— coauthored by Heike Moehlig-Zuttermeister, PhD, RQM+ VP Intelligence and Innovation - IVD and Carlos Galamba, RQM+ VP Intelligence & Innovation - IVD
State of the art (SOTA) is a key piece of the IVDR puzzle. Like many of the other required elements, it touches multiple sections of your technical documentation and must be consistently addressed throughout.
Article 56 of the IVDR states, “The clinical evidence shall be such as to scientifically demonstrate, by reference to the state of the art in medicine, that the intended clinical benefit(s) will be achieved and that the device is safe.” This emphasis on clinical relevance is new under IVDR and is one of the many changes from IVDD.
The concept of clinical benefit is also introduced within the clinical evidence definition of Article 2 (36): “Clinical evidence means clinical data and performance evaluation results, pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer.”
Clinical benefit is a new term under the IVDR and means to provide an accurate result which supports appropriate patient management decisions but has no direct impact on the clinical outcome as per Whereas 64. The SOTA is inherently linked to the clinical evidence and the clinical benefit of the respective IVD and needs to be continuously monitored throughout the lifetime of the IVD.
Although it’s clear that reference to SOTA is required under IVDR, there remains some confusion about how to approach it.
Defining State of the Art
Until publication of the MDCG Guidance MDCG 2022-2 “Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs)” in February 2022, there had been no official definition of SOTA in the IVDR regulatory landscape since the IVDR entered into force in 2017.
The MDCG Guidance merges the SOTA definitions given in the harmonized standard EN ISO 14971:2019 and the IMDRF/GRP WG/N47 2018 document and states, “Developed stage of current technical capability and/or accepted clinical practice in regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience. The state-of-the-art embodies what is currently and generally accepted as good practice in technology and medicine. The state-of-the-art does not necessarily imply the most technologically advanced solution. The state-of-the-art described here is sometimes referred to as the ‘generally acknowledged state-of-the-art.’”
Hence, when used in the context of technology and medicine, SOTA is understood to be the accepted standard clinical practice, which is not necessarily the most cutting-edge technology.
How SOTA Fits into the Technical Documentation
Although notified bodies appreciate the opportunity to review a stand-alone SOTA report, it is not a requirement. In order to be compliant, manufacturers must review SOTA when coming to conclusions based on clinical evidence, and the benefit/risk ratio must also be based on SOTA.
To that end, SOTA should be addressed when discussing clinical evidence and performance in the performance evaluation plan (PEP), performance evaluation report (PER), and the summary of safety and performance (SSP) if the IVD is a Class C or Class D device. References should be included in the PER and SSP to show SOTA, and any SOTA referenced in your documentation must also match the intended purpose, IFU, and intended patient population.
SOTA is also a key element of post-market surveillance (PMS) requirements. In PMS reporting activities, you have to show that your device is still based on SOTA or whether it has changed. SOTA monitoring is considered a proactive PMS activity and should be covered in the PMS plan. Device Classes C and D must include SOTA assessment in the annual PSUR, and Classes A and B must include it in the PMS report. If SOTA has changed, this might trigger design or performance changes to meet the evolved accepted clinical practice.
The Evolving State of SOTA
An important concept for manufacturers to keep in mind is that SOTA is not necessarily static and needs to be captured and monitored throughout the full lifecycle of the device. As an example, the state of the art for recommendations on biomarkers used for the diagnosis of myocardial infarction has changed significantly over the last decades. Cardiac troponin assays (cTn) and high-sensitivity cTn assays are now the recommended assays for routine clinical use and have replaced the creatine-kinase-MB assays (CK-MB). It should be noted that CK-MB assays are still recommended to use if cTn assays are not available.
This example illustrates that the state of the art concept is not black-and-white. Although some IVDs might be replaced over time, they can be still recommended for clinical routine use if the main IVD is not available - as outlined above in the cTn/CK-MB example. Hence the replaced IVD still provides clinical benefit, an accurate result in supporting an appropriate patient management decision.
Another example is the adoption of nucleic acid amplification technique (NAT) dual-target HIV tests used for screening blood donations in order to minimize HIV-1 RNA false-negative results or viral load underquantification, which has been observed in some mono-target assays. The dual-target NAT implies that at least two different sections of the virus genome are amplified independently from each other. Thus, if a mutation occurs in one target region, the second region will compensate for the potential failure and ensure detection of the virus.
The evolution to the dual target strategy for NAT HIV-1 started around 2009 as a result of a case of HIV transmitted through a blood donation where a mono-target NAT assay was the cause of false negative results. It took approximately 10 years until the common technical specifications (CTS) under the IVD Directive (98/79/EC) were updated to require a dual-target approach for qualitative HIV-1 NAT assay and present the current SOTA for these IVDs.
