The EU MDR officially replaces the Active Implantable Medical Device Directive [1] and the Medical Device Directive [2] for medical devices. The EU MDR has a key objective of ensuring health and safety of EU citizens by making the medical device regulation more stringent with respect to the requirements for clinical investigation and evaluation. The definition (Article 2 EU MDR [3]) regarding the term ‘medical device’ has been modified in the EU MDR as against the definition in the MDD. For example, terminologies such as the Unique Device Identifier (Definition 15), clinical data (Definition 48), clinical evidence (Definition 51), and serious incident (Definition 65) have been affected by the changes in the EU MDR. Clinical evaluation for medical devices is necessary to receive a CE mark which is imperative to market medical devices in the European Economic Area.
In the MDD, there was a single article, Article 15, covering the theme of “clinical Investigation”, which is now replaced by 20 articles in Chapter VI (articles 62-82). In the EU MDR, the requirements are addressed to the “Sponsor”, and not the “Manufacturer” as in the MDD. While MDD lays down the requirement to “notify” the regulatory authorities of an intention to perform a clinical investigation, it has been replaced by the requirement to submit an application to conduct a clinical investigation in the EU MDR. For devices with a ‘low risk’, the sponsor can proceed with the clinical investigation if the application is not refused and therefore, the EU MDR is not likely to cause delays, at least for the low risk devices.
With the EU MDR, it is the manufacturer who determines the level of clinical evidence that is required, based on the characteristics and intended purpose of the medical device. The manufacturer should identify and appraise all available clinical data to establish sufficiency and only in cases where the available data is insufficient, a clinical investigation needs to be planned to address the gaps in data.
Clinical investigations are a must for implantable and class III devices, but the legislation makes it possible that in specific cases, the requirement to conduct clinical investigation can be exempted.
The transition from MDD to EU MDR affects multiple evaluation procedures of medical devices and the impact on clinical evaluation is important with respect to the following points:
The regulatory authorities have the say in the re-review process of the technical documentation of high-risk devices prior to approval as per the EU MDR. In accordance with Article 44, they must submit new technical review reports. The procedure may result in extension of submission timelines due to the additional requirements. Clinical Evaluation Reports (CER) need to be reassessed considering limitations on equivalent devices, and the state of the art, and updated to withstand a higher level of scrutiny at the NB level and by the competent authorities. Updates to CERs may also trigger updates to ‘Instructions for Use’ requiring an alignment on the part of the manufacturer.
Under the EU MDR, medical devices may be reclassified, which is expected to be largely based on the clinical evaluation data. The MDD classification is based on associated risk i.e. Class I (low risk) to Class Active Implantable Medical Devices (AIMD) (implanted cardiac pacemakers). Transition to the EU MDR may require that the in vitro diagnostic devices under a general classification (not subject to Notified Body (NB) approval) may be reclassified to Annex II List A (requiring NB approval and additional audits and reviews). Evaluation of all class A devices will also require the approval of the NB.
Classification to a higher risk category: devices such as in vitro fertilization diagnostics, spinal devices, and AIMDs will be reclassified as Class III devices or a software deemed as Class IIa “devices”.
As per the EU MDR, comparative evaluations between medical devices is expected to be more stringent as against the MDD. Extra data requirements for establishment of product safety and performance need to be considered while planning clinical investigations. This will also involve a rigorous interpretation of the data from comparative evaluations. Furthermore, data requirements also state that the use of data from a comparator will require an approval from the manufacturer of the comparator device.
The EU MDR introduces a clinical evaluation consultation procedure, which will be coordinated by an independent expert panel and shall be based on the clinical evaluation assessment report of the NB (Article 54). Annex I specifies the general safety and performance requirements, while Annexes II and III specify the makeup of the technical documentation.
As per Article 10 paragraph 9 of the EU MDR, the QMS system for medical devices will also include the clinical evaluation and post-marketing clinical follow-up (PMCF). Additionally, there is a requirement for a clinical evaluation plan, which must precede the clinical evaluation as per Annex XIV, Part A of the EU MDR.
As per Chapter VI of the EU MDR, additional requirements for clinical investigations form one of the major group of changes in the EU MDR in comparison to the MDD.
Similar to the MDD, it includes collation of already available clinical data from the literature studies, and setting up of any additional, necessary clinical investigations. The concept of equivalence with other device-existing clinical data is still possible, but only in a limited number of cases and under more stringent conditions as per Article 61 paragraphs 4, 5 and 6. More specifically, Article 62 and Annex XV lay out the precise conditions for clinical investigations. Especially with respect to implantable Class III medical devices, all devices must go through clinical investigations with only some exceptions.
For all Class III devices, and for Class IIb devices intended to administer a medicinal product, the manufacturer has the option to consult a group of European experts to review its intended clinical development strategy (Article 61 paragraph 2). For the devices placed on the market in sterile condition, clinical evaluations may be required for aspects covering the establishing of sterile conditions, securing and maintaining sterile conditions.
