Clin Chem Lab Med 2023; 61(7): 1150–1157

Opinion Paper

Karine Charrière* and Lionel Pazart

Clinical evidence requirements according to the

IVDR 2017/746: practical tools and references for
underpinning clinical evidence of IVD-MDs
https://doi.org/10.1515/cclm-2022-1252 Introduction
Received December 9, 2022; accepted February 27, 2023;
published online March 15, 2023
The new European regulation for in vitro diagnostic medical
devices 2017/746 [1] (IVDR) came into force on May 2022 and
Abstract: In May 2022, the European Regulation 2017/746
replaces the directive 98/79/EC (IVDD) [2]. It reinforces the
(IVDR) came into force. It changes the approach of in vitro
requirements for manufacturers with a view to improving
medical devices (IVD-MDs) for industry and institutions. It
the performance and safety of devices and increasing
reinforces the clinical evidence requirements to improve
transparency throughout the industry sector.
performance, safety and transparency. Despite extended
Extensions to transition periods have been granted.
transition periods and existing guides, IVDR remains difficult
They depend on the class of the concerned device and the
to interpret and bringing devices into compliance requires
status of its CE marking under IVDD [3]. They are mainly
efforts. The generation of clinical evidence is essential to
justified by the lack of certified notified bodies (NB) able to
demonstrate compliance with IVDR, and encompasses scien-
deliver the CE marking. Under the IVDD, 8% of the in vitro
tific validity, analytical performance and clinical perfor-
diagnostic medical devices (IVD-MDs) on the market
mance. It is required to demonstrate, per intended use in the
involved CE marking with control by NB. With the new
target population and clinical care pathway, IVD-MDs clinical
performance (compared to a predefined clinical perfor- regulation, the proportion should increase up to 78% [4].
mance). Thus, there is a need for IVD-manufacturers and end- There are questions about the degree of preparation of
users in health care institutions, to obtain guidance on how to producers/users of IVD-MDs to meet these stricter obliga-
generate this clinical evidence. This article aims industrials tions, in particular on the point of demonstrating perfor-
and clinicians to identify key steps imposed by the IVDR for mances. Furthermore, only eight NB are currently certified,
bringing IVD-MDs to the EU-market. We propose a general compared to about 20 previously. The European Commis-
view of performance evaluation requirements for IVD-MDs sion wants to be reassuring [5], but the number of NB
and provide key references, including how to establish study remains largely insufficient and there is a risk that com-
design that will enable to document clinical performance of panies will not be able to market new IVD-MDs [6]. The
existing, refined or emerging medical tests. Finally, we pro- Medical Device Coordination Group (MDCG) proposed solu-
pose a roadmap to address the relevant questions and studies tions in the MDCG 2022-14 [7] and the European Commission
in relation to the documents requested in the IVDR. published an amendment in January 2023 providing a
phased roll out [8]. IVDR 2017/746 still leads to more threats
Keywords: 2017/746 IVDR; analytical performance; clinical than opportunities, especially for home-made test, high risk
evidence; clinical performance; in vitro diagnostic; perfor- IVD-MDs [9] or for IVD-MDs use outside their approved in-
mance evaluation. dications. Therefore, the authors highlighted the effort
required to ensure that all these tests can be performed in
compliance with the IVDR.
*Corresponding author: Mme Karine Charrière, PhD, Centre Others point out difficulties of understanding and
d’Investigation Clinique, Centre Hospitalier Universitaire de Besançon, implementing articles from IVDR, even if the MDCG has
INSERM CIC 1431, BioInnovation – 4 Rue Charles Bried, 25030, F-25000 published support documents to help with interpretation
Besançon, France, E-mail: kcharriere@chu-besancon.fr. https://orcid.org/
and despite the existence of international standards [7, 10].
0000-0003-4542-8003
Lionel Pazart, Université de Franche-Comté, LINC, CIC 1431 INSERM,
For example, van Deutekom and Haitjema raised the issue
Centre Hospitalier Universitaire de Besançon, Besançon, France; and that software development is not integrated into the
Tech4Health Network, FCRIN, Besançon, France ISO-15189 standard and note a lack of knowledge in medical
Open Access. © 2023 the author(s), published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License.
 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746 1151

