The ambitious research of the PROFID project will be mitigated by a carefully designed methodology and executed through nine work packages (WPs) as described below.

Work Package 1 – Risk score development

In WP1, University of Manchester will incorporate the data provided by the consortium partners and apply statistical modelling and machine learning methods in order to estimate the expected benefits of implantable cardioverter-defibrillator (ICD) implantation to prevent SCD within this cohort of individuals, across the whole range of left ventricular ejection fraction (LVEF).

Work Package 2 – Clinical trial preparation and set up

In WP2, preparation for the clinical trial, including preparation of the trial protocol, ethics approvals, collaboration policy (including each partners’ responsibilities regarding data security and governance), data management plan and clinical centre recruitment will be performed by partners CRI and Charité – Universitätsmedizin Berlin beginning from the start of the project (in parallel to WP1).

Work Package 3 & 4 – Clinical trial execution and monitoring & trial closure

WP3 covers the multinational clinical trial in post- myocardial infarction patients with reduced LVEF ≤ 35%. Experienced clinical contract research organisation (CRO) CRI will be responsible for overall management and monitoring of the trial. Charité – Universitätsmedizin Berlin will act as sponsor of the clinical trial. In WP4, CRI and Charité – Universitätsmedizin Berlin will ensure GCP-compliant data analysis and clinical trial closure.

Work Package 5 – Health economic analysis

In WP5, health economics analyses will be led by York to inform HTA considerations on the use of implantable cardioverter defibrillators guided by personalised risk predictions. In addition, specific national requirements for health economic assessments and decision-making on implementation and reimbursement will be determined by University of Bayreuth. York will develop the cost-effectiveness analysis model to evaluate the value for money of the risk prediction tool to guide personalised treatment decisions to prevent sudden cardiac death. To this extent, York will first analyse the (health-economics-relevant) data made available by the consortium partners with a view to derive pre-RCT input parameters for the cost-effectiveness model. The model’s inputs will be updated with estimates derived from the analyses of the data obtained in WP3 in order to derive the final version of the cost-effectiveness analysis model. A value-of-information analysis will be conducted as part of this work, to help identify the areas in which further research would be most valuable from the societal point of view.

Work Package 6 – Ethical und legal aspects of personalised ICD implantation

In WP6, AMC will examine the major ethical and legal issues that need to be overcome before a predictive model can be implemented throughout Europe, including data sharing, data sovereignty, GDPR implementation, self-determination, patient autonomy and ethical aspects of implementing personalised medicine guidelines. As part of this WP, a study on the patients’ perspective on the implementation of a predictive model will be performed through an international survey of patient preferences and a comparative analysis including the handling of regional differences, as well as to normative examinations. Moreover, AMC will develop a template matrix regarding data security and data governance to provide practical ethical and legal guidance to all partners.

Work Package 7 – Dissemination and implementation into guidelines

In WP7, ESC will ensure inclusion of the risk prediction and prevention in European clinical practice guidelines depending on the project results. All partners will collaborate in dissemination and communication efforts, e.g. academic partners will publish scientific papers, ESC will publish guidelines, payers will focus on reimbursement procedures and GHF will communicate project results and recommendations to patients, their families and the general public.

Work Package 8 – Project management

WP8 is dedicated to the organisational aspects of running such a large research collaboration. The tasks planned will ensure that the project’s main objectives are realised on schedule and within budgetary limits, and that activities of all partners involved are in conformity with the EC contract and the consortium agreement.

Work Package 9 – Ethics requirements

This work package sets out the ethics requirements that the project must comply with.