In the case of products that feature apps or other linked software, then that software must also prove compliance.

Figure 6. Hierarchy of the EC marking.

The Notified Body is the representative organization responsible for monitoring this process. The legal Manufacturer is the organization that is responsible for the design, manufacturing, and packaging of the product as well as selling the product, whether it fulfils those tasks or subcontracts them (Article 2 Paragraph 23); Obelis European Authorized Representative Center, 2011). The legal manufacturer is also the accountable party for EU compliance and possible damages done by the product due to malfunctioning or not achieving the desired performance. In the case where an organization is buying separate components and combines them to make a new product which is packaged and shipped to the EU, then that party is accountable for compliance and liabilities. After entering the market, a post- marketing surveillance system should be implemented as well to monitor their products (Cohen & Billingsley, 2011; Tarricone et al., 2017a)

4.3.4 Classification

Generally speaking, the higher the potential risk of the product, the more control will be applied to the product and development process. As can be imagined, a device that will be implanted into a person may pose more risk than a device that does not come in direct contact with a person or influences a vital health process, like surgical glasses for instance. To figure out how much control is needed, the classification rules must be followed to determine the class of the device. Important to notice, the ‘intended use’ of the device will be the defining characteristic in the classification process. The intended use means “the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements or as specified by the manufacturer in the performance evaluation” (Article 2 Paragraph 12). The intended use can include information on “(1) what is to be detected and/or measured; (2) its function such as screening, monitoring, diagnosis or aid to diagnosis, prognosis, prediction, companion diagnostic; (3)the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate; (4) whether it is automated or not; (5) whether it is qualitative, semi-quantitative or quantitative; (6) the type of specimen(s) required; (7) where applicable, the testing population; and (8) the intended user” (Annex II Article 1 Paragraph 1, under c). The intended for this device is dependent on its phase of implementation. In other words, the solution starts as a prototype and develops into a consumer product, which is later transformed into a medical device. More on this can be read in Part IV.

4.3.5 Clinical trials

“The purpose of clinical performance studies is to establish or confirm aspects of device performance which cannot be determined by analytical performance studies, literature and/or previous experience gained by routine diagnostic testing” (Annex XIII Article 2 Paragraph 1). These studies are measures to gather and source clinical evidence that can attest the performance of the device ((62)) as well as demonstrate its general safety. The gathered data shall be used in the evaluation process in which the NB

researches if the device demonstrates compliance. Clinical trials for in vitro diagnostics are significantly different from trials for other devices or pharmaceuticals, as the clinical benefit of an IVD is the ability to provide accurate medical information on patients usable for deciding on treatments and/or other diagnostic tests ((63)). The design of a clinical trial should be in line with international harmonised standards (specifically ISO 14155:2011, see also Appendix 11) It is the responsibility of the LM to specify and justify “the level of the clinical evidence necessary to demonstrate conformity with the relevant general safety (Article 57 and Annex I) and performance requirements. The performance of the device means “the ability of a device to achieve its intended purpose as claimed by the manufacturer”(Article 2 Paragraph 39) and can consist of (1) the diagnostic sensitivity and (2) diagnostic specificity, (3) positive and (4) negative predictive value, (5) the likelihood ratio, and/or (6) the expected values in normal and affected populations (Annex I Article 9 Paragraph 1, under b). The level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose” (Article 56 Paragraph1).

Clinical trials can best be described through their general process (Rodriguez, 2007; Genesis Research Services, 2018)). First, the process starts with an early research phase in which the type, protocol, and design of the clinical validation study is determined. This phase generally uses between 10 and 30 subjects and requires reasonable investments and effort. Second, a larger study is performed with 20 to 30 subjects, which are patients, that uses a (near-)final version of the device. The goal of this phase is to guide the study design of the pivotal study which will determine the efficiency and validity of the system. Third, the pivotal study must be performed which is a large study containing at least 100 subjects that must confirm the efficacy, safety, and risks concerning the device. Such a study is characterized by its dependence on statistics to confirm the claims of the LM. Last, the post market surveillance studies are included in the conformity process which monitor the long term effectiveness of the device on thousands of subjects.

