Oct 20, 2020

Many medical device manufacturers will be strongly impacted by new requirements for more clinical evidence once the European Medical Devices Regulation (MDR) comes fully into effect in May 2021. In order to obtain and renew their CE Mark certifications, companies will need to collect this evidence via clinical investigations or post-market clinical follow-up (PMCF) activities.

The proper conduct of medical device clinical activities will be regulated by the MDR, by national laws and regulations and finally by Good Clinical Practice (GCP) standards such as ISO 14155.

Generally, any clinical activity will require Ethics Committee or Institutional Review Board review, and a positive assessment of a submitted research proposal from one of these entities is needed. Also depending on a device’s risk class, market approval status and study design, European Competent Authorities might need to be notified or even approve the research proposal before the clinical study may start.

Whereas requirements provided by the MDR are easily identified, it is more difficult to understand country-specific regulations and legislations, which are often not available in English.

In addition, GCP should be implemented for both clinical investigations and PMCF studies. In Europe, ISO 14155, whose update was published in July 2020, sets the rules for conducting clinical investigations. Some of the stipulations in the standard can be found in the MDR and Notified Bodies have reached consensus that compliance with ISO 14155:2020 will be a prerequisite for acceptance of clinical investigations—with few exceptions.

Clinical evidence for in-vitro diagnostics (IVDs)

Requirements for clinical evidence will also increase for in-vitro diagnostic devices (IVDs) with the implementation of the new European In-vitro Medical Devices Regulation (IVDR), which comes fully into effect in May 2022. For most IVDs a Notified Body (NB) body will need to be involved for CE-Marking, and it is expected that NBs will require more clinical evidence, especially for products whose specimen collection procedures pose a risk to subjects, and when the information obtained from the IVD is used to make patient management decisions.

The IVDR as well as national laws and regulations plus GCP standards including ISO 20916 oversee these clinical activities.

Clinical performance (evaluation) studies will also need Ethics Committee approval, and Competent Authorities may have to become involved in order to approve research proposals. Identifying national prerequisites and requirements for the conduct of clinical activities for IVDs is even more challenging since IVDs and/or IVD performance evaluation studies are often not explicitly mentioned in their respective national laws and regulations.

Impact

Manufacturers have the responsibility to conduct clinical investigations, clinical performance (evaluation) studies and PMCF activities. Conducting clinical activities according to ISO14155 for medical devices or ISO 20916 for IVDs comes with a price, which not all manufacturers are able or willing to pay. This will lead to the withdrawal of some products from the European market when their CE certification expires. For other products manufacturers have the responsibility to conduct clinical investigations and PMCF activities. However, some manufacturers are not (yet) set up to conduct their clinical activities according to ISO14155 or ISO 20916.

Principles which might not be addressed adequately by manufacturers inexperienced in the conduct of clinical investigations or clinical performance studies include (the list is not exhaustive):

  • Written clinical quality procedures covering the compliant conduct of the investigation
  • Proper safety reporting covering national legislation in the countries where investigation are performed
  • Clinical monitoring (verifying correctness of data collected and entered into the database)
  • Accurate documentation of all clinical activities (“what is not documented did not take place”)
     

What are the risks?

Under MDR and IVDR, Notified Bodies will only accept clinical evidence, if the required regulations, laws and/or guidelines have been followed, including ISO 14155 or ISO 20916 requirements. In addition, if Notified Bodies come to the conclusion that clinical evidence which was used to obtain or maintain CE certification did not fulfill essential requirements – clinical activities can be reviewed even years after obtaining CE certification - the NB might withdraw or suspend a manufacturer’s CE certificate.

The outcome of a review of a company’s clinical activities might also result in the need to generate additional new clinical evidence, or repeat activities. This will be an additional and usually costly effort, which can and should be avoided.

What next?

If in doubt as to whether your clinical activities are compliant with the applicable EU laws, regulations and standards, it is recommended to hire external support experienced in the conduct of European medical device clinical investigations or IVD clinical performance studies. Even though this incurs initial costs, proper third-party support may help you to reduce overall costs by avoiding significant rework or remedial action taken by your Notified Body. Early partnership with an expert support provider will create confidence in your planned activities, and help you to decide on appropriate actions to improve your system and prevent regulatory intervention.

Any service can be tailored to your needs and might range from reviewing your quality procedures addressing the clinical activities to reviewing single clinical investigation or clinical performance study documents such as a Clinical Investigation Plan (Clinical Performance Study Protocol for IVDs), Informed Consent Forms and other documents for compliance with ISO 14155 or ISO 20916.

Dietmar Falke is Head of Clinical Research at Emergo by UL.

Learn more about MDR and IVDR clinical data requirements at Emergo by UL:

  • Post-market clinical follow-up (PMCF) study support for medical devices
  • Medical device clinical study audits and quality control consulting
  • MEDDEV 2.7.1 rev 4 and Clinical Evaluation Report (CER) consulting
  • Webinar: Optimizing your post-market surveillance (PMS) and clinical activities for MDR

 

Author

  • Dietmar Falke

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