September 16, 2020

[FREE WEBINAR] A Practical Guide: Conducting Systematic Literature Reviews in Support of IVDR Readiness

Get a copy of the slides from this webinar or click to watch the recording.

With the implementation of IVDR requirements, IVD manufacturers have been challenged to align their internal processes and systems to comply with these rigorous regulations. Companies realize the need to review published literature for device-specific clinical data to establish the state of the art (scientific validity) and clinical performance of their products, however many manufacturers may not be familiar with or have the capability to perform rigorous, IVDR-compliant systematic literature reviews (SLR), screening, selection and data extraction.

In this practical presentation, Criterion Edge breaks down the steps of the SLR process and takes a wholistic approach to conducting an IVDR-compliant SLR. Using case studies, the presentation illustrates the effective use of SLR-derived data to develop the Scientific Validity Report (SVR) and the Clinical Performance Report (CPR).

Key Takeaways:
• Review the essential steps for conducting a robust, methodologically-sound systematic literature review

• Using a typical case study scenario, learn how to effectively search, identify, screen, review and extract critical published clinical data on your subject IVD device to support the development of the Scientific Validity and Clinical Performance Reports.

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 Performance Evaluation Reports for EU IVDR submission, or anyone interested in learning more about IVDR requirements for PERs.

Sign up for future webinars here.


If you enjoyed this webinar and would like a free consultation, please contact us here.

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September 7, 2020

The Medical Device Regulation (MDR) and In Vitro Device Regulation (IVDR) Mandate that Device Manufacturers Have a Person Responsible for Regulatory Compliance (PRRC): Guidelines and Support

Author: Suzanne Broussard

The newly created Person Responsible for Regulatory Compliance (PRRC) position is a unique regulatory requirement that applies only to the European Union, and is a key area of responsibility for a person or persons under the Medical Device Regulation (MDR) and In Vitro Device Regulation (IVDR).  

The motivation for creating the PRRC positions is so that there is a qualified regulatory expert directly responsible for the manufacturing and the market surveillance and reporting systems to ensure the company is meeting the European Union requirements.  

The Regulations have a clear desire to add an additional level of scrutiny to the supervision and control of the manufacturing of medical devices, as well as relevant post-market surveillance and vigilance activities. Thus, the PRRC role is purposefully a unique position from the European Union Authorized Representative.  

The requirements, qualifications, and responsibilities of the PRRC is outline in Article 15 of both Regulation (EU) 2017/745 MDR and Regulation (EU) 2017/746 (IVDR). 

Article 15 of both MDR and IVDR state: 

“Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of in vitro diagnostic medical devices.” 

Manufacturers will be looking closely at how to fill these positions. Parent companies with more than one legal manufacturer under the organization needs to ensure that each legal manufacturer has its own PRRC. Micro or small business enterprises have the option to contract a PRRC (EU definition of micro and small businesses can be found in Regulation 2003/361/1C). 

Responsibilities 

The PRRC has at least 5 responsibilities clearly outline in Article 15. 

  1. Checking the conformity of medical devices in accordance with the quality management system (QMS) before the medical device is released; 
  1. Drawing up the technical documentation and keeping it up to date;  
  1. Making sure the post-market surveillance obligations are in compliance with EU regulations Article 10(9);  
  1. Fulfilling the reporting obligations referred to in reporting of serious incidents and field safety corrective actions (Article 82) and implementing acts (Article 86) 
  1. Ensuring the statement that investigational devices (Section 4.1 of Annex XIV) meet the GSPRs is signed.  

Guidance Document 

The Medical Device Coordination Group (MDCG) released a guidance document on 20 June 2020 addressing some of the questions about the person responsible.  

Medical Devices: Guidance document  

MDCG 2019-7 Guidance on Article 15 of the Medical Device Regulation (MDR) and in vitro Diagnostic Device Regulation (IVDR) regarding a “person responsible for regulatory compliance” (PRRC) 

The guidance clarifies the training and/or professional experience necessary to hold the position of PRRC. The qualifications for this role can be met with either education (certification/diploma) or experience. The PRRC does not have to perform all these duties themselves but is responsible for their completion.  

