3.1 Current regulations

The core EU regulatory framework related to safety and performance of implantable medical devices (IMDs) consists of two directives [18]:

• Council Directive 90/385/EEC on Active Implantable Medical Devices (AIMDD)(1990)
• Council Directive 93/42/EEC on Medical Devices (MDD)(1993)

The aim of the Directives is to ensure protection of human health and safety at a high level [18]). Medical devices are under the MDD classified into the classes I, IIa, IIb, and III according to risk profile. Dependent on the degree of risk, there are variations in the stringency of assessment (Table 1). IMDs, as elaborated on in this study, belong to class III devices with the highest risk.

Table 1: European Union Classification of Medical Devices.

3.2 Clinical evidence and conformity assessment process for medical devices in the EU

"The Notified Body plays a key role in the assessment and verification of clinical evaluations provided by medical device manufacturers to support demonstration of conformity of a device with the essential requirements of the relevant Directive"[19].

The conformity assessment process (CAP) for class III devices demonstrates that a device complies with the requirements of Directive 93/42/EEC. The classification of a device dictates the appropriate CAP and conformity route [20]. In either case, manufacturers need to provide clinical evidence for the safety and performance of a device to be granted conformity approval by a Notified Body. These shreds of evidence may include data generated through literature search, clinical experience and/or clinical investigations [19,15].

Clinical investigation is defined as “a systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device“[21]. However, despite recommended by the European Commission’s (EC) guidelines to clinical evidence, clinical investigation is not a requirement [22]. Several problems that can compromise patient safety have been identified in the European Union regulatory system [9]. There have been unacceptable high incidences of adverse clinical events and high recall rates where the regulatory framework has been portrayed as “fragmented, privatized and largely opaque; safety is dealt with in an unsatisfactory way and efficacy not at all” [15]. Moreover, time has shown that crucial areas of NBs’ approach across Europe show a key weakness. The control of NBs by National Authorities depends on local voluntary approaches, not a mandatory EU standard, leading to questioning transparency, legality, and trust [8]. Further, existing legislation for CE marking focuses on safety, device quality, and performance, with no requirement for assessment of clinical efficacy. Frequently, medical devices based on existing technology rely on literature review and clinical data from equivalent products. High-risk devices based on newer technologies though, with little or no experience or devices extending intended purpose, most often require clinical investigation data [22,19]. Whereby, the majority of clinical investigations used as clinical evidence are non-randomized single-arm studies and rarely include sample size calculation and study hypothesis. Moreover, there is little visibility to criteria used for market approval, allowing variations in data requirements and only limited information made available by the time of approval [16,23,22].

4.1 Controversial opinions

Negotiations to the content of the regulation have been particularly complicated [27]). Applicable to the regulatory goals, the primary focus of the negotiations is the impact these changes will have on NBs, safety and protection of patients and the ability of the new regulations to increase public trust. This to safeguard that high-risk devices are only brought to the market after being sufficiently conformity assessed [28].

4.2 Regulatory changes and their impact on manufacturers

Some significant changes in the proposals are introduced in the structure and supervision of NBs where previous experiences have determined deficiencies (Table 2). Thesedeficiencies include lack of transparency in NBs’ daily work, concerns about NBs’ competence and their independence against manufacturers that may affect decisions to CE marking [29]. These challenges haveamongst others, resulted in that all NBs will need to apply for re-designation and be audited for compliance by joint competent authorities from several Member States [30]. The requirements of technical, clinical and scientific competence have so far resulted in suspension or closedown of several NBs. This number is estimated to increase significantly. Due to the higher demand for in-house competence for medical devices, combined with narrower business opportunities, particularly the smaller NBs are believed to be affected [31,32].

Table 2: Extract of regulatory changes to Notified Bodies and conformity assessment processes.

