In vitro diagnostic medical devices influence some of the most important healthcare decisions made for patients. A test result can contribute to diagnosis, screening, treatment selection, disease monitoring, prognosis or assessment of physiological and pathological conditions.
Regulation (EU) 2017/746, commonly known as the In Vitro Diagnostic Medical Devices Regulation or IVDR, establishes the European regulatory framework for in vitro diagnostic medical devices and replaced Directive 98/79/EC.
The IVDR introduced a fundamentally different risk-classification system based on Classes A, B, C and D. It also strengthened requirements for performance evaluation, clinical evidence, scientific validity, analytical performance, clinical performance, quality management, post-market surveillance and traceability.
For many IVD manufacturers, one of the most significant changes from the former Directive is the greatly increased requirement for Notified Body involvement. Under the IVDR, most Class B, C and D devices require independent conformity assessment.
This GAR Insight explains IVD qualification, classification, General Safety and Performance Requirements, performance evaluation, conformity assessment, Notified Body involvement, technical documentation, UDI, EUDAMED, post-market performance follow-up and CE marking.
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Explore IVDR scope, Classes A–D, GSPR, performance evaluation, analytical and clinical performance, conformity assessment, technical documentation, UDI, EUDAMED and CE marking.
Understanding Regulation (EU) 2017/746
Regulation (EU) 2017/746 establishes requirements for in vitro diagnostic medical devices placed on the European Union market or put into service.
The Regulation repealed Directive 98/79/EC and introduced a substantially strengthened regulatory system based on risk classification, performance evidence and lifecycle oversight.
What Is an In Vitro Diagnostic Medical Device?
An IVD is generally a medical device intended by the manufacturer to be used in vitro for the examination of specimens derived from the human body, including blood and tissue donations, for the purpose of providing medically relevant information.
Reagents
Chemical or biological reagents used to detect, identify or measure an analyte or characteristic.
Calibrators & Controls
Products used to establish measurement relationships or verify assay performance.
Test Kits
Collections of components intended to perform a defined diagnostic examination.
Instruments
Analysers, readers and associated equipment intended for IVD use.
Specimen Receptacles
Devices specifically intended for the primary containment and preservation of specimens derived from the human body.
IVD Software
Software may itself qualify as an IVD when its intended purpose meets the applicable IVDR definition.
Defining the Intended Purpose
Intended purpose is central to IVDR qualification, classification and performance evaluation. It should explain what the IVD measures or detects, the specimen used, the target population and the medical information the result is intended to provide.
Analyte or Marker
Identify the substance, organism, genetic marker or other characteristic being detected or measured.
Specimen
Define the intended specimen type, such as blood, serum, plasma, urine, tissue or another human-derived specimen.
Clinical Purpose
Explain whether the result contributes to diagnosis, screening, monitoring, prognosis, treatment selection or another purpose.
Intended User
Identify whether the device is intended for professional, laboratory, near-patient or self-testing use.
IVDR Classes A, B, C & D
Annex VIII of the IVDR contains seven classification rules used to determine whether an IVD falls into Class A, B, C or D.
Classification reflects the potential consequences of an incorrect test result for both the individual patient and public health.
Class A
Generally lower-risk products such as certain instruments, specimen receptacles and general laboratory-related IVD products.
Class B
Devices not falling within the higher-risk rules and not qualifying as Class A are generally classified as Class B.
Class C
Includes many devices where incorrect results could lead to serious consequences for patients or clinical management.
Class D
Includes IVDs associated with particularly high public-health and individual risks, such as defined tests concerning transmissible agents.
General Safety & Performance Requirements
IVDs must comply with the General Safety and Performance Requirements established in Annex I of the IVDR.
Risk Reduction
Risks should be reduced as far as possible without adversely affecting the benefit-risk ratio.
Performance
Devices should achieve the analytical and clinical performance claimed by the manufacturer.
Chemical & Biological
Materials, substances and biological characteristics should be appropriately assessed.
Infection & Contamination
Risks associated with contamination, specimens and biological materials should be controlled.
Electrical & Mechanical
Instruments and systems should address relevant electrical, mechanical, thermal and other physical hazards.
Information Supplied
Labels and instructions should communicate the intended use, performance characteristics, limitations and safety information.
Performance Evaluation Under the IVDR
Performance evaluation is one of the defining components of IVDR conformity. It is a continuous process by which data are assessed and analysed to demonstrate the scientific validity, analytical performance and clinical performance of an IVD.
Scientific Validity
Establish the association between the analyte or marker and the relevant clinical or physiological condition.
Analytical Performance
Demonstrate the device’s ability to correctly detect or measure the intended analyte.
Clinical Performance
Demonstrate the device’s ability to yield results correlated with the relevant clinical condition or process.
Analytical Performance
Analytical performance demonstrates whether the IVD can reliably detect or measure the analyte under the conditions described by the manufacturer.
Analytical Sensitivity
Evaluate the device’s ability to detect low concentrations or relevant quantities of the target.
Analytical Specificity
Evaluate interference and cross-reactivity capable of affecting results.
Accuracy
Establish appropriate measures of trueness and precision where applicable.
Repeatability
Determine variation when measurements are repeated under the same conditions.
Reproducibility
Assess variation across relevant users, instruments, sites, lots or operating conditions.
Measuring Range
Establish applicable range, detection limits and quantitation characteristics where relevant.
