Takeda, TEVA In this task we will provide recommendations to enable analysis of suitability of trials for an RDCT model. These guidelines will be tested in different scenarios. An important aspect will be to ascertain how implementable the RDCT model would be for different types of trials (pre-licensing, post-licensing, CTIMP, non-CTIMP, trial procedures required and the ability to capture data remotely) and different disease areas / types of therapeutic interventions. Acceptability of such approaches with regulators, other regional regulatory processes, patient organisations and data standards will be included.

Detailed list of quality assessment criteria and assessment procedures (task 2.1.2)

"Task 2.1.2: Defining the quality criteria and assessment procedures for the quality assessment of the technologies resulting from 2.1.1 (Month 3-12) UMCU, JCR, JOANNEUM , MRN, eClinicalHealth, UNIVDUN, FISABIO, CERTH, DREEM, SARD, Janssen, Bayer, Allergan, BI Pharma, Covance, Takeda, Teva, Merck In this task, quality criteria and assessment procedures for the selection and ranking of RDCT-supporting technological solutions will be defined. Within the set of identified technologies and technological solutions, descriptive characteristics related to the following qualities and other important features will be extracted for prioritisation and combined with the features and criteria resulting from the best practices review performed in WP1 BEST: 1. Accessibility (availability in Europe, language, …) including type of platform, price, need for network connectivity, reach (#downloads, #users, #countries), interoperability, customizability 2. Primary functions, including classification, technology functions, target audience, 3. Source, including provider type and details, disclaimer presence, and technology update schedule, 4. Privacy and security, CE mark, including presence of an accessible privacy (data) policy, GDPR compliance, and the ability to password-protect data, 21 CFR Part 11 compliance, 5. Evidence, documentation on validation (i.e. usability, feasibility, accuracy, efficacy, compatibility and reliability), use in clinical studies 6. Patient/user satisfaction (user satisfaction questionnaires). In case it is unclear whether technological solutions support certain technologies, vendors of the respective technological solution will be contacted to provide elaboration on the capabilities of the technological solution in question. Subsequently, the quality assessment criteria will be defined in close cooperation with the ESP, and will serve as an initial set of (draft) criteria to be further refined through consensus-achieving processes (e.g., the Delphi method) involving focus groups (based on nominal group techniques). Through multiple iterations of such processes, a final consensus on the quality assessment criteria can be reached. In addition, an objective scoring system and assessment procedure for quality assessments that allows the ranking of evaluated technological solutions will be developed. The proposed collection of quality assessment criteria will be processed in an open call, to be coordinated by WP6 (see task 6.6). UMCU and JOANNEUM will coordinate the development of standardised assessment forms, the systematic review of all available information and the evaluation of evidence related to and use in clinical trials. JOANNEUM, eClinicalHealth and Janssen will specifically assess and define quality criteria for interoperability requirements. Furthermore, UMCU, MRN and FISABIO will specifically be responsible for capturing and harmonising input of patient groups, principal investigators, healthcare providers and other stakeholders through the ESP. The independent expert panel (as described in task 6.1) will review the quality criteria and assessment procedures that are developed under task 2.1.2, to avoid conflict of interest and ensure acceptance of the open call results."

Glossary of terms and definitions used within WP2 (task 2.1.1)

