The Medical Device Coordination Group (MDCG), an advisory body of the European Commission focused on the improvement of the regulatory framework in the sphere of medical devices, issued guidance dedicated to the safety reporting in clinical investigations under the Medical Device Regulation 2017/745 (MDR).
Safety Reporting in Brief
Accordance with the MDR, the responsibilities on safety reporting shall be duly carried out by the entity responsible for the medical device being placed on the market. In particular, the aforementioned Regulation states that the scope of cases and events to be reported includes the following ones:
a. Any serious adverse event that has a causal relationship with the investigational device, the comparator, the investigation procedure, or where such causal relationship is reasonably possible;
b. Any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate;
c. Any new finding in relation to any event referred to in points a) and b).
The particular period of time within which it is necessary to submit the report depends on the severity of the event. In certain cases, it is required to submit the initial incomplete report to provide the regulating authorities with the general information about the event and then later submit the final complete report based on the rigorous investigation.
It is important to clarify that the reportable events that occurred in the course of a clinical investigation should be reported by the sponsor of such investigation (e.g. the manufacturer of the device, its authorized representative, or any other party).
The scope of the present MDCG guidance also covers the post-market clinical follow up (PMCF) investigations to be performed regarding the CE-marked medical device placed on the EU market.
As it is also stated in the document, the reporting procedures set forth by the Regulation are partially impacted by the delay in the implementation of the EUDAMED – the main European database that would contain all important information related to medical devices available in the EU Member States, including the details about the device itself, and also about the medical device manufacturers, importers, authorized representatives, notified bodies, as well as about any special measures taken regarding the particular devices, such as granting a certificate or marketing authorization, recalls or withdrawals of the devices from the market. Since the actual launch of the EUDAMED would be delayed due to the numerous factors, the MDCG guidance describes the way the reporting obligations should be performed provided that the European database would be unavailable for a certain period of time necessary to deploy its modules. The document also describes the requirements related to the Serious Adverse Event (SAE) reporting.
Clinical Investigations of Medical Devices
The present MDCG guidance is intended to assist medical device manufacturers and other parties involved in maintaining compliance with applicable requirements related to reporting, set forth by the Medical Device Regulation. In particular, the scope of the document covers the following types of investigations:
- Pre-market clinical investigations to be performed regarding:
a. Non-CE marked devices,
b. CE marked devices used outside the intended use(s) covered by the CE-marking, and
c. Some additional studies covered by MDR Article 82.
The EU Member States are entitled to implement additional national requirements for clinical investigations, so besides the Regulation, the manufacturers should also comply with the appropriate national rules and regulations.
- Post-Market Clinical Follow Up (PMCF) investigations cover the situations when the CE-marked device is being properly used in accordance with its initial intended purpose indicated by the manufacturer.
It is also important to mention that in accordance with the transitional provisions, the scope of the guidance also covers ongoing clinical investigations commenced under the Medical Devices Directive 93/42/EEC (MDD) and Active Implantable Medical Devices Directive 90/385/EEC (AIMDD). As it is stated in the guidance, the reporting related to such trials should be performed in accordance with the requirements set forth by the MDR.
In a case, if the CE-marked medical device is being used in a clinical drug trial, the appropriate legislation regulating clinical drug trials should be applied.
The document also provides the most important definitions used to describe core concepts related to safety reporting in clinical investigations including, inter alia, the following ones:
Investigational devices – a device that is assessed in a clinical investigation. It is important to mention that this could be either CE marked or a non-CE marked device.
Adverse event – any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users, or other persons, in the context of a clinical investigation, whether or not related to the investigational device. The regulation also distinguishes a Serious Adverse Event (SAE) associated with a serious deterioration in the patient`s health.
Device deficiency – any issues related to the safety, effectiveness, or quality of the device, such as errors or malfunctions. This concept also covers cases when the information provided by the manufacturer is incorrect.
Clinical Investigation Reporting Requirements
The new MDCG guidance describes in detail the particular procedures to be applied by medical device manufacturers and other parties involved for the purpose of the reporting in accordance with the Regulation 2017/745.
As it was explicitly stated in the guidance, the obligations related to using the EUDAMED database would become effective as soon as the database would become operating. The document also describes the way the reports should be provided before the actual launch of the EUDAMED. It is also important to mention that it is still unclear whether it would be necessary to upload retrospectively the reports related to the adverse events that took place earlier to the new database.
The document also provided additional information regarding the reporting timelines to be applied. In particular, the MDCG guidance states that:
All events resulting in serious disorder on injury, or other severe consequences, should be reported immediately, but no later than 2 calendar days after the sponsor of the appropriate clinical investigation become aware of the incident itself or obtained any additional information related to such event.
All other events or any new updates and findings should be reported immediately, but no later than 7 calendar days.
It is also important to mention that under certain conditions other reporting periods could be additionally agreed between the sponsors of the clinical investigations and regulating authorities.
Another important requirement relates to the way the investigator carrying out the clinical investigation shall provide the sponsor with the information subject to obligatory reporting. According to such information, the investigator shall duly inform the sponsor about any adverse events or other incidents subject to reporting immediately, but not later than 3 calendar days after the investigator become aware of such event.
Another important concept to be described is a causality assessment. According to the applicable regulation, it is necessary to perform a rigorous assessment to identify the relationship existing between the use of the device in question and the particular incident that occurred. The appropriate report should include the indication of one of the following levels of causality:
- Not related,
- Possible,
- Probable,
- Causal relationship.
This information is vitally important to assess whether the adverse event is a consequence of the impact caused by any errors or malfunctions of a medical device.
Summarizing the information described hereabove, the present MDCG guidance provides medical device manufacturers with the detailed information and recommendations on safety reporting in clinical investigations in accordance with the requirements set forth by the MDR providing that the new EUDAMED database is still waiting to be launched.
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