IVDR Clinical Performance Studies: Considerations for EU Approval

In other articles, we have covered considerations for manufacturers about clinical investigations when pursuing CE marking under the MDR, in this article we cover considerations for manufacturers in obtaining approval and managing clinical performance studies in the EU to support CE marking under the IVDR. 

Obtaining approval for EU clinical performance studies under the IVDR

• • Clinical performance study planning
  • Parties involved
  • Approval & intention
  • Inspection & monitoring
  • Vigilance & recall 

Clinical performance study planning 

Among the minimum content requirements for performance evaluation plans (PEPs) under Section 1.1, Part A, Annex XIII of the IVDR is “an outline of the different development including the sequence and means of determination of the scientific validity, the analytical and clinical performance, including an indication of milestones and a description of potential acceptance criteria”. When considering the milestones and potential acceptance criteria, manufacturers should consider requirements beyond just those specifically for clinical performance studies under the IVDR, including the following: 

• • National Competent Authority(ies) requirements 
  • Requirements of the ethics committee(s) 
  • Applicable common specifications 
  • Applicable EU harmonized standards and relevant international standards 
  • EU and national guidance documents 
  • State-of-the-art in medical practice related to the relevant device technology / clinical application (e.g. relevant practice guidelines, device-related guidance, and medical professional association consensus statements/positions) 

The last bullet point above is particularly critical for manufacturers to consider within the context of the device performance evaluation report (PER) as this will include scientific validity and clinical performance data (and other clinical data) demonstrating device conformity with GSPRs, including those for which the manufacturer must take account of the generally acknowledged state of the art. Furthermore, under the IVDR, it is a requirement for clinical performance studies that the analytical performance has already been demonstrated, also taking into consideration the state of the art. 

Parties involved in EU clinical performance studies under the IVDR

Under the IVDD, only the manufacturer or (for foreign manufacturers) the authorized representative was responsible for the conduct of clinical performance studies. However, under the IVDR, any individual, company, institution or organization which takes responsibility for the initiation, management and setting up of the financing of clinical performance studies is a ‘sponsor’. This means that, under the IVDR, clinical investigators initiating clinical performance studies will be responsible for meeting IVDR clinical performance study-related requirements. Therefore, manufacturers are strongly encouraged to ensure that agreements between the organization and clinical investigators include provisions ensuring that clinical investigators acting as study sponsors are aware of their IVDR sponsor-related requirements. 

When sponsors of clinical performance studies to be conducted in the EU are not themselves located in the EU, under the IVDR, they must also assign a legal representative. The exception to this is if the clinical performance study is only being conducted in the territory of a single Member State and the Member State has not applied this requirement. 

The IVDR establishes requirements related to ethics committees, such as requiring clinical performance studies to undergo ethical review by an ethics committee by national law. The IVDR also establishes that the procedures for ethics committee review established by Member States must be compatible with IVDR procedures and that at least one layperson must participate in the ethical review process. While the IVDR has addressed some concerns related to the ethics committee clinical performance study review that existed under the IVDD, there is unfortunately still a lack of harmonization to the review process itself. This means that ethics committee procedures/processes are still quite variable amongst and within Member States, leading to ethics committee approval timeframes of between 30 to more than 90 days. Therefore, sponsors are recommended to verify all the relevant ethics committee review procedure requirements ahead of time to ensure timely processing, including: 

• • Requirements for the specific study category/type (e.g. pre-/post-market, registry, observational, interventional (e.g. in the case of companion diagnostics), other) 
  • Documentation and procedural requirements of each ethics committee, including the need for signed site contracts and necessary signatories 
  • Translation requirements 

Where clinical performance studies are intended to be conducted in a single Member State, it is the responsibility of the competent authority in that Member State to evaluate clinical performance study applications and determine whether regulatory requirements are fulfilled. However, the IVDR also establishes a new process for the coordinated assessment of clinical performance studies where such studies are intended to be conducted across multiple Member States. Under this process, the sponsor may submit a single application to all Member States in which the investigation is to be conducted and propose one Member State to act as the ‘coordinating Member State’. While initially this procedure will involve Member States voluntarily agreeing to apply this procedure, it becomes mandatory on 26 May 2029, unless this data changes as a result of a European Commission review that must be performed no later than 27 May 2028. 