Task 211 Technology scan Month 111UMCU JOANNEUM MRN eClinicalHealth UNIVDUN FISABIO CERTH DREEM SARD Allergan Janssen AZ Takeda Bayer BI Pharma Covance Takeda TevaTask 21 involves the performing of a broad technology scan based on a systematic review framework ie according to PRISMA guidelines for systematic literature review in scientific literature eg PubMed CINAHL Google Scholar etc app stores Google Play Apple store etc internet search registers such as ClinicalTrialsgov patent registers and other public sources The technology scan will include all patientfacing data collection and supporting software services include broader overarching technologies such as central research platforms that are likely to be required These solutions are classified per trial building block see figure 2 and screened based on predefined eligibility criteria To streamline and focus these scanning efforts a distinction will be made between Core technologies ie technologies for RDCTs that are independent of the therapeutic area of a trial and Specific technologies that are dependent of the therapeutica area of the RDCT To support standardised searches and to uniformly compare results a glossary of terms will be created for WP2 that includes search keywords To maximise the yield and efficiency of the search efforts both snowballing reference tracking and informal approaches asking around and being alert to serendipitous discovery will be used Here we will leverage the results of the RADARAD literature and market review see httpswwwimieuropaeuprojectsresultsprojectfactsheetsradarcns Both academic and industry partners will use their expert knowledge and experience to reach out to actors in the field assess whether their technology is in principle suitable for RDCTs even when not yet used andor not yet validated for clinical research In the beginning most research will be concentrated on the search and assessment of the core technologies After the choice for the therapeutic area for the WP3 panEU pilot has been made the focus of the technology scan will be further narrowed to disease andor outcome specific technologies A selection matrix for these technologies developed within this WP will involve but is not limited to the following questions1What is the technology How do we TrialsHome define it2Is the technology now or in the future key to RDCT development3Are there current suppliers or commercial entities with products or services in these technology areas If so what is novel about the technology that would provide solutions to new areas of inquiry4Is this technology immediately relevant potentially relevant in the future not directly relevant or modifying a current or future technology5How does this RDCT technology address the capture of novel end pointsGiven the rapid speed of technological innovation new technologies that are not ready or available at the start of the WP3 panEU pilot will be further investigated and evaluated after month 12 The continued technology scan has a synergetic relationship with WP1 BEST and other WPs new technologies found in this wider technological scan may drive new bestpractices thus potentially influencing findings in WP1 BEST In turn new bestpractices found in WP1 may drive the development of new technological solutions to support those practices influencing the results of WP2 TECH The same can be said about the relationships with WP4 EAGLE where technology and legislation influence each other in a similar way Results of the wider technology scan and interactions with other WPs will be included in the final recommendationsJOANNEUM UMCU and BI Pharma will coordinate the activities in the search based on a systematic review framework BI Pharma will develop a glossary of terms for the WP so that we are all speaking the same language

Open call for additional technology partners (task 6.6)

Task 66 Open call for additional technology partners Months 126UMCU SARD Lygature In order to ensure access to stateoftheart technologies for the pilot RDCT the consortium will consider enrolling additional technology participants to fulfil the relevant tasks identified in the Technology Package of WP2 TECH This technology package and proposed additional technology participants will be selected through an open call This open call will detail the technologies that comprise the Technology Package to be deployed in the WP3 panEU Pilot The Open Call will be developed in consultation with IMI to ensure compliance with the relevant EU and EU H2020 procedures and regulations The selection of the technology package and associated technology partners wil be done according to the guiding principles of fairness transparency and independency The open call will describe in detail the application requirements and procedures timelines and templates to be used as well as the eligibilty and evaluation criteria and processes applied A draft list of quality critera to be used in the open call and a description of how the criteria will be further defined and assessment procedures will be developed during the project is described in Task 212 Subject to further detailing as part of this task and the Technology assessment in WP2 TECH the conditions and evaluation criteria will includeApplicants if selected should be able to complete the necessary accession process in a timely mannerApplicants should have freedom to operateApplicants should be eligible for participation in IMI2JU projectsApplicants should adhere to the procedures and timelines set in the Open callProposals wil be evaluated according to common evaluation criteria and procedures developed by WP2 TECH D22 as published in the Open callBroad and timely dissemination of the open call will involve publishing of the call on the internet TrialsHome website and selected websites of linked IMI and EU funded projects IMI EFPIA supported by social media notifications in collaboration with WP5 Moreover the technology scan in WP2 will provide a list of relevant candidate technology partners that can be contacted directly and invited to submit proposals This way TrialsHome will seek to reach out to as many as possible candidate partners to submit their proposals in response to the open call The evaluation of proposals will be done by an independent internal expert evaluation panel specifically installed for this purpose by the ExBo with the agreement of the Partner Assembly leading to recommendations for the final technology package to be deployed in the panEU pilot External review of the technology scan and approval of the final technology package will be sought before any additional partners will be added to the consortium Depending on the independent expert evaluation and selection the outcome of the open call could be that part of the technology package will not require the accession of new partners eg the technology can simply be purchased from an external vendor or an existing consortium partner offers the technology In case the 30 of the IMIJU funding which is reserved to fullfil the tasks and expertise identified in the technology package including tech and other innovative operational solutions will not be utilised for this purpose in full this reservation will be reallocated to other activities and partners in TrialsHome following procedures as established in the Consortium Agreement

