The New EU Regulation on In Vitro Diagnostic Medical Devices: Implications and Preparatory Actions for Diagnostic Laboratories

Abstract

On May 26, 2022, after a transitional period of 5 years, the new Regulation (EU) 2017/746 on in vitro diagnostic medical devices1 (IVDR; Table 1) will fully replace Directive 98/79/EC on in vitro diagnostic medical devices2 (IVDD). The aim of the IVDR is to further establish a well-regulated and smoothly functioning market for in vitro diagnostic medical devices (IVDs; Box 1) within the European Union (EU) that is better aligned with international guidelines. Moreover, following vast technical and medical developments during the previous 2 decades—for example, in the area of genetic testing and companion diagnostics—it was deemed critical to secure protection of safety and health by setting high standards for safety and performance of IVDs.Box 1. Definition of in vitro diagnostic medical device (IVDR Article 2(2)).1 “‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following: (a) concerning a physiological or pathological process or state; (b) concerning congenital physical or mental impairments; (c) concerning the predisposition to a medical condition or a disease; (d) to determine the safety and compatibility with potential recipients; (e) to predict treatment response or reactions; (f) to define or monitoring therapeutic measures. Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices.”Table 1.: Structure of the IVDR and Recommended Reading for Diagnostic LaboratoriesBoth the IVDD and IVDR dictate that, depending on their intended use/purpose (and associated risk), IVDs either have to be assessed and certified by an independent third party (a notified body) or can be self-certified by their manufacturer. After certification, manufacturers are allowed to label products with the “Conformité Européenne” (CE) mark, which is required to distribute and sell “CE-IVD” products on the EU market. Even though both legislations share the general concept of IVD certification and CE marking, a much wider range of IVDs will have to be certified by notified bodies and more (clinical) performance data and documentation will be required to legitimately commercialize IVDs under the IVDR. However, the replacement of the IVDD by the IVDR will not only have major consequences for manufacturers of IVDs but also for all diagnostic laboratories. This report aims to help diagnostic laboratories understand the scope of the IVDR and its consequences for commercially available CE-IVDs and, even more importantly, for in-house devices (IH-IVDs). Although many aspects of the IVDR still have to be clarified, laboratories are urged to take a number of actions to prepare for this new regulation. Action 1: Appoint a dedicated team and stay informed It is worthwhile to appoint a small dedicated team with the responsibility for regulatory compliance with the IVDR as early as possible. Looking into the relevant articles and annexes of the IVDR (see Table 1 for recommended reading) is strongly advised for those working in diagnostic laboratories and involved in regulatory compliance. Regularly consulting other information sources, such as guidance documents, publications and white papers, as well as participation in (inter)national conferences and information/consultation sessions on the subject, will help to stay informed about the implementation of the IVDR and the consequences and requirements for laboratories. The IVDR will affect assay portfolios of diagnostic laboratories The IVDR primarily regulates CE-IVDs, but also addresses IH-IVDs that are manufactured and used by health institutions (referring to reagents, control materials, software, etc; see also Box 1). The requirements of the IVDR do explicitly not apply to the latter devices—with the exception of the relevant general safety and performance requirements (GSPR) in Annex I—as long as a number of conditions are met (see section “The IVDR dictates requirements for use of IH-IVDs” for details). Since the IVDR has major consequences for both categories of IVDs, an understanding of what the IVDR means for the availability and use of CE-IVDs and IH-IVDs is crucial for diagnostic laboratories. More demanding requirements for manufacturers will affect the availability of CE-IVD tests The IVDR requires that all existing and new IVDs are (re)classified on the basis of a risk-based classification system. The class of an IVD depends on its intended purpose and the level of associated risks to patients and the public. Table 2 lists the different classes described in the IVDR (see also IVDR Annex VIII). The highest risk class, class D, includes tests for infectious/transmissible agents that cause life-threatening diseases (eg, HIV, hepatitis B, and SARS-CoV-2) and the most critical blood grouping tests. Many other tests used in the hematology/hemato-oncology field, such as cancer tests and genetic tests, fall within class C.Table 2.: IVD Classes Under the IVDRThe IVD class determines the exact requirements and assessment route for a given IVD, as well as the depth of documentation required to demonstrate that all requirements have been fulfilled. Non-sterile class A devices can be self-certified by the manufacturer after reaching compliance with the IVDR. All other devices need to undergo conformity assessment by a notified body. In addition, expert panels and EU reference laboratories are also involved in the assessment procedure of class D devices. Following certification, manufacturers are required to update documentation whenever relevant, with a minimum of once per year for class C and D devices. Importantly, a direct result of the new classification rules is that many products that are currently self-certified according to the IVDD will have to be certified by a notified body under the IVDR. The percentage of IVDs that requires notified body certification is estimated to increase from 15% (or even less) under the IVDD to 70%–90% under the IVDR.3 Moreover, the requirements for clinical evidence (with a major emphasis on