laboratories on how to deal with software developed in- Note that the IVDR covers IVD-MDs throughout their life
house, using ISO-15189 in synergy with IEC-62304 [10, 11]. cycle. Consequently, follow-up to ensure post-marketing
They published recommendations to help the scientific com- performance monitoring, vigilance and market surveillance
munity to facilitate the compliance with IVDR and described must be performed and the technical documentation regu-
three use cases to illustrate their proposed methodology [12]. larly updated.
All IVD-MDs must comply with the new IVDR. This
includes up-classification of devices already on the market,
CE-marked devices under IVDD, using IVD-MDs outside their Key steps for bringing IVD-MDs to
approved indications and marking of new devices. This pa-
per aims at helping developers of IVD-MDs (researcher, the EU-market
manufacturer, labs staff) to better understand the key
requirements in the IVDR, such as the evaluation of clinical Throughout the lifecycle of an IVD-MD (see [13] for a detailed
evidence. We also provide references describing how to flow chart of the certification cycle), performance evaluation
meet them. is not the first step (Supplementary Figure SF1). Indeed, it is
necessary to ensure that the device is covered by the IVD-MD
definition. To summarize, an IVD-MD is a MD intended to
Overview of IVDR content be used in vitro for the examination of samples from the
human body, the purpose being to provide information on
The IVDR contains 10 chapters and 15 annexes (Supple- the patient’s health status. Specimen containers are also
mentary Table 1). It establishes the rules for placing on the considered as IVD-MDs.
market, making available on the market or putting into Once the IVD-MD status is identified, the intended use
service IVD-MDs for human use and their accessories in the of the IVD-MD must be precisely and carefully defined. The
European Union, and applies to performance studies con- compliance with the essential requirements must then be
cerning these devices and their accessories carried out in the demonstrated, including performance evaluation for the
Union. A number of new concepts compared to the IVDD are expected intended use of the IVD-MD. CE mark can be
included (near-patient testing devices, companion diagnosis obtained only if all conditions of performance and safety
devices, falsified device, kit, common specifications, genetic are met. It must be maintained by carrying out post-market
testing and single-use testing). All manufacturers have to surveillance and vigilance.
prove that their IVD-MDs comply with the general safety and
performance requirements, even for in-house IVD-MDs.
Classification of IVD-MDs is now based on the risk level. About clinical evidence
Class A corresponds to the least risky devices and includes
sample containers or buffer solutions (among others). Self- Clinical evidence must be provided during demonstration of
testing devices with no risk like pregnancy or fertility tests performance and more precisely during the demonstration
belong to class B. Companion devices, such as those used to of clinical performance. According to the IVDR, “clinical
screen for cancer, perform prenatal screenings or blood evidence means clinical data and performance evaluation
grouping devices are C classified. D is the riskiest class with results, pertaining to a device of a sufficient amount and
devices for the detection or diagnosis of life-threatening or quality to allow a qualified assessment of whether the device
transmissible diseases. The definition of the IVD-MDs class is safe and achieves the intended clinical benefit(s), when
conditions the whole CE marking process. For example, class used as intended by the manufacturer”.
A non-sterile devices can be self-certified. For other classes, In other words, clinical evidence demonstrates that the
conformity assessment involves a NB. For class B and above, intended clinical benefit(s) and safety is achieved in accor-
a quality system is required. For classes C and D, the device dance with the state of the art in the concerned medical field.
conformity can be proved in two ways: establishing a com- This clinical evidence is based on three main pillars (Sup-
plete quality management system or a type examination plementary Figure SF2).
and a “production quality assurance”. Class D devices also (1) Scientific validity proves that the analyte, marker or
involve batch control, but an additional opinion of a refer- molecule being studied is relevant to the physiological or
ence laboratory is required. pathological condition of interest.
Performance evaluations and interventional studies are (2) Analytical performance is the ability of the device to
reported as an addition to the initial technical or post- measure this analyte, marker or molecule accurately
marketing surveillance documentation. and reproducibly. It is strictly a technical performance
1152 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746

