Fostering Pragmatic Comparative-Effectiveness Trials in Non-communicable Diseases (EffecTrial)

Beneficiary & submission

Please, for all details on the scope and the requirements of the call, as well as national/regional specific requirements, refer to the full call text published on ERA4Health website (LINK EffecTrial 2025) Aim of the call: The EffecTrial Call has the aim to support randomised, interventional and pragmatic comparative-effectiveness multi-country Investigator-Initiated Clinical Studies (IICS) and to encourage and enable transnational collaboration between clinical and public health research teams that conduct comparative-effectiveness multi-country IICS. Proposals should address all the 4 following points: 1.Be a pragmatic comparative effectiveness trial, designed as randomised interventional trial. 2.Compare the use of currently approved healthcare interventions either to each other or to the current standard of care. 3.They shall consider healthcare interventions which could include but would not be limited to: diagnostic, screening, prevention and treatment interventions. The interventions can be pharmacological as well as non-pharmacological procedures like nutrition and/or lifestyle interventions, surgery, prognosis methods, use of medical devices, eHealth and digital interventions and other health interventions. 4.These interventions shall have high public relevance only in the fields of these specific diseases or conditions (that are of equal importance): -Cardiovascular diseases -Metabolic disorders -Nutrition and lifestyle-related diseases -Non-communicable respiratory diseases The focus of the multi-country Investigator-Initiated Clinical Studies should primarily address at least one of the abovementioned principal diseases/conditions, although the proposals can also address several of the mentioned diseases/conditions and/or other related comorbidities. Beyond the research topics, several following requirements and recommendations as well as the Out of scope conditions should be considered by applicants, including approaches to Responsible Research and Innovation (RRI) (please consult the Call text document and the Guideline for applicants document for further information, including the RRI guidelines and specific national/regional restrictions). Submission: The submission and evaluation procedure will be in two-steps for joint applications. The second step of the evaluation process will include a rebuttal stage and an interview with the coordinating investigator and the representative of the sponsor. For both steps, proposals (in English) shall be prepared by the consortium partners following the ERA4Health template (included in the website: LINK) and must be submitted via the electronic submission system tool Pt-outline (LINK will be published in the website EffecTrial 2025 as soon as available) by the project coordinator. Eligibility criteria Applicants must demonstrate that the research team contains the necessary breadth and depth of expertise in all the methodological areas required to deliver the proposed study. Principal Investigators should demonstrate experience and expertise in the conduct and delivery of clinical trials. Size of the consortium The number of participants and their research contribution should be appropriate for the aims of IICS and be reasonably balanced in terms of international participation. Each IICS should represent the critical mass to achieve ambitious scientific goals and should clearly demonstrate an added value from working together. Only transnational studies will be funded. A minimum of 3 (three) and a maximum of 5 (five) countries should be represented in the consortium (the countries of the collaborators (see below) are not considered in this number). A maximum of 3 (three) collaborators per consortium is allowed. Collaborators are self-funded partners. Please check the call text for further conditions that apply to the composition of consortia and for collaborators. Each study consortium must nominate a clinical study coordinator among its partners (NOT a collaborator). The clinical study coordinator cannot be an enterprise. Each Principal Investigator can submit only 1 (one) pre-proposal as coordinator or as simple partner (i.e. the coordinator or the partner of a proposal cannot be partner in another proposal). Financial and legal modalities Clinical study partners will be funded by their relevant national/regional funding organisations. Therefore, eligible costs, funding rules and other specific aspects allowed may vary between the respective funding organisations (see Annex I). Due to these differences, it is recommended that each clinical study partner defines its own budget in accordance with the funding rules of its own country/region. For information on the specific funding rules and eligibility criteria of the national/regional funding organization, please carefully read Annex I and the national/regional announcements of the call and the guidelines for applicants. Applicants are consequently strongly encouraged to contact their national/regional contact points to check their national/regional eligibility rules before submission (see Annex I). Please note in some countries/regions this may be mandatory. In addition, and with the respect of specific conditions detailed in the guidelines for applicants, an additional budget representing up to 15% of the total budget requested to the national/regional funders could be requested for covering the conduction of cross-cutting management activities (i.e. clinical study management activities at consortium level) such as trial authorizations, drug, safety and data management under the responsibility of the coordinating investigator and his/her legal entity. See section "Funding Mechanism” in the Guideline for applicants for more details. Please note that if a partner is found to be non-eligible at any step of the process by one of the funding organisations, the entire proposal could be rejected without further review. Therefore, please make sure to carefully read and follow the respective national/regional regulations in Annex I. Formal check and evaluation of pre-proposal After submission, the JCS will check all pre-proposals to ensure that they meet the call’s formal criteria (date of submission; number of participating countries; inclusion of all necessary information in English; appropriate limits on length). In parallel, the JCS will give access to the pre-proposals to the national/regional funding organisations, which will perform a check for compliance with national/regional regulations. The pre-proposal of each consortium passing the eligibility check (JCS and country/region) will be evaluated by external reviewers. Evaluation of a pre-proposal will be made by three reviewers with a scientific/clinical background. Potential conflicts of interests of the evaluators will be taken into consideration during the allocation of the proposals. The reviewers will perform the assessment of the pre-proposals and complete a written evaluation form with scores and comments for the evaluation criteria that they should evaluate. The evaluation will include an eligibility check that the proposal is included in the call scope (e.g. disease area, type of trial, etc). Based on the scores in the written evaluations, a ranking list will be established. The Clinical Study Steering Committee (CLSC) members will meet to decide which proposals will be invited to submit a full proposal based on the reviewers’ recommendations and to ensure a reasonable balance of requested and available national/regional budgets. Pre-proposals which do not pass this assessment will not be invited for the full proposal stage. All consortia will receive the full evaluation reports, excluding the evaluation scores. Formal check and evaluation of full proposals After submission, the JCS will check the full proposals to ensure that they meet the call’s formal criteria and have not changed substantially from the respective pre-proposals before sending them to the reviewers. Each full proposal will be allocated to three reviewers with a scientific/clinical background and taking into consideration the potential conflicts of interest between the reviewers and the applicants. One of these three reviewers will have specific expertise in clinical trial methodology and biostatistics. The reviewers will perform the assessment of the full proposal and complete a written evaluation form with scores and comments for each criterion (see evaluation criteria below). Additionally, a Patient Advocacy Committee will assess the patient involvement and relevance for patient needs in the full proposals and will complete a written review. Each coordinator is provided with the opportunity of getting acquainted with the assessments and commenting on the arguments and evaluations of the reviewers (see section “Rebuttal”) before the Peer Review Panel (PRP) members meet to discuss each full proposal in a PRP meeting. In addition, an online interview of the coordinator and the person responsible for the implementation of clinical studies in the sponsor organisation, according to the organisation's legal structure and identified by the consortia in the full proposal, will take place. This interview will evaluate the capacity of the sponsor and the coordinator to implement the clinical study. Apart from the coordinator and the representative of the sponsor, a maximum of two other additional representatives of the research consortium can attend this online interview, in case that their specific expertise is needed to demonstrate the capacity to implement the clinical study (e.g. biostatistician of the research consortium). During the PRP meeting, the reviewers will discuss all proposals and produce a ranking list of proposals recommended for funding. Two representatives of the Patient Advocacy Committee will be invited to take part in the discussion and present their assessment of the patient involvement of each proposal during the PRP meeting. They will have voting rights similar to the scientific evaluators attending the PRP, in case that a voting procedure is needed to take the final decision. Evaluation Criteria Proposals not relevant to the call topic and objectives (out of the scope) will be declared ineligible and will not be funded and forwarded to full proposal stage independently of their scientific quality. Pre-proposal 1.Excellence -Scientific relevance, scientific quality and target of an unmet clinical need. -Previous research and evidence, supporting the objective of the trial and the estimated effect size (i.e. background, state of the art); adequacy of search strategy to previous research evidence. 2.Impact -Impact on patient benefit, clinical practice, and the healthcare system (e.g. socio-economic impact) -Transnational added value rather than a national/regional study -Involvement of patients and other relevant stakeholders the design and execution of the IICS and the dissemination of its results. -Quality of the approach to RRI in realising the scientific and clinical objectives. 