Medical device and sufficient clinical evidence: case studies examples of clinical investigation and survey.

Di Annamaria Cimicata - Regulatory Affairs Manager

In recent years, following the entry into force of Regulation (EU) 2017/745 (MDR), more and more medical device manufacturers had to assess, for each of their legacy devices, the strength and completeness of the available clinical data. This, in order to establish whether or not their medical devices evidence of safety and clinical effectiveness was sufficient to prove compliance with the MDR General Safety and Performance Requirements (Medical Devices and Sufficient Clinical Evidence).

PRINEOS, as a Life Sciences consulting company, had the opportunity to work together with several medical device manufacturers  assessing the sufficiency of available clinical data on their legacy devices, and to support them in making the most correct choice for how to collect and submit such data to Notified Bodies (NBs), in order to obtain the MDR EC certification.

As reported in the MDCG 2020-6, it is important for a manufacturer to identify all available sources of clinical data from both the pre-market and post-market phases. This will include all of the clinical data which is generated and held by the manufacturer as well as clinical data for equivalent or similar devices.

For the purpose of legacy devices, pre-market sources of clinical data may include: 

  • Clinical investigation reports of the device concerned; 
  • Clinical investigation reports or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated in accordance with the MDR; 
  • Reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated; 
  • Other pre-market data, e.g. case reports on experience with the use of the device in question, such as compassionate or humanitarian exceptional use reports. 

Instead, post-market sources of clinical data refer to data collected following the initial EC marking under the Directives 93/42 EEC (MDD). This may include: 

  • PMS clinical data, complaint and incident reports; 
  • PMCF studies, including post-market clinical investigations; 
  • Independent clinical studies conducted using the device37; 
  • Device registries; 
  • Data retrieved from the literature

The Appendix III of MDCG 2020-6 suggests a hierarchy of clinical evidence (listed in decreasing hierarchical order, ranging from 1 - most robust evidence - to 12 - least robust evidence) used to demonstrate device compliance with the relevant General Safety and Performance Requirements of the MDR Regulations.
The results of high-quality clinical investigations covering all device variants, indications, patient populations, duration of treatment effect, etc. are on top of the hierarchy, as most robust evidence. Surveys are positioned almost in the middle of this hierarchy, with a rank of 8 and are referred to as an example of proactive Post Market Surveillance. Clinical data obtained from surveys fall within the definition of clinical data under MDR Article 2(48), but is not generally considered a high quality source of data due limitations associated with sources of bias and quality of data collection. It may be useful for identifying safety concerns or performance issues. Finally, pre-clinical and bench testing are reported at the bottom of this hierarchy.

To date, the most common scenarios PRINEOS has faced are:

  • manufacturers of EC-marked medical devices under the MDD Directive (legacy devices), who did not have clinical data on their products, as defined by Article 2(48) of the MDR;
  • manufacturers of EC-marked medical devices under the MDD Directive (legacy devices), who already had sufficient clinical data on their products, but for whom it was still necessary to put in place proactive post-market surveillance activities, in order to verify the medical device safety and performance for its entire life cycle.

In the first case, PRINEOS  prepared a proper post-market clinical investigation for manufacturers, in accordance with the requirements of UNI EN ISO 14155:2020 and MDR Regulation Articles from 62 to 82.
In the second case, PRINEOS  prepared surveys activities, using manual data collection in some cases, and electronic database collection in other cases.

Clinical Investigation
The MDR Regulation Article 2 (45) defines a clinical investigation as “any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device”.
Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust.
In compliance with the requirements of the MDR Regulations, PRINEOS prepared post-market clinical investigations by supporting legacy medical device manufacturers from the drafting of the Clinical Investigation Protocol (CIP) to the drafting of the Clinical Investigation Report (CIR). 
PRINEOS developed the study synopsis and its methodology, calculated the sample size, provided the CIP submission to the Ethics Committee - to obtain approval to initiate the clinical investigation - and finally managed, collected, and analyzed the obtained results at the end of the investigation.
An example of such an activity is that of a retrospective observational clinical investigation - Post-Market Clinical follow-up - that PRINEOS planned and executed for a legacy, sterile, ophthalmic, non-innovative, non-diagnostic medical device, class IIa according to the MDD Directive and placed on the market since 2017. The device for MDR EC certification will undergo a classification upgrade -Annex VIII MDR Regulation - to class IIb.

The clinical investigation synopsis included a collection of data registered in medical records from 1st May 2019 to 1st May 2022. Data were extracted from the medical records at the selected investigation center between January 2023 and March 2023, identifying relevant inclusion and exclusion criteria, planning the appropriate sample size and the performance and safety outcomes to be measured, and describing the statistical methodology and the analysis performed.
The clinical investigation outcomes provided sufficient clinical data (valid, reliable, and robust) on the clinical safety and efficacy of the medical device when used as intended by the manufacturer.

The survey is a means by which a medical device manufacturer can collect proactive Post-Market Surveillance data on its products.
Survey involves the preparation of questionnaires useful for collecting information related to the performance and safety of a medical device already EC-marked and placed on the market. The questionnaires should be addressed and delivered directly to the medical device user or to the distributors or healthcare professionals (physicians, pharmacists, etc.) who respectively convey or prescribe the medical device use.
An example of survey activities, managed by PRINEOS, involved the development of a questionnaire to be given to the users of a legacy device, EC marked according to the MDD Directive, intended to be use by lay users in the home environment.
The questionnaires were written in several languages so that the manufacturer could distribute and fill them out in most countries where the product is sold. Some questionnaires were filled out by physicians, on behalf of the user, others directly by users.
Upon completion of the collection of the completed questionnaires, PRINEOS performed a manual Data Entry activity, which allowed, based on careful analysis of the questionnaire responses, to gain statistically information to confirm the safety, performance, and usability of the product.
Based on client needs, PRINEOS also conducted survey activities in which the questionnaires access and completion, by end users, was via a link on the medical device manufacturer's website. After electronic completion, the various questionnaires were collected into an electronic database for the results analysis.
Finally, for an active medical device used for the monitoring and delivery of therapeutic gases to hospitalized patients, EC-marked according to the MDD Directive, and intended to be used in a hospital setting by qualified health care personnel appropriately trained in its use, the survey activity was set up by taking advantage of the device's operating data, recorded by the software on the device itself, without involving the patients or the health care personnel assigned to its use. 
The data collected by the software were then analyzed by PRINEOS to obtain statistically relevant information related to the device effectiveness and safe operation.