A year into the EU Medical Device Regulation (MDR 2017/745), it is safe to say the implementation of the MDR has been complicated, for both manufacturers and the notified bodies.
Even though the European Parliament voted for a partial delay of the In Vitro Diagnostic Medical Devices Regulation (IVDR 2017/746) in December 2021, the implementation date remains May 26, 2022, for Class A, self-certified IVDs. The remaining IVD classes can look forward to staggered implementation dates on May 26, 2025, 2026, and 2027, depending on the device class.
The main change in the IVDR compared to the IVDD is a change in risk classification that results in 12 times as many IVDs requiring notified body certification as under the IVDD – a whopping 84% of the IVDs on the European market.
As with any other medical device, in vitro diagnostic medical devices also require clinical evaluation before being placed on the market. For In Vitro Diagnostic medical devices the clinical evaluation is done through the performance evaluation – An assessment and analysis of data to establish or verify the scientific validity, the analytical, and, where applicable, the clinical performance of a device (EU 2017/746 (IVDR), Article 2 (44)).
In January 2022, the Medical Device Coordination Group (MDCG) issued guidance on the general principles of clinical evidence for In Vitro Diagnostic medical devices. In this article, we are taking a look at the MDCG guidance and what it means for the clinical evaluation of IVDs.
Performance evaluation of IVDs under the IVDR
The MDCG document guides the general principles of clinical evidence for IVDs, both before placing the product on the market and concerning post-market surveillance activities.
“Prior to placing an IVD on the market or putting it into service, the manufacturer must demonstrate compliance with all applicable requirements of the IVDR, in accordance with the appropriate conformity assessment procedure(s). Therefore, the manufacturer must demonstrate that the IVD achieves its intended purpose in accordance with the claimed performance over the lifetime of the device.”
The guidance mentions the requirement in the IVDR for manufacturers to specify and justify the level of clinical evidence required based on the intended purpose of the IVD, emphasizing the importance of properly defining the intended purpose and reflecting it accurately in the Instructions for Use.
Similar to clinical evaluation for medical devices, the performance evaluation for in vitro diagnostic medical devices is a continuous process throughout the lifetime of the IVD.
Essential parts of the performance evaluation of in-vitro medical devices
The performance evaluation is comprised of three essential parts:
Scientific validity is the extent to which the analyte, or marker to be determined by the IVD is associated with the targeted physiological state or clinical condition.
Scientific validity should be demonstrated and documented for each device. Similar to clinical evaluation in medical devices, it can be demonstrated with existing data and state-of-the-art knowledge from scientific literature, textbooks, market experience, and historical data, or through the generation of new or additional data if the In Vitro medical device has a high degree of novelty.
The analytical performance is the demonstration of the IVD’s ability to correctly detect or measure a particular analyte. Generally, analytical performance data should be generated by analytical performance studies, while published data can function as supporting evidence.
An important feature of the analytical performance is that all specimen types and conditions indicated in the instructions for use should be assessed and demonstrated. This also goes for storage and transport conditions, and information on the timeframe between sample collection and its analysis.
Clinical performance is the demonstration of an IVD’s ability to yield results that are correlated with a particular clinical condition or a physiological/pathological process or state per the target population and intended user.
It demonstrates that in-vitro medical devices, through reliable and predictable use, can achieve clinically relevant results as intended. The indicators of the clinical performance vary depending on the intended purpose and performance claims of the IVD.
It is important to demonstrate that the IVD has been tested for the intended use, target population, use conditions, and environment, and with all the intended user groups. This is to ensure the clinical performance complies with the intended purpose as described in the instructions for use.
Performance evaluation process
So how do you go about setting up performance evaluation for your IVD?
The process of performance evaluation is described in Article 56 and Annex XIII, Part A, 1 of the In Vitro Diagnostic Regulation.
The performance evaluation process is split into four parts:
- Planning: establishment and maintenance of a performance evaluation plan (PEP), and definition of an approach to generate the necessary clinical evidence
- Data establishment: Identification and evaluation of existing clinical data, and identification and/or generation of scientific validity, analytical performance, and clinical performance data needed
- Analysis, conclusions, and documentation: analysis and documentation of the scientific validity, analytical performance data, and clinical performance data.
- Continuous monitoring and updates
Performance evaluation plan (PEP)
The first step in your performance evaluation is to draft your performance evaluation plan.
The performance evaluation plan should demonstrate the characteristics and performance of the in vitro diagnostic medical devices included in the performance evaluation, and the process and criteria to be applied.
Not all performance evaluations will include the same elements, but generally, you should include:
- Detailed intended purpose
- Novelty and degree of innovation
- Scientific validity of the analyte
- Specification of methods
- Assay technology
- Risk to the patient
- Intended users, disease states, and target population
- Degree of the variability of the study subject population
- Prevalence of the clinical state
- Availability of reference materials or certified reference methods
- Stability of specimens, reagents, etc.
- Availability of Common Specifications (CS)
- Identification and specification of the applicable General Safety and Performance Requirements (GSPR). Even though they do not constitute clinical performance studies, testing conducted to demonstrate compliance to the applicable general safety and performance requirements should be included in the performance evaluation
- Assessment of benefit-risk ratio
The specific requirements for the performance evaluation plan are outlined in the In Vitro Diagnostic Regulation Annex XIII.
Once all the performance testing has been completed and documented, it should be put into a performance evaluation report. Similar to clinical evaluation reports for medical devices, the performance evaluation report allows the manufacturer to make a qualified assessment as to whether the IVD achieves its intended clinical benefit and safety, and whether the benefit-risk profile is acceptable. The performance evaluation report should be updated continuously throughout the lifetime of the IVD.
Post-market surveillance (PMS) and post-market performance follow-up (PMPF) are also required under the IVDR and should be included in post-market performance evaluation reports.
The guidance document issued by the Medical Device Coordination Group, MDCG 2022-2 Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs), can be found here.