Author: Suzanne Broussard
One of the recent announcements in the everchanging medtech sector is that the newest European database on medical devices (Eudamed 3) will roll out modules as they become functional. Eudamed 3 is the cornerstone for the new medical device regulations (MDR) and in vitro device regulations (IVDR) and is by all accounts an ambitious project.
The version of Eudamed currently in use (Eudamed2) is a secure web-based portal designed to conduct effective market surveillance on medical devices through information exchange between competent Authorities and the Commission.
Eudamed 3 will be dramatically different when it eventually rolls out. Eudamed 3 is designed to be multipurpose and function as a:
The original intention was that the newest Eudamed database would launch at the same time as the original MDR date of application. However, challenges in preparing the new updated system forced the delay by 2 years. Under this delay, Eudamed 3 will roll out on 26 May 2022.
Now, the European Commission has announced that the different modules will gradually be made available as they are functional. Here is the estimated rolled out of the modules.
The earlier release of the actor registration takes significant pressure off economic operators and competent authorities since all “actors’ are required to register on Eudamed 3 to obtain the required single registration number (SRN) created by Eudamed after the device validation by a competent authority. Obtaining the SRN much earlier than 2022 allows the economic operative the ability to proceed with labeling and design processes. The SRN is critical for compliance with product registration, submission of clinical trial dossiers, and post-market surveillance, as well as vigilance and market surveillance under MDR.
The large number of “Actors” required to register includes the manufacturer, authorized representative, importer, notified body, competent authority, Commission, and public. Getting all these actors registered was seen as a big bottleneck in the system, and the early release significantly dampens the time crunch faced by competent authorities.
If your organization needs support getting your technical documents ready for the transition to MDR or IVDR during this everchanging landscape of medical regulations, Criterion Edge has the expertise and bandwidth to work with you and get the job done.
What is the state of play of the implementation of EUDAMED?
We update the documents below under ‘functional specifications’, ‘MDR/IVDR UDI and device’, and ‘data exchange’ as new information becomes available. Please check back regularly for the latest versions as they are subject to adjustments and fine-tuning. Ref European Commission at this link.
Author: Suzanne Broussard
The In Vitro Diagnostic Device Regulation (IVDR) 2017/746 is making sweeping changes to the European Union regulatory requirements for in vitro diagnostic (IVD) devices. The expanded Technical Documents requirements and the need for a life cycle approach in the Quality Management System are some of the biggest changes.
A Technical Document is required for all classes of IVDs and mandates a Performance Evaluation Plan (PEP) and Performance Evaluation Report (PER), as well as Post-Market Surveillance Plan (PMSP) and Post-Market surveillance report.
It will be challenging to get your organization’s IVDs compliant by the May 26, 2020 deadline. The increased number of IVDs that will be up-classified and require Notified Body (NB) review will only make the transition much more difficult. Here we will introduce some of the major requirements and list some of the important considerations for IVDR 2017/746 compliance. As always, check with your regulatory and legal team to ensure you are in compliance with all country’s jurisdictions.
Technical Documentation
All four classes (A-D) require technical documentation for compliance. The scope of the technical documentation is extensive, and every IVD device will need to write or remediate its technical documents.
Annex II addresses required technical documentation, and Annex III focuses on post-marketing technical documentation. IVDR is clear that “The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organized, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex.”
The six sections of Annex II are:
To comply with the General Safety and Performance Requirements (GSPR), manufactures will need to perform a detailed gap analysis. Conformity with GSPR requires clinical evidence, and this is a significant change for many manufacturers. Furthermore, Performance Evaluation needs to be performed, and if studies are needed manufacturers will need to get up to speed quickly.
Legacy products still need to meet all the IVDR requirements; they will be re-classified, have increased clinical evidence needs, and will likely need NB review.
Class B, C, and D devices are subject to pre-market approval by NBs. These regulations include the safety and performance of medical devices, as well as the manufacturing process, to ensure that the product meets safety at all stages of production. All of these new requirements will increase regulatory and clinical costs.
The performance studies and evaluation requirements for IVDs outlined in Annex XIII of the IVDR in 2 parts: Part A and Part B.
