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The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications

De Gruyter
Clinical Chemistry and Laboratory Medicine
Authors:

Abstract

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantly we would like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs.
Opinion Paper
Paul C. D. Bank, Leo H. J. Jacobs*, Sjoerd A. A. van den Berg, Hanneke W. M. van Deutekom,
Dörte Hamann, Richard Molenkamp, Claudia A. L. Ruivenkamp, Jesse J. Swen,
Bastiaan B. J. Tops, Mirjam M. C. Wamelink, Els Wessels and Wytze P. Oosterhuis
The end of the laboratory developed test as we
know it? Recommendations from a national
multidisciplinary taskforce of laboratory
specialists on the interpretation of the IVDR and
its complications
https://doi.org/10.1515/cclm-2020-1384
Received September 14, 2020; accepted October 20, 2020;
published online November 23, 2020
Abstract: The in vitro diagnostic medical devices regula-
tion (IVDR) will take effect in May 2022. This regulation has
a large impact on both the manufacturers of in vitro
diagnostic medical devices (IVD) and clinical laboratories.
For clinical laboratories, the IVDR poses restrictions on the
use of laboratory developed tests (LDTs). To provide a
uniform interpretation of the IVDR for colleagues in clinical
practice, the IVDR Task Force was created by the scientic
societies of laboratory specialties in the Netherlands. A
guidance document with explanations and interpretations
of relevant passages of the IVDR was drafted to help labo-
ratories prepare for the impact of this new legislation.
Feedback from interested parties and stakeholders was
collected and used to further improve the document. Here
we would like to present our approach to our European
colleagues and inform them about the impact of the IVDR
and, importantly we would like to present potentially useful
approaches to fulll the requirements of the IVDR for LDTs.
Keywords: diagnostic test approval; diagnostic medical
devices regulation (IVDR); implementation; laboratory
developed test; laboratory medicine; legislation; medical
device legislation; quality assessment.
Introduction
In May 2017 the in vitro diagnostic medical devices regu-
lation (IVDR) developed by the European Union (EU) was
published as a follow-up to the in vitro diagnostic medical
devices directive (IVDD) [1, 2]. The IVDR and the accom-
panying Medical Devices Regulation (MDR) are a response
of the EU to scandals where implanted medical devices
caused serious adverse events [3]. These scandals
included harmful hip prostheses (2010), breast implants
(2012) and transvaginal pelvic oor meshes (2013) [46].
The aim of the EU is to guarantee patient safety as well as
*Corresponding author: Leo H. J. Jacobs, Chair Dutch Task Force IVDR,
Department Laboratory of Clinical Chemistry, Meander Medical Center
3813 TZ, Amersfoort, The Netherlands, Phone: +31 (0)33 850 5050,
E-mail: lhj.jacobs@meandermc.nl
Paul C. D. Bank, Department of Pharmacy, Amsterdam University
Medical Center, Amsterdam, The Netherlands
Sjoerd A. A. van den Berg, Department of Clinical Chemistry, Erasmus
Medical Centre, Rotterdam, The Netherlands
Hanneke W. M. van Deutekom, Department of Genetics, Section
Genomic Diagnostics, University Medical Centre Utrecht, Utrecht,
The Netherlands
Dörte Hamann, Department of Laboratory of Translational
Immunology, University Medical Center Utrecht, Utrecht,
The Netherlands
Richard Molenkamp, Department of Viroscience, Erasmus Medical
Centre, Rotterdam, The Netherlands
Claudia A. L. Ruivenkamp, Secretary Dutch Task Force IVDR,
Department of Clinical Genetics, Leiden University Medical Center,
Leiden, The Netherlands
Jesse J. Swen, Department of Clinical Pharmacy & Toxicology, Leiden
University Medical Center, Leiden, The Netherlands
Bastiaan B. J. Tops, Department of Pathology, Princess Máxima Center
for Pediatric Oncology, Utrecht, The Netherlands
Mirjam M. C. Wamelink, Department of Clinical Chemistry, Metabolic
Unit, Amsterdam University Medical Center, Vrije Universiteit
Amsterdam, Amsterdam, The Netherlands
Els Wessels, Department of Medical Microbiology, Leiden University
Medical Center, Leiden, The Netherlands
Wytze P. Oosterhuis, Department of Clinical Chemistry, Zuyderland
Medical Centre, Heerlen, The Netherlands
Clin Chem Lab Med 2020; aop
enforce transparency in the manufacturing process of
both implantable medical devices and in vitro diagnostic
medical devices (IVDs) by review by a notied body
appointed by a competent authority as well as ensure the
quality by manufacturers [2]. However, this regulation
will likely also have a large impact on (commercial) test
availability as a result of the lengthy certication process
executed by a notied body and on the ability of clinical
laboratories to create and implement laboratory devel-
oped tests (LDTs). To provide a uniform interpretation of
the IVDR for colleagues in clinical practice, the IVDR Task
Force was created by the scientic societies of laboratory
specialties in the Netherlands (Box 1). This article pro-
vides the interpretation of LDTs in the IVDR, its impact on
routine testing in clinical laboratories, the future of the
LDT under the IVDR and possible pros and cons of this
legislation.
Box 1: Dutch Task Force IVDR.
This task force consists of mandated members of the
Netherlands Society for Clinical Chemistry and
Laboratory Medicine (NVKC), Netherlands Society for
Pathology (NVVP), Dutch Society for Medical
Microbiology (NVMM), the Dutch Association of Clinical
Geneticists (VKGN)/the Association of Clinical Genetic
Diagnostic Laboratories (VKGL), Dutch Society for
Immunology (NVVI)/College of Medical Immunologists
(CMI) and the Dutch Association of Hospital Pharmacists
(NVZA).
