Linking IVDR Performance Evaluations and Risk Management

May 16, 2023

8 mins

EU IVDR General

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Similar to the MDR, one of the pillars of the IVDR regulatory framework is the device lifecycle approach which requires stronger interactions between a manufacturer’s performance evaluation, risk assessment, and post-market surveillance processes. It is the combination of the aforementioned processes that collectively drive the generation and assessment of clinical evidence during a device’s lifetime.

Linking a performance evaluation and a risk management documentation under the IVDR

While the requirements driving these interactions are established by manufacturers in their quality management system (QMS) procedures for these processes (which are commonly referenced in performance evaluation plans/reports), there are several specific IVDR requirements directly related to the interaction/relationship between performance evaluation and risk management, as discussed below which should be addressed in device performance evaluation documentation.

1. Justification of the level of clinical evidence

Under Article 56(1) of the IVDR, within the scope of performance evaluation, manufacturers must specify and justify the level of clinical evidence necessary to demonstrate conformity with the GSPR and this level of evidence should be appropriate based upon device characteristics and its intended purpose.

Those of you familiar with EN ISO 14971:2019 (harmonized under the IVDR) and Annex H of its corresponding guidance ISO/TR 24971:2019 will recall that there are several requirements and considerations for risk analysis documentation. These include documentation of the intended use (and reasonably foreseeable misuse) of the device as well as identification of characteristics related to safety.

Therefore, to ensure a consistent approach between IVDR risk assessment management and performance evaluation, it is recommended that manufacturers consider the following aspects of Annex H of ISO/TR 24971:2019 when justifying the level of clinical evidence in addition to the degree of novelty of the device, as applicable:

Intended use
- Analytical uses
- Clinical application
Characteristics related to patient safety
- Chemical, mechanical, electrical and biological characteristics
- (Analytical and clinical) Performance characteristics (for quantitative, semi-quantitative and qualitative assays)
- Reliability characteristics
- Digital information technology characteristic

2. Intended clinical benefits and acceptability of the benefit-risk ratio/determination

‘Clinical benefit’ is defined under the IVDR as “the positive impact of a device related to its function, such as that of screening, monitoring, diagnosis or aid to diagnosis of patients, or a positive impact on patient management or public health.” While ‘benefit-risk determination’ is defined as “the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer.”

Under EN ISO 14971:2019, manufacturers are required to perform benefit-risk analysis for individual residual risks and overall residual risk, both assessed according to methodology and criteria established in the risk management plan (RMP). A benefit-risk analysis is not a novel risk management concept and was also a requirement under EN ISO 14971:2012, however, IVD manufacturers have historically poorly defined the benefits (indirect or direct) of their devices in risk management files (RMFs). Therefore, manufacturers are encouraged to ensure that the clinical benefits of their devices are described consistently in both the IVDR risk assessment and performance evaluation documentation.

Furthermore, the IVDR requires that the performance evaluation plan (PEP) include an indication and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the intended purpose or purposes and for the analytical and clinical performance of the device. Therefore, it is strongly recommended that the methodology and criteria for the overall residual risk assessment analysis described in the RMP be aligned with the approach for determining benefit-risk ration acceptability established in the PEP.

3. Relevant GSPRs

The IVDR requires that the PEP include identification of those GSPRs between GSPRs 1 – 9 that require support from relevant scientific validity and analytical and clinical performance data. The assessment of this data against the identified GSPRs is correspondingly documented in the IVDR performance evaluation report (PER).

GSPRs 2 – 5 pertain to the establishment of a risk management process and requirements for this process and are not typically among those identified in the PEP/PER.GSPRs 2 – 5 pertain to the establishment of a risk management process and requirements for this process and are not typically among those identified in the PEP/PER.

As we have noted in a separate blog article (on performance evaluation and device stability studies, available here), both GSPRs 6 and 7 are related to device stability studies which are described and discussed in the performance evaluation. Where relevant, the RMF should include clear identification of stability-related hazards and include stability studies as one of the risk controls implemented to reduce risk as far as possible (AFAP). Where analysis of conformity with GSPRs 6 and 7 is performed in the PER, this can include a clear reference to the relevant information in the RMF and stability studies performed.

GSPR 9 pertains to device performance characteristics that are directly related to the design verification and validation activities realized by the manufacturer such as analytical and clinical performance studies, evidence of metrological traceability, usability studies, and stability studies. In a similar manner to GSPRs 6 and 7, the RMF should include clear identification of performance-related hazards and include relevant design verification and validation studies as one of the risk controls implemented to reduce risk as far as possible (AFAP). Analysis of conformity with GSPR 9 in the PER is typically performed referencing the relevant analytical and clinical performance data in the analytical performance report (APR) and clinical performance report (CPR) or other non-analytical and non-clinical verification and validation studies performed (e.g electromagnetic compatibility and electrical safety testing).

This leaves GSPRs 1 and 8 which should be identified in all PEPs and for which conformity should be assessed in all PERs. While these are both directly related to the benefit-risk determination, GSPR 1 is primarily focused on the overall safety of the device for patients, users, and other persons. The analysis of conformity with GSPR 1 in the PER can include:

References to all clinical risks described in the RMF, distinguished between three different data sources where these clinical risks have been identified during the performance evaluation:
- From information generated and held by the manufacturer (e.g. clinical experience outside the EU such as customer feedback and complaints, PMS data)
- From peer-reviewed scientific literature and other results of the literature search performed as part of the performance evaluation
- From searches of regulatory authority reportable event databases for the subject, equivalent or similar devices (if such data is missing from PMS data)
Each clinical risk identified from the above sources with the following information identified per risk (e.g. in a tabulated format):
- Hazard identification # (e.g. from the risk analysis)
- Hazard description
- Description of the risk controls implemented
- Indication as to whether the hazard risk level has been reduced AFAP or whether the manufacturer is in the process of implementing actions to address the identified clinical risk (e.g. CAPA #)
Discussions of how the risks associated with the device from each of the data sources described above are compatible with a high level of protection of health and safety taking into account the generally acknowledged state of the art, particularly comparing rates of occurrence of clinical risks for the subject, equivalent and similar devices.

4. Continuity of the IVDR performance evaluation and risk assessment processes

As stated at the beginning of this article, clinical evidence is continually generated and assessed during a device’s lifetime. While the IVDR has established annual PER updates as mandatory for Class C and D devices, post-market performance follow-up (PMPF) is the continuous process that updates the performance evaluation and must be addressed in manufacturers’ PMS plans. PMPF allows manufacturers to proactively gather and assess information on the use of CE marked devices and complement (and in some instances overlap with) PMS activities.

Regardless of whether the data is proactively or reactively collected, EN ISO 14971:2019 requires that, as part of their risk management process, manufacturers establish, document, and maintain a system to actively collect and review information relevant to devices in the production and post-production phases.

Therefore, it is important that both the performance evaluation and risk management documentation are aligned with the mechanisms/processes through which updates are made to both, particularly where data gathered indicates a change in the benefit-risk determination of the device.

Learn more about IVDR performance evaluations and evaluating risk assessment with MedEnvoy

If you have any additional questions regarding performance evaluation, risk assessment needs, or require relevant training / consulting services, get in touch.