“Using the current directives while preparing for the new medical device regulation and IVD regulation”
Modern medicine strongly depends on the use of medical devices for purposes of both care and cure. Medical devices have become a vital part of modern healthcare and practically no diagnosis or treatment is possible without them. Types of medical devices range from large capital hospital fixed equipment, through high-technology implants, surgical and monitoring equipment, to more familiar products such as wheelchairs, sticking plasters, syringes, incontinence aids, and spectacles.
In the medical device industry, the success of a novel medical device launch can often determine the positioning of the company for the coming years. Having a great product is essential and a good starting point, but is not enough to ensure it succeeds in the market. One of the most important determinants is obtaining a so-called CE mark before the device can circulate on the single European market. According to the European directives, a CE-mark (‘Conformité Européenne’, i.e. European Conformity) is mandatory for medical devices placed on the European Union single market. The CE-mark indicates product’s compliance with EU legislation and thus, implicates that these devices meet EU safety, health, and environmental protection requirements. By bearing a CE-mark, the medical device is considered as a product with sufficiently proven performance and safety for application in clinical practice and enables free marketability in the European Economic Area. Thereby the manufacturer declares, on his sole responsibility, conformity with all of the legal requirements to achieve CE-marking.
Throughout this article the manufacturer will appear and the definition is as follows: ‘manufacturer’ means the natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.
The requirements to obtain a CE-mark vary among the different types of medical devices and may result in a significant expense with respect to certification (resulting in costs of thousands up to million Euros) and long process (varying between a couple of months and several years). Preparation in an early development process is, therefore, essential to deal efficiently with this burden and warrant making the right legal choices; this last point will prevent costly changes in the design of the device in the latest stage of the development process (to minimise the risk of non-compliance with the requirements of Notified Bodies (NB) and thus to minimise costs and time).
Currently, medical device and in vitro diagnostic developers need to demonstrate that their medical device meets the requirements of respectively Directive 93/24/EEC and Directive 98/79/EC (in this article the active implantable medical devices are out of scope) . These Directives describe the approaches that have to be followed in order to obtain CE marking. However, the regulatory landscape is about to change significantly. In 2020, Europe’s Medical Device Regulation (MDR) and in 2022 In Vitro Diagnostic Regulation (IVDR) will come fully into force, which will impact all medical device and in vitro medical device developers, respectively. Even though the final version has not been approved yet (expected May 2017), it is clear that Europe’s new MDR and IVDR will bring substantial changes to the way medical device manufacturers bring their devices to the European market, and how they maintain compliance throughout the product’s lifecycle.
Figure 1. Transition period new MDR and IVDR.
This article will not deal with the changes that will take place but will explain the ins and outs of the current legislation. The reason for this is that during the transition period (Figure 1), which is between the publication date of the MDR and IVDR and May 2020 (MDR) and May 2022 (IVDR), it is still possible to CE-mark devices according to the current legislation, i.e. the Medical Device (93/24/EEC) and In Vitro Diagnostic Directives (98/79/EC). Especially for start-ups it could be strategically beneficial to CE-mark their products according to the current legislation and make the switch to the future legislation at a later stage. In this way, the increased regulatory burden that is imposed by the MDR will be spread over several years and also time to market could be shortened. Also, manufacturers that have products on the market and want to expand their product portfolio could take advantage of this approach; for example, the In Vitro Diagnostic industry will be faced with major changes and it could be advantageous to continue using the IVDD and wait until the dust has settled. Because the CE-marking process is often regarded as a confusing, costly and complex procedure which takes up a lot of a company’s precious time, this article will discuss the most important steps and will provide more clarity and an overview in the complex matter of CE-marking.