Part A focuses on the pre-market phase, and Part B focuses on Post-Market performance. The IVDR views the performance and evaluation of an IVD as a cyclic event that occurs during the entire life-cycle of the device. The 3 parts of the performance evaluation in Part A are compiled into a Performance Evaluation Report in which the manufacturer must demonstrate there is sufficient clinical evidence to support the device’s intended use. In Part B, the manufacturer continuously reviews the Performance Evaluation Report to ensure the device is meeting conformity. This includes a periodic “state of the art” review. Here is an outline of these requirements.
Part A: Performance Evaluation & Performance Studies
Performance Evaluation
– Key evidence for the Performance Evaluation Report (PER)
Clinical Performance Studies:
A Performance Evaluation Report documenting scientific validity data, analytical performance data, and clinical performance data, as well as their assessment and the clinical evidence derived from them, is required.
Further instructions for performance evaluation in Chapter VI Article 56 (3) states that manufacturers must follow a defined and methodologically sound procedure for the demonstrations of the following in accordance with Article 56 and Part A of Annex XIII:
(a) Scientific validity
(b) Analytical performance
(c) Clinical performance
Annex XIII Part A 1.2 provides the general principles by which manufacturers must demonstrate scientific validity and analytical and clinical performance.
Scientific Validity
In order to demonstrate scientific validity, the manufacturer must use one or a combination of the following criteria, and this must be demonstrated and documented in the scientific validity report. Annex XIII Part A, 1.2.1
See our white paper on how to perform a ‘state of the art’ literature review or contact us directly to see how we can help demonstrate scientific validity.
Analytical Performance
Analytical performance, as defined in Annex XIII Part A, 1.2.2, must be demonstrated on the basis of analytical performance studies and must be demonstrated and documented in the analytical performance report.
Clinical Performance
The clinical performance study plan (CPSP) provides the basis for clinical performance studies. Annex XIII Part A, 2.3.3 outlines the particular information that needs to be addressed in the CPSP, which is outlined in the clinical performance study:
Clinical performance studies are required to obtain data and the subsequent assessments and conclusions that provide clinical evidence. The performance evaluation reports for class C and D devices must be updated annually, or earlier as necessary. There is a dramatic increase in clinical performance studies requirements for IVDs, and meeting these criteria will take time.
Furthermore, the quality of the clinical evidence will be more heavily scrutinized by NBs. The IVDR clearly states that the clinical evidence must support the intended purpose of the device as stated by the manufacturer. Note, this is based on a continuous process of performance evaluation.
The IVDR 2017/746 Corrigendum published in May 2019 amends IVDR 2017/746 replacing the international standard ISO 14155:2011 with ISO 20916:2019 In vitro diagnostic medical devices – Clinical performance studies using specimens from human subjects – Good study practice.
Part B: Post-Market Performance Follow-up (PMPF)
PMPF is a continuous process to update the performance evaluation and addresses the post-market surveillance plan.
Post-market Surveillance
Post-market Surveillance requirements are detailed in Annex XIII and Article 78. The Post-Market Performance Follow-Up (PMPF) needs to be designed as a continuous process that updates the performance evaluation and specifically address the manufacturer’s post-market surveillance plan. This plan needs to proactively collect and evaluate data on device performance, as well as other relevant scientific data.
Labeling
The IVDR requires that every device have a Unique Device Identifier (UDI) on the label.
This is Big – Every Label Will Change!
Major changes to labels will be needed to accommodate UDI. The UDI system applies to all devices placed on the market, with devices used for performance studies being the exception.
The use of the UDI is intended by the EU to provide traceability of IVDs, and thus “significantly enhance the effectiveness of the post-market safety-related activities of the devices, which is owing to improved incident reporting, targeted field safety corrective actions and better monitoring by competent authorities. It should also help to reduce medical errors and to fight against falsified devices.”
The European database on medical devices (EUDAMED) will use the UDI to track devices. The EUDAMED provides a secure, web-based portal that EU competent authorities use to enter information from NBs and manufacturers to exchange information with the European Commission.
As with many aspects of the new regulations on medical devices, information continues to evolve. The Medical Device Coordination Group (MDCG) released 2 new documents in April of 2019 to clarify the inconsistencies in the timelines. These considerations apply mutatis mutandis to the IVDR”.