TEAM-PRRC 

To support those with the role of PRRC, a new not-for-profit European associating has been launched – TEAM-PRRC. The association represents it members at the highest level – the European Commission and Medical Device Coordination group (MDCG). TEAM-PRRC plans to provide the framework and rigorous analysis required to gain insight and influence the guidance that is being developed for the PRRC role. TEAM-PRRC aims to: 

  • Bring together all people with PRRC functions; 
  • Exchange experience on issues faced by PRRC in their daily activities; propose and exchange solutions. 
  • Establish, maintain, and develop a high level of professionalism of PRRC. 
  • Exchange information with health authorities in charge of national, European, and international regulation; promote understanding of PRRCs’ responsibilities to other stakeholders. 
  • Act as a moderator and support PRRCs in conflicts or disputes encountered during their day-to-day activities. 
  • Aim for enhancement of Public Health. 
  • Pursue for mutual assistance between TEAM-PRRC members. 

The newly created role of PRRC will bring many challenges for manufacturers and regulatory specialist, and there is a lot at stake for those considering taking this role. The regulations mandate penalties that are decided on the level of the member states for noncompliance and individuals taking this role need to be aware of the potential consequences.  

Criterion Edge is dedicated to providing support for medical device and pharmaceutical manufacturers, and we do this in part by keeping device manufacturers up to date on current events. For more information on the new MDR guidance documentsextension, and grace period, see our previous posts. 


Either way, Criterion Edge is prepared to provide expert medical writers to facilitate a timely submission.  

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July 27, 2020

The European Commission Pledges Make the Different Eudamed Modules Available On A Rolling Basis

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: 

  • Registration system 
  • Collaborative system 
  • Notification system 
  • Dissemination system (open to the public) 
  • Interoperable 

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 module on actor registration will be the first deployed (latest deployment date of March 2021).  
  • The unique device identification (UDI) module will be available no later than May 2021. 
  • The device registration module will be available no later than May 2021. 
  • The notified bodies certificates will also be available no later than May 2021. 
  • The remaining vigilance, market surveillance, and clinical investigations modules will be active once they are functional or 26 May 2022 at the latest. 

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? 

  • The development and implementation of EUDAMED is a high priority for the Commission. 
  • We have pledged, in agreement with the MDCG, to gradually make the different modules available as soon as they are functional. 
  • We will make the module on actor registration available first, deploying it by March 2021 at the latest. 
  • We will make the module on UDI/device registration (second module) and the module on certificates and notified bodies (third module) available by May 2021. The remaining modules will become available afterwards as soon as they are functional. 

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

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July 13, 2020

In Vitro Diagnostic Devices Require Extensive Analytical and Clinical Technical Documentation for IVDR 2017/746 Compliance

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.    

Change in direction

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: 

  1. DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 
  1. INFORMATION TO BE SUPPLIED BY THE MANUFACTURER 
  1. DESIGN AND MANUFACTURING INFORMATION 
  1. GENERAL SAFETY AND PERFORMANCE REQUIREMENTS 
  1. BENFIT-RISK ANALYSIS AND RISK MANAGEMENT 
  1. PRODUCT VERIFICATION AND VALIDATION 

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 

  • Performance Evaluation Plan 
  • Scientific Validity, analytical performance, and clinical performance 

– Key evidence for the Performance Evaluation Report (PER) 

  • Clinical Evidence and PER 

Clinical Performance Studies: 

  • Purpose of clinical performance studies 
  • Ethical considerations for clinical performance studies 
  • Methods for clinical performance studies (design, plan, report)

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. 

  • Identify through a systematic scientific literature review the available data relevant to the device and its intended purpose and identify any remaining unaddressed issues or gaps in the data;  
  • Appraise all relevant data by evaluating their suitability for establishing the safety and performance of the device; 
  • Generate any new or additional data necessary to address outstanding issues.

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  

  • relevant information on the scientific validity of devices measuring the same analyte or marker; 
  • scientific (peer-reviewed) literature; 
  • consensus expert opinions/positions from relevant professional associations;
  • results from proof of concept studies;
  • results from clinical performance studies.

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: 

  • rational
  • objectives
  • design and proposed analysis
  • methodology
  • monitoring
  • conduct
  • record keeping

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.  

  1. (66) The rules on performance studies should be in line with well-established international guidance in this field, such as the international standard ISO 2019 on clinical performance studies using specimens from human subjects, currently under development, so as to make it easier for the results of performance studies…’. 

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.  

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July 6, 2020

IVDR 2017/746 Implements Risk-Based Classification of IVDs that Focuses on Intended Use

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: 

  • products for general laboratory use, accessories which possess no critical characteristics, buffer solutions, washing solutions, and general culture media and histological stains, intended by the manufacturer to make them suitable for in vitro diagnostic procedures relating to a specific examination;  
  • instruments intended by the manufacturer specifically to be used for in vitro diagnostic procedures;  
  • specimen receptacles. 

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.

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