As per Article 32 of the EU MDR, manufacturers of Class III and implantable devices will have to produce a summary of the safety and clinical performance of the concerned device in a form that is understandable for the intended users/patients, where applicable, and this summary has to be a part of the technical documentation sent to the NB.
The EU MDR requires medical device manufacturers to have the risk (paragraph 2) and quality management (paragraph 9) systems in place; to conduct clinical evaluations (paragraph 3); compile technical documentation (paragraph 4); and apply a conformity assessment procedure (paragraph 6). Manufacturers will also be liable for the medical devices once the devices are placed on the market (paragraphs 12, 13, 14). Furthermore, in light of the scandals affecting the medical device industry in recent past, the device manufacturers will also have to have systems in place to cover their financial responsibility for harm caused by defective devices (paragraph 16). The EU MDR, will require Notified Bodies (NBs) (Chapter IV) to be designated and meet stringent criteria, especially with respect to clinical competence. A database for all NBs (NANDO) is also enlisted. A manufacturer must verify if the NB concerned with its medical device is designated under the EU MDR. It is also necessary to start working early with the NB to plan the timing of certification for the product portfolio considering factors such as the availability of the NB and the requirement for additional data on devices.
Conformity assessment for CE marking depends on the risk class and specific features of devices and NB intervention is needed for all Class IIa, IIb and III devices, as well as some specific Class I devices and may need planning with respect to the timelines.
The EU MDR requires an update on all clinical evidence for existing medical devices which has to be made publicly available. Additionally, CERs and summaries of safety and clinical performance for implantable devices and Class III devices should be updated at least once every year. The frequency of CER updates must be justified by the manufacturer considering factors such as risks involved, scientific developments, and design changes.
The rationale behind the EU MDR is to make medical devices safe for the general public, while enhancing the traceability and transparency in the EU. While generation of clinical evidence for medical devices is not new, under the MDD, lower risk devices were required to have CERs and higher risk devices needed clinical data. CERs are still required but with changes to content requirements and acceptability conditions with the MDR (EU MDR Annex XIV, Part A). Additionally, a public summary of safety and clinical performance is required, as per the MDR, for certain types and classes of devices. This summary is to be prepared considering the therapeutic/diagnostic options addressed in the CER and available alternatives. Class III and implantable devices should have clinical data from clinical investigations conducted under the supervision of a sponsor.
NBs now must provide a clinical evaluation assessment report (CEAR), which will be subject to a mandatory analysis by an “expert panel”. The Competent Authorities expect to be notified of any device receiving a certificate post-conformity assessment involving an expert panel, to develop Common Specifications for higher risk devices.
NBs will have a higher level of oversight and scrutiny and therefore, CERs must be reassessed considering limitations on equivalent devices and state of the art. CERs should be updated to meet the higher level of scrutiny from the NBs. Updates to CERs may also trigger updates to the ‘Instructions for Use’. It is also expected of the manufacturer to have an integrated program incorporating the risks in the labeling in order to limit the number of reportable events. Events need to be reported if they are not identified as a ‘known risk’ in the concerned device. The reporting timeline has also been reduced to 15 days.
The EU MDR mentions a term ‘sufficient clinical evidence’, but there is no specific definition or the extent to which data will be expected to meet this criterion. There is no ‘one solution fits all’ when it comes to this criterion, and each device must be investigated independently to satisfy the requirement for ‘sufficient clinical evidence’ expected on the manufacturer’s behalf.
As each device has a different predefined intended use, target populations, performance, safety profile, and claims, all these factors affect the quantity and quality of clinical evidence required to meet the criteria of sufficiency.
The definition of “sufficient clinical evidence” can be found in the guidance document on clinical evidence as per MEDDEV 2.7/1, revision 4, page 8, which states that sufficient clinical evidence: an amount and quality of clinical evidence to guarantee the scientific validity of the conclusions [4]. The definition is derived from the evidence-based medicine and is based on the following characteristics:
The data collated should be enough data to support the performance and safety requirements for a medical device. The quantity of data required may be different to establish the aspects related to performance and safety respectively. Furthermore, it can be interpreted that the CER should justify the quantity of data presented for the performance and safety of a medical device. The quantity aspects cover questions related to the sample size chosen for the clinical evidence generation, evaluation of rare adverse events, conducting meta-analysis, and statistically relevant safety and performance analysis when patient subgroups are involved.
The quality of clinical data presented in the CER must be as per the acceptable clinical standards (ISO 14155), ethical standards (Declaration of Helsinki), and in accordance with the region that the clinical data is produced. Quality aspects cover questions related to the design of the clinical trial, relevance to the selected patient population, the intended use, risk of bias, trial execution and any ethical concerns.
Considering dealing with statistical probabilities to derive a conclusion of a clinical evidence, the design, data analysis and data interpretation of clinical evidence for a specific medical device, statistical analysis must validate the available clinical evidence.