This example shows how SOTA adoption has been driven by post-market surveillance information of CE-marked NAT HIV assays and triggered design and performance changes to these IVDs to meet the intended clinical benefit.
Thus, it’s never safe to assume that the SOTA for your device has not changed. The current global pandemic is another excellent example of how quickly the state of the art can change. In these scientifically dynamic times, the state of the art has evolved so quickly that the SOTA described at the design/development stage may already have changed some months later, before the assay might have been ready for product launch.
In order to ensure that IVDs are based on the current SOTA, they must be monitored with proactive surveillance activities to gather real-world information on how the IVD is actually used and is performing. The standard ISO/TR 20416:2020 "Medical devices - Post-market surveillance for manufacturers" provides a good source on post-market surveillance activities.
Acceptable methods for determining SOTA can include:
- Standards used for the same or similar devices
- Clinical guidance documents and medical textbooks
- Best practices as used in other devices of the same or similar type
- Expert consensus documents
- Publications from regulatory authorities or additional information for similar other products
- Recommendations from medical or laboratory associations
- Comparison of the benefits and risks of the device under development with the benefits and risks of similar devices available on the market
In a nutshell, a SOTA device is the one that is the most accepted by the clinician. This can change over time at a slow or rapid pace based on factors such as:
- Ethical considerations
- Economical considerations
- Whether it is helpful for the individual patient management decision
Biggest Challenges Around SOTA
In addition to understanding what SOTA means in the context of IVDR, there are some common challenges that manufacturers face.
Manufacturers of legacy devices must monitor the evolution of SOTA and have a process for doing so, which could be quite complex. It’s also important to note that for IVDR compliance, you must capture SOTA in the EU. When SOTA is understood to be the accepted clinical practice, the question becomes, how do manufacturers gather information about the accepted clinical practices?
Some solutions for monitoring SOTA include:
- Follow clinical guidelines (when they exist), such as from the World Health Organization, European clinical guidelines, or national clinical guidelines.
- Apply regulatory standards or guidelines such as MDCG Guidances, CTS, and common specifications (CS). Also, monitor published expert views under the Performance Evaluation Consultation Procedure (PECP) for Class D devices, which serve as a SOTA source for the IVDs concerned as long as no CS have been published.
- Check competent authority websites for public information about health technology assessments.
- Monitor European technology application associations.
- Perform surveys in clinics or laboratories to gather routine diagnostic information.
When evaluating SOTA, some IVDs may no longer be considered the standard of care but are still recommended to use when the primary test is not available. In these cases, manufacturers need to acknowledge and justify why and how the device in question is still used in clinical practice despite the current state of the art being another IVD.
SOTA for New Devices
A truly innovative device will not be able to demonstrate that it is state of the art because it is essentially creating new SOTA. In this case, manufacturers must support SOTA with relevant publications or expert input from key opinion leaders that support that the device meets its intended clinical benefit. During post-market surveillance, it is critical to monitor and document routine diagnostic use of the device and how the SOTA evolves.
Finding a Good Comparator
When it’s not possible to find enough SOTA for your own device, you can compare it to other similar products. When taking this approach, you must justify why the other device is a good comparator by verifying performance to show similarity and demonstrating that the clinical benefit is the same. This is similar to the 510(k) process in the U.S., so IVDs approved in this way by the Food and Drug Administration (FDA) will have a good starting point for compliance in the EU.
Consequences of Not Getting SOTA Right
Although a SOTA definítion is provided in the MDCG 2022-2 Guidance, there is still some room for notified bodies to interpret what is required in your technical documentation and the practical implications remain vague. In the ideal scenario, notified bodies will come out with a position to help manufacturers understand the expectations. Until this time, you need to actively monitor the regulatory landscape because what notified bodies think right now may change.
The reality is, most manufacturers have the data they need to demonstrate SOTA, but they don’t always spell it out in the technical documentation. This can result in unnecessary delays and additional burden on your resources.
How RQM+ Helps
The team at RQM+ is highly skilled at putting together a data story that backs up SOTA for IVDR. Our experienced staff includes not only former notified body leaders but also EU, FDA, and international bodies, and clinicians to help you put together a comprehensive clinical data story. We have real-world experience with SOTA in design and manufacturing, including utilizing new chemicals and the state of the art with respect to hazards and biohazards. Whether you need help with the transition to IVDR or ongoing post-market support, our team is here for you.
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