The goal and timeline of IVDR
With the IVDR, named EU IVDR 2017/746, the IVDD 98/79/
EC has been replaced by a regulation in parallel with the
replacement of the Medical Device Directive into the formal
Regulation named EU MDR 2017/745 [13, 7]. Patient safety
concerns are the driving force in choosing to impose the
rules in a regulation. As such, adherence to the timeline by
the European Parliament (EP) has been strict and ambi-
tious and until recently it was unlikely that the imple-
mentation of the IVDR in May 2022 will be delayed [8, 9]. Of
course, the outbreak of Coronavirus disease (COVID-19)
and the challenges surrounding the (in-house) develop-
ment, use and availability of diagnostic tests could result in
a more cautious implementation timeline. For example, the
MDR was postponed with a year due to COVID-19 and the
fear for a shortage of medical devices [10].
Compared to the previous IVDD traceability throughout
the supply chain and greater transparency will be deman-
ded under the IVDR. Authorities and notified bodies will be
challenged, not only because the amount oftests that need a
certification will drastically increase, but also more expert
knowledge is required. Additionally, the IVDR requires
manufacturers to establish post market surveillance mech-
anisms. They will need to actively collect and evaluate
performance from the use of a device. Finally, under this
new regulation IVDs will be classified based on their related
risk on personal or public health. Although this classifica-
tion is based on the Global Harmonization Task Force
(GHTF) risk classification there currently still some ambi-
guity on the exact classification of certain assays.
Impact for manufacturers
The most significant change for manufacturers as a result
of the IVDR is the level of third-party oversight required by
a notified body appointed by the competent authority,
whereas under the IVDD the manufacturers of IVDs that
were controlled by a self-declared procedure. Approxi-
mately 20% of tests required a notified body under the
IVDD. This is a big contrast compared to the situation un-
der the IVDR, where almost 80% of IVDs on the European
market that are currently controlled by a self-declaration
procedure are estimated to require conformity assessment
by notified bodies [9, 11, 12]. Clinical evidence is likely to be
the most difcult challenge for the manufacturers. For
some manufactures this challenge might be too big and/or
too costly, and may opt not to certify their product resulting
in a diminished availability of IVD certied assays.
Impact for clinical laboratories
The new IVDR will also have a large impact on clinical
laboratories. Clinical laboratories are mandated by the
IVDR to use IVDs marketed by manufacturers which have
received CE-IVD certification. However, the IVDR recog-
nizes the possibility of manufacturing LDTs (see Box 2) to
address the specic needs of patient groups that otherwise
cannot be met (art.29). These IVDs when used exclusively
in the hospital laboratory where they are madeare exempt
from many of the requirements of the IVDR (see Box 3). This
also applies for IVDs that are modied and for off label use
of the IVDs. Clinical laboratories in large peripheral hos-
pitals such as laboratories for clinical chemistry, hematol-
ogy, immunology, handle large volumes of samples, often
in automated tracks which predominantly use IVDs from
2Bank et al.: Recommendations from the Dutch Task Force IVDR
commercial manufacturers. However, other clinical labora-
tories providing specialized analyses more often use LDTs,
this includes specialties such as clinical genetics, pathology,
microbiology, therapeutic drug monitoring, toxicology and
clinical laboratories in academia. For low volume, special-
ized analyses in these latter groups of laboratories commer-
cial assays were often not available in the past, forcing them
to develop and use LDTs. Once an LDT is developed, vali-
dated according to EN-ISO 15189 standards and implemented
in clinical practice there is little incentive to switch to a
commercial alternative when available. However, once the
IVDR takes effect, switching to equivalent commercial al-
ternatives will become mandatory, requiring a process of (re)
validation of new assays for analyses that are currently
already executed in routine practice. Additionally, as a result
of the mandatory switch from an LDT to a commercial assay
some laboratories probably will have to purchase new
equipment resulting in higher costs for laboratory specialties.
Finally,Vermeerschetal.haveshowninacase-studyin
preparation for the IVDR that the process of inventorying
which assays are classied conform the CE-IVD and justi-
cation of LDTs in a laboratory in a large academic hospital
willrequirealotoftimeandeffort[13].
Box 2: What is an LDT?
Based on the IVDR art. 5, in the following cases the test
can be considered an LDT:
1) An in-house developed and produced test;
2) Tests that are labeled research use onlyand that are used for
diagnostics;
3) A CE-IVD certied test in which adjustments are made that
change the intended use;
4) A CE-IVD certied test in which adjustments to the protocol are
made without changing the intended use
Box 3: Articles in the IVDR regarding laboratory
developed tests & interpretation by the task
force*
Art. 5a. the resources are not transferred to another
legal person.
It is permissible, and necessary, for the quality and
accessibility of healthcare, that test results and
corresponding analytical or clinical interpretations
(if applicable) can be shared with referring healthcare
providers. The LDTs cannot be transferred to other legal
entities, the results produced with the LTDs can.
Sharing relevant protocols, work instructions, clinical
validations and describing LDTs performed within the
(continued)
Art. 5a. the resources are not transferred to another
legal person.
It is permissible, and necessary, for the quality and
accessibility of healthcare, that test results and
corresponding analytical or clinical interpretations
(if applicable) can be shared with referring healthcare
providers. The LDTs cannot be transferred to other legal
entities, the results produced with the LTDs can.