The clinical trial should be sponsored according to the regulation ((71)). A sponsor can be both the manufacturer or another natural or legal person ((62)). The sponsor is also responsible for publishing the results of the clinical trial(s) in a way that is understandable for the intended user ((71); Article 68 Paragraph 3). During the process of clinical validation, the LM is also responsible for performing a systematic scientific literature review in which the device, its intended use, intended users, and more are investigated. The LM must also identify “unaddressed issues or gaps in the data” and, when necessary, generate new or additional data to address these issues (Annex XIII Article 1 Paragraph 2). This review shall contain relevant information on the scientific validity of other devices that measure the same biomarker, (peer-reviewed) literature, interviews and positions of experts and related associations, results from proof of concept studies, and available results from clinical performance studies (Annex XIII Article 12 Paragraph 2). When the device contains novel markers or markers of which no literature is available, the LM is allowed to employ different approaches that can demonstrate the scientific validity (Annex XIII Article 12 Paragraph 2). The benefits of performing such a clinical validation can be reduced to the argument of developing proof. Such a trial confirms the effectiveness and reliability of the system and allows the LM to sell the device on the market. Convincing stakeholders has become easier as proof can be shown that the system delivers what has been promised. Additionally, venture capital firms are more likely to fund start-up companies that have clinical data (pre-pilot data) and a clearly defined regulatory path (Huryn, 2013).

4.3.6 Quality Management system

A Quality Management System (QMS) is a system designed by the company itself or purchased from a retailer that is capable of collecting and processing all information related to the development of a medical device. E.g., to make the link with well-known product development systems: a QMS could be part of, or a combined system with, a PLM or ERP system. Additionally, the manufacturer must provide authorisation to the NB to execute yearly (on-site) audits regarding the functioning of the system (Annex IX Article 3 Paragraph 2 & 3). During such audits, the system will be tested for its performance, proper functioning, and if information is stored correctly. Therefore, the QMS should be updated frequently ((75)) Even more so, the NB is allowed to audit the manufacturer’s supplier(s) and subcontractor(s), if appropriate (Annex IX Article 3 Paragraph 3).

4.3.7 Post-market surveillance system (PMSS)

Post-market surveillance is the practice of monitoring the devices which are in use by “actively and systematically gathering, recording and analysing relevant data on the quality, performance and safety of a device throughout its entire lifetime, and to drawing the necessary conclusions and to determining, implementing and monitoring any preventive and corrective actions” (Article 78 Paragraph 2) in a manner that is proportionate to the device risk class. The overall goal of such a system is to ensure the safety of its users and guarantee its performance ((63)). Such a system should be part of the QMS and its data used be to improve the risk management and its mitigation strategies (Annex I), update design, manufacturing, and performance evaluation information, and, if possible, contribute to the post-market surveillance of other systems.

4.3.8 Traceability

Traceability is very important in the medical device industry, as can be deducted from both the QMS and PMSS. Even more so, in a situation in which the system harmed a user, the manufacturer is required to deliver all information regarding the system within reasonable time (within 2, 10, or 15 days, Article 82). In the theoretical case that a supplier has delivered a faulty product, then the manufacturer should be able to explain to the NB where the wrongdoing has occurred, which processes where used, which employees were connected to the process and above-all, whose fault it actually was. It is in the best interest of the manufacturer to pinpoint in any case who is responsible, as a supplier can also be sued for damages based on liability. To improve the traceability across Europe, a database will be26 _{established containing unique codes of all medical devices; the Unique Device Identification}

system (UDI system) ((38)). Additionally, another database will be created that should be able to integrate different electronic systems that collect information about the conformity and post-market surveillance processes; the European database on medical devices (Eudamed) ((41)). Even more so, the legal manufacturer also needs to register as a company to the CIBG27 _{when it places an IVD on the Dutch}

market for the first time, regardless of geographical location of its headquarters.

26 _{Bear in mind that this Regulation will become active in 2022.}