Jul 14, 2022

In previous posts we have outlined basic requirements for performing adequate clinical performance studies for in vitro diagnostic (IVD) devices including companion diagnostics (CDx) under the European In Vitro Diagnostic Medical Devices Directive (IVDD) and/or under Regulation (EU) 2017/746 (IVDR) on IVD medical devices.

Here, we address two recently published documents from the European Medical Device Coordination Group (MDCG), the MDCG 2022-2 document “Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs),” published in January, and the MDCG 2022-10 document “Q&A on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and IVDR,” published in May. Both guidance documents provide additional clarity on the adequate interpretation of the requirements for clinical performance studies conducted for CE Marking under the IVDD and IVDR. Like every guidance, these MDCG documents reflects current official understanding and is intended to inform manufacturers, sponsors, regulators, notified bodies and other stakeholders when collecting data for clinical evidence. The content is available to the involved parties, e.g., for assessing the adequacy of clinical evidence for CE Marking. For this reason, the content and interpretations of these documents should be carefully understood and considered.

Why is the MDCG document 2022-2 important?

The MDCG document 2022-outlines the general principles of clinical evidence and provides guidance on the continuous process of performance evaluation for IVDs. The document gives guidance on how “collection, generation and documentation of supporting data for an IVD may be conducted prior to the placing on the market or putting into service.” It provides overall guidance on the life cycle concept of performance evaluation, including the Performance Evaluation Plan (PEP) and  Performance Evaluation Report  (PER), covering scientific validity , analytical and clinical performance in order to define clinical evidence.

 What are the main components of MDCG 2022-2?

  1. It is important to understand that MDCG document 2022-2 applies to ALL products meeting the definition of an IVD per Article 2(2) of the IVDR.

This document further emphasizes that the IVDR has defined basic criteria for the intended purpose in Annex 20.4.1.c that every IVD must meet. One of these requirements is to define the clinical use scenario of the subject IVD. Consequently, the intended purpose for many IVD products under the IVDR must be updated from a pure analytical definition to include clinical use. Such changes in the intended purpose and claims, however, might automatically raise new questions on the clinical evidence which will then need to be addressed with analytical and clinical performance studies, and which might have not been considered before.

  1. The MDCG document 2022-2 demands that each manufacturer must specify and justify the level of clinical evidence in view of the characteristics of the device and its intended purpose (Art. 56 of the IVDR). The guidance refers to the IVDR, which underlines the basic requirement that “the necessary clinical evidence should be based on a sufficient amount and quality of data in order to allow a qualified assessment of whether the IVD is safe, performant and achieves the intended clinical benefit(s), when used as intended.” Manufacturers might often struggle with this IVDR concept of sufficient clinical evidence and may ask, “What is sufficient and what is adequate?” However, this cannot be answered in general, because the explicit level of data needed for a specific IVD can solely be determined and justified by the manufacturer. This guidance provides the general considerations how to achieve this under the IVDR.
  2. The document specifically notes that clinical evidence “may include data from devices which are claimed to be equivalent to the device under assessment.”

We would like to point out that this MDCG document reinforces the IVDR requirement that “the handling of equivalence should be defined in the manufacturers QMS (Annex IX 2.2.c).” Only if the manufacturer has adequate QMS process(es) for the equivalence assessment in place will the manufacturer be able to demonstrate equivalence to similar devices placed on the EU market.

The guidance further refers to additional processes and plans to be in place in order to adequately demonstrate clinical evidence under the IVDR. It also provides definitions and terms from the IVDR or guidance documents, which are relevant for the manufacturer’s clinical evidence generation process. Finally, a flowchart on the “methodological principle for generation of clinical evidence” is provided in Annex 1. This flowchart provides decision-making guidance on which processes should be considered for the generation of clinical evidence for the respective IVD. Processes outlined in this flowchart should have been implemented by every manufacturer to achieve IVDR compliance.

Learn more about European IVDR compliance and timelines

What is the intention of the MDCG document 2022-10?

