The introduction of new guidelines for the diagnostics industry, outlined by the In-Vitro Diagnostics Regulation (EU) 2017/746 (known as IVDR), imposes significant changes for many manufacturers, who need a robust strategy to adequately support diagnostic products and meet the new requirements. As seen in the corresponding EU-MDR medical device regulatory requirements, Medical Device Regulation (EU) 2017/745, many products will need new intended purpose statements, technical documents, and internal reviews before a declaration of conformity can be drawn up. The date of application is the deadline by which all revised technical documentation is required to be submitted to notified bodies for approval. For IVDR compliance, this falls on May 26, 2022. Methodologically-sound literature reviews can help you keep track of clinical evidence to support performance & safety requirements as well as establish State-of-the-Art for medical devices and reduce the risk of non-compliance.
First Things First: MDR and IVDR Compliance Are Not the Same Thing
Though IVDR is similar in many ways to MDR, there are a number of key differences between the two regulations that companies must fully understand to be compliant:
- EU-MDR applies to all medical devices manufactured or sold in the European Union that will be used on human subjects. By contrast, the IVDR pertains only to in-vitro diagnostic medical devices, broadly described as devices intended to be used outside the body for monitoring purposes, for example, to provide information on physiological or pathological processes, physical or mental impairments, the diagnosis of disease states or conditions, or treatment responses and safety. More specifically, devices considered in scope for IVDR include reagents, kits, instruments, apparatuses, pieces of equipment, calibrators, control materials, and software or systems. This list is broad but stands in direct contrast to the MDR in-scope products, which include medical devices intended for use on or within human subjects. These include surgical instrumentation, wound care products, and device implants, among other products.
- Although both Medical Devices and In-Vitro Diagnostics regulations categorize devices across four regulatory classes, MDR classifies products differently than IVDR regulation. For instance, MDR classifies products from lowest to highest risk as Class I, Class IIa, Class IIb, and Class III devices, respectively. IVDR, on the other hand, classifies products from lowest to highest risk as Class A, Class B, Class C, and Class D devices. It should be noted that both Class I devices (MDR) and Class A devices (IVDR) can be evaluated via self-assessment, whereas all higher-risk devices require notified body approval under both MDR and IVDR. Compared with their predecessor regulations, these changes broadly increase the scope of notified body approvals needed for both medical devices and in-vitro diagnostic devices.
- Pre-market data is handled slightly differently between regulation (EU) 2017/245 (MDR) and regulation (EU) 2017/246 (IVDR). The MDR regulation requires clinical evaluation reports (CERs) to be based on the evaluation of clinical evidence and clinical data. The IVDR instead requires a performance evaluation report (PER) as well as performance studies for in-vitro diagnostic devices. Both the CER and the PER documents become part of the CE technical file upon completion.
- Post-market surveillance (PMS) and vigilance requirements differ between the two regulations:
- The MDR requires a post-market surveillance plan, a post-market surveillance report (PMSR), ongoing post-market clinical follow-up (PMCF) on device performance, and in some cases, a periodic safety update report (PSUR).
- The PMCF is a specific form of post-market surveillance and is required for medical devices of Class IIb and Class III and for implantables. The PMCF document captures clinical evidence from actual and similar devices and may include literature on medical device safety and performance.
- The PMSR is required for Class I MDR products and summarizes conclusions of the PMS data.
- The periodic safety update report (PSUR) is similar to the PMSR but for Class IIa, Class IIb, Class III, and implantable products.
- The IVDR sets out similar requirements, but a PMS report is only needed for in-vitro diagnostic device Class A and Class B products, and the PSUR requirement only applies to Class C and Class D products.
Significant changes across both MDR and IVDR are accelerating the need for enhanced product traceability and identification of devices used in the field. The unique device identification (UDI) number is now required on all devices. UDI requirements are very similar between the MDR and the IVDR, with both organized into Basic UDI-DI and device DI attributes. However, the MDR requires more attributes than IVDR and may therefore pose a greater compliance challenge for manufacturers. The European Commission has designed and developed the European Databank of Medical Devices (EUDAMED) platform, which is an IT system that will house device data for both MDR and IVDR products. EUDAMED is structured around six interdependent modules for both MDR and IVDR devices. These modules include the actor registration, UDI/devices registration, notified bodies and certificates, clinical investigations and performance studies, vigilance and post-market surveillance, and market surveillance modules.
Looking Ahead to May 2022 – the New IVDR Deadline
Here’s a quick checklist to get you started on the path to compliance:
1. Get your performance evaluation reports (PER) right
One aspect of IVDR that has the potential to cause delays in timelines and product readiness is the performance evaluation report (PER). While specific guidance documents provided by the Medical Device Coordination Group (MDCG) pertain to SARS-CoV-2-related IVDR products and medical device software, the majority of in-vitro diagnostic products will be governed by the definitions outlined in IVDR Section 1, Article 2. Furthermore, Annex XIII, Part A, Section 1.3.2 outlines the basic requirements of IVD performance evaluation reports.
Let’s start at the beginning. The first step in the performance evaluation report (PER) is the performance evaluation plan (PEP). This plan must cover the following requirements for the device in question, as recently introduced by the new IVDR:
- Establish the specifications for the analyte or marker to be determined by the device, the intended purpose of the device, and the device’s characteristics
- Identify the source for reference materials and establish the measurement procedures or the metrological traceability.
- Indicate target patient groups, limitations, and contraindications.
