Prior to CE Marking an in vitro diagnostic (IVD) medical device in Europe, manufacturers must compile technical and performance documentation to demonstrate compliance with the applicable Directive or Regulation.
Further, if the IVD device is not self-certified, manufacturers must undergo conformity assessment review by a Notified Body. Notified Bodies are accredited and supervised by the European national Competent Authorities, and their role is to evaluate if products have met the minimum safety and efficacy requirements. The Notified Body grants “CE Mark Approval” by issuing a CE certificate.
IVDR Progressive Rollout Timing
The EU Parliament and European Council have adopted an amendment to push out the IVDR application dates for most, but not all, IVDs. This amendment provides a deadline extension to the IVDR implementation date.
The rollout staggers the compliance dates over the next five years. Below are the new IVDR transition timelines by device classification.
26 May 2022
No transition period granted. Must comply immediately.
26 May 2027
An additional five years to transition has been granted.
26 May 2027
An additional five years to transition has been granted.
26 May 2026
An additional four years to transition has been granted.
26 May 2025
An additional three years to transition has been granted.
This is not a delay of the IVDR, per se. Instead, it is a delay of the compliance date for IVDs already on the European market, that require Notified Body certification. This is an important distinction because there is a severe lack of notified bodies accredited to the IVDR and an extensive number of IVDs on the market that need certification.
Further, some elements of the IVDR will apply to all IVDs on its date of application (DoA). For example, IVDR vigilance, post-market surveillance and market surveillance requirements will apply to every IVD on the market, even those that are IVDD CE marked as ‘legacy’ devices under the above transition period.
IVDs newly CE marked on or after 26 May 2022 are not eligible for the above transition dates and must comply with the IVDR in order to be placed onto the market.
IVDR Requirements Overview
Under the IVDR, devices are classified as:
Class A non-sterile
Class A sterile
Only Class A non-sterile devices are exempt from Notified Body involvement. These devices are self-certified by the manufacturer, who self-affix the CE marking.
All other IVD classes require conformity assessment by a Notified Body and a CE marking certificate.
All IVDs irrespective of classification and risk level, require the following elements from the IVDR:
- Annex II – Technical Documentation File (TDF), which includes information related to product design and manufacturing, product verification and validation, and risk analysis and management
- Annex III – Post-Market Surveillance (PMS) appendix
- Annex XIII – Performance Evaluation Report (PER)
Not all the requirements outlined in Annexes II, III and XIII may apply to your specific device. Manufacturers should determine which sections are appropriate. Where a section is deemed not applicable, manufacturers should document a rationale as to why this has been excluded from the Technical Documentation File (TDF) and/or Performance Evaluation Report (PER).
The information detailed in the TDF and PER should provide evidence that the General Safety and Performance Requirements (GSPRs), described in the Technical Documentation Files overview section, have been sufficiently addressed.
The documentation requirements for Class D IVDs align with the above but are more comprehensive. In addition to Notified Body CE marking, all Class D devices must undergo testing at an EU reference laboratory (EURL). The EURL is responsible for verifying the performance claims made by the manufacturer.
In addition to the above, manufacturers of certain types of IVDs, such as companion diagnostics and near-patient testing devices, may have other requirements to consider.
Technical Documentation File Overview
Basic information regarding the key elements of the IVDR TDF are outlined below. Upon reading, you will notice that several of the sections are intertwined. This is because manufacturers should consider the technical file as a whole when drafting, rather than looking at the sections as standalone items. For example, the General Safety and Performance Requirements (GSPRs) include information from the Risk Management section, and elements of the Risk Management section need to be considered for the Post-Market Surveillance (PMS) plan.
Manufacturers should utilize European harmonized standards and Common Specifications, when available. Doing so presumes compliance with that requirement; further, while use of standards is theoretically voluntary, in practice it is expected that where one exists, it will be utilized. If a standard has not yet been harmonized in Europe for the IVDR, then the international version of the standard can be referenced instead.
The list of harmonized standards can be found on the European Commission’s website.
Similar to the IVDD, the main body of an IVDR complaint TDF should include key details and documentation related to the device, including the description, labeling/IFUs, design and manufacturing information, product verification and validation (i.e., data to prove the safety and efficacy of the device).
