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The Essential IVDR and the Challenges it Presents

Posted 11 September 2019 | By Sue Spencer  | ©

The Essential IVDR and the Challenges it Presents

This article discusses key elements of the In Vitro Diagnostic Regulation (IVDR) and the challenges it presents to manufacturers. The author covers device classification changes, oversight, clinical evidence and performance evaluation, and postmarket vigilance. She cautions about the effects of notified body reductions and the consequences. She concludes by warning that significant changes may impede market launch for some products.
 
Introduction
 
It is essential when reading the IVDR to not skip the preamble because it sets the “scene” and the priorities of the European Union (EU) in writing the regulation. The In Vitro (IVD) Directive was never updated, while the Medical Device Directives (MDD) have experienced a series of five gradual changes and the IVD sector will be increased significantly from one to six.1,2 While the IVDD was ready for a review, the Poly Implant Prothese Breast Implant (PIP) scandal, where a manufacturer deliberately used industrial grade silicone to make breast implants, occurred in the medical device sector.3 The “fall out” from this scandal can clearly be seen in the text of the IVDR. Both the IVDR and the MDR aim to address concerns, such as patient safety and transparency and, as a result, the text includes increased expectations for clinical evidence, scrutiny of manufacturers data, greater expectations for both competent authorities and notified bodies, traceability throughout the supply chain and greater transparency.
 
It is important to remember the driving forces behind the changes when trying to understand the requirements and proposed implementation. The objective to address patient safety concerns is one of the criteria driving the timelines of the IVDR and promises have been made to parliament to protect patient safety. As a result, it is unlikely that the implementation of the IVD will be delayed, despite the number of challenges.    
 
IVDR Scope
 
The scope of the IVDR regulation has not expanded significantly. The breadth of products to be legislated under the IVDR remains the same; however, the depth the expectations for the documentation and review have significantly increased. There are minor tweaks to the wording of the IVD definition, but these are really clarifications that ensure new advances in diagnostics are clearly included within the scope of the IVDR.
 
Classification
 
The classification under the IVDR will be based on the Global Harmonization Task Force (GHTF) (Figure 1).4 It is important to recognize that it is “based” on the GHTF, but is not identical. Interpretation of the rules will, therefore, be key. The GHTF and IVDR both consider Class D devices to be the highest risk; they present a personal and public health risk. Class C devices have a high personal health risk, but lower public health risk, while Class B have a low to medium risk and Class A devices are considered low risk. A competent authority lead group, chaired by France, is creating a guidance document not yet in the public domain. This guidance will significantly aid consistent interpretation. However, as with any new system, borderline cases will arise and take time to resolve. Disputes will be sent to the borderline decision group of the Medical Device Coordination Group (MDCG). There will be significant competition for this group’s time; past experience suggests they will take some time to reach an opinion. In the absence of official guidance, manufacturers need to make judgements based on the text of the Annex VIII of the IVDR, and provide a clear justification and agree upon this position with their Notified Body (NB).
 
Figure 1. IVDR Classification

Spencer-fig-1.jpg

 
There will be significantly more products in Class D as compared to Annex II List A of the IVDD. The largest proportion of IVDs will fall into Class B, but there are a significant number of devices, including companion diagnostics, cancer diagnostics and those for infectious diseases falling into Class C. Classes B, C and D will require oversight by an NB who will sample more Class C devices than Class B. Only instruments and simple devices, such as wash solutions, will remain in Class A and continue to be self-declared.
 
Conformity Routes and the Scrutiny Process
 
The most significant change created by the IVDR is the level of third-party oversight required by a NB. Initial estimates predict only 20% of manufacturers need an NB under the IVDD and under the IVDR 80% will require an NB. Manufacturers have now started to assess their portfolio and some manufacturers have realized over 90% of devices will need an NB.
 
Figure 2. Conformity Routes

Spencer-fig-2.jpg

While the demand for NBs increases, the number of NBs is decreasing and, as a result, NB capacity has become a concern. 
 
The number of NBs is decreasing for several reasons, including:
 
  • The expectations for NBs have increased.
  • The number of in-house experts required by the NB to achieve designation has increased.
  • It takes two years to fully train an NB expert and during this time, they have limited utilization.
 
There are many new analytes that will require an NB and since these experts cannot perform gap assessments prior to designation, the NB must carry the cost of the new staff for up to two years, requiring significant commitment and investment from the NB.
 