- Outline general safety and performance requirements (GSPR) (Annex I, Section 1–9), which must be supported by scientific studies and analytical and clinical performance data.
- Detail the statistical tools and methods used to collect these data, statements on state of the art, as well as benefit-risk ratio for the intended purpose of the device.
- Describe the post-market performance follow-up (PMPF) planning.
2. Keep track of the clinical evidence in your literature review in a transparent, audit-ready manner
Once you’ve completed your performance evaluation plan (PEP), you can start working on your PER. At this point, you should ensure that the clinical evidence (i.e., the published literature and evidence from clinical studies that justifies the intended use of the device) is properly documented and in audit-ready condition. Other PER requirements include in-vitro diagnostic product classifications and details on the intended purpose of the device, its safety performance, and the technology used.
Aspects of the literature review process and the PMPF study results, which are outlined in Annex XIII, Part B, also need to be documented prior to commercialization in order to avert audit findings from notified bodies.
For many medical device manufacturers, the process of conducting a literature review might be entirely new as they get acquainted with the In-Vitro Diagnostics Regulation (EU) 2017/746. In this case, it is key to source professionals who are well-versed in PER management.
There are several types of systematic literature reviews. In the medical device and IVDR contexts, the state of the art (SOTA) literature review is critical to ensure successful product readiness and compliance. The review will support a product-specific report and comparative device summary that will assess a product against its competition and further substantiate the scientific validity of your PER safety & performance indicators.
Literature reviews are not one-time events in the product regulatory lifecycle. Rather, while Class A and Class B IVD product performance evaluation reports can be updated on an as-needed basis, Class C and Class D reports must be updated at least every year. This schedule has the potential to impact legacy devices and must be accounted for by manufacturers.
Compliance challenges abound throughout the literature review process. The use of automated software solutions, such as DistillerSR, can dramatically improve the outlook for manufacturers by reducing chances for human error and increasing the overall efficiency of the literature review process. These tools can be leveraged to assist with project management organization, ensure your robust processes are consistent across reviews, automatically capture every decision for a complete audit trail, and streamline yearly updates with automatic reference imports.
3. Avoid common mistakes in the literature review process for EU-IVDR submissions
There are several challenges that manufacturers commonly encounter in the literature review process of the systematic review lifecycle for EU in-vitro diagnostic product submissions.
The first can occur if manufacturers underestimate the complexity of the literature review search process or fail to implement appropriate search criteria. Adequate planning is needed up front, and time must be spent determining appropriate search criteria in order to thoroughly provide evidence for the research question. Many attempt to skirt this complexity and reduce the time spent manually screening reports by narrowing their search criteria, which often leads to an incomplete literature review that excludes entire databases, landmark studies, or key papers written in other languages. Once you submit your reports, auditors will determine whether an adequate literature search has been performed.
Limiting searches to only one database may exclude large amounts of favourable or unfavourable data from the results. Conversely, searching in multiple databases can lead to duplicate results. Writing more than one summary on the same paper is a potential audit red flag and may invite further scrutiny. Duplicate detection tools enable efficient identification and quarantining of duplicate literature before you spend effort on the additional copy. Many literature review platforms have duplicate detection engines built in, and some — like DistillerSR, which uses natural language processing — are able to detect inexact matches caused by formatting variations between databases.
Your audit trail plays a critical role in supporting audit discussions and can also justify why some papers are included in the literature summary and others are not, so proper and thorough tracking is vital throughout the literature review process. Reviews that are performed manually, particularly those using Excel-based methods, often fail to capture the necessary information to provide an adequate audit trail, and, as mentioned above, they are prone to human error. Literature review platforms help to facilitate adherence to specific protocols while automatically tracking each action. DistillerSR, for example, makes it easy to view the provenance of every data cell and ensures complete transparency and auditability of the entire process, resulting in a fully defensible, transparent, and repeatable review.
A carefully documented and transparent audit trail will reduce the regulatory risk that could potentially lead to compliance and product delays.
Consistency is also key to reducing the risk of compliance delays. Lack of consistency across variables when capturing data may require extensive data cleaning before analysis can properly be done or variables effectively searched. Tools like DistillerSR have built-in validation that help generate consistency, such as requiring data be captured as non-integer numbers within a particular range or requiring the user to select from a pre-existing set of variables to reduce spelling or phrasing variation.
4. Revisit legacy processes and accelerate time to compliance
The introduction of IVDR requirements may prompt a need for businesses to assess and replace outdated processes. This can lead to complications in existing workflows, shepherding inefficiencies into business operations. The need for adequate resources to address the growing needs of IVDR submissions also poses a challenge. Furthermore, literature search records must be rigorous and demonstrate transparency and reproducibility. Monitoring must be ongoing and occur on a continual basis in order to maintain compliance with IVDR standards.
Overall, the challenges imposed by the IVDR are substantial, and manufacturers should leverage tools such as automation software solutions, like DistillerSR, that allow for the most efficient resource allocation and significantly streamline the time to compliance. By automating a majority of the manual administrative tasks, accelerating literature screening to get you started on later stages of your review sooner, and maintaining a comprehensive audit trail, literature review applications help to optimize your work so you can easily meet upcoming and ongoing submission deadlines.
Developing a repeatable, transparent process that will lead to streamlined, audit-ready, and compliant literature reviews for your PER submissions will not only check the box for the upcoming EU regulations for in-vitro devices, but will also enable you to work more efficiently with distributed teams, cope with the unprecedented pace and volume of evidence-based research, and minimize the chance for errors that can negatively impact go-to-market timelines and revenue.