It is expected that intensified control on NBs will increase the quality of conformity assessments and reduce approvals lacking sufficient clinical evidence. This has a direct effect on manufacturers, whereby the proposed regulations require increased involvement of competent authorities when conformity assessing high-risk devices [33]. This will in turn increase costs and the duration to reach market approval and consequently, patient availability [30,31,34]. Coggi in Ulmann [35] states that these authorities not only add focus to safety and regulatory compliance by manufacturers and NBs, but also increase evidence requirements before receiving a CE mark. Yannakoudakis in Ulmann [35] is concerned that increased involvement of the EC, Medical Devices Coordination Group (MDCG) and Assessment Committee for Medical Devices (ACMD) will result in unnecessary bureaucracy. This might further delay medical device marketing without adding any real value to patient safety. There is also a worry that it result in fewer innovations and longer clinical investigations to gather sufficient clinical evidence. DonDiego [32] and Bartl [33] report that the additional entities involved in the review process are expected to increase patient safety and product quality. On the other side, they may add time and complexity to the CAP.

Eucomed, an organization representing the medical technology industry in Europe, questions the mentioned random sampling scrutiny process to be unable to adequately address issues to increase patient safety, ensure consistency of high-quality NBs or standardize guidelines for medical devices. This is because only a small sample of all class III medical devices applying for CE certificates will be randomized to the scrutiny process. Eucomed further has worries that it will result in duplication of work in the CAP, increase red tape and wasted time on bureaucracy, and result in a false security, as most devices will bypass the MDCG and ECs’ scrutiny control [36].

Traditionally, medical devices have been enabled approval based on equivalence to an already established product, in which published clinical data, commonly from different products were used as clinical evidence. With the new regulations, approval based on equivalence alone will include stricter criteria requiring more extensive clinical investigation for high-risk devices [37]. It must also be justified to apply for a CE mark without own clinical investigation [4]. This will likely increase manufacturer costs and require additional resources, patients, and time. The EP has suggested in Amendment 340 "As randomized controlled investigations usually generate a higher level of evidence for clinical efficacy and safety, the use of any other design or study has to be justified. In addition, the choice of the control intervention shall be justified. Both justifications shall be provided by independent experts with the necessary qualifications and expertise" [38]. Thomas Klein [38] however, states that randomized controlled trials might not always be ethical or feasible and should be optional, rather than a requirement likely to limit clinical investigation of medical devices.

7.1 Overview

This study was designed as a quantitative survey research. A crosssectional descriptive study was carried out to investigate the impact the proposed new regulations on Notified Bodies (NBs) have on clinical investigation. The study focuses on the perspective of clinical research specialists (CRS) working for manufacturers of implantable medical devices (IMDs) in Europe. The quantitative questionnaire was designed specifically related to changes in regulations on NBs and conformity assessment that might affect clinical investigation prior to gaining CE Mark and access to the market. The purpose of the chosen methods is to address the aim and objective of this study and enable answering the research question. The underlying purpose is to add focus to the industry's view, whereas most articles on this subject focus on deficiencies to NBs and patient safety.

7.2 Target population

The target population for this study was CRSs working for manufacturers of IMDs in Europe. With the use of convenience sampling, manufacturers were identified and localized from publically available online resources. The selected companies were contacted by phone to determine the targeted CRSs and their e-mail address. The survey was then sent to the CRSs by email from the software Survey Monkey. Only one CRS per company were invited for participation. Most dedicated CRSs had the role as quality manager, development manager, director or clinical manager. All will be recognized as CRSs throughout this survey.

7.3 Inclusion and exclusion criteria

Participants were selected by the following criteria:

Inclusion criteria:

1. Clinical research specialists currently employed by European companies manufacturing implantable medical devices classified as high-risk in the EU.
2. Clinical research specialists involved in regulatory compliance to medical device approval and clinical investigation.

Exclusion criteria:

1. Clinical research specialists currently employed by European companies that do not manufacture implantable medical devices.
2. Manufacturers of in vitro devices.
3. Clinical research specialists not involved in regulations to medical device approval and clinical investigation.