Class D devices present both high personal and public health risks. Common Specifications (CS) will be required for all Class D devices. Common Technical Specifications (CTS) exist for devices currently in Annex II List A, but these do not contain all the criteria required in the IVDR and will need to be revised. More devices are included in Class D than in the IVDD Annex II List A. As a result, there will be many devices which do not have a CS when they are presented to the NB for the first time for conformity assessment. Where no CS exists, the NB will inform an expert panel formed by the Commission in consultation with the Medical Device Coordination Group (MDCG). The expert panel will examine the NB’s review of the manufacturers performance evaluation report and provide comments which the NB must take into consideration. The expert panel will then start to draft a CS for the analyte based on their experience so that future devices can be reviewed to the CS without the need for an expert panel.
 
Class D devices also will require testing by a designated reference laboratory. At present, there is no indication who will be designated as a reference laboratory and the designation process will not start until 18 months before the end of the transition period. This forces the approval of high-risk devices to the end of the transition period and it is likely they will need to make use of the two-year post transition “grace period.” At present, it is difficult to determine how much capacity there will be within the reference laboratories, but it is anticipated that NBs and reference laboratories will pose a “bottle neck” for Class D devices. 
 
The IVDR requires that the reference laboratory confirm compliance to the CS by conducting independent testing as part of the initial conformity assessment process. This is a new expectation and it is not yet clear how much testing will be needed or how long it will take. At present, test laboratories are subcontractors to the NB. However, in the future, they will be designated, which reduces the visibility and control of the NB through review process and makes it more difficult to estimate approval times. Class D products will continue to require the release of each batch by the NB following testing by the reference laboratory. NBs currently use a notified body recommendation, which provides criteria under which diagnostic, but not screening products, with a good compliance history can be tested every fifth lot. There is no indication whether this will be able to continue under the regulation.
 
Clinical Evidence and Performance Evaluation
 
Clinical evidence is likely to be the greatest challenge for all manufacturers. If a manufacturer already has all the data needed to support compliance with the IVDR, for each device they still must prepare a scientific validity report, analytical and clinical performance reports, plus a performance evaluation report. They also must locate all supporting data so that it is available for review, this is can be a significant body of work. Manufacturers also must determine and document how relevant the data they have is to a device s currently on the market. Many devices will have undergone several changes since the initial data was created and claims may have been adjusted or clarified to meet the IVDR. As a result, careful consideration and justification needs to be given to the relevance of the data to the product on the market and submitted for CE marking.
 
The GHTF document on Conformity Assessment SG1(PD)/N046R3 suggests only summary documentation or a Summary Technical Documentation (STED) document is required for Class B devices.5 Early indications suggest this will not be accepted and that while fewer Class B devices will be sampled than Class C devices, when a Class B device is sampled data will be required, not just a data summary. Sufficient data needs to be available to confirm statistics. This may not just include original instrument print outs and could be summarized in tables, spreadsheets and statistical packages, but also require indications from the Clinical Investigation and Evaluation (CIE) group. A high level summary of performance alone for Class B devices will not be accepted. 
 
Postmarket and Vigilance
 
The IVDR requires manufacturers to have a postmarket surveillance plan and proactively collect and evaluate performance and relevant scientific data from the use of a device. The postmarket performance follow-up (PMPF) should confirm the safety, performance and scientific validity of the product during its time on the market and, particularly, the continued acceptability of the benefit-risk ratio and any new emerging risks or changes in the way the device is clinically used. Under the IVDD, manufacturers were required to conduct postmarket surveillance; however, under the IVDR the requirements are more prescriptive and link to specific new elements within the IVDR, such as confirming scientific validity. Thus, manufacturers will have to upgrade their current processes to meet the new requirements and ensure they have appropriate plans and reports in place.
  
Similar Features to the MDR
 
There are some new features of the IVDR in common with the MDR. For example, the IVDR outlines additional responsibilities for economic operators who have additional responsibilities for traceability and reporting of adverse events. IVD manufacturers and authorized representatives will also require a Person Responsible for Regulatory Compliance (PRRC). Because a key aim of the new regulations is to improve the traceability of devices, the IVDR includes requirements for Unique Device Identification (UDI).
 