MDCG 2019-4 Timelines for registration of device data elements in EUDAMED
MDCG 2019-5 Registration of legacy devices in EUDAMED
Keep these documents in mind when considering your transition game plan.
Quality Management System (QMS)
The biggest change to the QMS it the need for a life cycle approach. Article 9 (4) states that “Manufacturers shall draw up and keep up to date the technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III.”
For example:
The PMPF is an integral part of the manufacturer’s quality management system and is active for the life of the IVD. Technical documents need to update accordingly.
The GSPR is integrated into the QMS. The GSPR must be taken into account in the QMS such that the GSPR must be identified and guide the process.
The QMS must demonstrate that it is responsible for the Vigilance process, with the manufacturer doing its due diligence in reporting serious incidents and field safety corrective actions “with deadlines, responsibilities and reconciliation management.” This may be challenging in supply lines that use importers and distributors.
CONCLUSION:
The implementation of IVDR 2017/746 regulation is in full swing and it will significantly affect the manufacturers of IVDS by forcing them to focus on clinical proof and the maintenance of a robust QMS.
Criterion Edge is ready to help your organization meet these challenges. Contact us to find out how we can help.
Get a copy of the slides from this webinar or click to watch the recording.
In this second part of our 2-part webinar series, Criterion Edge will continue to present strategies for assessing key components of your CER for possible misalignment with key EU MDR requirements. Presented from the perspective of seasoned regulatory writers with deep experience authoring MedDev rev. 4 and MDR-compliant CERs, this practical presentation will help you assess your document through the critical lens of a writer and identify possible gaps for mitigation before prior to submission to regulatory authorities. In this series, we will examine the Clinical Data Sources, Equivalence, and Risk/Benefit Analysis Profile sections of the CER.
In the first webinar of this series, we discussed the State of the Art, Safety & Performance Criteria, Equivalence, and Systematic Literature Review.
Click here to get the slides and watch the recording for part 1.
Key Takeaways:
• Understand the key components of a clinical evaluation report (1-min review of last webinar, clinical evidence, SLR, risk benefit, conclusion – have you ensured that your conclusion reflects conclusions from other sections/data?)
• Determine how to evaluate your CER for key requirements of the MDR
Who should watch this webinar?
Those Regulatory, Quality and Clinical leaders and regulatory writers who are tasked with the development, writing, review or approval of Clinical Evaluation Reports for EU MDR submission, or anyone interested in learning more about MDR requirements for CERs.
Sign up for future webinars here.
If you enjoyed this webinar and would like a free consultation, please contact us here.
Author: Suzanne Broussard
The new In Vitro Diagnostic Regulation (IVDR) 2017/746 brings significant changes to the regulation of In Vitro Diagnostic (IVD) devices in the European Union (EU). One of the biggest changes is the use of risk-based classes for IVDs that require significant clinical support and regulatory oversight, and the deadlines for compliance are looming as the IVDR transition period ends on May 25, 2022.
The switch to IVDR will have an enormous impact on the requirements to obtain a CE Marking. Under current European Union regulations, only 10% to 20% of IVDs sold under the In Vitro Diagnostic Directive (IVDD) require Notified Body (NB) assessment. This flips with under IVDRs new risk-based classification system, and an estimated 70% to 80% of IVDs will requiring Notified Body (NB) review.
The new IVDR 2017/746 classification of IVDs is based on an internationally recognized risk-based classification system that places IVD devices in four classes (A-D) based on the intended use of the device, which ultimately determines the risk to both the patient and the general population. Class designation is determined using 10 implementing rules and 7 classification rules.
Classification: Risk-Based Class Designation is Determined Using 7 Classification Rules
IVDR classes are based on globally accepted criteria developed by the Global Harmonization Task Force (GHTF) in February 2011 (GHTF evolved into what is now known as the International Medical Device Regulators Forum [IMDRF]). The risk classes are A through D; class A devices have the least risk, and class D devices have the most risk. This risk-based classification is replacing the list-based classification of the IVDD 98/78/EC and will result in the vast majority of IVDs being up-classified.