Figure 2 represents the steps in chronological order on how to develop and CE-mark your product. These steps include (1) identifying the directive(s) applicable to the device by identifying the type of your device, as there are different directives for each different type of device; (2) verifying the device-specific requirements and (harmonised) standards, as each type of medical device is further specified within classes or lists; (3) identifying if an independent conformity assessment from a notified body is required, as for some medical devices the involvement of a notified body is required (see 1.3); (4), further designing and developing the medical device and checking its conformity since each design of a device has to be carefully verified and validated according to the EU directives; (5) drawing up and keeping required technical documentation available, which has to be presented on request to the appropriate national authorities or sent to a notified body for review; (6) affixing of the CE-mark to the device and generating a declaration of conformity, as the CE-mark must be affixed accordingly, visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.
Figure 2. Steps to undertake in order to obtain a CE-mark.
First, the appropriate directives, standards, and requirements must be identified since the requirements to obtain a CE-mark vary amongst the different types of medical devices. To determine the appropriate directives, one must first determine the appropriate type of medical device. Medical devices are divided into three categories; medical devices (MD), in vitro diagnostic devices (IVDs) and active implantable medical devices (AIMDs) each with their own EU directive (93/42/EC, 98/79/EC and 90/385/EC respectively).
Medical devices; 93/42/EC. According to 93/42/EC, a ‘medical device’ means any instrument, apparatus, appliance, software, material or another article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.
IVD; 98/79/EC. According to 98/79/EC, an ‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment 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:
Specimen receptacles are considered to be in vitro diagnostic medical devices. ‘Specimen receptacles’ are those devices, whether vacuum-type or not, specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination. Products for general laboratory use are not in vitro diagnostic medical devices unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination.
AIMD; 90/385/EC. This category of devices fall outside the scope of this article and will not be further dealt with. However, it is important to determine if the device can be defined as an AIMD or not.
After the right category of device has been selected, the appropriate device-specific requirements have to be determined. The medical device categories are further subdivided into classes or lists for each medical device directive. The applicable class or list for both MDs and IVDs has to be determined in order to verify which tests are required to obtain a CE-mark.
The MDs are classified in either Class I (including Is & Im), Class II (IIa or IIb) or Class III that covers the highest risk devices. The classification rules are set out in Annex IX of the directive 93/42/EC. These rules include:
how long the device is intended to be in continuous use,
whether or not the device is invasive or surgically invasive,
whether the device is implantable or active,
whether or not the device contains a substance, which in its own right is considered to be a medicinal substance and has action ancillary to that of the device.
The IVDs are categorised in either self-testing, list A, List B or other/general devices. To verify the category of the medical device, the flowchart presented in Figure 3 can be used.
Figure 3. Flowchart for verifying the classification of IVDs.
In order to generate evidence for conformity of the medical device to the applicable directive and specific requirements for each class of devices, multiple verifications, and validation studies must be executed and documented. Although the directives do not prescribe a specific methodology on how to perform these studies and leave the choice to the manufacturer, it is best to follow widely accepted methodologies described in standards (that can, for example, be obtained via the European Commission). For example, if a medical device is a sterile product, then the sterilisation process must be validated and for different sterilisation processes specific standards do exist; they are most often published by the well-known ISO organisation. In case a standard has been adopted by either CEN or Cenelec (Commission of the European Union) they are considered to be harmonised. The advantage of such a harmonised standard is that when a medical device (i.e. its design and the required manufacturing and packaging processes) is in conformity with a harmonised standard, the compliance with the essential requirement is presumed.
After identification of the type of device and its class or list, the manufacturer should determine the involvement of a notified body (NB) as a third step in the procedure. For low-risk medical devices the involvement of a NB is not required, as explained in the next paragraph.
A notified body is an organisation which is accredited by a competent body to verify whether a medical device meets the essential requirement of the applicable directive and eventually provides a CE-certificate. Each member state of the European Union specifies its own competent body (-ies) to enact the directive within its territory. Each competent body selects its own NBs in each state, where the competent body controls the NBs. These NBs are registered at the EU New Approach Notified and Designated Organisations (Nando) information system. Today, around sixty NBs are present in the European Union.
To obtain a CE-certificate that allows the manufacturer to CE-mark the device, the manufacturer must apply at a NB for many types of medical devices. As observed in Table 1, this is mandatory for MDs class IS, IM, IIa, IIb and III, IVD list A, B and self-tests, which are all part of the high-risk IVDs. The manufacturer can, however, apply to any NB in the EU that is capable of carrying out the desired procedure, regardless of which Member State that NB is established in.
