The Complete Guide to EU IVDR Scientific Validity and Performance Evaluation
EU IVDR Scientific Validity Guide for IVD Devices
The Regulation EU IVDR 2017/746 of the European Union places high standards on the manufacturers of IVDs, particularly on establishing scientific validity with its focus on the safety of patients. The concept of scientific validity is one of the key aspects of the EU IVDR, as it requires the establishment of scientific validity by the manufacturers for each individual in vitro diagnostic device for demonstrating its relationship to a specific medical condition or physiology.
Definition of scientific validity and its Role under EU IVDR 2017
According to Article 56 and Annex XIII of the EU IVDR 2017/746, scientific validity means an association of an analyte to the clinical condition or physiological state that the IVD device can support for its intended use through diagnosis, monitoring, or predicting of the disease. It means that there should be an association of an analyte to the clinical condition which is needed to prove the effectiveness of IVD devices in order to help with diagnosis, monitoring, or prediction of a disease. Scientific validity of IVD devices should be based on the latest scientific evidence including systematic literature review and research papers.
Scientific Validity Documentation in Manufacturers
Systematic Literature Review: Manufacturers must perform systematic literature review that would be thorough and objective in order to demonstrate scientific validity. Manufacturers need to review peer reviewed scientific literature, consensus, guidelines as well as perform proof of concept studies where necessary.
Traceability: It is crucial for the manufacturers to ensure that the sources utilized in the process of scientific validity demonstration are traceable. Traceability guarantees credibility of the scientific evidence and ensures the connection between the analyte and intended medical purpose of the device.
Methods and Approach: Manufacturers need to document the approach utilized in gathering and appraising scientific data in the performance evaluation plan (PEP). This would include description of selection, appraisal and analysis of scientific data and sources of information that could be obtained from different scientific databases and expert opinions.
State of the Art: Manufacturers need to ensure that the scientific validity is consistent with the latest state of the art in the field. That means manufacturers need to find relevant standards, consensus and knowledge of the scientific community about clinical significance of the analyte.
Performance evaluation : Performance evaluation includes demonstration of scientific validity among other criteria such as analytical and clinical performance of the device. Scientific validity proves the theoretical background of the device, analytical performance – its ability to measure the analyte and clinical performance – its clinical utility.
Continuous Updates: Documentation of the scientific validity is not a one-time process. Manufacturers need to constantly update the performance evaluation reports based on new evidence.
The Regulatory Environment: EU IVDR and its Development
The EU IVDR that was implemented in 2017 and entered into application in May 2022 is significantly tougher towards IVD manufacturers than its predecessor IVD Directive (IVDD). Such differences concern the classification process, increased involvement of notified bodies, and additional post market surveillance. According to the regulation, all CE marked IVDs should comply with the safety, performance, and scientific validity criteria. Healthcare organizations that use “in house” IVDs should meet basic safety and performance criteria; however, they are not obliged to have their products assessed by regulatory authorities in case of their non commercial distribution. The IVDR necessitates additional documentations, namely, the manufacturer has to prove the scientific validity of his/her product, which means that it should not only be safe and effective but also scientifically validated.
Core Requirements for Demonstrating scientific validity (SV)
For every in vitro diagnostic device (IVD), the scientific validity should be demonstrated. For this purpose, the manufacturer should demonstrate:
Current state of scientific knowledge regarding the biomarker and its association with the disease.
Systematic review of the literature with emphasis on peer reviewed research articles, meta analyses, and clinical guidelines.
Sources tracing and quality appraisal of all literature being referred to.
Methodology, which includes literature search and evaluation methodology.
Overall conclusion about the strength of association and justification, if required, due to lack of or conflicting data.
Validity of scientific evidence for the overall safety and performance requirements mentioned in Sections 1 to 9 of Annex I is essential, along with data on the performance of the product.
Performance Evaluation Under IVDR
Performance assessment of IVD devices is done in terms of three main components:
scientific validity,
analytical performance, and
clinical performance.
Scientific validity is proof of the scientific relevance of the biomarker to the medical condition or physiologic state in question. Analytical performance involves ensuring that the device is capable of measuring the desired analyte, while clinical performance links the performance of the device to the clinical outcomes, making sure that the device works in reality. All these three components make up the basis of the performance assessment, and each of them should be documented and continuously updated in the technical documentation of the device.
Procedures for Compliance with Scientific Validity in Manufacturing
Ensure that there is an efficient performance evaluation program, which includes scientific validity assessment as per Annex XIII of IVDR.
Perform regular literature searches, keep up to date with evidence, and ensure that all processes and results are recorded.
Put in place clinical evaluation procedures if the literature gap exists, e.g., proof of concept and clinical performance studies.
Remark: For the case of interventional clinical performance study, the analytical performance and scientific validity have been proven, having taken into account the state of the art. In the case where scientific validity of the companion diagnostic has not been established, scientific justification for biomarker use must be made.
Official Guidance and Support Materials
As for the scientific validity of the devices in line with the IVDR, one can use such official guidance as MDCG documents, especially MDCG 2020-16 that gives an insight into classification and compliance with the IVDR. Moreover, manufacturers can review the IVDR Annex XIII to get familiar with procedures of performance evaluation that includes scientific validity. Regulatory authorities and consultancy organizations provide their support materials to assist manufacturers in dealing with the processes of scientific validity and performance evaluation under the IVDR. It is critical to constantly follow EMA regulatory updates and peer reviewed articles.