Sharing relevant protocols, work instructions, clinical
validations and describing LDTs performed within the
professional discipline in scientic publications is
allowed.
Art. 5b. the devices are manufactured and used in
compliance with an appropriate quality
management system.
In general, the quality management system under EN ISO
15189 can be seen as an appropriate quality management
system. Nonetheless, there is a considerable heterogeneity
in manufacturing processes and we cannot exclude the
possibility of additional requirements.
Art. 5c. the healthcare institutions laboratory
complies with standard EN ISO-15189 or, where
applicable, with applicable national provisions,
including national provisions regarding
accreditation.
Being EN ISO 15189 accredited is the most effective way to
comply with this part of the law.
5d) the healthcare institution justies in its
documentation that the specic needs of the patient
target group cannot be met, or cannot be met at an
appropriate level of performance, by an equivalent
tool available on the market.
The health institution must, for each LDT, justify its use. It
will be necessary to demonstrate and prove that the
specic needs of the patient group cannot be met, or not at
the right performance level, with a comparable IVD device
available on the market.
Arguments that can be taken into consideration to
demonstrate the necessity and superiority of the LDT:
Technical:
Working principle
Critical performance requirements
Required amount of patient material
Type of (body) material
Reliability of the device/test
Turn-around times
Bank et al.: Recommendations from the Dutch Task Force IVDR 3
Clinical compatibility and interdependent comparison of re-
sults from the same material (taken at the same time). For
example: a multiplex assay can measure multiple parameters
simultaneously in one analysis, instead of several indepen-
dent tests.
Clinical:
Is the device used for the same clinical condition or purpose?,
including:
the same severity and stage of the disease
in the same place in the body
in a comparable population, including age, anatomy and
physiology
comparable relevant critical performance in view of the
expected clinical effect for a specic intended purpose.-
Substantiation of the above can be based on (but is not
limited to):
National guidelines from professional associations/ interna-
tional guidelines
Scientic literature
Expert opinion e.g. clinical utility cards Clarication: The IVDR
does not specify when the lack of an alternative for the device
must be justied. An appropriate moment is at the start of the
LDTs development process, when the functional requirements
and the patient target group are known. Subsequently, a -
re-assessment will have to be performed at the end of the
life cycle of the LDT or when the LDT is changed. For medical
devices (LDTs) that are produced without a clear (end of) life
cycle or that are not subject to change, market orientation
needs to be performed at a reasonable frequency to check
for the availability of equivalent, commercially available
alternatives. The information published in EUDAMED is
leading for this.
5e. the healthcare institution shall provide its
competent authority with information on the use of
such devices, including justication for their
manufacture, modication and use.
All previously mentioned items must be documented and
must be able to be handed over to the competent
authorities upon request.
5f) the healthcare institution draws up a statement
that makes it public and contains the following
elements: i) The name and address of the
manufacturing healthcare institution, ii) data
identifying the devices, iii) a statement that the
devices comply with the general safety and
performance requirements set out in Annex I to this
regulation and, where applicable, information on
requirements that are not fully met, with a reasoned
justication for that.
(See Supplementary Document I for example
explanation).
5g) for devices classied in class D according to the
rules of Annex VIII, the healthcare institution shall
prepare documentation explaining the production
facility and the production process, design and
performance data of the devices, including the
intended purpose, which is sufcient detailed to
enable the competent authority to assess whether
the general safety and performance requirements
set out in Annex I to this Regulation are being met.
Member States may also apply this provision to
devices classied as class A, B or C in accordance
with the rules set out in Annex VIII.
For the time being, the Task Force assumes that this
requirement only applies to class D.
5h) the healthcare institution takes all measures
necessary to ensure that all devices are
manufactured in accordance with the
documentation referred to in point g), and i) The
healthcare institution evaluates the experience
gained with the clinical use of the devices and takes
all required corrective actions.
Here too, EN-ISO 15189 accreditation provides assurance,
in particular on the basis of Section 4.14 Evaluation and
Audits.
* Quoted elements from the IVDR are bolded and
interpretations from The IVDR taskforce are displayed in
italics.
The call for a task force
As the scientific societies of laboratory specialties in The
Netherlands envisioned that the European IVDR legislation
will have large consequences for the use, availability and
costs of in vitro diagnostic tests, a multidisciplinary task
force was convened to meet the possible challenges of the
IVDR (see Box 1).
The main goal of this Task Force was to aid the imple-
mentation of the IVDR by providing a practical interpreta-
tion for their members of this legislation and to provide
clarity on the impact on the field in daily practice. With this
interpretation of the regulation the Task Force aims to
harmonize the interpretation of the articles in this regulation
by professionals in the field. Additionally, the Task Force
aimed at maximizing the possibility for laboratory special-
ists to develop diagnostic procedures to address unmet
needs within the limits of best practices, current standards
and legislation. During multiple meetings the text of the
IVDR was discussed until a consensus on the interpretation
4Bank et al.: Recommendations from the Dutch Task Force IVDR
was reached and a draft document was developed con-
taining the interpretation by the Task Force of article 5.5 of
the IVDR which encompasses LTDs and other relevant ar-
ticles for clinical laboratories. In the next step multiple
stakeholders and interested parties, including the Dutch
Ministry of Health Welfare and Sport (VWS) and Health and
Youth Care Inspectorate (IGJ) (who are likely to fulfill the
role as competent authority in the Netherlands), were con-
sulted to check whether they agreed on the interpretation
and to provide feedback on the document. The consulted
stakeholders greatly valued the proactive initiative taken by
the taskforce and welcome the input from the medical lab-
oratory experts. Of course, our recommendations are only
one of several considerations that have to be taken into
account and at this stage our guidance document should be
considered as a non-binding practical advice for laboratory
professionals.