All manufacturing companies that by phone appeared eligible were invited to participate. This resulted in 107 invited.

7.4 Questionnaire design

There were 15 questions in the distributed survey. The first four questions were used for study inclusion confirmation and to determine company size and knowledge level of the participants. Questions 5-14 have been divided into sections of the new regulatory framework. These regulation changes were recognized through literature review to possibly impact clinical investigation. Within each section, ten likert items were repetitive assessed in all questions 5-7 and 9-14. Additionally one likert item questioning whether all IMDs would need to be tested through clinical trials was raised in question 5 and 6 and is separately analyzed for distribution. All likert items were identified as items within clinical investigation that might be affected by the proposed regulatory changes (Table 3). The last question intends to obtain an overall assessment to CRSs perspective on the proposed regulatory changes.

Table 3: Overview regulatory changes.

The closed survey used fixed checkboxes for answers in the form of rating questions for participants to indicate their view. With use of likert scale, the respondents were offered five pre-coded alternatives ranging from not at all to always. It is thereby assumed that the strength is linear and that assumption attitudes can be measured. The use of a closed survey limits the amount of data that may be generated when using open-ended questions [39]. By use of multiple choices, it was feasible to filter differences associated with company size and clinical research specialists’ knowledge to the proposed regulatory framework.

14.1 Stricter requirements on NBs

More rigorous requirements on NBs, like documentation of competence, were stated by 73.3% of the participants to “always, in most or some cases” increase costs. Further 66.7% respondents stated that it “always or in most cases” will increase need for resources, requirement of regulatory compliance and requirements for clinical evidence (Figure 3).

Most of the participants (86.7%) believe the stricter requirements on NBs will “not at all, in a few cases or some cases” increase product quality and patient safety post marketing. 80% stated that it will “not at all, in a few cases or some cases” increase patient safety during a trial. There are diverging opinions among the participants to the grade of impact the proposed stricter requirements have on the remaining analyzed likert items.

14.2 Regulations on NBs conformity assessment process

78.6% of all respondents stated that the new regulations on NBs’ conformity assessment process would “not at all, only in few cases or in some cases” increase product quality, patient safety during trial or patient safety after market release (Figure 4). 64.3% respondents stated that this part of the regulatory proposal would “always or in most cases” increase costs, and 57.1% respond that there “mostly or always” would be an increase in need for resources or requirements to regulatory compliance. 71.4% participants were of the opinion that “in most cases or always” there will be an increase in requirements for clinical evidence.

There was no clear distinction to whether the proposed changes would increase the number of clinical trials and sample size or decrease innovations and product development. There was, though, a contrasting reply observed to whether all implantable medical devices would require clinical investigation, where 50% stated “not at all or in a few cases” and 50% “in most cases or always.”

14.3 Requirement of randomized controlled trials

The majority of participants (84.6%) answered that randomized controlled trials (RCT) and the need for justification to use any other trial design in “some cases, most cases or always” will increase costs, the need for resources, requirement of clinical evidence, trial sample size, as well as decrease innovations and product development (Figure 5 ). Additionally, 69.2% respond it to increase the number of trials. In contrast, most respondents are of the opinion that a requirement to use RCT to collect clinical evidence will “not at all, only in a few cases or in some cases” increase product quality (92.3%) and patient safety during trial (92.3%) or post marketing (84.6%).

14.4 Me-too products

The larger percentage (76.9%) respond that removing the ability to approve an implant based on equivalence data, would in “some cases, most cases or always” result in that fewer “me-too” products are brought to the market (Figure 6).

14.5 CE-mark based on equivalence data

All (100%) of the participants agreed that removing the ability to gain market approval based on equivalence data to an already established product will in “some cases, most cases or always” result in increased costs, number of trials, clinical evidence and trial sample size. Moreover are 91.6% of respondents of the opinion that it would increase need of resources, requirement for regulatory compliance and decrease innovations and product development (Figure 7).

