Medical Device and sufficient clinical evidence

Di Eliana Russo - Head of Regulatory Affairs

The issue of collection, management and interpretation of clinical data is, as known, currently much debated. 

In our country about 20% of these data come from medical devices, yet they are not very usable as they do not flow into a common database that allows them to be integrated, extracted and analyzed in an autonomous and controlled way. There is a lot of talk about Real Word Evidence, a term that generates both attraction, like any new trend that begins to spread, but also distrust, since the methods of application still have too little defined and clear contours to make tangible the possibility of analyzing real-world data. If the FDA in the United States has already shown how it is possible to use Real World Data to monitor post-market safety, adverse events and to make regulatory decisions, to evaluate guidelines and choices of clinical practice, to demonstrate the value of the device at all stages of the life cycle, in Italy we are somewhat behind because the sources of the data are very heterogeneous.  They are difficult to access and are not organized in complete databases that can be used in a short time.
In light of the current situation, it is evident that it is necessary to generate clinical data on medical devices.
The Medical Device Regulation (MDR) 2017/745 gives great emphasis to this concept, which calls for sufficient clinical evidence on the efficacy and safety of the medical device.
Unlike Directive 93/42 EEC (MDD), the MDR Regulation makes it more complex for manufacturers to be able to demonstrate the equivalence of their devices with those already CE marked and, on the market, so much so that they can no longer consider sufficient clinical evidence deriving from clinical literature data produced on similar devices, unless equivalence is proven in accordance with ANNEX XIV point 3 of the MDR. In this is clearly indicated that, a manufacturer shall, in addition to biological, technical and clinical criteria, demonstrate equivalence with a device on the market of a different manufacturer, that it has sufficient levels of access to data relating to the device with which it is declaring equivalence. 

Clinical evidence is defined as clinical data and results related to a medical device and must be of sufficient quantity and quality to allow a qualified assessment of safety and achievement of the expected clinical benefits.
This evidence is the core of the clinical evaluation of the medical device from which the manufacturer generates the Clinical Evaluation Plan (CEP) and the Clinical Evaluation Report (CER), updating them periodically throughout the life cycle of the device.
The clinical data on which the evaluation of the device is based can be originated from different sources, including, primarily, clinical investigations related to the device of interest.
A clinical investigation is intended as a systematic investigation involving one or more human subjects to assess the safety and/or performance of a device.
It is true, the clinical investigation is not always mandatory: the Regulation (MDR) 2017/745 provides for implantable and class III devices, with some exceptions, and for innovative devices. It must, however, be conducted whenever the available clinical data are not sufficient to demonstrate compliance with one or more essential safety and performance requirements of the medical device. 
And here the real challenge introduced by the MDR is precisely the design and execution of a clinical study with medical devices. It is essential to have clear endpoints of the study regarding efficacy and safety, which must be adequate to respond to the study objectives, defined with precision, measurable, ordered. Crucial from an ethical, methodological and financial point of view, is the sample size: few patients will not provide results regarding the effectiveness and safety of the device, too many patients are not acceptable from an ethical point of view, they represent a useless economic investment in the management of the clinical trial and do not guarantee the success of the study at all.
The definition of the study objective, the ends points and the justification of the sample size are, among others, essential elements of the methodology of clinical trials based on clinical and statistical skills, the same as an Ethics Committee that will evaluate the quality of the clinical study with the medical device.

In order to generate evidence of efficacy and safety on the medical device, in addition to conducting a clinical investigation, it is possible to resort to data from studies published in the scientific literature, relating to a device that has the same indication of use and the same characteristics; reports on other clinical experience relating to the device or a device for which equivalence can be demonstrated, published in the peer-reviewed scientific literature; clinically relevant information resulting from post-market surveillance, and in particular post-market clinical follow-up (PMCF).
The Regulation (MDR) 2017/745 appears vague in the definition of the expected requirements for clinical evidence on the medical device. 
The Guideline MDCG 2020-6 “Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC – A guide for manufacturers and notified bodies” aims to provide recommendations on the requirements that clinical data must meet to demonstrate the compliance of a medical device with the MDR.
The MDCG 2020-6 provides guidance for manufacturers and notified bodies on how to collect and analyze clinical data related to medical devices.
The MDCG 2020-6 is particularly interesting for:

  • Manufacturers of legacy devices. They can use the transitional period before they must renew their MDR certificate to collect enough clinical data about their device.
  • Manufacturers developing a new device. The MDCG 2020-6 provides definitions for several terms that are not explicitly defined in Article 2 of the MDR, but which are very important with regard to the evaluation of the benefit-risk ratio and the conclusions of the clinical evaluation (e.g., indication, state of the art, level of clinical evidence).

The MDCG 2020-6 recommends the following hierarchy for clinical and non-clinical data sources that manufacturers can use to demonstrate the conformity of their legacy device:

  • Results of high-quality clinical investigations covering all device variants, indications, patient populations, duration of treatment effect, etc.
  • Results of high-quality clinical investigations with some gaps
  • Outcomes from high-quality clinical data collection systems such as registries
  • Outcomes from studies with potential methodological flaws but where data can still be quantified and acceptability justified
  • Equivalence data (reliable / quantifiable)
  • Evaluation of state of the art, including evaluation of clinical data from similar devices
  • Complaints and vigilance data; curated data
  • Proactive PMS data, such as that derived from surveys
  • Individual case reports on the subject device
  • Compliance to non-clinical elements of common specifications considered relevant to device safety and performance
  • Simulated use / animal / cadaveric testing involving healthcare professionals or other end users
  • Pre-clinical and bench testing / compliance to standards

The level of clinical evidence for the medical device under assessment shall be determined by the manufacturer in order to be appropriate to the characteristics of the device and its intended purpose.
If we consider the vast number of medical devices, the various intended purposes and the risk levels, it begins to make sense to talk about sufficient clinical evidence by attributing to them a less obscure definition. 
It is not reasonably possible to a priori define which and how much clinical evidence should be collected, except from the manufacturer of the medical device who knows the clinical, technical and biological specifications on which to base the clinical evaluation of the device, considering expected clinical benefit and safety requirements.