Part of the activities of the NB is to assess the quality management system of the manufacturer by performing an audit. Besides NBs, also so-called registrars can perform this activity and even issue a certificate of compliance to the applicable standard, i.e. the ISO13485 standard. Although it is allowed to use a registrar for this, the disadvantage is that the registrar cannot issue a CE-certificate that is required for CE-marking. Also, the registrar charges additional prices and, therefore, it is recommended to use a registrar for assessment of the quality management system.
Table 1. Conformity routes of medical devices and in vitro diagnostic devices.
The selection of a NB should be a performed with utmost attention. Quality and costs amongst different NBs can differ and in addition, it should be taken into consideration that not all NBs can assess all categories of medical devices and in vitro diagnostics. The following aspects could enhance the proper NB selection:
For the conformity assessment, different routes can be chosen from. In most of the cases, the Annex II route is chosen because this allows the manufacturer a greater freedom to operate. The differences between the routes are mostly determined by the level at which the NB is involved in the assessment of the device’s design and the way it is secured that produced devices are appropriately controlled.
For certain medical devices (MDs class I and low-risk IVDs) the CE-certification by a notified body is not mandatory. The manufacturer can continue the following steps independently, ending in a self-certification that will be described later on in this article.
The design and development process of a medical device is one of the most important steps, because it will render to documented evidence by which the safety and performance of the device is guaranteed. Especially for devices where the involvement of a NB is required and that are at higher risk, it advisable to start with a regulatory strategy before finalising the design and development of your device. The requirements for CE-certification by a notified body and an overview of these steps to meet the requirements can be preliminarily reviewed by the notified body. After agreeing on this strategy by both partners, the manufacturer and the notified body, agree on this strategy, including the category and classification of the medical device, the manufacturer can finalise the design and development of its device. Discussing this strategy before finalising the design and development of the device will notably shorten the duration of the official CE procedure since it will prevent non-compliance with the NB requirements.
In addition, compliance with quality management system requirements described in the ISO13485 standard ensures the manufacturer’s ability to meet customer and regulatory requirements. This will not only facilitate the CE-certification process but also provide added value for the reputation of your company.
Besides a structured and standardised approach for the design and development process, including proper design inputs and application of risk management, also the verification testing to be performed is essential. Because of the variety of medical devices, including in vitro diagnostics, is enormous, it is impossible to go into detail into this topic here. In general, ample attention should be given to topics such as sterility, biocompatibility, electrical safety, electromagnetic compatibility and usability (of course only if they are relevant to the medical device in development). Each and every verification test must be documented, meaning that pre-approved protocols and reviewed and approved reports should be generated. Verification testing is also sometimes referred to as bench testing and can be done in the facilities of the manufacturer or outsourced to third parties. In the latter situation, the manufacturer should keep in mind in the case of outsourcing the final responsibility remains with the manufacturer.
The testing of the medical device (or the in vitro diagnostic) by the user in the actual situation where the device will be used is named design validation or clinical validation. It is required to obtain clinical evidence based on actual data to demonstrate compliance with the essential requirements described in the applicable directive. Guidance on how to obtain clinical evidence can be found in the guidance documents Meddev 2.7/4 and Meddev 2.7.1. The collection of clinical data can be completed by execution of a clinical investigation unless it is duly justified to rely on existing data. Naturally, such justification will have to be based on a proper clinical evaluation. In general, the higher the risk class of a medical device, the higher the chance is that clinical investigations with the device should be executed. By comparison with suitable comparators, additional clinical investigations may be feasible to support the existing clinical evidence. The provided clinical data, for all types and/or classes of medical devices, must consist of:
Safety and performance can often be demonstrated by other means. However, for IVDs in list 2 and MDs class III, in particular, data must be generated to:
Thus, a clinical investigation on a non-CE-marked device must be designed to prove that the performance claimed by the manufacturer can be demonstrated and that the device is judged to be safe to use on patients. A clinical investigation on a non-CE-marked device must at least be considered when:
Alternatively (in particular for line extensions to products or for products already on the market outside the EU), clinical data may include a complaints analysis in combination with a literature compilation with an expert summary, post-market surveillance data, and so on and this might be sufficient. Clinical evaluation is based on the assessment of the risks and the benefits, associated with the use of the device, through either:
After these steps, the technical file can be created which includes general aspects of the device, device description, essential principles and evidence of conformity, risk management, summary of design verification/validation, manufacturer information for process and accessories, and labeling. The summary of design verification/validation includes the required evidence which differs for each type of medical device.