NB capacity is the greatest concern for the implementation of both the IVDR and the MDR. The number of IVD NBs has been reduced and the NBs are already under pressure and a significant number of IVDs will now require NB services. This situation may lead to a “perfect storm.” Too, it will likely be a frustrating time for manufacturers as this situation is beyond their control and could limit their ability to place products on the market. This scenario may be difficult to explain to senior management and customers and could lead to patient safety concerns if products become unavailable. It is essential part of the IVDR readiness process to start talking to a NB as soon as possible. Manufacturers need to understand NB expectations and their ability to deliver audits and availability to review the Technical Files (TFs). Manufacturers need to be well-prepared, so a high first pass approval rate will maximize the capacity of the NBs.
 
Quality Management Systems
 
As the “devil is always in the detail,” and while the harmonized standard will remain ISO 13485, the IVDR has new requirements for specific plans and subsequent reports with prescriptive content.6  These will need to be embedded into the quality management system and staff will need to be trained to follow the IVDR and the new procedures. Manufacturers also will need to include the IVDR in their routine internal audits before their first IVDR audit to ensure that the requirements have been addressed.
 
Status
 
Progress to meet the requirements of the IVDR is slow. At the half-way point in the transition period, even the largest and best resourced manufacturers have completed only a handful of pilot IVDR technical files and are in the process of scaling up preparation. To put this into perspective, many IVD manufactures can have hundreds or thousands of products required to meet the IVDR. Manufacturers are much further behind with their implementation plan than they were at the comparable time during the implementation of the IVDD, and many manufacturers have struggled to meet the transition deadline despite an earlier start. Any manufacturer who has not started preparations needs to urgently look at ways to catch up and avoid product availability issues.
 
Summary
 
The IVDR presents an enormous change to the IVD industry, not only because it requires a significant change to technical documentation and the quality management system, but also because it changes the relationship with economic operators and their responsibilities. Manufacturers have often launched in Europe before the US; however, under the IVDR the requirements are more onerous and will take more time for approvals to be completed, and this may change the way products are launched in the future. While there is undoubtedly a huge amount of work required to transition from the IVDD to the IVDR, manufacturers should recognize the IVDR is more complex and detailed and will require more resources to maintain as well as implement. Finally, it is important to anticipate change. Many guidance documents have not been published and further implementation and delegating acts are yet to be published, which will change expectations and inevitable lead to rework of the documentation and quality management system. The IVDR is very much in its infancy and all stakeholders need to be prepared for its evolution over the coming years.
 
References
 
  1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02017R0745-20170505. Accessed 9 September 2019.
  2. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02017R0746-20170505. Accessed 9 September 2019.
  3. Kirsh D. “PIP Breast Implant Scandal: A Story That Triggered Change.” 13 November 2017. Mass Device Medical Network. https://www.massdevice.com/pip-breast-implant-scandal-story-triggered-change/. Accessed 9 September 2019.
  4. Principles of In Vitro Diagnostic (IVD) Medical Devices GHTF/SG1/N045:2008 Classification. http://www.imdrf.org/docs/ghtf/final/sg1/procedural-docs/ghtf-sg1-n045-2008-principles-ivd-medical-devices-classification-080219.pdf. Accessed 9 September 2019.
  5. GHTF SG1(PD)/N046R3: Principles of Conformity Assessment for In Vitro Diagnostic (IVD) Medical Devices. International Medical Devices Forum (IMDF) website. http://www.imdrf.org/ghtf/ghtf-archives-sg1.asp. Accessed 9 September 2019.
  6. ISO 13485 Medical Devices. International Standards Organization (ISO) website. https://www.iso.org/iso-13485-medical-devices.html. Accessed 9 September 2019.
 
About the Author
 
Sue Spencer is principal consultant and IVD lead at Qserve Group. She has more than 30 years of experience in the medical device and IVD industries, including extensive notified body experience. Spencer has worked for several IVD companies, ranging from start-ups to large multinationals, where she has held positions in R&D, manufacturing and quality assurance. She worked for three notified bodies, establishing two “from scratch.” She chaired the European IVD Notified Body Working Group coordinating the notified body responses to the regulations and has participated in the Commission IVD Technical Work Group for many years. She may be contacted at sue.spencer@Qservegroup.com.
 
Cite as: Spencer S. “The Essential IVDR and the Challenges it Presents.” Regulatory Focus. September 2019. Regulatory Affairs Professionals Society.

 

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