Let’s look directly at the IVDR regulation’s seven Classification Rules that are outlined in Annex VIII of IVDR 2017/746. These rules first define each class and are explained in each class below. The rules start identifying devices that have the most risk to both the patient and population (Class D) and then continue with criteria for IVDs that pose less risk. Correctly determining the device classification is critical as the class dictates the level of clinical support and documentation required and the need for NB review. It is important to understand that the classification is based on the devices intended purpose, and thus the risk to the patient and population.
Class D devices have a high risk to the patient and a high risk to public health, and therefore must meet the highest level of conformity. Rule 1.
Class D devices are governed by Rule 1 under Classification Rule 2.1. They include devices that detect the presence of, or exposure to, transmissible agents, life-threatening transmissible agents, and infectious disease with a high risk of propagation.
Class C devices have a high risk to the patient and/or medium risk to public health, and are defined in Rules 2, 3, 4.
The IVD devices in class C according to Rule 2 are intended to be used for blood grouping or tissue typing, blood components, cells, tissues or organs intended for transfusion or transplantation, with some exceptions explicitly stated.
Devices in class C according to Rule 3 are intended to be used for infectious agents without a high risk of propagation, pre-natal screening, companion diagnostics, monitoring levels of medicinal products, detecting congenital disorders in embryos, foetus, or new-born babies; and genetic testing.
Rule 4 further defines class C devices as those that are intended for self-testing “except for devices for the detection of pregnancy for fertility testing and for determining cholesterol level, and devices for the detection of glucose, erythrocytes, leucocytes and bacteria in urine, which are classified as class B.
Class B devices have moderate individual patient risk and/or low public health risk. Class B devices are defined under Rule 4 and 7; class B is also the default class for devices that do not fall within the scope of any stated rules (Rule 6).
Class B devices are less risky than class C devices and include the self-testing devices that are exempt from class C in Rule 4 (see class C above), such as those used to detect glucose. Rule 7 states that “Devices which are controls without a quantitative or qualitative assigned value are classified as class B.”
Class A devices have a low risk to the patient and low public health risk
Under Classification Rules 2.5 Rule 5, the following devices are classified as Class A:
Under the new classification rules, it is estimated that the vast majority of IVDs will be class B or class C. When classifying an IVD, it is important to first look at the implementing rules, 1.1 to 1.10 of the Classification Rules. As you can see below, the implementing rules provide manufacturers with additional information as to which class the device is categorized, especially in regard to combination products and multiple-use devices.
Implementing Rules (Annex VIII)
1.1 Application of the classification rules shall be governed by the intended purpose of the devices.
1.2 If the device in question is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices.
1.3 Accessories for an in vitro diagnostic medical device shall be classified in their own right separately from the device with which they are used.
1.4 Software, which drives a device or influences the use of a device, shall fall within the same class as the device. If the software is independent of any other device, it shall be classified in its own right.
1.5 Calibrators intended to be used with a device shall be classified in the same class as the device.
1.6 Control materials with quantitative or qualitative assigned values intended for one specific analyte or multiple analytes shall be classified in the same class as the device.
1.7 The manufacturer shall take into consideration all classification and implementation rules in order to establish the proper classification of the device.
1.8 Where a manufacturer states multiple intended purposes for a device, and as a result the device falls into more than one class, it shall be classified in the higher class.
1.9 If several classification rules apply to the same device, the rule resulting in the higher classification shall apply.
1.10 Each of the classification rules shall apply to first line assays, confirmatory assays, and supplemental assays.
It is projected that the vast majority of IVDs will fall into class B or class C. Many devices currently on the market will be reclassified into a higher risk based on the IVDR classification and, thus, require significant investment from the manufacturer to remain regulatory compliant. All devices that fall in Class B, C, and D have conformity assessment procedures that require NB assessment, as do some class A devices that require sterilization.
Our next blog will cover Analytical and Clinical Technical Documentation for IVDR 2017/746 Compliance and Software as Part of IVDR. Also, check out to the first post in this series.
Please reach out to us with any questions or to find out how we can help your organization transition to compliance with IVDR 2017/746.
Author: Suzanne Broussard
In vitro diagnostic (IVD) medical devices in the European Union are being held to a higher standard of scrutiny with the introduction of In Vitro Diagnostic Regulation (IVDR) 2017/746 by the European Commission (EC).