First set of recommendations for RDCTs (to be implemented in the pan-EU pilot RDCT)

Task 1.1 Define criteria for analysing the RDCTs model and processes. UNIVDUN, UMCU, UOXF, eClinicalHealth, SDU, MRN, CERTH, FISABIO, SARD, Allergan, AZ, Bayer, Novartis, Janssen, Covance, Takeda, TEVA We will conduct a review of the literature and interviews with investigator and industry teams to summarise the current position and experience regarding RDCTs. The review will focus on Europe and North America but will also take into account other examples from around the world. Reference will also be made to relevant guidelines e.g., Clinical Trials Transformation Initiative Decentralized Clinical Trials (US FDA, Duke University), 21st Century Cures Act https://www.fda.gov/medicaldevices/digitalhealth/), learnings from the Mobile Clinical Trials program (https://www.ctti-clinicaltrials.org/programs/mobile-clinical-trials) and Transcelerate. We will develop a matrix for collection of data and processes from partners with case studies in advance of the project start to facilitate initial data collection and to agree upon which data will be shared prior to project start. Criteria will then be defined by the cross-project working group for analysing the building blocks of the RDCTs model and processes: • Set-up and Design activities will include funding/contracting agreements, legal aspects, ethical approvals (liaising with WP4 EAGLE) and considerations and other regulatory approvals, site selection, trial medical and operational feasibility, third party vendor set-up and supplies, randomisation and treatment allocation processes, database design and set up, infrastructure and technology validation and testing. Mechanisms for distribution of Investigational Medicinal Products (IMP) in the RDCT model will also be considered and the supply chain described including differences in country requirements regarding direct-to-participant IMP shipment. Experience of remote distribution and administration of IMP in different geographical regions exists within the consortium. • Recruitment and Enrolment will include a comparison of traditional recruitment methods with novel methods including digital (social media and online advertisements), advocacy groups, strategies to broaden geographical participation, and enrolment without a formal initial ‘in-person’ study visit. • Intervention and Follow up will include evaluation and definition of patient oversight and management in the different models. Safety of participants (and staff) will be an overarching feature to be explored at all stages of trial process. • Close out and Reporting will evaluate any aspects of site close out, finalisation of data and reporting that are different between the models. • Data Acquisition and Processing will include data collection, processing and quality. Data collection will include methods of collecting data that are different from traditional methods making use of technologies such as apps, wearables, telemedicine, use of eSource, and direct online data entry by patients or observers or linkage to real-world data. Data quality will include assessing whether remote methods of data collection are of higher or lower quality than traditional models and ways of ensuring adequate data quality and aspects of patient retention/empowerment and adherence to trial procedures. Validity of data will also be considered e.g. statistical review where possible to identify potential differences in data collected using decentralised processes compared to data collected using traditional methods. Data processing will include aspects of data collation, cleaning, codifying, output, analysis and reporting e.g. for pharmacovigilance purposes and archiving. • Operations and Coordination will include evaluation and definition of all operational aspects of running RDCTs. Relevance will include whether it is appropriate to use a RDCT design and whether this model adequately answers the scientific question of a trial. Clinical trials of investigational medicin

Ethics D1a, GEN-Requirement: Independent Ethics Advisor appointed to participate in the independent external expert panel

