Safety reporting is a crucial aspect of a successful clinical investigation for medical devices. In addition to the Good Clinical Practice (GCP), stakeholders are required to comply with the Medical Devices Regulation (EU) 2017/745 (MDR) and follow the safety reporting MDCG guidance (2020-10/1) when conducting clinical investigations in Europe.

The current article aims to clarify the adverse events reporting expectations during clinical investigations in Europe.

Definitions

The MDR defines Adverse Events (AE), Serious AE (SAE), Device Deficiencies (DD) and Incidents as follows:

Adverse event (AE): 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.

Serious adverse event (SAE): any adverse event that led to any of the following:

  1. Death.
  2. Serious deterioration in the health of the subject, that resulted in any of the following:
    • life-threatening illness or injury,
    • permanent impairment of a body structure or a body function,
    • hospitalisation or prolongation of patient hospitalisation,
    • medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function,
    • chronic disease,
  3. Foetal distress, foetal death or a congenital physical or mental impairment or birth defect.

Device Deficiency: Any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer.

Incident: Any malfunctioning or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect.

Regulatory background for safety reporting

The transition from the Medical Devices Directive 93/42/EEC (MDD) to the MDR has impacted safety reporting procedures when performing clinical investigations. Whilst the MEDDEVs already included guidance documents regarding safety reporting and vigilance, the MDR and the MDCG 2020-10 sets more robust requirements that allow a a better traceability of events related to the procedure or the device. Besides complying with the MDR, it is fundamental to ensure that safety reporting for clinical investigations is performed according to the international standard ISO 14155:2020 on Good Clinical Practice (GCP).

In addition, the new MDR establishes a European database called EUDAMED, which will be used as an IT system for registration, collaboration, notification, and dissemination of clinical studies with medical devices, including safety reporting. Nevertheless, the full launch of EUDAMED has been delayed, and therefore safety reporting under this platform is unavailable for the time being.

To facilitate safety reporting under the MDR in the absence of EUDAMED, the MDCG published a guidance document for medical device manufacturers (MDCG 2020-10/1).

What to report?

MDR Article 80 (2) lists events that shall be reported while conducting a clinical investigation:

  1. Any SAE with a causal relationship with the investigational device, the comparator or the investigational procedure or where such causal relationship is reasonably possible.
  2. Any device deficiency that might have led to an SAE event if appropriate action had not been taken, the intervention had not occurred, or circumstances had been less fortunate.
  3. Any new findings in relation to any event referred to the previous points.

To shed further light on the causal relationship of the event with the procedure or device, MDCG 2020-10/1 defines how to classify SAE according to four levels of causality:

  • Not related
  • Possible: weak relation but cannot be ruled out completely.
  • Probable: relevant relation that cannot be reasonably explained by another cause.
  • Causal relationship: relation beyond a reasonable doubt.

Hence, sponsors are expected to report any possible, probable and causal SAE related to the investigational device or procedure. Note that when the level of causality is uncertain, the sponsor should not exclude the relatedness and the event should be classified as “possible”.

Please note that post-market clinical follow up (PMCF) investigations of CE-marked devices used within the intended use covered by the CE-marking should follow the vigilance reporting mechanisms.

To whom? When?

Reportable events must be reported to National Competent Authorities (NCA). The list and contact of such operating NCAs can be found on the Commission’s homepage and the following link. Additionally, member states may also require separate reporting to the ethics committee(s).

Regarding timelines, investigators must report to sponsors immediately, and no later than 3 calendar days after investigation site study personnel’s awareness of the event. Sponsor, on the other hand, and depending on the category of the clinical study and the severeness of the adverse event, must follow the reporting timelines as follows:

Table showing the timelines and entity to report adverse events

Additionally, note that in observational studies where the standard of care is kept, only non-expected side-effects that are not documented in the product information and quantified in the technical documentation shall be reported according to the surveillance/ vigilance plan.

How can AKRN support you?

AKRN’s clinical team has thorough expertise in designing, conducting, recording, and reporting clinical investigations, including safety reporting following MDR requirements. Our team specialises in:

  • Designing and conducting pre- and post-market clinical investigations across Europe
  • Package preparation and regulatory submissions to Ethics Committee and competent authorities
  • Designing and managing of CRFs and EDC platforms
  • Clinical project management
  • Site selection and qualification, and contact with key opinion leaders
  • Clinical Investigation monitoring
  • Data management
  • Biostatistics and data analysis
  • Medical writing

Please do not hesitate to contact us for further information regarding clinical investigations support for medical devices.

About the authors

Laura Martínez Rachadell, Ph.D. Clinical Research Scientist
Albert Negrete Hurtado, Ph.D. Regulatory Affairs Scientist
Ariadna Navarro Aragall, Ph.D. Associate Director RA & QA
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