as no correlation with the targeted pathology is documents [7, 13, 17], ISO 20916 [18] can be used to ensure
required. It is possible to demonstrate the analytical that the clinical performance study will result in reliable and
performance of an IVD-MD with artificial samples. This robust results.
must demonstrate the accuracy, the measurements
reproducibility, the limit of the blank, the analytical
specificity and all other technical parameters ensuring Writing the performance evaluation plan
the reliability of the measurements. (PEP)
(3) Clinical performance is the ability of an IVD-MD to
produce results which correlate with the actual clinical The starting point of the process is the performance evalu-
condition, depending on the target population and user. ation plan (PEP). The PEP identifies the approach, the
There exists an underlying intention of use that can method to be used and the steps required to generate clinical
be highlighted by a performance indicator. In order to evidence. Although it remains very global, it describes how
demonstrate clinical benefit, dedicated guides depict the to prove that the three above-mentioned pillars are robust.
general principles of clinical evidence [7, 14]. It thus integrates basic elements concerning the IVD-MD
(intended use, characteristic, analyte, type of patients, gen-
Two other concepts are important to stakeholders but are eral requirements), more precise elements concerning the
addressed differently by the IVDR: clinical benefit and clin- evaluation itself (methods, statistical analysis plan, state
ical utility. The notion of clinical benefit often appears in the of the art, benefit/risk ratio) and steps planned for post-
IVDR but no mention of clinical utility is found. marketing performance monitoring (Figure 1A).
Clinical benefit “means the positive impact of a device To write an appropriate PEP, it is important to define
related to its function such as that of screening, monitoring, minimum clinical performance levels a new test must reach
diagnosis or aid to diagnosis of patients, or a positive (Figure 2, 1). Lord et al. propose a 5 steps approach to help
impact on patient management or public health”. Impor- achieving this goal [19]. The first step is to define the inten-
tant, clinical benefit is not identically addressed by MDR ded benefits: improving disease outcomes, reducing iatro-
and IVDR. While for MD, clinical benefit is measured genic harm or other benefits (reducing cost for example).
directly by a positive impact on the patient’s health, for The second step is to map current practice. The third step
IVD-MDs, the objective is to obtain precise medical infor- is to propose test role by redrawing the clinical pathway
mation on the patient. The positive impact on the patient is with the new test positioned in: add-on, triage, replacement
therefore indirect, since the final clinical result depends on test. It can be a new pathway (fulfilled an unmet need) if
other therapeutic options. there is no existing test. The fourth step is to link clinical
Clinical utility is “the likelihood that a test will, by performance requirements to intended benefits such as
prompting an intervention, result in an improved health improving detection, improving rule out or improving test
outcome” (National Institute of Health). In their article, process. The final step is to set minimum acceptable clinical
Horvath et al. defined clinical utility as “Ability of a test to performance levels.
improve health outcomes that are relevant to the individual
patient” [15]. The clinical utility clearly targets the patient,
whereas the clinical benefit is a broader concept extended to Collecting existing data
public health but potentially with no direct benefit for the
tested patient. For example, screening for COVID 19 allows With these elements, data can be collected and analysed
protecting populations by implementing an adapted public (Figure 2, 2 and 3). As described by Leeflang and Aller-
health policy more than improving a patient health outcome. berger the first point is to check the scientific validity i.e. to
Furthermore, clinical benefit is clearly defined and will not discriminate patients with the disease of interest from
be in the “eyes of the beholder” like clinical utility could be, those without using the studied analyte. The second is to
as explain by Lesko et al. in their interesting issue [16]. validate the analytical performance with evaluation of the
metrological traceability of test results and verification
whether the results are within allowable limits of mea-
Performance evaluation process surement according to ISO 17511:2020 [20]. If the results are
robust clinical performances with the targeted population
Collection of clinical evidence is a part of a performance can be validated [21].
evaluation process. This process is maintained throughout For each of these aspects, data could already exist
the lifecycle of the IVD-MD. In addition to the IVDR and other in scientific literature and the preferred method to collect
 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746 1153

Figure 1: Documentation to be produced for the performance evaluation. The performance evaluation plan is used to plan the entire process (A), while
the clinical performance evaluation plan should be thought of as a clinical investigation protocol (B). After the completion of one of the three types of
clinical performance studies (C), a clinical performance evaluation report (D) is written. It will be added to the performance evaluation report which also
includes the scientific validity and analytical performance reports (E).

existing data is systematic reviews. The PICO method is guidance, constructs a flow diagram for the primary study,
frequently used for formulating research questions: define and judges bias and applicability [25].
the Population of interest (Patient/Problem), the interven- Quadas-C is an adaptation of Quadas-2 for comparative
tion (mean treatment) performed on the Population, the diagnostic test accuracy studies [26] and investigates the
Control treatment and the Outcome [22]. To check the quality same domains as Quadas-2 (patient selection, index test,
of included articles, PRISMA is a recommended method reference standard and flow and timing).
(Preferred Reporting Item for Systematic Review and Meta- It is also possible to use QUIPS (Quality In Pronosis
Analysis) [23, 24]. Studies) and PROBAST (Prediction model Risk Of Bias
Quadas-2 (QUality Assessment of Diagnostic Accuracy ASsessment Tool) for assessing the risk of bias and appli-
Studies) is the recommended method to assess the quality cability of diagnostic and prognostic prediction model
of diagnostic accuracy studies. It summarizes the review studies. QUAPAS has been recently proposed [27]. It is based
questions, tailors the tool and produces review-specific on Quadas-2, QUIPS and PROBAST.
1154 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746

Figure 2: Roadmap for the collection of clinical evidence for relevant questions, performance assessments and mandatory reporting to comply with
IVDR.