The final document includes a list of the paragraphs of
the IVDR which are relevant for clinical laboratories and
provides an explanation of the text and directive for the
members of the associations on how to implement the
relevant paragraphs of the IVDR. Additionally, the Task
Force provided interpretation in linking Appendix I of the
IVDR to sections of the EN-ISO 15189:2012, which helps
clinical laboratories to create a gap analysis. Finally, the
document provides support to prepare for the introduction
of the IVDR by an active assignment to its members to start
to investigate which LDTs are used in their clinical labo-
ratories and if they comply with the IVDR validation re-
quirements (see Supplementary Document 1).
Although the document created by the Task Force
currently holds no legal value, as of today, the content of
the document and associated files is supported by all
scientific societies of diagnostic specialties in the
Netherlands. As mentioned above, the IVDR prohibits the
use of LDTs when equivalent commercial alternatives are
available. However, abiding article 5 of the IVDR (see
Box 3) LDTs are exempt from the IVDR when used on a
non-industrial scale and no equal or superior performing
commercial CE-IVD diagnostic test is available. The major
caveat is currently that precise denitions of the limits,
and criteria when a use-case is dened as industrial are
still open for interpretation. In a general sense, it is the
Task Forces view that any test developed in-house and
used for patient care, is not applied on an industrial scale.
This is especially the case in clinical laboratories in an
academic setting, where many specic assays are not
commercially available and laboratories should have the
possibility to help clinicians in their process of diagnosis
and patient monitoring and by fullling the EN-ISO 15189
requirements.
Furthermore, minor modifications should be possible
without the test being considered an LDT. This includes
dilutions, reaction times, etc. Such an adaptation shifts the
responsibility from supplier to laboratory and the labora-
tory is required to substantiate the adjustment by per-
forming a validation (in particular according to EN-ISO
15189) of the aspects that could reasonably be assumed to
be influenced by the adaptation. Finally, there are situa-
tions where adjustments are made only by exemption in
individual cases. These are often ad hoc decisions that
require adjustments to answer an urgent, specific clinical
question. In those cases it could be necessary to indicate
that the reported results have been generated using an
unvalidated analysis not covered by EN-ISO 15189.
Discussion
As a result of multiple scandals, the EP has provided
Europe with a new regulation which aims to protect
patients from harmful medical devices including IVDs.
As medical laboratory specialists we aim to provide high
quality and safe in vitro diagnostic testing procedures to
clinicians in our hospitals and associated primary care
centers to diagnose and monitor patients. To ensure that
our laboratory tests are of high quality and results are
reproducible we hold ourselves to strict quality control
procedures and require this from our colleagues as well.
With the arrival of the IVDR the implementation of a quality
management system (EN-ISO 15189 or equivalent) is
mandatory for clinical laboratories, a decision that we fully
support [9, 12].
The IVDR forces the manufacturers to provide trans-
parency in the manufacturing process by certification
through a notified body appointed by the competent au-
thority, for the majority of products used by clinical lab-
oratories. The removal of the option of self-certification
and implementation of obligatory certification by trusted
third parties for most products will likely result in the
removal of IVD products from the market which do not
uphold their quality claims. Moreover, the requirement
for the manufacturers to gather clinical data as part of the
certification will likely result in a further increase of the
quality of the IVDs and will result in an easier imple-
mentation procedure. The manufacturers will have to
provide the majority of the data necessary for validation
as part of the certification process by the notified body.
Post marketing surveillance of the assays will result in
continuous monitoring of the IVD in clinical practice as a
requirement in the certification process and prevent
Bank et al.: Recommendations from the Dutch Task Force IVDR 5
possible tampering with the IVD by the manufacturer
once certification has been granted by the notified body.
With the implementation of the IVDR an international
database (EUDAMED) will become available which will
provide an overview of the commercial CE-IVDs for various
platforms possibly including the specifications of the as-
says so laboratory specialist can make a more informed
choice on which assay to use on their platform. Instead of a
laborious validation from scratch, a verification of the as-
says claims will be sufficient for implementation in clin-
ical practice [14].
Although the IVDR will likely result in a step forward in
the quality assurance and control in medical laboratories
(in the future possibly by uptake of the IVDR in the ISO
guideline), some concerns must be addressed too. As a
result of a lack of notified bodies and the large number of
medical devices currently marketed in clinical practice
there is a worry that products critical for the processes in
daily practice will not receive certification in time. This
could result in certain IVDs, required for daily clinical care,
being withdrawn from the market. Additionally, the pro-
cess of certification by a notified body is a laborious,
expensive and time-consuming process. Smaller enter-
prises that currently provide a high quality assay for a
niche in laboratory medicine might not have the resources
to follow through with the certification process. Similarly,
American companies that currently also sell their products
on the European market might opt out of providing their
products to clinical laboratories in European countries.
The REACH (Registration, Evaluation, Authorization and
Restriction of Chemicals), an area of EU regulation, has had
a similar result. Both scenarios might have implications for
the diagnostic process and monitoring of specific groups of
patients.
