Europe and the rest of the in vitro diagnostic (IVD) device world know that the European Union’s new In Vitro Device Regulation (IVDR) is coming. The deadline to comply with IVDR is May 26, 2022, which is not as far off as it may seem. Device manufacturers need to begin transition preparations now in order to minimize the hiccups the new regulation is likely to cause.
One of the key issues all manufacturers are grappling with is the requirements for intended purpose. Intended purpose is key because it is a key input into the design of a device, risk management, performance evaluation and classification.
Everything starts with a good intended purpose statement. The IVDR requires a clear statement that must stipulate whether your device is for screening, monitoring, diagnosis or aid to diagnosis, prognosis, prediction, or is a companion diagnostic. The intended purpose must be included in the labeling as described in the regulation’s General Safety and Performance Requirements (GSPR) 20. It needs to be clear and support the classification defined by the manufacturer plus all claims as required in Article 7. The intended purpose needs to be consistent with the classification of the device. If the classification is for screening blood donations for syphilis this should be described in the intended purpose statement. This is key because an assay for diagnosis would be in Class C whereas a screening assay would be in Class D.
The next step is to establish the state of the art for devices with your documented intended purpose. This does not mean it has to be best in class; however, it needs to be able to perform so that it can clinically meet it’s intended purpose. It is therefore important to identify the critical characteristics of the device. For example, if you consider a device for screening blood donations then assay sensitivity and specificity may be important, whereas the accuracy and repeatability of a device may be more important for a diagnostic or monitoring assay.
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The performance evaluation plan (PEP) identifies what data would be needed to support the intended purpose. Under the regulation, these are documented in the scientific validity, the analytical performance, and the clinical performance report and pulled together into the performance evaluation report. The scientific validity report (SVR) documents the association of the analyte to the clinical condition or physiological state described in the intended purpose and requires a formal literature search or studies as objective evidence. The state of the art will also require literature to support your conclusions; this may include common specification (CS), product standards, clinical guidelines as well as scientific papers. New or novel markers may require testing and medical opinions to support the scientific validity and state of the art.
The performance evaluation plan also requires the preparation of an analytical performance report, which describes the performance necessary to meet the intended purpose and objective evidence that it has been achieved. For example, the test should have an appropriate sensitivity and specificity to meet the intended purpose and to ensure that it is state of the art. Finally, the clinical performance should support the populations and intended users described in the intended purpose. The data from these reports is then summarized into the performance evaluation report to demonstrate compliance and confirm that the PEP has been completed.
There is some crossover in the performance evaluation plan with the GSPR checklist, as it allows a manufacturer to identify and point to documentation that supports compliance with individual requirements but does not usually include a detailed summary of how the compliance is achieved. The analytical performance report and the clinical performance report should include a summary of the data and a discussion and conclusion about how this meets the specific IVDR requirement and the intended use.
If we consider interfering substances as an example, this should be first identified in risk management, the PEP would then identify the necessary studies to be performed to confirm risks have been managed. The output of this study will be a report and conclusions of whether acceptance criteria were met. The analytical performance report then summarizes the data for all analytical studies and clearly documents that IVDR requirements have been met as well as the claims. Residual risk should to be described in the instructions for use (IFU).
The GSPR checklist is, as the name suggests, a list that enables a manufacturer to ensure they have addressed all the requirements, but it will lack detailed summaries and most importantly, clear conclusions. In the past, the essential requirements checklist may have referenced many individual reports; however, it is now more relevant to reference the analytical performance report (APR), which in turn will reference the original reports.
When compiling IVDR files based on existing devices, the APR should be used to compile data from existing sources, summarize the findings and making clear statements of compliance to the IVDR, these should be consistent with the intended purpose and the claims. Notified Bodies (NBs) are not allowed to look at your data and conclude whether it is compliant to the IVDR; NBs look at your discussion and conclusions, and then look at the data to see whether they agree. In some cases, this will require a deep dive into the full data, and then they will decide whether they agree with your conclusion. You cannot supply the NB with lots of data and expect them to review the data and determine if it is compliant; you must make clear conclusions. Reports referenced in the APR may have been created prior to the IVDR and so they will not make clear conclusions that the requirements of the IVDR have been met.
For example, the IVDR requires data from three batches of product to meet stability requirements while the ISO standard allows some flexibility about the number of batches; as a result, a stability study compliant with the IVDD may not be compliant with the IVDR. The conclusion at the end of the stability study may be that the data supports the essential requirements. However, there needs to be a statement that the IVDR requirements have been met, that the APR can reference the existing report, and that describes how the data demonstrates compliance to the IVDR. Where there is insufficient data to make this conclusion additional on‐market data will be required. Stability is an area that seems to be a frequent problem for manufacturers and unfortunately it can take the longest time to remediate.
When deciding how to transition IVDD files to meet the IVDR, it is important to understand the flow of documents. The PEP uses inputs from risk management, the intended purpose and state of the art to determine what data is needed to support both IVDR requirements and the broader claims made for the device as required by Article 7 of the IVDR. For a new device, the PEP determines what studies have to be run to create the data to support the requirements; whereas for existing devices this data is usually repurposed from the original design verification and validation, on-market design changes, postmarket surveillance activities and other real‐world data.
In summary, it is important to understand how the IVDR documents fit together. Understanding intended purpose and state of the art are key to creating good performance evaluation reports. Potential gaps in stability need to be identified early because they will take the longest time to remediate.
If your transition to the IVDR requires a change to the intended purpose or claims, it may result in a change to the IFU with a domino effect on global labelling. If this is required, it will have far-reaching effects on the rest of world submissions, so evaluating gaps in intended purpose and ensuring all claims can be supported is an essential first step to IVDR compliance.
Sue Spencer is head of IVD and a principal consultant with the QServe Group. She has over 30 years’ experience in the medical device and IVD industries, including extensive notified body experience. Her key areas of expertise include IVDD and IVDR regulations; QMS implementation; internal, supplier and compliance edits; risk management; training; and working with small startups and multinationals.
Spencer has worked for several IVD companies ranging from startups to large multinationals, where she has held positions in R&D, manufacturing and quality assurance. She worked for three Notified Bodies establishing two from scratch. Spencer chaired the European IVD Notified Body Working Group coordinating the Notified Body responses to the regulations. She also participated in the Commission IVD Technical Work Group for many years. Spencer is an experienced trainer on a variety of IVD topics and particularly enjoys creating workshops to improve hands-on experience with the requirements. QServe is an enterprise partner with MasterControl.