Comparison Study: EU IVDR with Other International IVD Regulatory Frameworks
In order to get a clear understanding of how EU IVDR differs from other international frameworks, here is the comparative table:
Aspect | EU IVDR 2017/746 | US FDA (510(k) / PMA) | Japan (PMDA) | Canada (Health Canada) | India (CDSCO) |
|---|---|---|---|---|---|
Risk Classification System | Four class system (A, B, C, D) | Risk based, no official classification scheme | Risk based, similar to US and EU systems | Similar to EU’s classification system | Risk based, aligned with global norms |
Scientific Validity Requirement | Must demonstrate association of analyte with clinical condition | Required for new tests but less structured | Similar to EU, requiring validation studies | Similar to EU, requires evidence for clinical validity | Mandatory for all IVDs, documented evidence required |
Performance Evaluation | Must document scientific validity, analytical and clinical performance | Focuses on analytical performance; clinical performance required in some cases | Emphasizes clinical and analytical performance | Requires both analytical and clinical performance validation | Requires scientific validity and performance data |
Classification of Risk and Scientific Validity
According to the EU IVDR regulation, the amount of evidence needed to prove scientific validity depends on the classification of risk for the device. The classification based on the risk is divided into four categories in accordance with the IVDR: Class A, B, C, and D. Class A is the category that is the lowest risk while Class D is the highest risk category.
Class A: Low risk devices must be proved scientifically valid by means of literature review and there should be enough information to prove the biomarker's relevance to medical purpose. The number of references and the amount of data may not be as much as those for the other types of devices.
Class B: These devices are of moderate risk and the evidence of scientific validity should be comprehensive. In such a way, there should be at least a systematic literature review but there can also be other sources of evidence proving the connection between the analyte and the disease.
Class C: High risk devices must have the highest level of scientific validity evidence. In order to do so, there should be many references and information about the clinical validation and research.
Class D: The highest risk devices require the highest level of proof for scientific validity. There should be the highest possible level of scientific validity evidence, which includes peer reviewed literature and clinical validation.
Validity of Class A In Vitro Diagnostic Devices under Rule 5(b) of IVDR
The IVDR Rule 5 classifies a wide range of in vitro diagnostic devices into different groups; among these are Class A in vitro diagnostic medical devices. Rule 5(b) describes instruments that have been specially manufactured by manufacturers with the intention of being used in such in vitro diagnostic procedures as belonging to Class A in vitro diagnostic devices.
Scientific validity of such in vitro diagnostic devices is important because of the need to guarantee that the device will perform its intended purpose effectively and efficiently. Scientific validity for the in vitro diagnostic devices in rule 5(b) is described as proofing that the device has met certain standards of quality to provide an accurate result. The standard includes not only the manufacture and intended purpose of the device, but also the ability of the device to provide a diagnosis as stated by the manufacturer.
Manufacturers of the in vitro diagnostic devices must provide proof for the suitability of the performance of the instrument as required in the rules of the IVDR. The documentation provided should prove that the instrument performance is suitable for its intended in vitro diagnostic procedures despite its relatively low risk.
Relevant Software Models Identification and Creation of Scientific Validity for IVD MDSW
For the case where there is medical device software (MDSW) in relation to In Vitro Diagnostic medical devices (IVDs), it is important for manufacturers to make sure that they classify the software in terms of scientific validity.
There are different models of software according to their purposes:
Independent MDSW with clinical benefit: The model of software that is intended to be used for medical purposes with the purpose of offering clinical benefits, therefore needs much clinical and performance assessment (software that can detect or assist with diagnoses of diseases)
Software driving or influencing another medical device: Software that drives or influences another medical device and not intended for direct clinical benefits (e.g. software used in controlling insulin pumps). Here, clinical performance is determined by the device it drives.
Scientific Validity for IVD MDSW
In order to prove the scientific validity for IVD MDSW, the manufacturers need to prove that the output of the software, based on the input of the software and the algorithms used, are scientifically valid, as well as related to the clinical condition or physiological state, which is the objective of the device.
It can be proven through:
Literature Review,
Clinical Performance Studies,
Curated Database/Registry Data, and
Own Clinical Investigations by Manufacturer
Scientific Validity Requirements for Calibrators and Control Materials in IVDs
The scientific validity of calibrators and control materials in In Vitro Diagnostic (IVD) devices is essential to ensure the correctness and reliability of the results obtained. According to the IVDR, the scientific validity of a device can be defined as a connection between an analyte and a clinical condition or physiological state. For calibrators and control materials, the scientific validity should be confirmed by showing that the analytes contained therein have an accurate correlation with certain clinical conditions. It may be possible to use already available information from the literature or other sources to confirm the scientific validity. However, in cases when there is not enough information on the matter or if the device is a new one, some additional information (performance studies, for example) may be necessary.
Enforcement of the IVDR Impact
To meet the enforcement of the IVDR, the manufacturer will need to supply scientifically valid and updated information as part of the conformity assessment and technical documentation. In this case, it implies that in the course of the IVDR submission, the manufacturer will not only need to make updates to the technical file but also to prove its scientific validity according to the latest scientific standards. The process will include an evaluation of biomarkers and other scientific data, which may take time due to the high standards set by the IVDR submission process.
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