This is a summary of the most important rules and articles of the Regulation This summary consists of rules applicable to class C, but could also be applicable to other classes of the Regulation.

Figure 33. System overview of the solution during the clinical validation in phase two.

x _{An insurer might be willing to provide financial support for a clinical validation study. However, this is not guaranteed.}

Figure 34. System work-flow in the super-system perspective during phase 2.

16.1.2 Clinical validations and test design

Clinical evidence of the effectiveness of the device can only be sourced through performance studies. These performance studies must be under the responsibility of a sponsor, which can be both the manufacturer as any other natural or legal entity ((62)). For class C devices, this validation process will be monitored by a NB on “an appropriate level of involvement” ((56)). As has been mentioned in Part I Chapter 4.3, the IVDR states that the clinical performance study should be in line with international guidance, like the standard ISO 14155:2011 (Appendix 11). Which allows the company to be (somewhat) free to determine the test design and the process of the validation. Therefore, for this case it is highly advised to toil specialist(s) and employ them in the development and trial studies of this solution. Such an expert panel will increase the chance of success of the validation study itself, as well as increase the convincing power of the company in regard to the Notified Body. As has been mentioned, the results from these performance studies must be published (Article 29 Paragraph 1), so that the intended user is capable in deciding whether or not to use the device, and the outcome must be updated frequently (Article 56 Paragraph 6).

Developing a clinical trial is the responsibility of the company and beyond my personal competencies and my role during this project. Therefore, I have to assume that the company is capable of either developing the test itself or finding someone capable and willing to do so. For illustrative purposes, I depicted the test design as a common A-B test design where one group is subjected to the device and the other is not. Which can be seen in figure 33. For the rest of this chapter, I will describe the capitals in familiar order and depict the necessary investments in each of the capitals.

16.2 KEY ACTIVITIES

A short description is provided detailing the key activities that the company must undertake to secure the survivability of the project as well as the company. These activities provide an overview of the main focus of this phase and what the company must do or a successful execution. In the following paragraphs, more detail is spent on the implications of these activities in light of each of the capital perspectives.

First, a subsidiary of the holding company must be established. Doing so, any risks concerning the clinical validation as well as the necessary financial transactions due to funding, can become the responsibility of the subsidiary. Therefore, making a clear division between the company involved in the clinical validation of the consumer product and the company that develops, constructs, and sells the consumer product. From legal and risk perspectives, this offers serious benefits. Second, to perform the clinical validation, new talent must be present possessing the necessary competencies. What has been mentioned before (e.g. ‘wrong proof’), it is very important to decide on the test methods, proposed outcome, conditions, and more before starting the actual validation trial. Especially, if the company’s desire is to capitalize on the medical application as then both the care professionals as well as the insurers should be on board. Additionally, the company will undergo structural changes, due to up- scaling of the development processes, and needs new employees to adjust for this growth. Third, in the case of clinical validation, most likely some sort of cooperation must be established with third parties:

(1) the care professionals performing the validation and monitoring the patients will have to know about the technology they are working with, and (2) the control party (NB) that will evaluate the process and the outcome will need information about the technology. As also in this phase, the intellectual property of the company is vital for its succession and existence, therefore correct protection measures should not be disregarded. It should not necessarily be assumed that the organizations cooperating on the validation studies will make use of the newly learned information, yet it must not be underestimated that these organizations are for-profit too. Fourth, a clinical validation performance study is extremely expensive74_{. From the test design, defining the method for testing, to analysing the results, and reporting}

on the outcome of the study, all components add significant costs to the entire project. Additionally, to perform such a clinical validation, additional people have to be employed: from medical staff to the data analysts that perform the statistical analyses. Luckily, the shear amount75 _{of subsidies and funds}

that can be addressed for performing a clinical trial is plentiful (Appendix 10). As long as the academic benefits as well as the value for the population are clear, it is possible to get access to multiple financial funds and support structures.

16.3 SOCIAL CAPITAL

The social capital perspective looks at the relevant stakeholders that should become involved in the development of the solution and what the relationship must be like.

16.3.1 Target group

Assuming the device is approved and has shown its conformity to the IVDR Regulation, then the intended target group can be divided into two segments. The first group is similar to the target groups of phase 1, as the interested or worried people are most likely interested in purchasing such a solution. As the device is capable of screening for CRC (with a certain sensitivity and specificity), these people might opt for such a device instead of the bi-annual national screening. Another group can be ‘created’ if a deal with insurance companies can be made. Such a deal would entail a discount on the insurance fee when the device is bought, or reimbursement of the system. The insurance company would have to be convinced of the fact that owning and using such a device will, in the long run, save healthcare expenditure of its users. More on this will be explained at the business model paragraph (Chapter 16). 16.3.2 Relevant stakeholders and their relations

In this phase, the number of stakeholders involved expand significantly. Two groups of stakeholders are discussed: (1) the stakeholders related to the validation and implementation process, and (2) the sponsor of the validation process. Later, the key partners necessary for the resources during this phase are discussed. First, the stakeholders involved in the validation process will be discussed. These stakeholders include the dominant stakeholders (Chapter 5), the EU, the MVWS, and the RIVM, as well as the definitive stakeholders, the specialists, the NZa, the IGJ, the ZiNL, and the NB. As their roles and influences on the validation and implementation have already been discussed, a look will only be taken at the dependency on the specialists when designing and executing the validation study, as well as attract resources, human capital, and funding. Specialist play the most predominant role in convincing other stakeholders. (1) When consulting GP’s, it is often mentioned that there are two organizations that can shape the opinion of a general practicioner76_{: the NHG, the scientific GP organization that develops}

the guidelines and advises on the newest technologies, and the specialist. The NHG itself also consults experts before approving any new technology and communicating this to all connected member GP’s. Therefore, from the GP perspective, the specialist is the stakeholder with the most influence in the acceptance of the technology. An example can be found in the situation regarding the initial start of CRC screening: in 2004, a questionnaire among GP’s from Amsterdam (response rate 32%) showed that only half of them were of the opinion that a national screening was necessary, while 92% of gastroentologist were in favour of the screening (Terhaar sive Droste et al., 2005; 2006). (2) From a

74 _{Factual numbers cannot be found. Emergo, (n.d.) depicts figures related to the costs regarding the regulatory approval (ranging} from less than $5.000 to more than $50.000) of medical devices for the European market. The clinical validation study or the QMS implementation is not included.

75 _{As has been said by numerous experts in business development. See Appendix 2.}