If studies address the question of test-treatment stra- studies with leftover specimens, prospective sample studies,
tegies on outcomes (such as morbidity or mortality) other and interventional studies (Figure 1C).
tools could be more appropriate (like RoB 2 for assessing Studies with leftover specimens do not require autho-
risk of bias in randomized trials and ROBINS-I for assessing rization from the competent authorities but do require
risk of bias in non-randomized studies of interventions) sponsoring (an ethical and data protection framework for
[28, 29]. individuals). Studies with prospective samples (without
risk for the subjects and non-interventional) add the
constraint of obtaining authorization from the competent
Generating new data authorities. Finally, interventional studies or studies with
potential risks for subjects have extra obligations for
In the majority of innovative devices, existing data will sponsors and considerations to ensure the safety of in-
not be sufficient. Manufacturers or researchers have to dividuals undergoing research. Only this category requires
create their own datasets and perform evaluation tests reporting to the European database Eudamed. They all start
(Figures 2, 4). Even if analytical tests can start with labora- by writing a Performance Study Plan (Figure 1B) and end by
tory calibrated artificial samples, it is essential to confront writing the performance study report (Figure 1D).
the device to a real situation in which samples come from Sometimes, guidance exists. For example, an effort has
patients or volunteers. been made by the European Union (commission imple-
The IVDR identifies three different types of clinical per- menting regulation (EU) 2022/1107) to define test standards
formance studies with increasing stringency: retrospective for class D IVD-MDs [30] like those intended for detection of
 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746 1155

blood group antigens in blood group systems for example. Evaluation performance report and follow-
Other documents are available on a disease-by-disease basis. up
For example, MDCG 2021-21 defines performance evaluation
of SARS-CoV-2 in vitro diagnostic medical devices [7] or The final performance evaluation report compiles the sci-
instructions given by the WHO [31]. entific validity, analytical performance and clinical perfor-
The GHTF/SG5/N8:2012 is a good tool with a decision tree mance reports of the device (Figures 1E and 2, 5). It allows the
to help manufacturers or researchers to choose a study reviewer judging the safety and effectiveness of the IVD-MD.
design [32]. It highlights that most of the studies for IVD-MDs However, the performance evaluation process does not stop
are observational and describes different possible designs: here. Post-marketing surveillance and post-market perfor-
cross-sectional studies (single time-point design), longitudi- mance follow-up must allow a long-term control of the safety
nal studies (the same analyte measured over a period), of the IVD-MD and its performance in real life. Monitoring
prospective or retrospective studies. The choice between and updating should also allow identifying any misuse or off-
different designs depends on various considerations such as label use of the IVD-MD. For example, cross-reactivity with
study objectives, intended use, targeted analytical perfor- macroprolactin is a cause of positive interference in pro-
mance (precision, accuracy and metrological traceability, lactin immunoassays but the instructions for use are not
linearity …), clinical characteristics (diagnosis sensitivity/ sufficient to deal with. This problem would be solved if
specificity) and test results. For example, if the test results manufacturers complied with IVDR, developing a specific
are continuous like a concentration, the concordance test for the 23 kDa monomeric form of prolactin or at least
between new test and gold standard method can be properly informing users and explain how to detect or
investigated through the Bland-Altman method [33]. If mitigate this interference [38].
results are categorical or dichotomous, the κ statistics can It is therefore essential that IVD manufacturers rem-
be used [34]. edy medical tests that are not sufficiently appropriate for
One other important point is the number of samples. clinical use, such as prolactin immunoassays, and seek
Indeed, an oversized sample will lead to a loss of time and partnerships with end-user representative organizations,
money for a potentially very limited precision gain. An such as the Scientific Division of the International Federa-
undersized sample will not lead to a relevant conclusion. tion of Clinical Chemistry.
Stergiou et al. illustrate these effects in blood pressure
measurements. They showed that a study with sample size
of n=35 is adequate for a high accuracy device (<14%
chance of failure) but inadequate for a moderate accuracy Conclusions
device (28% failure probability). A sample size of n=80
would be adequate for a moderate accuracy device (18%). The IVDR reinforces the notions of traceability in terms of
Increasing the number of patients would not be relevant safety and performance of in vitro devices. This leads to
since the gain would be only 1% for 10 additional patients an increase of the documentation to be produced and
(n=90, 17%) [35]. induces additional administrative constraints. Since the
Sammut-Poxell et al. made simulation study to time required to obtain the necessary authorizations can be
examine the effect of sample size on specificity and sensi- long (without any guarantee of a favorable outcome), this
tivity of COVID-19 diagnostic tests [36]. They showed that difficult and time-consuming work should be anticipated.
the probability of failure by testing only 30 negative sam- For existing devices, peer-reviewed literature or
ples was 38.9%. By increasing the number of negative cases published experience with routine diagnostic tests can be
to 250, the probability of failure is reduced to 1.9%. For an important source of clinical performance data. This is,
sensitivity, using 30 positive cases leads to a 10.9% proba- for existing tests, sufficient in many cases. Review of sci-
bility of failure compared to 1.7% when testing 150 positive entific literature should follow established guidance, like
cases. They also studied impact of prevalence to calculate PRISMA for systematic review [24, 25]. Specific tools could
sample size. be used for assessment of diagnostic accuracy studies [26]
The main studied parameters of clinical performance or comparative diagnostic test accuracy studies [27]. For
are diagnostic sensitivity and specificity, areas under the others, analytical performance tests should be performed in
curve (ROC curve), positive or negative predictive values, or the same way as before (sensitivity, specificity, accuracy,
positive and negative likelihood ratio. Some formulae to linearity, etc.). For almost all, NBs also expect data from
calculate the needed sample size based on the precision clinical performance studies with leftover specimens, pro-
around these parameters exist [37]. spective samples and/or from interventional studies. Study
1156 Charrière and Pazart: Clinical evidence requirements according to the IVDR 2017/746