Stability
Establish shelf life, in-use stability, transport stability and other relevant conditions.
Specimen Handling
Evaluate relevant specimen collection, storage, preparation and transport characteristics.
Cut-Off Values
Establish appropriate cut-off or decision limits where these influence interpretation of results.
Clinical Performance
Clinical performance concerns the ability of the IVD to produce results that correlate with a particular clinical condition, physiological or pathological process or state in accordance with its intended purpose.
Diagnostic Sensitivity
Evaluate the ability of the device to correctly identify subjects associated with the relevant condition where applicable.
Diagnostic Specificity
Evaluate the ability to correctly identify subjects not associated with the relevant condition where applicable.
Predictive Values
Positive and negative predictive values may be relevant depending on the test and intended clinical context.
Clinical Studies
Performance studies may be necessary where sufficient clinical performance evidence cannot otherwise be established.
IVDR Technical Documentation
IVDR technical documentation should demonstrate that the device has been designed, manufactured and evaluated in accordance with the applicable requirements.
Quality Management Under the IVDR
Manufacturers must establish and maintain a quality management system appropriate to the device, risk class and regulatory responsibilities.
Design Controls
Development of assays, instruments and software should be planned, reviewed, verified and validated.
Supplier Controls
Critical raw materials, reagents, components and outsourced processes should be appropriately controlled.
Production Controls
Manufacturing processes should consistently produce devices meeting approved specifications.
Lot Control
Reagent and test-kit production can require appropriate lot qualification and release controls.
CAPA
Quality issues and nonconformities should feed into corrective and preventive action processes.
Post-Market Feedback
Complaints, vigilance and performance data should feed back into quality and risk-management processes.
IVDR Conformity Assessment by Device Class
Device classification determines the level of conformity assessment and degree of third-party involvement required.
| IVD Class | General Conformity Position | Notified Body |
|---|---|---|
| Class A — non-sterile | Manufacturer can generally complete conformity assessment without Notified Body involvement. | Generally no |
| Class A — sterile | Notified Body involvement applies to the aspects concerned with establishing, securing and maintaining sterile conditions. | Yes — limited scope |
| Class B | Requires conformity assessment involving an appropriately designated Notified Body. | Yes |
| Class C | Requires Notified Body conformity assessment and more extensive technical and performance evidence appropriate to the risk. | Yes |
| Class D | Subject to the highest level of IVDR conformity assessment, including additional requirements applicable to highest-risk devices. | Yes |
The Role of the Notified Body
Notified Bodies designated under the IVDR assess conformity for devices requiring independent third-party involvement.
QMS Assessment
The manufacturer’s quality management system can be audited against the applicable IVDR conformity requirements.
Technical Documentation
Device documentation and performance evidence are reviewed according to the applicable conformity assessment route.
Performance Evidence
Scientific validity, analytical performance and clinical performance evidence may form part of the assessment.
Surveillance
Continuing surveillance is performed where required to maintain certification.
UDI, EUDAMED, Declaration & CE Marking
IVDR market access includes device identification, registration, economic-operator requirements, the EU Declaration of Conformity and CE marking.
UDI
Unique Device Identification supports traceability of IVDs throughout the supply chain and device lifecycle.
Basic UDI-DI
The Basic UDI-DI provides a regulatory identifier for a device family and is used within key regulatory documentation.
EUDAMED
Applicable actor, device and certificate information is managed through the European Database on Medical Devices.
EU Declaration
The manufacturer draws up the EU Declaration of Conformity after applicable conformity requirements have been satisfied.
CE Marking
CE marking is applied after the applicable conformity assessment procedure has been satisfactorily completed.
Authorised Representative
Manufacturers established outside the Union require an EU authorised representative in accordance with the IVDR.
Post-Market Surveillance & Performance Follow-Up
IVDR compliance continues after the device is placed on the market. Manufacturers must actively collect and evaluate information about device quality, safety and performance.
Post-Market Surveillance
PMS should systematically gather and analyse information from marketed devices.
PMPF
Post-Market Performance Follow-Up supports continuous evaluation of scientific validity, analytical performance and clinical performance.
Vigilance
Serious incidents and field safety corrective actions must be handled according to applicable IVDR requirements.
Performance Updates
New performance data can require updates to the performance evaluation and technical documentation.
Risk Updates
Post-market information should feed back into the risk-management process.
CAPA
Quality and performance problems should trigger appropriate investigation and corrective action.
From IVD Development to Demonstrable European Conformity
Successful IVDR compliance begins with a clearly defined intended purpose and defensible classification. Those decisions determine the performance evidence, conformity assessment route and level of independent regulatory scrutiny that follow.
Manufacturers should then build a connected evidence system linking risk management, General Safety and Performance Requirements, scientific validity, analytical performance, clinical performance, verification, quality management and technical documentation.
For most Class B, C and D devices, this evidence must support conformity assessment by an appropriately designated Notified Body before CE marking.
The responsibility continues after market entry through post-market surveillance, vigilance and post-market performance follow-up.
The Performance Question
Does the available scientific, analytical and clinical evidence demonstrate that the IVD reliably performs for its stated intended purpose and patient or population context?
The Conformity Question
Can the manufacturer demonstrate through classification, performance evaluation, risk management, technical documentation, quality controls and post-market processes that the IVD continues to satisfy Regulation (EU) 2017/746?