Another major concern regarding the IVDR is its
impact on innovation. With the strict regulation regarding
the use of LDTs, laboratories in academia and large pe-
ripheral hospitals are less likely to develop new assays for
use in clinical practice to respond to (rapid) changes in
healthcare (see Box 4). The investment of a time-
consuming and expensive process of developing a new
assay can be undone after the introduction of a newly
marketed commercial CE-IVD alternative. This could result
in an increase of the costs of medical care. Due to the funds
and manpower required for the certication process, clin-
ical laboratories are unlikely to have their own LDTs
certied by a notied body. This might also reduce the
pressure on manufacturers to improve upon their regis-
tered products. For example, in the past it has become clear
that LDTs developed on a mass-spectrometer platform
used for the quantication of tacrolimus were signicantly
better than a commercial product based on an immuno-
assay available at the time [15]. This has resulted in the
development of commercial mass-spectrometer assays for
immunosuppressants which are currently available for
multiple mass-spectrometers platforms. A downside
experienced by Le Goff et al. is the ability to troubleshoot
with commercial ready-to-use mass-spectrometry assays
as the kit has become a black box [14].
Box 4: The use of LDTs in a global emerging health
emergency.
In December 2019 an outbreak of the novel SARS-CoV-2
coronavirus in Wuhan, China was recognized. The virus
spread rapidly and caused the current global COVID-19
pandemic [16]. Reliable laboratory diagnosis of the
SARS-CoV-2 virus is an important requisite for both
public and clinical healthcare. Due to international
collaboration between WHO reference laboratories,
diagnostic assays for the detection of the novel
SARS-CoV-2 were designed and validated despite the
absence of samples or virus isolates [17]. These LDTs
provided hospitals and public health institutions with
tools for clinical care and public health response in the
absence of commercial assays.Although the rst
commercial CE-IVD marked assays for this novel virus
became available in March-April, unprecedented market
failure resulted in scarcity of these CE-IVD assays as well
as general reagents and consumables which forced
laboratories to modify procedures or switch assays
multiple times.Fortunately, this situation beneted from
experience that laboratories maintained through
development of LDTs in general. However, with the
introduction of (article 5.5) of the IVDR, this experience
will decrease and this will likely impede the future
responses to rapidly evolving health emergencies and
may severely impair clinical care and public health
response.
In conclusion, the IVDR will likely improve the overall
quality of IVDs, result in a higher uptake of commercial
CE-IVD products and diminish the use of LDTs by clinical
laboratories. However, there are also concerns regarding
the availability of certified products, the impact on inno-
vation of novel diagnostics and possible barriers to
respond to changing (public) health challenges. Addi-
tionally, for the diagnosis and monitoring of disease in
specific patient groups the use of LDTs will still be neces-
sary. With the provided document the Task Force aims to
provide an instrument for our colleagues to act upon the
IVDR in clinical practice.
6Bank et al.: Recommendations from the Dutch Task Force IVDR
Research funding: None declared.
Author contributions: All authors have accepted
responsibility for the entire content of this manuscript
and approved its submission.
Competing interests: Authors state no conict of interest.
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Bank et al.: Recommendations from the Dutch Task Force IVDR 7
... This non-standardized ICC landscape is now challenged with the introduction of the new EU IVDR. According to this regulation, ICC on cytological slides falls under the category of Laboratory-Developed Tests (LDT) which require rigorous validation and thorough quality management compliant with ISO 15189 [47,48]. ...
... The most important thing to understand is that like any other diagnostic test, all IHC/ICC tests must be properly optimized, verified, and validated according to EN ISO 15198 or other relevant quality management standards before being used to test patient specimens [3,11,20,21,47,48]. Optimization involves adjusting and fine-tuning the analytical steps in the ICC procedure (such as antigen retrieval, antibody dilution, incubation time, counterstaining, etc.) to achieve the expected and optimal results with a strong specific reaction, while minimizing nonspecific or background staining. ...
... Validation should provide objective evidence that the test works as expected and that it is fit for purpose [8]. Thoroughly elaborated and welldescribed different levels of validation for IHC [2,3,8,11,47,48,69] is completely relevant also for ICC and is beyond the scope of this review. ...
Article
Background: Immunocytochemistry (ICC) is a widely available and extensively used ancillary method in diagnostic cytopathology with great variability in all test phases and a low level of adequate quality management. The non-standardized ICC landscape is now challenged with the introduction of the new European (EU) In Vitro Diagnostic Medical Devices Regulation (IVDR). According to this regulation, ICC on cytological slides falls under the category of Laboratory-Developed Tests (LDT), which requires rigorous standardization, validation, and thorough quality management. Summary: Complete standardization of pre-analytical and analytical steps in ICC is impossible due to the complexity of the method and the constantly evolving antibodies, detection systems, and platforms. However, similar to the approach in immunohistochemistry, improving and standardizing "best practices" in quality management will result in high-quality, correct, accurate, and reliable ICC results. In this review, the current challenges of ICC in diagnostic cytopathology will be discussed, along with practical insights into ICC standardization and validation. Key messages: Control slides prepared in the same manner as the patient samples, optimized ICC protocols, and participation in external quality control for ICC are the pillars of good quality management and essential to ensure safe and reliable patient diagnostics.
... Without clear guidelines/guidance for LDTs, it becomes challenging for laboratories to meet regulatory requirements and for health authorities to assess the quality and reliability of these assays, including their use in clinical practice. 10 To support clinical laboratories, guidelines/guidance for LDTs should be available, especially for assays that are recommended or suggested in clinical practice, such as PSA. ...