Task 6.5 Establishment and management of the Trials@Home External Stakeholder Platform - Months 1-60 UPPMD, and collaboration with all WP co-leads This task involves the establishment and secretarial/organisational support to the External Stakeholder Platform. This involves: the development and implementation of the ESP Terms of Reference, describing the expected roles of the ESP, way of working, confidentiality agreements and arrangements, travel policy, reimbursement processes and procedures); maintaining up to date contact details, distribution of meeting documentation (e.g. locations, agendas, required reading) and meeting minutes; planning and organising the WP-ESP meetings in close consultation with the WP leads concerned. For efficiency reasons and to promote ESP interactions, WP-ESP meetings will be organised as much as possible in a combined manner, at central locations; managing the budget for the ESP meetings, centrally allocated to UPPMD. Meetings between the ESP coordinators and the WP leads will be scheduled around M3 to determine in detail at which moments and for which Milestones and Deliverables the ESP will be engaged in which way. For example, for the PILOT WP this could encompass that besides the continuous interaction, at two predefined time points the ESP will be consulted in a F2F meeting, first on the (draft) study design and protocol (M10-12, in the process of making the pivotal choices), and second on the semi-final protocol (M18-20, semi-final protocol going through dry run), possibly supplemented by a very early meeting at M6 (when the drafting of the protocol starts, depending on the outputs from the other WPs at that point in time).

Map of the EU legislation on RDCTs including legal, regulatory, ethical and stakeholder recommendations for conduct of the pan-EU pilot

Task 41 Mapping of the EU legislation and guidelines on RDCT UUUCB UMCU FISABIO MLCF SARD AZ Janssen Bayer Covance PfizerTask 41 will map the EU legislation and guidelines on RDCTs by providing a taxonomy of the legislative landscape The mapping will provide metrics for the assessment of the best practices link with WP1 and allow for identifying possible impacts of RDCTs Through literature search consultation of experts and mapping of guidelines we will perform a review of the changing EU clinical trial ecosystem incl CTD CTR ICH E6 R2 CTTI recommendations The result will be compared with current best practices WP1 to identify high level disconnects between the launch of a panEU RDCT model WP3 and current legal including GDPR and eIDAS regulation regulatory and ethical frameworks The mapping will be complemented with grey space knowledge by the pharmaceutical industry partners The mapping will take into consideration the type of digital technologies used in the panEU pilot WP2 as well as facilitators or barriers of country specific law and regulations where the panEU pilot will be conducted WP3 The scoping of the EU clinical trial ecosystem will provide WP1 with a list of considerations to use in their choice of best practices that can be implemented as well as the design of the WP3 panEU pilot

Trials@Home website, templates, and social media tools

SubTask 5.1.1 Branding/Web Creation/External Communication (VT, UPPMD, SARD, BI Pharma) Branding ideation, web development/hosting, twitter address (@Trailsathome), communication tools/ppt templates, social media style guides, content style guides. The website will be a window into the project. It will house original content generated by the project partners: • All research outputs/peer review publications, • Public events, • Social media actions including webinars, podcasts, • Training sessions/kits, • Project structure and management, • Deliverables by work-package and their current status, • The RDCT check list, • A list of project partners, • Members only section.

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Publications

COVID‐19 and the Emerging Regulatory Guidance for Ongoing Clinical Trials in the European Union

Author(s): Amos Jochanan Jong, Yared Santa‐Ana‐Tellez, Ghislaine José Madeleine Wilhelmien Thiel, Mira Gerta Petra Zuidgeest, Satu Johanna Siiskonen, Dinesh Mistry, Anthonius Boer, Helga Gardarsdottir
Published in: Clinical Pharmacology & Therapeutics, 109/6, 2021, Page(s) 1517-1527, ISSN 0009-9236
Publisher: Nature Publishing Group
DOI: 10.1002/cpt.2225

Learning from remote decentralised clinical trial experiences: A qualitative analysis of interviews with trial personnel, patient representatives and other stakeholders

Author(s): Joanne Coyle, Amy Rogers, Rachel Copland, Giorgia De Paoli, Thomas M. MacDonald, Isla S. Mackenzie
Published in: British Journal of Clinical Pharmacology, 2021, ISSN 0306-5251
Publisher: Blackwell Publishing Inc.
DOI: 10.1111/bcp.15003

A Systematic Review of Methods used to Conduct Decentralised Clinical Trials

Author(s): Amy Rogers, Giorgia De Paoli, Selvarani Subbarayan, Rachel Copland, Kate Harwood, Joanne Coyle, Lyn Mitchell, Thomas M MacDonald, Isla S Mackenzie, on behalf of the Trials@Home Consortium
Published in: British Journal of Clinical Pharmacology, 2021, ISSN 0306-5251
Publisher: Blackwell Publishing Inc.
DOI: 10.1111/bcp.15205