Depending on the strategy chosen, the technical file can contain more or less of the original verification and validation documents. If the original document is not included, then providing a summary and making reference is acceptable. A reason to keep the technical file lean and mean is that will be easier to maintain throughout the lifecycle of the medical device. On the other hand, reviewers could always ask for the original documentation, which could result in a slower review process.
The technical file is handed over to the NB for review In addition to this review, the NB will also audit the manufacturer on site in order to assess the quality management system and the processes for manufacturing and packaging. Also, on-site audits for critical subcontractors are often part of the review.
After completion of technical file, the manufacturer should generate a Declaration of Conformity (DoC). In case the medical device classification required the involvement of a notified body, there is the logical prerequisite that the review and approval process by the NB should have been successful and a CE-certificate issued. With the DoC generated, the manufacturer then affixes the CE-mark. As mentioned in the beginning of this article, the CE-mark must be affixed visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.
Once the device is correctly CE-marked it does not need the additional approval to be marketed in the EU, EEA or Switzerland as the CE-marks represents free movements in these states. However, these states can request the manufacturer to register the device and can require device information in the respective language. Thus, in case if the device will be marketed in a state other than registered the national authorities should be contacted.
One final note should be made for those medical devices for which there is no NB involvement; these devices need to be registered at Eudamed, the European databank for medical devices. Eudamed is a secure web-based portal acting as a central repository for information exchange between national Competent Authorities and the Commission in accordance with the Medical Devices Directives. The information in it is not publically available. It also contains data on devices where a NB was involved and the information is entered by the NB self.
Within this article, the complex CE-marking process is simplified by providing a comprehensive 6-steps route towards obtaining a CE-mark. Even though the current legislation will be replaced, it could be a strategic choice to continue to comply with the Directives during the transition period and switch over to the Regulations at a later stage. Essential steps, such as verifying the applicable directives by defining the appropriate class/list of your device, should be addressed before finalizing the design and development of your device. It should be noted that discussions with a notified body (if relevant) is of utmost importance before undertaking this finalization step. Neglecting advice from NBs can result in unnecessary (high) costs and time. After finalizing the design and development, collecting clinical data regarding the safety and performance of your device is a crucial next step in convincing NBs. However, it should be noted that the CE-marking process is a rigorous complex procedure that should be implemented in an early development stage and often warrants additional advice from experienced consultants, such as provided by Xendo. In addition, the CE-marking process is expected to get more complicated with the new Regulations that will come into force in May 2020. A comprehensive overview of this process will be published mid-2017 by ttopstart and Xendo.
|Contact ttopstart if you need assistance with financing crucial development steps, such as to cover the costs of the regulatory approval procedure, of your medical device (e.g. finding relevant subsidies and applying for them).||
|Contact Xendo if you need assistance with the regulatory approval procedure. This includes defining the appropriate strategy and planning for your device and setting up the required quality management system.|
|Michelle van Wijk - Consultant||Marc Klinkhamer - Principal Consultant|
|ttopstart is a science and business consulting company that serves leading researchers and innovative companies in the fields of life sciences, medical technology and health. ttopstart is specialised in the markets life sciences, medical technology and healthcare. ttopstart empowers biomedical innovators by supporting them with convincing VCs, subsidy providers, strategic partners and other stakeholders around the world to invest in their product. We want to enable their success in tackling the challenges associated with disruptive healthcare innovations, for the benefit of patients.|