Contrary to other responses in this survey, more than half (66.7%) state that restricting use of equivalence data as clinical evidence increases product quality and patient safety during trial, as well as that 58.3% respondents, stated it to increase post marketing patient safety. Still, 1/4give the response that removing the ability to use equivalence data as clinical evidence to gain CE-mark would “not at all” increase safety or quality.

14.6 Notified Bodies’ challenges

More stringent requirements leading to NBs experiencing challenges like fewer designations or more expensive services, were noted in responses by 72.7% to increase costs in “most cases or always” (Figure 8). 63.6% stated that the need for resources and number of trials would “mostly or always” increase, and 54.5% that it would increase the requirement for regulatory compliance, requirement of clinical evidence and trial sample size.

Contrary, do 63.6% state that such challenges to NBs would “not at all or only in a few cases” increase post marketing patient safety and 54.5% respondents that product quality and patient safety during trial “not at all or only in a few cases” increase.

14.7 Cooperation between NBs and manufacturers

The major proportion of respondents answered that more stringent regulations for cooperation between NBs and manufacturers will “in most or all cases” increase the number of trials (72.7%), costs (81.8%), need of resources (72.7%), requirement of regulatory compliance (63.6%), requirement of clinical evidence (72.7%) and trial sample size (63.3%)(Figure 9). Further, 90.9% respond that it in “some, most or all cases” decreases innovation and product development. Slightly more than half (54.5%) moreover state that it will “not at all or only in few cases” increase quality and patient safety during trial or after a product receives CE-approval.

14.8 Involvement of other competent authorities

There is a broad agreement (90.9%) among participants that the scrutiny process involving other competent authorities in the CAP will increase costs, requirement of clinical evidence and trial sample size in “some cases, most cases or always”. Additionally, all participants stated an increase in the need for resources in “some, most or all cases” and 80.8% that the scrutiny process increases the number of trials and requirement of regulatory compliance.80.8%respondents further believed that innovations and product development in “some, most or all cases” decreases.

45.5% respondents answered that the scrutiny process does “not at all” increase patient safety during trial and after marketing a product, whereas 36.4% stated it to “not at all” increase product quality. Paradoxical, 55.6% were of the opinion that patient safety and product quality in “some cases, most cases or always” increases.

After clarifying in a follow-up question that all applications will be randomized for scrutiny, the responses were slightly different. The percentage of respondents stating that it will “not at all” increase patient safety during trial stepped up from 45% to63.6%, as well as that 54.5% respondents found it does “not at all” increase product quality or patient safety post marketing (Figure 10).

14.9 Annual audits by Notified Bodies

80.8% of the respondents found that annual audits by Notified Bodies would “not at all” have an impact on patient safety after a products market entrance or during trial (Figure 11). There are 45.5% responses stating that annual audits will “not at all” increase number of clinical trials or product quality; however, 80.8% of participants believe that it in “most or all cases” increases costs and 72.7% that it increases requirement of regulatory compliance. The distribution of answers to the impact annual audits have on the remaining items of clinical investigation, is widespread.

15.1 Regulatory impact on clinical investigation

Questions 5-7 and 9-14 have been divided into the previously mentioned five sections that might impact on clinical investigation (overview in Table 3). There were 1105 replies to the ten different likert items. Patient safety during trial and post marketing, as well as product quality showed the largest amount of replies that they would “not at all” increase due to regulatory changes. The distributions of answers were therefore categorized in two groups. The three likert items to patient safety and product quality were separately evaluated in the second group to not skew the results of the proposed regulations’ overall impact.

In the first group, the sections have been analyzed to determine the regulation changes that will impact clinical investigation in “some cases, most cases and always” (Figure 12). These responses were cumulatively selected 763 times. Stricter requirements to cooperation between manufacturers and NBs show to have the slightly highest impact on clinical investigation (21.8%) followed by monitoring of NBs and scrutiny process (21.1%), and requirement of clinical evidence (20.7%). Stricter requirements to NBs (19.7%) and annual audits (16.7%) were stated to affect clinical investigation less than the other evaluated regulatory changes.