3.Quality and efficiency of the implementation -Adequacy of study design, suitability of methodological approach -Ethical acceptability, feasibility of the project -Quality of the research team (complementarity of expertise, expertise in relation to the project, expertise in multicentric clinical studies). Full proposal 1. Excellence - Innovation and scientific relevance of the study and how it will contribute to extend the knowledge beyond the state of the art, potential to change the current medical/clinical practice. -Relevance for patient needs. -Scientific quality and pertinence of the objectives -Soundness of the evidence presented (supported by an adequate search strategy) in support of the medical need, the study rationale, and the estimated effect size; including presentation of other existing trials addressing a comparable question (if applicable) and documentation of clinical safety of the agent(s), if applicable.     2.  Impact   -Added value of transnational collaboration   -Expected impact of the study at short-term and long-term level related with the duration and budget. Potential of the expected results in terms of potential impact for: patients, public health, clinical practice and/or other socio-economic health relevant applications and potential commercial exploitation.  -Effectiveness of proposed measures to exploit and disseminate the study results (including engagement with patients and other public groups) and manage research data -Substantive involvement of pertinent patient organisations or patient representatives or other relevant stakeholders (in planning and execution of the trial, and dissemination of the results).  -Appropriate integration of RRI dimensions within the study design. 3. Quality and efficiency of the implementation -Adequacy, coherence, and feasibility of the study design to verify the hypothesis(es) and to respond to the medical need     -Feasibility of the study according to the planned duration and available budget    -Coherence and effectiveness of the work plan and study design (appropriateness of the allocation of tasks, resources, timeframe, infrastructural support to the clinical trial -Feasibility of recruitment (Feasibility of recruitment rates; Feasibility of the trial in the proposed population/time frame; Adequateness of the site selection criteria; Adequateness of the documented feasibility of the recruitment by the recruiting centres. -Appropriateness of the management structures and procedures, including risk and innovation management and the communication flow among partners and among the different boards/committees.    -Description of potential risks, including the recruitment risks, and adequate pre-planned counter measures, including involvement of and charter for independent data monitoring and safety committee where relevant  -Adequacy of resources, staff and activities dedicated to RRI, including ELSI (Ethical, Legal and Social Issues) aspects, in design and implementation of the clinical study. -Adequacy of the plan for compliance with regulatory requirements and international standards (GCP, Declaration of Helsinki, CONSORT-Statement). -Management of research data according to FAIR data principles and where relevant, adequateness of planned strategies for long-term accessibility and potential re-use of study data.      4.Competence of the research team and quality of research environment   -Competence and experience of participating partners (previous work in the field, specific technical expertise, proven track record in multicentre clinical trials)    -Complementarity and completeness of skills within the consortium (clinical, methodological, biostatistical expertise)    -Meaningful links to multinational networks and existing infrastructures.    5.Methods and Design of the clinical trial     -Relevance and adequateness of the outcome measures with respect to the overall objectives of the trial; Relevance of chosen primary and secondary outcomes for patients.  -Adequacy of the target and study population and of the controls and/or comparators     -Adequacy of the consideration of the potential clinical and epidemiological consequences of the trial results    -Adequacy of randomisation criteria  -Adequacy of methods against bias and the proposed strategy for statistical and biostatistical analysis and sample size calculation     -Impact of non-compliance and missing values on the sample size.  A consortium will not be funded if the sponsor does not present the capacity to implement the clinical study, independently of the scientific quality of its proposal. Scoring system Evaluation scores will be awarded for each main criterion. Each criterion will be scored out of five. The weight of each main criterion is equal.  0 = Failure. The proposal fails to address the criteria or cannot be assessed due to missing or incomplete information. 1 = Poor. The criteria are inadequately addressed, or there are serious inherent weaknesses. 2 = Fair. The proposal broadly addresses the criteria, but there are significant weaknesses. 3 = Good. The proposal addresses the criteria well, but a number of shortcomings are present. 4 = Very Good. The proposal addresses the criteria very well, but a small number of shortcomings are present. 5 = Excellent. The proposal successfully addresses all relevant aspects of the criteria. Any shortcomings are minor. Only integer values are accepted. The maximum scoring for pre-proposals will be 15 points and for full proposals 25 points.  