CER should include inputs from risk analysis, claims, state of the art, PMS data, sales data (e.g., experience on the market) etc. If there is no alignment between clinical performance claim and the available clinical evidence, it generates a gap in the CER that must be compensated with additional data or may require a change in the ‘claims’ statement.
Once the EU MDR is fully implemented, it is likely to affect reclassification of several medical devices across all classes. It is important for the manufacturers to determine if this reclassification will impact their device, as it could trigger a requirement for additional preparation and allocation of resources to demonstrate compliance with MDR for already approved devices. Medical devices that are reclassified to a higher class will require a detailed review by the NBs, and therefore, may extend the timelines to achieve the necessary additional conformity assessment procedures. Reclassified devices will also have to undergo a higher level of scrutiny with respect to the available clinical data review by the NB (also applicable to implantable devices without any changes to the class level). Reclassification to a higher class is likely to affect implants in the orthopedic space, and active therapeutic devices, such as automated external defibrillators among others. The MDR also lays down the classification rules for software and devices incorporating nanotechnology.
While it is possible to place devices on the market that are compliant with the MDR before the end of the transitional period, devices subject to the “clinical evaluation consultation procedure“, or those reclassified into Classes IIb and III, may not be placed on the market before the Medical Device Coordination Group (MDCG) and the expert panels have been established.
When the EU MDR is fully implemented, the device manufacturer must have a comprehensive plan to ensure the maintenance of its CE marked devices in accordance with the full requirements of the EU MDR. It is practical to consider the products in the development pipeline for compliance with the EU MDR, as this review can provide an opportunity to rationalize the product portfolio and possibly eliminate marginal products from the portfolio.
Portfolio review and assessment needs to be critically evaluated by the manufacturer against the requirements of the EU MDR. The manufacturer clearly needs to assess which products will be affected by reclassification and therefore attract a higher scrutiny from the NBs. For example, a product previously classified as an accessory may as well be classified as a medical device as per EU MDR. Others may be reclassified to a higher risk category and may require clinical evidence generation. The EU MDR also provides a huge opportunity to assess the impact of EU MDR on the need to redesign the product or develop a new manufacturing process. The manufacturer can also negotiate new supplier agreements and evaluate the opportunities to diversify its portfolio through acquisitions to meet the demands of the EU MDR.
The EU MDR poses several challenges and provides a great opportunity to reform the medical device industry in the EU. Challenges are expected in the transitional phases when the NBs will be required to undergo the process of recertification and retraining of personnel. From the manufacturer’s point of view, the kind of clinical evidence to be generated which requires the definition of ‘sufficient’ remains one of the toughest challenges. As the generation of ‘sufficient clinical evidence’ will require an assessment by a clinical expert (i.e. a medical doctor), the manufacturer will need to consider consulting with experts in the field. The same level of expertise will also be required from the NBs and the competent authorities.
The evaluation procedure for clinical evidence in the EU MDR involves a 3-tier process with the following steps:
The clinical evaluation team of the manufacturer, who prepares the CER.
The clinical expert team performing the evaluation at the NB level.
The clinical expert panels advising the Competent Authority.
Evidently, the evaluation process can be nonhomogeneous, and the same device analyzed by 2 different groups of clinical experts can lead to different outcomes. It is important to address this issue across tier levels such that the terms used to evaluate clinical evidence are harmonized across tiers. The EU MDR places the burden of classification of medical devices on the manufacturer who then must evaluate the regulations and understand its impact on their portfolio.
As NBs must apply for designation under the MDR, the process can be time consuming, increasing the risk that NBs currently designated under the MDD may not achieve designation under the EU MDR, restricting their capacity to create backlogs towards the end of the transition period.
For manufacturers who have experience in conducting clinical investigations for their medical devices, the new EU MDR will not have much of an impact on the timelines, considering that their Quality System is compliant to the MDD/AIMDD, ISO 14155:2011 and Declaration of Helsinki. It can be seen as an opportunity, as the manufacturers who transition early to align with the requirements of the EU MDR can gain larger market share for devices, in comparison to those who transition closer to the deadline of 2020.
The EU MDR introduces EUDAMED, the centralized electronic system for the registration of clinical investigations, which will capture registration details of the devices, accredited NBs, Serious Incidents, Safety and Clinical Performance Reports (SSCP), Periodic Safety Update Reports (PSUR), Surveillance Activities and Clinical Investigation Data. It is likely that EUDAMED will ease the coordination between the manufacturers, NBs and the competent authorities with respect to the data requirements for compliance with the EU MDR.
1. EU, COUNCILDIRECTIVE of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (90/385/EEC). Official Journal of the European Communities, 1990. L189/17.
2. EC, COUNCIL DIRECTIVE 93/42/EECof 14 June 1993 concerning medical devices. L 169, 1993.
3. EC, REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC Official Journal of the European Union, 2017. L117.
4. EC, GUIDELINES ON MEDICAL DEVICES: CLINICAL EVALUATION: A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES UNDER DIRECTIVES 93/42/EEC and 90/385/EEC 2016.