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Accurate assessment of platelet secretion is essential for the diagnosis of inherited or acquired platelet function disorders (PFDs) and more specifically in identifying δ-storage pool disease. Mepacrine, a fluorescent dye, specifically accumulates in platelet δ-granules. The mepacrine flow cytometry (FCM) assay has been used for more than half a century in the clinical laboratory as a diagnostic tool for platelet δ-granule disorders. The assay requires a small volume of blood, can be performed in thrombocytopenic patients, provides rapid assessment of δ-granule content and secretion and, thus, enables differentiation between storage and release defects. FCM has been shown to have added value compared to light transmission aggregometry. There is however a broad heterogeneity in methods, reagents, and equipment used. Lack of standardization and limited data on analytical and clinical performances have led the 2022 ISTH SSC Subcommittee on Platelet Physiology expert consensus to rate this assay as simple but of uncertain value. Yet, the data used by experts to formulate the recommendations were not discussed and even not mentioned. Guidance for laboratory studies of platelet secretion assay would be very helpful for clinical laboratories and health authorities especially considering the implications of the new In Vitro Diagnostic Regulation (IVDR) in Europe. The purpose of the present work was to systematically review the reported methodologies for the mepacrine FCM assay and to offer an example of detailed protocol. This would help standardization and pave the way for more rigorous comparative studies.
... Lacking service-level agreements in Europe makes the implementation of these robots in ISO-15189 accredited laboratories difficult. From May 2024, in-house developed in-vitro diagnostic devices may only be used in European laboratories that are compliant with EN ISO 15189 and attention is also needed to fulfill the other requirements of the In Vitro Diagnostic Regulation (IVDR) in a timely manner 28 . ...
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Whole-genome sequencing (WGS) is currently making its transition from research tool into routine (clinical) diagnostic practice. The workflow for WGS includes the highly labor-intensive library preparations (LP), one of the most critical steps in the WGS procedure. Here, we describe the automation of the LP on the flowbot ONE robot to minimize the risk of human error and reduce hands-on time (HOT). For this, the robot was equipped, programmed, and optimized to perform the Illumina DNA Prep automatically. Results obtained from 16 LP that were performed both manually and automatically showed comparable library DNA yields (median of 1.5-fold difference), similar assembly quality values, and 100% concordance on the final core genome multilocus sequence typing results. In addition, reproducibility of results was confirmed by re-processing eight of the 16 LPs using the automated workflow. With the automated workflow, the HOT was reduced to 25 min compared to the 125 min needed when performing eight LPs using the manual workflow. The turn-around time was 170 and 200 min for the automated and manual workflow, respectively. In summary, the automated workflow on the flowbot ONE generates consistent results in terms of reliability and reproducibility, while significantly reducing HOT as compared to manual LP.
... With PCR being the method of choice in the early diagnosis of a variety of EBV-asso ciated diseases and in monitoring the efficacy of therapies (3), there is an increasing need for reliable, automated EBV assays on consolidated high-throughput platforms to substitute manual or semi-automated commercial assays or laboratory-developed tests (LDTs) with long turnaround times (TAT). This trend is reinforced by the increas ing regulation of test procedures within the framework of the new European In Vitro Diagnostic Regulation (7). ...
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Detection and monitoring of acute infection or reactivation of Epstein-Barr virus (EBV) are critical for treatment decision-making and to reduce the risk of EBV-related malignancies and other associated diseases in immunocompromised individuals. The analytical and clinical performance of the Alinity m EBV assay was evaluated at two independent study sites; analytical performance was assessed by evaluating precision with a commercially available 5-member EBV verification panel, while the clinical performance of the Alinity m EBV assay was compared to the RealTi me EBV assay and a laboratory-developed test (LDT) as the routine test of record (TOR). Analytical analysis demonstrated standard deviation (SD) between 0.08 and 0.13 Log IU/mL. A total of 300 remnant plasma specimens were retested with the Alinity m EBV assay, and results were compared to those of the TOR at the respective study sites ( n = 148 with the RealTi m e EBV assay and n = 152 with the LDT EBV assay). Agreement between Alinity m EBV and RealTi m e EBV or LDT EBV assays had kappa values of 0.88 and 0.84, respectively, with correlation coefficients r of 0.956 and 0.912, while the corresponding observed mean bias was −0.02 and −0.19 Log IU/mL. The Alinity m EBV assay had a short median onboard turnaround time of 2:40 h. Thus, the Alinity m system can shorten the time to results and, therefore, to therapy.
... Note that for all devices for general laboratory use, the processing and operating instructions in a given laboratory are not subject to this new regulation [3]. [4,5] for further details and explanations. ...
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IVDR regulation represents a major challenge for diagnostic microbiology laboratories. IVDR complicates a broad range of aspects and poses a risk given the high diversity of pathogens (including rare but highly virulent microbes) and the large variety of samples submitted for analysis. The regular emergence of new pathogens (including Echovirus E-11, Adenovirus 41, Monkeypox virus, Alongshan virus, and Enterovirus D68, as recent examples in Europe in the post SARS-CoV-2 era) is another factor that makes IVDR regulation risky, because its detrimental effect on production of in-house tests will negatively impact knowledge and expertise in the development of new diagnostic tests. Moreover, such regulations negatively impact the availability of diagnostic tests, especially for neglected pathogens, and has a detrimental effect on the overall costs of the tests. The increased regulatory burden of IVDR may thereby pose an important risk for public health. Taken together, it will have a negative impact on the financial balance of diagnostic microbiology laboratories (especially small ones). The already-high standards of quality management of all ISO-accredited and Swissmedic-authorized laboratories render IVDR law of little value, at least in Switzerland, while tremendously increasing the regulatory burden and associated costs. Eventually, patients will need to pay for diagnostic assays outside of the framework of their insurance in order to obtain a proper diagnostic assessment, which may result in social inequity. Thus, based on the risk assessment outlined above, the coordinated commission for clinical microbiology proposes adjusting the IvDO ordinance by (i) introducing an obligation to be ISO 15189 accredited and (ii) not implementing the IvDO 2028 milestone.
