Registering a device investigation while Eudamed is delayed
The EU Medical Device Regulation ties the registration of a clinical investigation, its application documents and its results to the European Database on Medical Devices, Eudamed, which was not ready when the Regulation was first due to apply. Until it is, a sponsor works under the provisions the Regulation leaves in force, decides whether to register an investigation prospectively in an existing registry or to wait for the database, and prepares the documents the database will later make public.
Eudamed's clinical investigation module
Under the EU Medical Device Regulation, conducting clinical investigations requires transparency and public disclosure of key information and documents, and the key factor in all these disclosure activities is a fully functional new Eudamed (Article 73). Eudamed is the platform to be used for the prospective registration of clinical investigations for medical devices under the Regulation. Article 73 requires the registration of clinical investigations and the publication of their results to be on a publicly accessible electronic system that is part of Eudamed, and Eudamed's module for clinical investigations will be publicly accessible.
This module, the Clinical Investigation and Performance Studies module, will contain the key data from clinical investigations. Under Article 73, its user interface will be available in all official EU languages, and each clinical investigation will be assigned its own identification number. The sponsor will apply to conduct an investigation, follow it up, report its results and terminate it through the module, and serious adverse events and device deficiencies that arise during the investigation will be reported through it. Member states will be able to exchange certain sensitive information on investigations that only they and the Commission can access, and participants' personal information will not be accessible to the public. Sponsors' confidential information, including the investigator's brochure and the status of the device's conformity assessment, will not be accessible to the public unless there is an overriding public interest in disclosing it, and all other information, the clinical investigation report included, will be accessible to the public.
The Regulation's three disclosure duties
The Regulation sets three disclosure requirements for a clinical investigation. The first is registration: an investigation must be registered in the electronic system for clinical investigations within Eudamed (Article 73(1)), each investigation is assigned a unique identification number (Articles 70(1) and 73(1a)), and this information is publicly accessible through Eudamed (Article 73(3)). The second is the application documents: the clinical investigation application, the clinical investigation plan and the investigator's brochure must be submitted in the same electronic system (Annex XV, Chapter II), the plan must describe the policy on the publication of results (Annex XV, Chapter II, 3.17), and this information is potentially publicly accessible through Eudamed (Article 73(3)). The third is results reporting and publication: a clinical investigation report will be prepared within one year of the end of the investigation, or within three months of its early termination or temporary halt, irrespective of the outcome, and it is accompanied by a summary easily understandable by the intended user (Article 77(5)). Results should be published according to legal requirements and recognised ethical principles (Annex XV, Chapter II, 3.17), which the Regulation's preamble names as the latest version of the Declaration of Helsinki and ISO 14155:2011, since replaced by ISO 14155:2020 (Preamble 64). This information too is publicly accessible through Eudamed (Article 73(3)).
Eudamed's delay
The new Eudamed and all its modules were intended to replace the existing Eudamed and to be available well in time for the Regulation's date of application, 26 May 2020, but by late 2019 it had been announced that Eudamed would be delayed by at least two more years. By early 2023 delays to Eudamed's original go-live date of May 2020 had been announced three times, in October 2019, October 2021 and July 2022. At that point the Clinical Investigation and Performance Studies module was one of three of Eudamed's six modules still in various stages of readiness. Its first playground launch was in mid-July 2022. All modules were expected to be fully functional by the second quarter of 2024, and the Clinical Investigation and Performance Studies module was one of four whose use was to become mandatory by the end of 2024, the remaining two becoming mandatory by the second quarter of 2026.
The delay affects many of the Regulation's activities, and the processes surrounding clinical investigations are especially important for novel and high-risk devices for which clinical data must be generated.
The provisions in force until Eudamed is functional
The Regulation seems to have anticipated the delay in Article 123d: until Eudamed is fully functional, the corresponding provisions of the Active Implantable Medical Device Directive (90/385/EEC) and the Medical Device Directive (93/42/EEC) continue to apply to the exchange of information, in particular on vigilance reporting, clinical investigations, registration of devices and economic operators, and certificate notifications. So clinical investigation application and approval and the reporting of results follow the requirements of each member state, which are not harmonised across the EU. At a minimum each member state requires a unique study ID and registration on a public site, but the preferred registration platform can vary.