design depends, among others, on objectives, expected per- 5. European Commission. New Approach Notified and Designated
formances and intended use. GHTF/SG5/N8:2012 provides Organisations. [Internet - cited 2022 Aug 18]; 2022. Available from:
https://ec.europa.eu/growth/tools-databases/nando/index.cfm?
different designs and examples [33]. It is also crucial to
fuseaction=directive.notifiedbody&dir_id=35.
define the sample size based on predefined clinical criteria 6. Ries F. Question parlementaire | Manque d’organismes notifiés à
such as area under the curve, positive or negative predictive l’aube de la mise en application du règlement relatif aux dispositifs
value, or positive and negative likelihood ratio and preva- médicaux de diagnostic in vitro | P-001914/2022 | Parlement
lence [36, 37]. européen [Internet]; 2022. Available from: https://www.europarl.
europa.eu/doceo/document/P-9-2022-001914_FR.html [Accessed 4
To summarize, a single approach does not exist. The
Jan 2023].
roadmap proposed in this paper, inspired by articles from
7. The Medical Device Coordination Group. Guidance - MDCG endorsed
Lord et al. [19] and from Leeflang and Allerberger [21] aims documents and other guidance [Internet - cited 2022 Aug 22]; 2022.
at helping researchers, manufacturers and laboratories Available from: https://health.ec.europa.eu/medical-devices-sector/
staff asking the relevant questions related to the documents new-regulations/guidance-mdcg-endorsed-documents-and-other-
requested in the IVDR (scientific validity report, analytical guidance_en.
8. The European Parliament. EUR-Lex - 32022R0112 - EN - EUR-Lex
performance report, clinical performance report). A large
[Internet - cited 2023 Feb 4]; 2022. Available from: https://eur-lex.
number of documents and guidelines describing the IVDR europa.eu/eli/reg/2022/112/oj/eng.
roll out and how to conduct performance studies exist. In 9. Cobbaert C, Capoluongo ED, Vanstapel FJLA, Bossuyt PMM, Bhattoa HP,
this paper, we provide key references which, we believe, Nissen PH, et al. Implementation of the new EU IVD regulation – urgent
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[Internet - cited 2023 Feb 4]. Available from: https://www.iso.org/fr/
standard/76677.html.
Research funding: None declared. 11. The International Electrotechnical Commission. IEC 62304:
Author contributions: All authors have accepted 2006+AMD1:2015 CSV | IEC Webstore | cyber security, smart city
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publication/22794.
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Informed consent: Not applicable. paper with three use cases. Clin Chem Lab Med 2022;60:982–8.
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