Facilitating the conduct of multinational clinical studies of orphan devices and/or of highly innovative (“breakthrough”) devices

This topic aims at supporting activities that are enabling or contributing to one or several expected impacts of destination “Maintaining an innovative, sustainable, and competitive EU health industry”. To that end, proposals under this topic should aim to deliver results that are directed, tailored towards and contributing to all the following expected outcomes:

• Healthcare providers increase their hands-on experience regarding the clinical use of orphan devices^[1] and/or of highly innovative (“breakthrough”) devices and get timely access to such devices with demonstrated clinical benefits;
• Developers and manufacturers collect and obtain scientific evidence on their proposed intervention/ approach with the device under investigation;
• Patients benefit from the development, studies and use of orphan devices and/or of highly innovative (“breakthrough”) devices;
• Companies in the EU and associated countries get a better market position in this field and improve their knowledge on how to conduct multinational clinical studies for these devices.

The focus of this topic is on multinational clinical studies^[2] of orphan devices^[3] and/or of highly innovative (“breakthrough”) devices, including digital and Artificial Intelligence (AI) based tools and techniques.

The emphasis within rare disease research and innovation has predominantly centred on pharmaceuticals, leaving a noticeable gap in the support for developing orphan devices. Orphan devices are specifically intended for use in rare diseases or conditions or in specific indications for rare cohorts of patients with an otherwise non-rare disease or condition. As, by their nature, orphan devices are intended for use in a small number of individuals each year, often infants and children, generating clinical data within an appropriate period of time and conducting clinical investigations is especially challenging due to low patient recruitment volumes.

Besides orphan devices, also highly innovative (“breakthrough”) devices are in the scope of this topic if they are expected to provide major clinical benefits for the treatment, diagnosis or prevention of a life threatening, seriously debilitating or serious and chronic disease or condition, regardless of whether they target small patient populations. Highly innovative (“breakthrough”) devices^[4] aim to address unmet medical needs. ‘Unmet medical needs’ should be understood as a condition for which there exists no satisfactory method of diagnosis, prevention or treatment in the EU or, even if such a method exists, in relation to which the device concerned will be of major advantage to those affected^[5]. Those may include devices using digital tools and AI based technologies.

Developers of such devices often face challenges to generate clinical data in the pre-market phase in a timely manner.

Time and cost of clinical data collection can adversely affect public health by significantly delaying the availability of devices needed to treat or diagnose rare diseases or conditions or that may improve patient care or public health. Many devices are used off-label to respond to this unmet need. Nonetheless, a high level of clinical evidence based on thorough clinical data is needed to ensure patient safety.

Clinical development strategies for implementing multinational clinical studies have the potential to offer improved efficiency and to reach larger patient samples. Challenges may arise from the potential uncertainty regarding how regional disparities in regulatory, clinical, business, ethical and cultural practices may affect study design, conduct, data interpretation and various other outcomes.

This topic targets those challenges by supporting multinational studies aiming to gather pre- or post-market clinical data to demonstrate the device’s safety and performance (including determination of any undesirable side-effects and their acceptability when weighed against the expected clinical benefits).

The proposals should demonstrate that they address all the following activities for a device that is an orphan device or a highly innovative “breakthrough” device (or both), at any point of the pre-or post-market stage, including the development stage, with the overall purpose to generate data in support of CE marking under the Regulations on medical devices (MDR) or in vitro diagnostic medical devices (IVDR):