Overview of In Vitro Diagnostic Regulation 2017/746
The implementation of IVDR dramatically changes the regulatory landscape for IVD medical devices. Some of the biggest changes include an expanded definition of IVDs, a new classification of IVDs, the requirement of Unique Device Identification (UDI) on each device, an expansion of the Quality Management System, and the increased need for Notified Body (NB) review.
The transition into IVDR is already underway. IVDs marketed in the EU will continue to require a CE Marking certificate to verify that the device meets all the regulatory requirements. Failure to meet the IVDR deadlines could be very costly to manufacturers that would either lose their CE Marking or fail to obtain one. The timeline below outlines the deadlines for manufacturers to become compliant with IVDR 2017/746.
IVDR Timeline
The IVDR is being implemented over a 5-year transition period in which it will fully replace the current In Vitro Diagnostic Directive (IVDD) 98/78/EC (Figure 1). IVDR 2017/746 was published May 5th, 2017, in the Official Journal of the European Union, and officially went in to affect May 25th, 2017; that means we are almost halfway through the transition period. During the transitional provisions, manufacturers can meet either IVDD or IVDR requirements. However, starting May 26, 2022, all new IVDs must go through IVDR. Some devices that lawfully obtained IVDD certificates have another 2-year grace period and may continue to be made available until May 27, 2025 (depending on serval factors).
Article 110 Transitional provisions state that “Certificates issued by notified bodies in accordance with Directive 98/79/ED[EC] prior to 25 May 2017 shall become void by 27 May 2024.” IVDs that obtained certificates in accordance with IVDD prior to May 25, 2017 are valid until the end of the period indicated on the certificate, with some exceptions. Certificates issued under Directive 98/79/EC Annex VI become void at the latest May 27, 2024. If a device is lawfully placed on the market under IVDD prior to May 26, 2022 and placed on the market from May 26, 2022 by a certificate (refer to paragraph 2 and 4), the IVD can be on the market or put into service until May 27, 2025.
See IVDR Article 110 and the IVDR Corrigendum number 8 for specific details.
Starting May 26, 2024 IVDR will be full application, and all IVDs must be fully compliant.
Figure 1. IVDR Timeline
It may seem that there is plenty of time to obtain IVDR compliance, but there are many hurdles to obtaining CE Marking under this new regulation. Also consider that there are major changes in almost every aspect regulation for medical devices in the EU, including MDR, MedDev2.7/1 rev.4, and CERs.
Scope of IVDR
The scope of IVDR is massive, and it impacts all aspects of in vitro diagnostic device manufacturing.
If you are marketing or intend to market any type of In Vitro Diagnostic Medical Device in the European Union, it is time to act. With the need for NBs substantially increasing, it is important to start the process of performing a Gap analysis and finding a NB.
Let’s start by first looking at the newly expanded definition of IVDs under IVDR 2017/746.
If you are marketing or intend to market any type of In Vitro Diagnostic Medical Device in the European Union, it is time to act. With the need for NBs substantially increasing, it is important to start the process of performing a Gap analysis and finding a NB.
Let’s start by first looking at the newly expanded definition of IVDs under IVDR 2017/746.
Definition of In Vitro Diagnostic Devices
Section 1, Article 2 of IVDR 2017/746 expands the definition of IVDs. The addition of software and companion diagnostics to the definition of in vitro diagnostic devices significantly expands the definition of IVDs. Software is a medical device according to the definition of IVD if that is its intended purpose; thus, software as part of an instrument, software as a medical device, and apps are included in the definition of IVDs and fall under IVDR regulation. This includes genetic testing, companion diagnostics, as well as stand-alone software.
The specific definition of In Vitro Diagnostic devices from IVDR 2017/746 is below.
(2) ‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following:
(a) concerning a physiological or pathological process or state;
(b) concerning congenital physical or mental impairments;
(c) concerning the predisposition to a medical condition or a disease;
(d) to determine the safety and compatibility with potential recipients;
(e) to predict treatment response or reactions;
(f) to define or monitoring therapeutic measures.
Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;
Section 1, Article 1, 3. Defines what the IVDR does not apply to:
The next blogs in this series will cover the new Classification Rules.
Please reach out to us with any questions or to find out how we can help your organization transition to compliance with IVDR 2017/746.
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