... Most innovative tests are introduced as lab-developed tests (LDTs). Although LDTs can be exempt from the IVDR, there are several conditions that need to be met that are mentioned in chapter 2, article 5.5 of the regulation [93,94]. The two most important thereof are that the laboratory is compliant with EN ISO 15189 standards or, where applicable, national provisions (article 5.5c) and provides a justification for the use of the LDT, i.e., why the specific needs for that test cannot be met by an equivalent (IVD) device on the market (article 5.5d). ...
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In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, 'histomolecular' diagnosis is required. A variety of approaches exists for determining the status of the underyling molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analysis, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
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In the Netherlands, newborn screening (NBS) for tyrosinemia type 1 (TT1) uses dried blood spot (DBS) succinylacetone (SUAC) as a biomarker. However, high false-positive (FP) rates and a false-negative (FN) case show that the Dutch TT1 NBS protocol is suboptimal. In search of optimization options, we evaluated the protocols used by other NBS programs and their performance. We distributed an online survey to NBS program representatives worldwide (N = 41). Questions focused on the organization and performance of the programs and on changes since implementation. Thirty-three representatives completed the survey. TT1 incidence ranged from 1/13,636 to 1/750,000. Most NBS samples are taken between 36 and 72 h after birth. Most used biomarkers were DBS SUAC (78.9%), DBS Tyrosine (Tyr; 5.3%), or DBS Tyr with second tier SUAC (15.8%). The pooled median cut-off for SUAC was 1.50 µmol/L (range 0.3–7.0 µmol/L). The median cut-off from programs using laboratory-developed tests was significantly higher (2.63 µmol/L) than the medians from programs using commercial kits (range 1.0–1.7 µmol/L). The pooled median cut-off for Tyr was 216 µmol/L (range 120–600 µmol/L). Overall positive predictive values were 27.3% for SUAC, 1.2% for Tyr solely, and 90.1% for Tyr + SUAC. One FN result was reported for TT1 NBS using SUAC, while three FN results were reported for TT1 NBS using Tyr. The NBS programs for TT1 vary worldwide in terms of analytical methods, biochemical markers, and cut-off values. There is room for improvement through method standardization, cut-off adaptation, and integration of new biomarkers. Further enhancement is likely to be achieved by the application of post-analytical tools.
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Quality control practices in the modern laboratory are the result of significant advances over the many years of the profession. Major advance in conventional internal quality control has undergone a philosophical shift from a focus solely on the statistical assessment of the probability of error identification to more recent thinking on the capability of the measurement procedure (e.g. sigma metrics), and most recently, the risk of harm to the patient (the probability of patient results being affected by an error or the number of patient results with unacceptable analytical quality). Nonetheless, conventional internal quality control strategies still face significant limitations, such as the lack of (proven) commutability of the material with patient samples, the frequency of episodic testing, and the impact of operational and financial costs, that cannot be overcome by statistical advances. In contrast, patient-based quality control has seen significant developments including algorithms that improve the detection of specific errors, parameter optimization approaches, systematic validation protocols, and advanced algorithms that require very low numbers of patient results while retaining sensitive error detection. Patient-based quality control will continue to improve with the development of new algorithms that reduce biological noise and improve analytical error detection. Patient-based quality control provides continuous and commutable information about the measurement procedure that cannot be easily replicated by conventional internal quality control. Most importantly, the use of patient-based quality control helps laboratories to improve their appreciation of the clinical impact of the laboratory results produced, bringing them closer to the patients.Laboratories are encouraged to implement patient-based quality control processes to overcome the limitations of conventional internal quality control practices. Regulatory changes to recognize the capability of patient-based quality approaches, as well as laboratory informatics advances, are required for this tool to be adopted more widely.
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Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1–4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a novel coronavirus (2019-nCoV) which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started from 12 December 2019, has caused 2,050 laboratory-confirmed infections with 56 fatal cases by 26 January 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The 2019-nCoV virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.
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Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur.AimWe aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available.Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology.ResultsThe workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive - Global (EVAg), a European Union infrastructure project.Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
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The healthcare and life science sector is growing inexorably, and is now a multi-billion dollar industry. In 2016 the companies in this sector posted sales of USD 140 billion, and their profitability more than doubled by comparison with 2010. The pharmaceutical, diagnostics, medtech and chemical sectors have become Switzerland's most powerful export industry, and significant number of approved medications and diagnostics contain biotech elements.
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Objectives The new European In Vitro Diagnostic (IVD) Regulation 2017/746 (IVDR) restricts the use of lab-developed tests (LDT) after 26th May 2022. There are no data on the impact of the IVDR on laboratories in the European Union. Methods Laboratory tests performed in UZ Leuven were divided in four groups: core laboratory, immunology, special chemistry, and molecular microbiology testing. Each test was classified as Conformité Européenne (CE)-IVD, modified/off-label CE-IVD, commercial Research Use Only (RUO) or LDT. Each matrix was considered a separate test. Results We found that 97.6% of the more than 11.5 million results/year were generated with a CE-IVD method. Of the 922 different laboratory tests, however, only 41.8% were CE-IVD, 10.8% modified/off-label CE-IVD, 0.3% RUO, and 47.1% LDT. Off-label CE-IVD was mainly used to test alternative matrices not covered by the claim of the manufacturer (e.g., pleural or peritoneal fluid). LDTs were mainly used for special chemistry, flow cytometry, and molecular testing. Excluding flow cytometry, the main reasons for the use of 377 LDTs were lack of a CE-IVD method (71.9%), analytical requirements (14.3%), and the fact the LDT was in use before CE-IVD available (11.9%). Conclusions While the large majority of results (97.6%) were generated with a CE-IVD method, only 41.8% of laboratory tests were CE-IVD. There is currently no alternative on the market for 71.5% of the 537 LDTs performed in our laboratory which do not fall within the scope of the current IVD directive (IVDD). Compliance with the IVDR will require a major investment of time and effort.