Two key components that manufacturers need to develop for the IVDR TDF are the General Safety and Performance Requirements and Risk Management section.
General Safety and Performance Requirements (GSPR)
- The GSPRs detail the specific criteria manufacturers must meet to establish minimum safety and efficacy requirements for their device, e.g., requirements for performance, risk management, design, etc.
- The GSPRs, located in Annex I of the IVDR, are similar to the Essential Requirements Checklist (ERC), located in Annex I of the IVDD.
- Current versions of the EU harmonized standards should be noted in the GSPR, where available.
Risk Analysis & Management
- Manufacturers must assess possible risks related to their device and rate the probability of occurrence against the severity of harm if it does occur. Manufacturers should detail the procedures in place to mitigate the risk or actions to take if it occurs. An approach some companies follow is to incorporate a Failure Mode and Effects Analysis (FMEA) template as part of their overall risk management system.
- EN ISO 14971:2019 is not yet a harmonized standard under the EU IVDR. However, it is best practice and manufacturers will generally comply with the IVDR if they follow this standard.
- Annex I, section 3 of the IVDR includes specific criteria that manufacturers must meet when implementing their risk management system. This section states that risk management is “a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating”.
Post-Market Surveillance (PMS) Plan
- The Post Market Surveillance (PMS) section of the TDF details the manufacturer’s plan to collect and assess post-market data. The PMS Plan should include information from serious incidents, complaints, public information on other similar medical devices, and more (refer to IVDR Annex III, Section 1(a)).
- The PMS Plan must also establish how the manufacturer will use the data collected to take action when needed. Actions may include making updates to device documentation, such as the PER, improving the risk management and/or taking preventative or corrective action.
Post-market Performance Follow-up (PMPF) Plan
- The Post-market Performance Follow-up (PMPF) plan is a subset of your PMS Plan and is very much intertwined with your risk management and clinical evaluation. The PMPF plan is intended to help identify previously unknown risks and to confirm the device’s safety and performance.
- A PMPF Plan can include a PMPF study when warranted. However, other methods can also be used to address gaps in your pre-clinical data and to demonstrate a continued positive benefit-risk ratio, when appropriate. Examples include feedback via patient or physician surveys and screening of scientific literature.
Post-Market Surveillance Report (PMSR)
Manufacturers of Class A and B devices must prepare a post-market surveillance report (PMSR) based on data collected once the product is on the market. The PMSR is generated through review and analysis of the gathered PMS data and should also include any preventative or corrective actions taken.
The IVDR states the PMSR should be updated ‘when necessary’ and made available to the notified body and competent authorities ‘upon request’.
Periodic Safety Update Report (PSUR)
Manufacturers of Class C and D devices are required to prepare a Periodic Safety Update Report (PSUR) for each device.
The PSUR is a living record in which the manufacturer systematically assesses their PMS data to ensure the device continues to be safe and effective and to provide an accurate picture of the products’ performance post-market. This includes any preventative or corrective actions taken and volume of sales.
The PSUR must be updated at least annually. A Class C manufacturers must make the PSUR available to its notified body, upon request. Manufacturers of Class D IVDs must provide its updated PSURs to its notified body and the PSUR will further be accessible to all national competent authorities and the EU Commission.
The Performance Evaluation Report (PER) is a crucial element of the technical file, and includes the following information:
- basic device information,
- Performance Evaluation Plan (PEP),
- common specifications and harmonized standards,
- a literature review,
- data from a performance study (if required),
- Post-Market Surveillance (PMS) data,
- Post-Market Performance Follow-Up (PMPF) data,
- a plan for continual updates to this section, and
- other relevant device documentation, such as the IFU.
Per the information in the IVDR, the PER is intended to be a ‘living’ document and should be continually updated. Specifically, the regulation states that the “clinical evidence and its assessment in the performance evaluation report shall be updated throughout the life cycle of the device concerned with data obtained from the implementation of the manufacturer’s PMPF plan…and the post-market surveillance plan…”.
Additional PER Resources
In addition to the information located in the IVDR, the Medical Device Coordination Group (MDCG) released MDCG 2022-2 – a guidance document related to the clinical evidence for IVDs, available here on their website.