The Q&A MDCG document 2022-10 picks up the clinical evidence considerations addressed in MDCG document 2022-2. This guidance document, however, focuses on topics specific for combined studies of medicinal products and IVDs (CDx) in the EU. MDCG 2022-10 has been developed by experts from the medicinal product and the IVD field. It is important, that personnel involved in the investigational medicinal product (IMP) study component under regulation (EU) No 536/2014  (CTR) AND personnel involved in the clinical performance study component under the IVDR of combined studies are aware, that CTR and IVDR requirements will need to followed.

What does the MDCG document 2022-10 clarify?

The MDCG 2022-10 document provides general information and clarifications for IVDs or assays used in clinical studies. This includes CE-marked devices, accessories or product-specific study assays (in an IMP study) that are not meant to be developed as IVDs. Many questions and answers, however, are addressing the co-development of CDx together with an IMP.

The intention of these Q&As is to clarify the regulatory status of such assays (IVD or non-IVD) performed on human samples in studies and to clarify the regulatory expectations toward the clinical study sponsors.
Please note that for combined studies the sponsor of the trial is always legally responsible for ALL parts of the trial, including compliance with IVDR.

Overall the Q&A document addresses different clinical scenarios. One of the most critical topic in our view is described in the answer to Question 5, “When does an assay used on human samples qualify as an IVD in a clinical trial?” This seems to be the key question to answer in order to understand whether IVD performance study and/or CDx study requirements apply or not.

Following the known concept of the IVDD and IVDR, this Q&A document clarifies that “an assay is considered an IVD if the manufacturer assigns an intended purpose that fulfils the definition of an IVD” (as defined in the IVDR Article 2 (2)).” This means, that, independent from any clinical scenarios or use in research only, the first and fundamental decision to be taken (for NBs and regulators) will ONLY be made based on the intended purpose of the product. This applies to ALL assays--for example assays used to guide medical management decisions or follow-up fulfill the IVD definition regardless of whether the assay is intended to be marketed as an IVD or not.

The answer to Question 6 (examples of assays that are IVDs used in clinical trials) further describes simplified scenarios for the use of assays, which would qualify as IVDs and which would not be considered IVDs. Unfortunately, clear criteria are not given in this guidance document on how to define studies using assays that do not qualify as IVDs. Emergo believes that in these situations it will be up to the interpretation by an EU member state's National Competent Authority (NCA) to decide whether the assay is considered an IVD or not, and consequently on whether clinical performance study requirements need to be applied.

It is also worth to point out that the involved pharmaceutical company, usually acting as the clinical trial sponsor, may assume the role of the manufacturer under the IVDR in combined studies. It is the sole responsibility of the clinical trial sponsor to determine the regulatory status of the assay, which will be based on the planned use in the clinical trial. It follows that assays used in these combined clinical studies can be either one of the following: 

  1. An investigational IVD
  2. An approved CE-Marked IVD used within the intended purpose claims
  3. An in-house test developed, manufactured, and used within a health institution established in the EU (no transfer to another legal entity is allowed)
  4. Validated assay used in an accredited laboratory
  5. Research assay (without having ANY medical purpose)

The MDCG document 2022-10 does not give explicit explanations for Scenario C, but makes clear that in-house tests must also comply with the IVDR and national provisions to be used lawfully in a clinical study.

The document also doesn’t address Scenario D in detail, but it is Emergo’s understanding that requirements would include the need to meet accreditation guidelines, which vary across EU member states, but generally should follow accreditation standard ISO 15189. In this scenario the use of a validated assay in clinical studies is the sole responsibility of the laboratory and shall not be part of a commercial IVD development effort, nor should the study be conducted with the intention of gaining data for placing the assay on the EU market by the manufacturer.

What does it mean for manufacturers and/or sponsors of CDx studies?

The status of all assays, test methods or IVDs must be clearly listed in the respective clinical performance study protocol (CPSP); the assay status assessment conducted by the manufacturer/sponsor needs to be based on the intended medical purpose defined by the manufacturer/sponsor following the IVD definition under the IVDR.