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Historically, the determination of low concentration analytes was initially made possible by the development of rapid and easy-to-perform immunoas-says (IAs). Unfortunately, typical problems inherent to IA technologies rapidly appeared (e.g. elevated cost, cross-reactivity, lot-to-lot variability, etc.). In turn, liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are sensitive and specific enough for such analy- ses. Therefore, they would seem to be the most promis- ing candidates to replace IAs. There are two main choices when implementing a new LC-MS/MS method in a clini- cal laboratory: (1) Developing an in-house method or (2) purchasing ready-to-use kits. In this paper, we discuss some of the respective advantages, disadvantages and mandatory requirements of each choice. Additionally, we also share our experiences when developing an in-house method for cortisol determination and the implementa- tion of an “ready-to-use” (RTU) kit for steroids analysis.
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Therapeutic drug monitoring of tacrolimus and cyclosporine is crucial to the success of organ transplantation. We evaluated the analytical performances and accuracy of two commercially available tacrolimus and cyclosporine assays (Roche ISD and Siemens) in comparison with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 342 leftover whole blood samples requested for tacrolimus or cyclosporine assays were stored at −20 °C until analysis. Repeatability and between-run imprecision were evaluated using quality control materials provided by the manufacturer. Ring trial samples were used for the assessment of recovery. The results of the Roche ISD assay were compared with those of Siemens tacrolimus and cyclosporine assays and LC-MS/MS. Repeatability and between-run imprecision were 2.1–5.3% and 2.6–7.5%, respectively. Recovery of Roche ISD was 85.7 − 90.6% for cyclosporine and 96.2–98.5% for tacrolimus. The two immunoassays showed slight positive biases relative to LC-MS/MS for cyclosporine. For tacrolimus, Roche ISD produced virtually identical results to those of LC-MS/MS, whereas Siemens showed proportional differences, especially in patients receiving kidney transplantation. The analytical performances of Roche ISD were generally acceptable, especially regarding accuracy. Clinical laboratory staff should be aware of the strengths and weaknesses of commercial immunoassays in order to ensure accurate results.
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In our efforts to advance the profession and practice of clinical laboratory medicine, strong coordination and collaboration are needed more than ever before. At the dawn of the 21st century, medical laboratories are facing many unmet clinical needs, a technological revolution promising a plethora of better biomarkers, financial constraints, a growing scarcity of well-trained laboratory technicians and a sharply increasing number of International Organization for Standardization guidelines and new regulations to which medical laboratories should comply in order to guarantee safety and effectiveness of medical test results. Although this is a global trend, medical laboratories across continents and countries are in distinct phases and experience various situations. A universal underlying requirement for safe and global use of medical test results is the standardization and harmonization of test results. Since two decades and after a number of endeavors on standardization/harmonization of medical tests, it is time to reflect on the effectiveness of the approaches used. To keep laboratory medicine sustainable, viable and affordable, clarification of the promises of metrological traceability of test results for improving sick and health care, realization of formal commitment among all stakeholders of the metrological traceability chain and preparation of a joint and global plan for action are essential prerequisites. Policy makers and regulators should not only overwhelm the diagnostic sector with oversight and regulations but should also create the conditions by establishing a global professional forum for anchoring the metrological traceability concept in the medical test domain. Even so, professional societies should have a strong voice in their (inter-) national governments to negotiate long-lasting public policy commitment and funds for global standardization of medical tests.
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A Cochrane systematic review has concluded that artificial mesh has some advantages over native tissue for the surgical treatment of vaginal prolapse but is associated with increased morbidity.1 Research published in the Cochrane Library showed that, while transvaginal permanent mesh probably reduces the risk that women will be aware of a prolapse when compared with tissue repair, the overall benefit was small. Permanent mesh was also associated with higher rates of reoperation for prolapse, stress urinary incontinence, and bladder injury during surgery. A vaginal prolapse occurs when the walls of the vagina become weak and collapse inwards. It is common, affecting as many as half of women who have had children. Symptoms include pelvic heaviness, backache, and bladder, bowel, or sexual dysfunction. The traditional method of repairing vaginal prolapse using native tissue is associated with …
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The ASR (articular surface replacement) XL (DePuy, Warsaw, Ind) metal-on-metal hip arthroplasty offers the advantage of stability and increased motion. However, an alarming number of early failures prompted the evaluation of patients treated with this system. A prospective study of patients who underwent arthroplasty with the ASR XL system was performed. Patients with 2-year follow-up or any revision were included. Failure rates, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and radiographs were evaluated. Ninety-five patients (105 hips) were included. There were 16 revisions. Thirteen (12%) were aseptic acetabular failures. Eight were revised for aseptic loosening; 4, for metallosis; 1, for malposition; 2, for infection; and 1, for periprosthetic fracture. Mean time to revision was 1.6 years (0.18-3.4 years). The ASR XL with a revision rate of 12% is the second reported 1 piece metal-on-metal system with a significant failure rate at early follow-up. This particular class of implants has inherent design flaws that lead to early failure.
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