When separating the various questions inquired in the survey, it is determined that more rigorous regulations to approve a device based on equivalencies the regulation change that affect most likert items with 96.4% responding “in some cases, most cases or always”. These responses indicate this regulatory change to be the one most likely to increase costs, number of trials, need of resources, requirement of regulatory compliance and clinical evidence, increase trial sample size and decrease innovations and product development as seen from the perspective of CRSs (Figure 13). Additionally, the scrutiny process of involving other authorities than NBs in the conformity assessment process is by the respondents found to have a significant impact “in some, most or all cases” (89.6%).

The second group evaluates the distribution of replies to what regulatory change that would have the least impact on patient safety and product quality(“not at all and in a few cases”)(Figure 14). These responses were cumulatively selected 327 times.Within the various sections, the highest response rate (25.5 %)was that annual audit requirements most often do notincrease safety and quality. Additionally, there were frequent responses registered that enhanced requirements for competence within NBs and monitoring of NB and scrutiny process,would have little impact on increasing patient safety and quality (20.8%).

When separating the sections into the various questions inquired in the questionnaire, NBs competence and audits are still the regulatory changes stated by 90.9% respondents to “not at all, in a few cases or some cases” increase patient safety and product quality (Figure 15). Interestingly 89.7% also state that requirements to use randomized controlled trials will “not at all, in a few cases or some cases” increase safety and quality. Overall 71.4-90.9% of the participants stated that product quality; patient safety during trial and after a product has entered the market will “not at all, in a few cases or in some cases” increase due to the proposed regulatory changes.

15.2 Likert items –what part of clinical investigation is mostly impacted?

1118 cumulatively selected responses to questions 5-14 were distributed over the likert scale and scaled answers. The mean of the responses is 3.2102 (s=1.42983). When separating the likert item responses, there are 763 cumulatively selected responses in the first group with a mean of 3.57841 (s=1.31896). 33.3% of all replies in this group are “always”. In the second group, there are 327 answers with a mean of 2.33028 (s=1.3157). 38.5% of all replies in this group are that safety and product quality will “not at all” increase.

The distribution of responses to the different likert items from questions 5-7 and 9-14 is illustrated in percentage in Figure 16. Question 8 has been excluded from this evaluation, as it does not consider each likert item separately.

All nine questions were used to evaluate the likert item(s) mostly affected by the regulatory changes expanded on in this study (Figure 17 ). Of the total 291 responses “always”, cost is the likert item most participants (18.6%) respond to “always” increase. This distribution is followed by stricter requirements of regulatory compliance (15.8%), increased need of resources (13.4%), increased requirements of clinical evidence (13.4%) and increase in trial sample size (13.1%). Contrary, only a few participants respond the remaining items to “always” be affected.

When analyzing the 195 cumulatively selected choices that a likert item would “not at all” be impacted by the proposed regulations (Figure 18), patient safety after a product has entered the market (26.2%) and patient safety during trial (20.5%), as well as product quality (18%) was most often repeated. The remaining likert items were only selected by few of the respondents to “not at all” be impacted by regulatory changes.

19.1 Patient safety, product quality and innovative medical devices- the overall aim of the medical device regulation

Between 71.4 and 90.9% of the respondents state that product quality and patient safety both after the product has entered the market and during a trial will rarely increase as a result of the five regulatory changes expanded on in this study. Despite literature vaguely suggesting a lack of increased safety, the responses raise concerns as observed results are in high contrast to the primary goals of the proposal published by the EC in 2012. It was here stated,„ This revision aims to overcome these flaws and gaps and to strengthen further patient safety. A robust, transparent and sustainable regulatory framework should be put in place that is ‘fit for purpose'. This framework should be supportive of innovation and the competitiveness of the medical device industry and should allow rapid and cost-efficient market access for innovative medical devices, to the benefit of patients and healthcare professionals” [48]. The results of this study are also a countermove to the overall agreement among stakeholders that a harmonization of rules and decisions at Member State level is needed to make certain that diverging competencies, procedures, and requirements by NBs, would not lead to approval of suboptimal products and compromise patient safety [49].