• Design and conduct multinational clinical studies in a minimum of two different countries in the EU or Associated Countries, with a focus on orphan devices and/or highly innovative (“breakthrough”) devices, with a view to demonstrate the safety and clinical performance of the device(s) subject to the study.
• Present a sound clinical study feasibility plan, including an appropriate patient selection and realistic recruitment plans at different sites, justified by scientific publications or preliminary results. Proposals should adopt a gender-sensitive and intersectional approach, considering individual characteristics such as gender, sex, race, ethnicity, disability and age. Additionally, socioeconomic, lifestyle and behavioural factors should be taken into account. For this, the topic requires the effective contribution of social sciences and humanities (SSH) disciplines and the involvement of SSH experts, institutions as well as the inclusion of relevant SSH expertise, in order to produce meaningful and significant effects enhancing the societal impact of the related research activities.
• Demonstrate potential clinical benefit^[6] for patients and healthcare providers, including quality of life and consideration of patient-reported outcomes when relevant.
• Involve patients, patient organisations, carers and healthcare professionals in the design of the clinical studies.
• Identify, collect and record relevant good practices and experiences related to the design, conduct, sample handling, data analysis and results reporting of multinational clinical studies. In addition, provide appropriate recommendations and lessons learned.
• For multinational clinical studies, authorisation for the study approval by more than one national competent authority may be necessary. Develop a regulatory strategy and interaction plan for generating appropriate evidence as well as engaging with regulators and other relevant bodies (e.g., European Medicines Agency (EMA), EMA expert panels^[7], national regulators, Health Technology Assessment bodies, etc.) in a timely manner. Consider also the potential for future regulatory impact of the results.

Proposals may include multiple devices, but the minimum expected is one device.

Participation of small and medium-sized enterprises (SMEs) is strongly encouraged.

For orphan devices or highly innovative devices relevant to rare disease patients, applicants should look for complementarities and potential synergies with actions implemented under ERDERA^[8] the co-funded European Partnership on Rare Diseases proposed under Horizon Europe^[9], as well as synergies with actions implemented under the EU4Health programme.

The Joint Research Centre (JRC) may participate as a member of the consortium selected for funding. Proposals should consider the involvement of the European Commission's JRC regarding its experience in this field and with respect to the value it could bring in providing an effective interface between research activities and pre-normative science as well as strategies and frameworks that address regulatory requirements. In that respect, the JRC will consider collaborating with any successful proposal and this collaboration, when relevant, should be established after the proposal’s approval.

Applicants should provide details of their clinical studies^[10] in the dedicated annex using the template provided in the submission system. As proposals under this topic are expected to include clinical studies, the use of the template is strongly encouraged.

[1] For the purpose of this topic, the reference to ‘devices’ includes both medical devices and in vitro diagnostic medical devices, unless otherwise specified.

[2] See definition of clinical studies in the introduction to this work programme part.

[3] A device should be regarded as an ‘orphan device’, if it meets the following criteria: i) the device is specifically intended to benefit patients in the treatment, diagnosis, or prevention of a disease or condition that presents in not more than 12.000 individuals in the European Union per year and ii) at least one of the following criteria are met:

- there is insufficiency of available alternative options for the treatment, diagnosis, or prevention of this disease/condition, or

- the device will offer an option that will provide an expected clinical benefit compared to available alternatives or state of the art for the treatment, diagnosis, or prevention of this disease/condition, taking into account both device and patient population-specific factors. MDCG 2024-10 Guidance on clinical evaluation of orphan medical devices: https://health.ec.europa.eu/document/download/daa1fc59-9d2c-4e82-878e-d6fdf12ecd1a_en?filename=mdcg_2024-10_en.pdf.

[4] See Appendix 8 to MEDDEV 2.7/1 revision 4 (https://ec.europa.eu/docsroom/documents/17522/attachments/1/translations) or the FDA’s Breakthrough Devices Program (https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program).

[5] Based on Article 4(2) of Commission Regulation 507/2006 which defines the term ‘unmet medical needs’ in the field of medicinal products.

[6] ‘Clinical benefit’ is defined in the Medical Device Regulation (EU) 2017/745, Article 2(53) as follows: Clinical benefit means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health.

[7] EMA pilots scientific advice for certain high-risk medical devices - European Medicines Agency (EMA): https://www.ema.europa.eu/en/news/ema-pilots-scientific-advice-certain-high-risk-medical-devices

[8] ‘European Rare Diseases Research Alliance’, https://erdera.org, https://cordis.europa.eu/project/id/101156595

[9] https://ec.europa.eu/info/funding-tenders/opportunities/portal/screen/opportunities/topic-details/horizon-hlth-2023-disease-07-01

[10] Please note that the definition of clinical studies (see introduction to this work programme part) is broad and it is recommended that you review it thoroughly before submitting your application.