clinical performance; Table 3) and post-market surveillance (systematic evaluation of experience with IVDs as a basis for necessary corrective and preventive action) will become more stringent under the IVDR.4Table 3.: Specification of Clinical Evidence Requirements According to the IVDRFor IVD manufacturers, these changes translate to a need for additional well-trained staff, increased time investment and higher costs. In addition, the fact that many IVDs cannot be self-certified anymore means a huge workload for notified bodies. As only 4 notified bodies have been designated for the IVDR so far,5 the total notified body capacity might not be sufficient to assess all IVDs by May 2022. Finally, other vital infrastructure (eg, EU reference laboratories) and official guidance documents are still lacking. This means that companies might fail to engage with a notified body on time or might otherwise come to a halt in the conformity assessment process, and as a result do not manage to have all their IVDs certified before full application of the IVDR. This makes clear that, even though the overall quality of CE-IVDs is expected to increase under the IVDR (consistent with its objectives), it is likely that there will be consequences for the availability of CE-IVDs. Manufacturers might need to prioritize, for example, their most important and profitable products will be submitted for CE marking, while other products might be temporarily unavailable or even discontinued. Use of IH-IVDs will be restricted under the IVDR IH-IVDs are described in the IVDR as in vitro diagnostic medical devices (IVDs; see Box 1)1 that are manufactured and used by a health institution. They are often referred to as laboratory-developed tests (LDTs), but it must be stated that the term “LDT” is not used in the IVDR. Importantly, the IVDR sets out the (quality) requirements for IVDs, but not for the complete diagnostic testing process chain as covered by ISO 15189 (Figure 1). For example, protocols for medical laboratory examinations are not themselves considered to be medical devices in the of the Moreover, the scope of the term and to what it CE-IVDs and use only to be in the of the “LDT” can be as a term to to 1.: the ISO 15189 and the IVDR. the important ISO 15189 and the in equipment, and other in vitro diagnostic medical ISO 15189 is an important basis for compliance to the IVDR for diagnostic laboratories. the ISO 15189 a much range of quality including and IVDR Regulation (EU) 2017/746 on in vitro diagnostic medical on the diagnostic and level of of a IH-IVDs can a of its assay laboratories and in the that in 1 in 4 of the tests are IH-IVDs (Figure clinical and general laboratories use CE-IVDs, such as and medical are expected to use IH-IVDs much more 2.: Use of IH-IVDs by and laboratories in the the share of institutions that use in-house devices or not 2 of laboratories have IH-IVDs and in 1 of 4 laboratories more of the IVDs are IH-IVDs The was on data from the for and the CE-IVDs CE in vitro diagnostic medical IH-IVDs in-house in vitro diagnostic medical is with a that diagnostic tests that of tests in the laboratories CE-IVDs, CE-IVDs, and tests. The latter categories often used in the and Finally, data the of the European a with laboratories that on of the tests in these laboratories are to be more and CE-IVDs are not available (eg, the that for of 4 CE-IVD is currently available on the It can be that IH-IVDs are used and for in many diagnostic The IVDD not tests that are and used within health laboratories in a In the IH-IVDs are in with and the used by the rules and can from one to In to the the IVDR conditions and requirements for IH-IVDs that need to be by and the IVDR use to for which CE-IVD is available (see for a more of the conditions and requirements for Even though the exact of the requirements for IH-IVDs to be this means that use of IH-IVDs will be more restricted under the IVDR. Action an assay As described the IVDR will affect the availability of CE-IVDs as well as a and to their assay under the an for diagnostic laboratories is to an assay (Figure This can be according to the following 3.: and IVDR compliance The assay laboratories to their assay under the IVDR on the tests that are currently are whether CE-IVD tests will be CE under the IVDR the intended and whether for in-house devices are available (see also the on IVDR for all IH-IVDs that are used after May 2022, the conditions and requirements for IH-IVDs as by the IVDR be fulfilled. The most important requirements are and are in more in the Finally, of the requirements be in the technical documentation and stated in the of CE-IVDs CE in vitro diagnostic medical IH-IVDs in-house in vitro diagnostic medical IVDR Regulation (EU) 2017/746 on in vitro diagnostic medical devices. CE-IVDs and IH-IVDs are currently be that CE-IVDs be used in with their intended purpose and for it is not clear to what will be all CE-IVDs stay on the that will the manufacturers CE the tests under the IVDR on For most CE-IVDs, this means that will have to be certified by a notified body by May 2022. Even though might be notified in time in the of of CE-IVDs, laboratories are advised to manufacturers or in the of In this it is also relevant to that all IVDD CE-IVDs on the market before the of for example, a can still be May and that CE-IVDs with a IVDD by a notified body can be May that this only see IVDR new IH-IVDs be to replace CE-IVDs that will be CE-IVDs available that are to currently used will these be certified according to the such CE-IVDs have an level of the IH-IVDs cannot be used anymore after May 2022. it will be to these for CE-IVD tests, for it might be necessary to an informed on available information and to a manufacturer can more For information on CE-IVDs might only become available a many manufacturers have certified their tests under the IVDR and the European on has been will be to information about all of their medical devices that are available in the EU to this In addition, a more of the IVDR requirements for IH-IVDs is to the for