Full proposal will be considered fundable if the threshold score for individual criterion is 3 points and the overall score is at least 17 points. Rebuttal stage Before the PRP members meet to discuss the full proposals in a PRP meeting, each coordinator is provided with the complete reviewers’ assessments. This stage allows applicants to comment on factual errors or misunderstandings that may have occurred in the review process and to reply to reviewers’ questions. However, issues not related to reviewers’ comments or questions cannot be addressed and the work plan cannot be modified at this stage. The applicants will have up to 12 calendar days (25 August to 05 September, 2025) for this optional response to the reviewers’ comments. Answers sent after the notified deadline, or not related with reviewers’ comments or questions will be disregarded. Interview of the coordinating investigator and the representative of the sponsor The coordinating investigator and the representative of the sponsor will be jointly interviewed by an interview committee (formed by 3 experts that will be part of the PRP) to determinate the capacity of the coordinator to implement the proposed clinical study and of the sponsor to manage it. The JCS will attend the interviews as observer. During the interview, a qualitative assessment of the feasibility of the trial will be performed. All PRP members will receive the feedback of the interview committee (which will be a qualitative gradual assessment of the feasibility of the study) which will be considered during the PRP discussion in the PRP meeting. PRP meeting The JCS will give the PRP members access to all full proposals, reviews and rebuttals, outcomes of the interview of the coordinators and sponsors, avoiding any conflicts of interest. The PRP will meet to discuss each proposal and, after consideration of the evaluation criteria, external reviews (patient representatives), rebuttals, interview outcomes, their own reviews and discussions, the PRP will assign final scores, make a classification of the proposals, and rank proposals recommended for funding. The final summary review report prepared by the PRP members will be sent to the respective coordinating investigators. Ethical clearance After the PRP meeting, ethics experts will remotely check the full proposals, which are recommended for funding by the PRP and selected for funding by the CLSC, for alignment with ethical norms and regulations. A meeting will also be organised for a discussion between the different ethics experts, if necessary. The ethics experts may ask the consortium for clarifications on the ethical points related to the proposed research approaches. The Ethics experts may highlight some vigilance points that need to be monitored during the implementation of the funded clinical study. Only those proposals approved by both the scientific evaluation and ethical assessment (complying with all central Horizon Europe and regional/national ethical requirements), will be funded. Clinical study selection and reconfiguration process A first selection of the clinical studies for funding identified as the main list will be made by the national/regional funding organisations based on the ranking list established by the PRP, available funding and the ethical clearance outcomes. After the establishment of the main list, additional clinical studies that have been assessed to be of good quality by the evaluation process could be invited to restructure their consortia, if there is any remaining funding budget. Research consortia will be provided 10 calendar days for this reconfiguration process. Restructuring may take place, taking into account the boundary conditions that are specified in the call text. The clinical studies that are invited to resubmit their proposal with a restructured consortium must still meet the eligibility criteria of the call. In principle, the JCS will check the restructuring process. Only if needed, it will be checked by an independent expert(s) or PRP member(s) to ensure that there is no loss of quality in the proposal. The selection of the clinical studies to be funded among the resubmitted proposals will be guided by the outcome of the evaluation process and the availability of national budgets. After the approval of the CLSC, a second selection of studies for funding can be established. IMPORTANT: If at any point of the proposal selection phase, or the clarification and negotiation phase, a clinical study partner or collaborator with a crucial role in the study (e.g. to ensure the number of patient recruitment, drug/intervention provider) withdraws from the clinical study, is ineligible or not able to fulfil its commitment as stated in the proposal, the proposal is irrevocably disqualified without the opportunity of restructuring. Furthermore, if at any point, the coordinating investigator withdraws from the clinical study, is ineligible or not able to fulfil its commitment as stated in the proposal, the clinical study proposal is irrevocably disqualified without the opportunity of restructuring. In any case, a restructuring of the consortium can lead to a re-evaluation of the proposal. Coordinating investigators having submitted an eligible proposal will be informed about the funding recommendation regarding their proposal by the JCS. Coordinating investigators are responsible to communicate this information to their clinical study partners. Redress procedure Applicants can appeal against the evaluation outcome if they suspect a breach in the application of the evaluation and selection procedures. This redress procedure only covers the procedural aspects of the evaluation and/or central formal eligibility checks. Requests for redress on national/regional eligibility decisions will not be handled by the JCS and need to be addressed to the responsible national contact point. A mere disagreement with peer reviewers or panel members’ comments are not grounds for an appeal. The redress procedure will not call into question the scientific or technical judgement of appropriately qualified experts. In this case the applicants shall submit their appeal to the JCS via email (EffecTrial@isciii.es) up to 7 calendar days after the date of the eligibility check or evaluation outcome email notifications by the call secretariat at the end of each step (eligibility check, first or second evaluation stage). Please check the call text for further information regarding this redress procedure.