Eucomed [50] wrote in its position paper on the ECs proposal that most of the recommended measures are welcomed as they among others increase patient safety. Eucomed further specified that for patient safety to increase, one essential element that needs improvement is to “ensure that all Notified Bodies have a consistent, mandatory and transparent high level of competency and expertise for reviewing the broad range of different medical technologies“[50]. Only 10-15% of respondents were of the opinion that higher competence level would increase patient safety and product quality. It is notable that in the overall analysis to patient safety and quality, only a small percentage indicates that they will increase as a result of the proposed regulations discussed in this study (Figure 19).The benefits of regulatory improvements to raise patient safety and product quality could rarely be persuasive and might rather be overshadowed by the requisitions that potentially challenge revenue.

19.2 Notified Bodies and conformity assessment- a challenging improvement

It was determined in this study that stricter regulation for cooperation between NBs and manufacturers impact clinical investigation the most where for instance 82% respondents state that costs will “always or in most cases” increase. It was to be expected that the regulatory changes affecting NBs would be stated to have a large effect on multiple items of clinical investigation, both in the limitations of cooperation, but also in the supervision and designation of NBs, the annual audits, and the role of NBs in the CAPs. It is frequently discussed that tighter regulations for cooperation between manufacturers and NBs are needed to prevent manufacturers shopping around for best price and easier CAPs to gain CE mark [53]. This possibility has long been considered a problem that results in diverging quality of NBs work where some have been recognized to cut corners to get customers. Despite challenging safety and quality issues, it has been beneficial to manufacturers, resulting in among others lower prices, negotiable prices and disconcertingly unethical compromises to requirements of clinical evidence [53].These pitfalls have contributed to the necessity of closer cooperation between the different NBs to ensure homogenous assessments and prices. In the European Councils’ proposal from 11. June 2015 it is communicated that “Manufacturers shall declare whether they have withdrawn an application to another notified body prior to the decision of that notified body or provide information about any previous application for the same type that has been refused by another notified body" [1].

There is already an agreement that manufacturer audit by NBs represents an important part of the stricter regulations on medical devices. The suggested annual audit for increased inspection is intended to increase product quality and patient safety. However, this approach introduces challenges to both NBs and manufacturers. It has been foreseen that competent employees might be absent, misunderstandings may occur, or circumstances related to product and production arise that influence the purpose of an audit [54]. The parliament has suggested unscheduled annual audits with the intention to increase patient safety and promote quality [54]. In this study, the opposite was determined where annual inspections by NBs and requirement of medical device competence within NBs are found to be the regulatory change least likely to increase safety and quality (90.9%). This result however, might be flawed as it is only related to clinical investigation.

Manufacturers of IMDs are reliant on NBs to gain CE mark on each product intended for the European Market. Further, it is said that particularly high-risk devices and innovations will be subject to joint assessments following the scrutiny process where other authorities like MDCG and ACMD are involved in the CAPs [55]. As a result, manufacturers will potentially experience a delay in market access, particularly considering that the Council has tightened the scrutiny process even further than was originally proposed [1]. 90.9% of the participating CRSs found the scrutiny process to in “some, most or all cases” increase costs, requirements of regulatory compliance, the requirement of clinical evidence and trial sample size, as well as decrease innovations and product development. Moreover, the vast majority believe that product quality and patient safety will not increase. This response is in agreement with MedTech’s press release on June 19. 2015,stating the opinion that the scrutiny process is superficial and do not add any value. This view was based on the fact that the requirement on NBs, the designation procedure, the oversight by national authorities and the requirements of clinical evidence have been sufficiently tightened in the Councils proposal to ensure an optimization of clinical investigation, product quality, safety documentation and CAPs [56].