Listing the status of all assays used in a study is also required for every combined clinical study protocol under the new Clinical Trials Regulation (CTR) (EU) No 536/2014, which demands, among other things, to include in the study protocol and cover letter list of medical devices which are to be investigated in the clinical trial but which are not part of the investigational medicinal product or products, together with a statement as to whether the medical devices are CE-marked for the intended use (“Annex I.B.7 (i) ).” Again, like other MDCG guidance, this MDCG document specifically clarifies the responsibilities of the sponsor in a combined study by stating, “It is the responsibility of the clinical trial sponsor to ensure compliance with relevant provisions of Union and national law, including the IVDR.”

How are current or previously conducted CDx studies impacted?

The guidance documents MDCG document 2022-2 and MDCG 2022-10 do not provide significant new information, but do clarify common misinterpretations of the regulatory requirements that might exist among many IVD manufacturers and sponsors of combined studies. As explained in our previous blog posts the basic concept for clinical performance studies has already been provided under the IVDD and has not changed under the IVDR. Performance study requirements for IVDs have had to be followed since 2002 and 2003 when the standards EN 13612 and ISO 14155 (updated in 2011 and 2020) were published. Starting in 2019, the standard ISO 20916 on good study practice has also had to be followed. These documents reflect the basic ethical and legal study requirements every sponsor/manufacturer should follow.

The provided clarifications on specific definitions, on the interaction of IVDR processes, and on clinical performance study requirements (required to finally address the clinical evidence) may raise critical questions when manufacturers are now re-assessing their previously collected clinical performance data and when they plan and start writing their clinical evidence justification for their PEP/PER under IVDR.

All manufacturers planning new IVD or CDx studies should therefore carefully consider the use of the correct IVDR terminology and the provided interpretations when using assays (IVDs) in combined trials with medicinal products (studies with CDx). MDCG 2022-2 specifically gives excellent guidance on these IVDR concepts and may help many manufacturers to better understand the intention of these requirements and guide them in compliance.

Specifically, manufactures that have conducted clinical performance studies should carefully review whether these basic study requirements have been followed, specifically regarding whether the CDx has been adequately listed as an IVD under performance evaluation in the study protocols, and whether this study has been conducted and officially approved respecting clinical performance study requirements. If this is not the case, if for example a favorable opinion from the involved Ethics Committee for the IVD study component was not obtained it is very likely that none of these clinical performance data can be used to support the clinical evidence under the IVDR. A whole new clinical performance study might then be required to comply with IVDD and IVDR requirements.

For legacy devices, the essential requirements of IVDR Annex I and the device’s CE Marking are automatically affected if a study has not been lawfully conducted and the product’s CE Mark certification is based on data from that study. As a result, a recall or withdrawal of CE status of the IVD in question may be required until the necessary clinical performance data have been lawfully collected and included in the technical documentation (TD) according to the IVDD.

When applying for the CE Mark for a new device under the IVDR,  manufacturers will be questioned by their NBs as to whether clinical data and/or clinical evidence included in the TD data (PEP, PER, PMPF, etc.) was collected in accordance with IVDR requirements. Again, a CE Mark will not be granted until sufficient clinical evidence is demonstrated.

It remains unknown whether medicinal products that use data obtained via combined studies that have not been legally conducted or that did not obtain adequate regulatory approval will also be impacted; the respective authorities have not yet provided official feedback on this topic. Emergo however, is aware that this topic is under critical discussion with authorities, and the issue may come up during NB reviews of IVD (CDx) devices, as well. For this reason, manufacturers of IVDs as well as pharmaceutical companies are strongly encouraged to provide objective evidence and clarity on their performed clinical studies as well as on the adequate legal authorization for these studies, which must clearly identify the correct status of the assay (IVD, CDx) used.

A re-assessment of available performance data by applying the interpretations from these two important MDCG documents should be considered by each manufacturer. If manufacturers identify open questions, it is highly recommended to clarify these BEFORE sending their TD to a NB.

Dr. Dietmar Falke is Head of Clinical Research and Dr. Oliver Eikenberg is Senior Consultant RA/QA at Emergo by UL.

 

Author

  • Dietmar Falke and Oliver Eikenberg

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