whether or not to their IH-IVDs under the diagnostic laboratories are advised to assess whether the use of IH-IVDs can be (see on IVDR on currently available not to risk in diagnostic the of application of the IVDR. This that to regulatory compliance with the IVDR and their assay after the period The IVDR dictates requirements for use of IH-IVDs As described in and the IVDR also to the highest level of health protection by and the rules that in-house devices. However, not all the requirements for CE-IVDs need to be for IH-IVDs only the in Annex as according to the aims of the IVDR still be met in a Importantly, this for EU health institutions with the purpose to for or or to the for example, and health for IH-IVDs only in a number of conditions are This that from the of application of the IVDR all diagnostic laboratories in the EU that IH-IVDs for diagnostic are to be in compliance with the health of the IVDR. The conditions and requirements to IH-IVDs are for health institutions that use IH-IVDs A number of conditions that apply to laboratories that use of IH-IVDs are in Article of the IVDR for health institutions that use IH-IVDs (IVDR Article the exception of the relevant general safety and performance requirements out in Annex the requirements of this Regulation shall not apply to devices manufactured and used only within health institutions in the that all of the following conditions are (a) the devices are not to (b) and use of the devices under quality (c) the laboratory of the health is with ISO 15189 or including (d) the health in its documentation that the cannot be or cannot be met the level of performance by an device available on the (e) the health information on the use of such devices to its which shall a of their and (f) the health a which it shall the and of the health the necessary to the a that the devices the general safety and performance requirements out in Annex to this Regulation and, information on which requirements are not fully met with a as class D devices in with the rules out in Annex the health documentation that makes it to have an understanding of the the process, the and performance data of the including the intended and that is to the to that the general safety and performance requirements out in Annex to this Regulation are apply this also to class B, or C devices in with the rules out in Annex the health all necessary to that all devices are manufactured in with the documentation referred to in and the health experience from clinical use of the devices and all necessary corrective that such health institutions to the any further relevant information about such devices which have been manufactured and used on their shall the to the and use of any of such devices and shall be to the of the health This shall not apply to devices that are manufactured on an of devices It is not allowed to distribute devices such as and control to other of for quality assessment are an exception to this (see IVDR It is also allowed to distribute documents such as as these are not devices. Moreover, there is on testing from reference can for example, that are not to the in as long as this is not on an (see Article 15189 Diagnostic laboratories IH-IVDs are required to with the ISO 15189 which requirements for quality and in medical or with required by is not but it is to be that are a basis for a A that is under ISO 15189 is for and use of It will be important to determine the to with ISO 15189 and the IVDR requirements in Annex in as there is (a has been by the Article of use Under the use of CE-IVDs is the CE-IVD is or a cannot be met the level of performance by an use of an IH-IVDs is allowed (Figure This that IH-IVDs can be used that their use the safety and health of A the and use of IH-IVDs be available for by the which is in of the IVDR and the of the of the use of in CE-IVDs are is one of the most that still requires as will on what is by and by cannot be met the level of A better performance a better clinical performance (eg, higher or higher and time this is to be (see also The European of Clinical and has a to the of the need for IH-IVDs in a and of clinical according to a Definition of the and of the clinical including a of the of use is a responsibility of laboratories that have so need to and new CE-IVDs for the of the of the from CE-IVDs and IH-IVDs will be worthwhile in this However, what is expected from laboratories in of CE-IVD of and of implementation in an CE-IVD available to be on this laboratories will need to a to the requirements to CE-IVD to define and often to for such Importantly, clinical evidence by manufacturers will be for and an assay Article A available the and of the health and that of the In addition, the that the IH-IVDs the of Annex or a requirements are not fully requirements of Annex for example, of information on the and performance of the device and setting a risk (see Article requirements for class D devices For class D tests, the requirements are for tests in class according to the classification rules as to In additional information on and performance of the IH-IVDs is This means that the for class D tests be met and with an of that more that of CE-IVDs, that according to the requirements for technical documentation in Annex institutions are required to that all IH-IVDs are manufactured in with their Article of use from clinical use be and corrective be A for evaluation of use of IH-IVDs can be on relevant of Article and Annex post-market surveillance for Article requirements The for health institutions not apply to devices that are manufactured on an that to be Finally, the be to health institutions to their They can to that the health institutions any additional relevant as well as the and use of any of safety and performance requirements for IH-IVDs In to the conditions described the relevant in Annex of the IVDR need to be met for important requirements risk and performance A risk to be for all IVDs (see Annex is a of ISO 15189 that to the evaluation and of risks that might affect so ISO 15189 compliance a risk