19.3 The price to pay or end of a story?

The vast majority of the participants report costs to be the factor of clinical investigation that will increase the most. Moreover, there is an observed significant increase in requirement of regulatory compliance and clinical evidence, the need for resources, number of clinical trials and sample size that subsequently also result in higher expenses. This result is supported by literature where among others Eucomed and MedTech Europe conducted a survey in summer 2013 to the financial impact this revision will have on the medical device industry [50]. Medical technology companies estimated for instance that for an SME to comply with the ECs scrutiny procedure it would cost an approximate of 2.5million euro for bringing a class III product yearly to the market [50]. Rob Packard [30] further expressed concerns that increased costs following unexpected audits and the scrutiny process would add minimal benefits to manufacturers.

It has been added to knowledge that there is an overall agreement the proposal will result in substantial repercussion on the clinical investigation process and that there are several main outstanding concerns like impact on costs, innovation and product development, safety and product quality.

Manufacturers must be aware that a new MDR might result in compromising other functioning parts of the clinical investigation process. The consequences of increased costs could be fatal. There are 25000 medical technology companies in Europe. 95% of these companies are small-or-medium-sized enterprises (SME)[51,52]. This corresponds with the 95% respondents in this study being defined as SMEs. Often, an SME has little or no revenue, as well as frequently being innovative start-up companies. Such companies are challenged with barriers like product registration, reimbursement, procurement, and access to R&D incentives preventing them from developing according to potential [8].

The Council has partly recognized the need for cost awareness within the MDR. Among others, did it propose that the EC, and not the NBs as suggested by the EP, would need to carry the costs of involvement of MDCG. This will in turn prevent another cost increase to manufacturers. Another example is that micro-andsmall enterprises will not be required to have a dedicated in-house regulatory specialist [1]. Nonetheless, there is a possibility that larger companies would interpret the increase of costs and requirements differently. This could not be evaluated in this survey due to the under-representation of large-sized manufacturers.

20.1 Limitations, implications, and recommendations for future research

While several articles have been published to the impact of the ECs regulatory proposal and the EPs amendments, there is a gap in the literature regarding manufacturer’s perception on how regulations on NBs and CAPs impact clinical investigation. This study adds to the body of knowledge and may be utilized in the further process of considering the benefits and drawbacks of the proposed regulatory framework before an acceptance of a final new MDR.

The research question asked "What impact does the new regulatory framework for Notified Bodies and conformity assessment of high-risk medical devices have on clinical investigation from the perspective of clinical research specialists from manufacturers of implantable medical devices in Europe?“. In compliance with literature, this study confirmed that the implications of increased costs, resources and regulatory compliance, impact clinical investigation of IMDs. This study also displayed that the belief in increased product quality and patient safety is not as evident as the aim of the proposal indicates. Whereas some of the regulatory changes like annual audits and requirement of dedicated regulatory compliance specialists have been implemented to recommendations and requirements, the regulation still recognizes several concerns and thus warrants more work.

The study is limited by the low response rate representing 14% of the estimated total population of manufacturers in Europe. The results can therefore not be used to represent the total population. There is a chance that it would result in a different outcome. There could also not be any pattern determined to whether company size or knowledge level impact on responses, as 95% of the participants works for SMEs. Although these responses could be interpreted to mirror the reality, it might skew the results of this study due to the underrepresentation of larger companies. There is a concern that barriers to the regulatory changes that could prevent them from reaching their potential, might influence SMEs and thereby skew the tendencies of significance the regulatory proposal has on clinical investigation

A larger study of the population is needed to confirm the significance of the results. Moreover, the data collection tool in this study is limited to exclusively consider whether and where there is an impact. Therefore, more in-depth knowledge about the background of the replies could further advance the observations made in this study and give a broader understanding. This may include ascertaining the portability of costs to the expected increase to enable accounting for manufacturers’ acceptability of risk. It may also include demonstrating motives for the small increase in patient safety and product quality and a justification of costs related to the intended increased benefit of patient safety and product quality.