Clinical performance study approval & initiation

Article 66 of the IVDR establishes the steps and specific periods that are to be respected throughout the clinical performance study application process, such as sponsors having to update any change in submitted documentation within one week of making such changes. While the Member State may request any additional information from the sponsor beyond the documentation listed in the IVDR (Annex XIII, Chapter II), the date on which the sponsor is notified that the application is complete is considered its validation date. In the case of clinical performance studies where the specimen collection does not represent a major clinical risk to the subject of the study unless otherwise stated by national law, these can be initiated immediately, provided that no negative opinion valid for the entire Member State has been issued by the relevant ethics committee. In the case of clinical performance studies for all other devices, the clinical performance study may be initiated as soon as the Member State has notified the sponsor that the study is authorized (which must be within 45 days of the validation date, with a 20-day extension permissible for expert consultation). 

Among the documentation submitted and reviewed by the Member State is the Clinical Performance Study Plan (CPSP). Among the content requirements of the CPSP is a policy regarding follow-up and management of any amendments to, or deviations from, the CPSP at the study site and a clear prohibition of the use of waivers from the CPSP. Therefore, caution should be exercised when preparing the CPSP to avoid compliance challenges. 

Inspection & monitoring 

Among the responsibilities of Member States is the inspection (at an appropriate level) of clinical performance study site(s) to ensure that clinical performance studies are being performed by both the IVDR and CPSP. Therefore, sponsors should ensure that these sites maintain a level of preparedness for such inspections. 

To ensure that the level of preparedness is maintained by these sites, the IVDR requires that sponsors adequately monitor the conduct of the clinical performance study. The purpose of this monitoring is to verify that the: 

• • Rights, safety and well-being of subjects are protected 
  • Reported data are reliable and robust 
  • Conduct of the clinical performance study is in compliance with the IVDR, CPSP, Good Study Practices (GSPs) and other applicable regulatory requirements 

The extent and nature of the monitoring must be determined by the sponsor based on an assessment that considers all characteristics of the clinical performance study, including its: 

• • Objective and methodology 
  • Degree of deviation of the intervention from normal clinical practice (i.e. its degree of novelty) 

Furthermore, it is an IVDR requirement that the assigned monitors be independent of the study site to ensure impartiality in their monitoring activities. 

Monitoring should be understood to be of a broader scope than GSP inspections, which sponsors are also obliged to (internally or externally) perform, to provide evidence that the clinical performance study is being performed in line with GSPs. Annex I of ISO 20916 guides the areas that can be covered in such inspections. 

Vigilance & recall 

Sponsors are also obligated to record and report adverse events that occur during clinical investigations, however, there is a critical difference in serious adverse event reportability under the IVDR compared to the IVDD. While all serious adverse events require reporting under the IVDD, only those where there is a causal relationship with the device, the comparator, or the study procedure (or where such a causal relationship is reasonably possible) must be reported to all competent authorities of the Member States in which the clinical performance study is being conducted. In addition to these serious adverse events, the following must also be reported: 

• • Any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate 
  • Any new findings in relation to reportable serious adverse events or above device deficiencies 

Lastly, sponsors must also establish a procedure for emergency situations that enables the immediate identification and, where necessary, an immediate recall of the devices used in the clinical performance study, with the expectation that such procedures will also be managed within the manufacturer’s QMS.

Learn more about clinical performance studies under the IVDR with MedEnvoy

This article provides an overview of several considerations for manufacturers in performing clinical performance studies for CE marking under the IVDR, however if you have any questions regarding clinical performance studies, or require relevant training/consulting services, get in touch. 

Related articles:

• • Understanding Clinical Performance Reports(CPR) under the IVDR: A Guide for IVD Manufacturers
  • Planning for Performance Evaluation Under the IVDR
  • Analytical Performance Characteristics for IVDs: What Manufacturers Need to Know