However, there are compliance with the IVDR for example, much is on of the ISO 15189 and often the risk be For more guidance on this it is advised to into ISO of risk to medical or ISO of risk to medical ISO or ISO compliance is not an IVDR evaluation and clinical performance 3) of all IVDs be A of what the requirements for manufacturers are for these of clinical evidence can be in Article and Annex but guidance from the European on performance evaluation for CE-IVDs or IH-IVDs is not institutions can a by into the medical devices 4 on clinical In addition, a new for concerning of clinical performance to assess IVDs for regulatory has been which has been with the IVDR In vitro diagnostic medical performance from human of documentation for IH-IVDs might be can be in a guidance on the health of the of the can the regulatory for IH-IVDs The is that IH-IVDs are and used by a health but by (inter)national of health This is for the in of diagnostic laboratories. can share of the required by the IVDR to regulatory compliance for For example, performance data are often in and it is to of the required documentation and to use their can even for from might also medical or other their for by papers, and guidance Action regulatory compliance for IH-IVDs a assay under the IVDR is the is to the the information that is and the information that will be required to with IVDR Article and Annex (GSPR) for all on these the required to the information and data can be (Figure In to or compliance with ISO 15189 (and of on the for example, and or risk of performance data and documentation can be a major of clinical performance data can be a process, so a for this be a exact on to the requirements for and to the are still lacking. As clinical evidence and evaluation of surveillance are critical requirements for IH-IVDs as well as for CE-IVDs, the requirements for manufacturers can an of what might be expected for it will be to guidance documents that are for manufacturers of CE-IVDs on these and other and to the manufacturers with the requirements of the IVDR. However, the of health it might not be (or to compliance to the as is required for CE-IVDs. an official guidance on for in-house devices is expected to the conditions and requirements for but of this has only been by the European of IVDR The IVDR into in May into EU are and by in all EU On of the of the that has been available many additional in for manufacturers, notified health institutions and other to understand in more the requirements for be are by the European in the of guidance The of of the European and all EU the European with the implementation of the IVDR and the (EU) on medical of the of the is to that guidance documents for the IVDR and For guidance a is that principally of from a number of However, relevant, as of manufacturers, notified bodies or medical are a to on the A number of medical is by the which is as a relevant by the European The of full application of the IVDR is Many guidance documents are still such as the documents on evaluation and on for in-house the latter one relevant for diagnostic laboratories. In the many independent (inter)national IVDR working and have been to on of the IVDR to their or the European and to their about the of IH-IVDs can the regulatory for laboratories. the such have the potential to quality and of health institutions will be by the for all of its They need to to under an to the use of to the documentation that has been and to a The IVDR has major for diagnostic laboratories and the CE-IVDs IH-IVDs in their assay This report that, the and laboratories can to prepare for the of full application of the IVDR 26, Appoint a small dedicated team for regulatory compliance and stay informed about the IVDR an assay to their assay under the IVDR. IVDR compliance a on the intended for their can be a of of laboratories. of and implementation of IH-IVDs that laboratory However, whether it or any other it is important to that of the IVDR is the responsibility of EU of the of are this As a the exact of the might This an need for of and of the health so that to and share information and to IH-IVDs are not It can be for diagnostic laboratories to establish a with their to about their of the IVDR and their as well as to any and the of the laboratories have to to EU for the for laboratories that use many different the workload to the IVDR requirements can be guidance on in-house devices is critical for for the as in this guidance documents on this and on other are still The of these documents is an process by the European Box However, the European has available for implementation of the IVDR and the new on medical Box have so been to the even more so of the and the of the of application of the from May to May of the with the IVDR implementation and the of the diagnostic health (eg, the and the as well as other IVDR have about the of the IVDR However, to the application of the IVDR (or to the IVDR has been by the European and of a is an will only become clear while the is In the of complete regulatory to the and do what This will out to be a or but that not be a as long as are and documentation is according to new information and also be in that laboratories are on their tests and what to quality and what laboratories are advised to to IH-IVDs that are used most are associated with the highest in with the risk-based that will by the Finally, implementation of the that of the and given that the is on the as the it is also to from the implementation In it will be to see the requirements are what to the availability of CE medical devices the of the and the with the for in-house devices. In the IVDR will about a for diagnostic laboratories. Even though the exact requirements of the IVDR are not in it is advised to to regulatory compliance in a and to take new information it for participation in from and and from and is of from for reference from and and from from on and which are to and to the and to be of the which from which are by the of the In addition, an with and a with with for The other have of to

Topics & Concepts