The existing device database under the two directives cannot be used to register clinical investigations in Eudamed's place, the way the existing EU Clinical Trials Register is still used for prospective registration and the posting of results for medicines, because it is not designed for clinical investigation disclosure requirements: it is a central repository for information on market surveillance exchanged between national competent authorities and the Commission, its use is restricted to national competent authorities, and it is not open for consultation or publicly accessible. Until Eudamed is fully operational, MDCG 2021-1 provides guidance on alternative technical solutions.
Registering prospectively or deferring registration
Without a fully functional new Eudamed, a sponsor has two options: register the investigation prospectively in another existing clinical trial registry, such as one of those listed in the World Health Organization's International Clinical Trials Registry Platform, or defer registration until Eudamed is available, which is retrospective registration. In 2020 the approach among device manufacturers was to prepare all Eudamed requirements proactively, not only those on clinical investigations, and upload them retrospectively once Eudamed was operational. But deferring registration does not meet the requirement for prospective registration of clinical study information that the healthcare sector has established over the years.
Outside the Regulation, other legislation and guidance documents, including those the Regulation references, require prospective registration and the posting of clinical investigation results, so manufacturers should consider registering their investigations prospectively in existing registries. The Regulation refers to the most recent version of the Declaration of Helsinki, and the 2013 version states that every research study involving human subjects must be registered in a publicly accessible database before the first subject is recruited. ISO 14155:2020, released in July 2020, added Section 5.4 on registration in a publicly accessible database. It states that, in accordance with the Declaration of Helsinki, a description of the clinical investigation shall be registered in such a database before recruitment starts, updated throughout the investigation and completed with the results, and it does not specify any preferred registry. The Regulation also calls for a clear policy for publishing investigation results and places increased emphasis on the use of literature data in a manufacturer's clinical evaluation. To publish in reputable biomedical journals, device manufacturers or sponsors must consider the International Committee of Medical Journal Editors' recommendations, which as updated in December 2019 require a clinical study to be preregistered in a registry that is a primary register or a data provider of the WHO International Clinical Trials Registry Platform.
Until Eudamed is available, posting on other databases is recommended, so that manufacturers can meet the requirements for clinical investigation transparency and disclosure while sharing the clinical investigation information necessary to maintain public trust. Manufacturers will benefit from fulfilling those requirements proactively, as data sharing will help maintain public trust in the medical device industry. Data submitted to existing clinical trial registries can also easily be reused for Eudamed, whose launch had in 2020 been delayed until 2022.
Registries open to a device investigation
In the absence of an operational Eudamed, sponsors can use several publicly accessible registries, including those that are part of the WHO International Clinical Trials Registry Platform. ClinicalTrials.gov is by far the largest clinical trial registry globally, covering drugs, biologics, surgical procedures and devices, and although it is not a primary WHO registry, it is recognised as a WHO data provider. The European Clinical Trial Register is a primary WHO registry covering interventional clinical trials on medicines and gives no information on clinical trials of medical devices and procedures, but it does not preclude sponsors of devices, especially of drug-device combination products, from using it to register a clinical investigation. Germany and the Netherlands have country-specific registries in the WHO platform, and neither distinguishes trials of medicinal products from those of medical devices; both cross-reference the International Committee of Medical Journal Editors' recommendations. Sponsors and manufacturers should still consult the national competent authorities of the relevant member state about their preferred register, if any.
Updating the entry and preparing the documents for disclosure
Registration of the clinical investigation protocol is the first step. The sponsor also needs to update the registry entry for changes and amendments and post results once the investigation is completed. The timing of results depends on the register, and in the EU it is generally one year after the end of the investigation for adult subjects, the end being the date of the last visit of the last subject enrolled (Article 77(2)). Under the Regulation, disclosure of results consists of making the clinical investigation report and the lay summary publicly available through Eudamed (Article 77(5)), and other documents such as the clinical investigation plan and the investigator's brochure may also be disclosed. Any information, data or document posted publicly, on any register, database or electronic system, must comply with the personal data protection requirements of the General Data Protection Regulation. So the clinical investigation report and other documents should be written with data privacy in mind, so that they are ready for disclosure when Eudamed is.