Clinical evaluation is the analysis and evaluation of clinical data pertaining to a medical device, in order to verify the clinical safety and performance. Clinical evaluation is an ongoing process conducted throughout the life cycle of a medical device. It is performed during the conformity assessment process that leads to the authorization to place the medical device on the market, and it is repeated periodically during the use of the medical device in order to gain new information about its clinical safety and its performance. The information acquired during the clinical evaluation are used in the analysis of the risk and may result in changes to the Instructions for Use. It a specific responsibility of the producer to perform a clinical evaluation suitable to provide information on the efficacy and safe use of the device.

The EC guideline MEDDEV 2.7.1 is the reference document setting the principles to be followed during the clinical evaluation. The requirements here identified for clinical evaluation apply to all classes of medical devices.

According to the guideline, the clinical evaluation is based on a comprehensive analysis of available pre - and post-market clinical data relevant to the intended use of the device in question, including clinical performance data and safety data. These data might come from many sources: literature data, databases of adverse events or safety alerts (such as those held by many authorities), results of pre-clinical and clinical investigations, biocompatibility tests, analysis of equivalent products available on the market and feedback from the final user (in case of devices already on the market). The data collected must demonstrate the compliance of the device with the Essential Requirements.

The clinical evaluation is usually divided into different steps: data collection, weighing of the data collected in order to identify those most significant and final analysis of selected data. The results of this process are documented in the clinical evaluation report. The report must contain all the collected and analysed information. The organization of the information must reflect all phases of clinical evaluation (data collection, their assessment and subsequent conclusions) and make clear followed by the producer the scientific rationale on which the conclusion are drawn.

The clinical evaluation report is the only way to prove to the notified bodies and to the competent authorities (for example during CE marking procedure, to fulfill with post-market surveillance or during surveillance procedures) the clinical evidence supporting the use of the device.

As said before, the clinical evaluation is an ongoing process and the clinical evaluation report must be regularly reviewed and updated. Notably, MEDDEV 2.7.1 does not specify the frequency of the review but it is responsibility of the producer to define and justify the frequency at which the clinical evaluation needs to be actively updated.

RPN can support its clients in all phases of the process, from the preparation of the document (including the bibliographic research) to the maintenance and the update of the clinical evaluation reports of medical devices.

The European regulation 2017/745 of medical devices will become effective in May 2020 and manufactures, authorized representatives, distributors and all relevant stakeholders involved in medical devices field, will be asked to fulfill new requirements and obligations.

One of the new elements introduced is the Person responsible for regulatory compliance (Article 15).

The presence of this new figure in the company’s organization is mandatory for all manufacturers and for their European authorized representatives.

In order to fulfill the role of person responsible for regulatory compliance, it is necessary to meet specific requirements as concerns educational background and work experience.

These requirements are the following:

• University degree (or a course of study recognized as equivalent by the Member State concerned) in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices;

or

• four years of professional experience in regulatory affairs or in quality management systems relating to medical devices (two years for custom-made devices)

The person responsible for regulatory compliance plays a critical role within the company organization, as he/she should ensure that:

• the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released;
• the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date;
• the post-market surveillance system is implemented and effective;
• the incidents reporting obligations are fulfilled;
• the statement of general safety and performance requirements compliance of an investigational device is issued (in case of investigational devices only)

It should be highlighted that there may be more responsible persons within the organization, provided that each person is responsible only for one or more of the points listed above and that the division of roles is well described in company’s quality documentation.

Furthermore, it should be pointed out that in certain cases the person responsible for regulatory compliance can be outsourced to third parties (such as consultant).

Regulatory Pharma Net is at your disposal to offer companies additional information and support on quality and regulatory aspects to be compliant to the new Regulation 2017/745.

The European regulation 2017/745, that will become effective in May 2020, introduces several new requirements with an impact on several aspects of the medical device field, including the classification criteria. Although the classification into risk classes (class I, class IIa, class IIb and III) has remained unchanged, new classification rules have been introduced and others have been further detailed.

This is also reflected by the the number of classification criteria that increased to 22 classification rules foreseen by the new regulation.

Therefore, specific criteria were introduced as concern software (Rule 11), nanomaterials (Rule 19), medical devices intended to administer medicinal products (Rule 20) and active therapeutic medical devices (Rule 22).

Rule 21 is of great impact for substances-based devices. In fact, according to rule 21, medical devices that are composed of substances, intended to be introduced into the human body or applied to the skin and  absorbed by or locally dispersed in the human body, will be classified as class IIa devices or higher risk class (class IIb or class III), depending on the intended use of the device itself.

Therefore, many medical devices based on substances will be subject to reclassification and this will be of great interest especially for those medical devices based on substances that were classified as class I; indeed the CE marking of a class I medical device is self-certified by the manufacturer, whereas in case of classes IIa, IIb and III the CE mark procedure requires the assessment of a notified body.

In conclusion, manufacturers should perform an assessment of the classification of their devices, in order to avoid critical issues, to adopt any possible action and to be prepared for the new requirements.

Regulatory Pharma Net is at your disposal to offer companies support for the assessment on the classification of your devices, as well as, to provide additional information and advice on quality and regulatory aspects to be compliant to the new Regulation 2017/745.

The entry into force of the new regulation is now close. From 26 May 2020 it will no longer be possible to obtain a CE mark compliant with the Directive 93/42/EEC.

In any case, this does not mean that all CE certificates complying with the Directive 93/42/EEC will be canceled or that the devices currently on the market, in accordance with the Directive 93/42/EEC, will be immediately withdrawn.

Article 120 of the European Regulation 2017/745 states the clarifications you might need about this.
According to Article 120, all the CE Certificates issued by notified bodies in accordance with Directive 93/42/EEC prior to 25 May 2017 will remain valid until the end of the period indicated on the certificate, with the exception of the certificates issued in accordance with Annex IV to Directive 93/42/EEC that will become void not later than 27 May 2022.

The CE Certificates issued in compliance with Directive 93/42/EEC from 25 May 2017 will remain valid until the end of the period indicated on the certificate. However, they will become void not later than 27 May 2024.

In the cases described above, CE marked medical devices may be placed on the market or put into service, provided that from 26 May 2020 it continues to comply with the Directive, and provided that there are no significant changes in the design and intended purposes.
Additionally, all the devices placed on the market under Directive 93/42/EEC will still be available on the market or put into service until 27 May 2025.

It should be highlighted that the requirements of the European Regulation 2017/745 relating to post-markets surveillance, vigilance, registration of economic operators and devices will replace the old directives.

To sum up, this means that it will still be possible to use the CE certificates obtained with the old directive (at least for a few years) and that all the medical devices put on the market according to the directive won't have to be withdrawn (at least till May 2025).

However, companies must in all cases comply with all the requirements of post-market surveillance, market surveillance and vigilance therefore the internal organization, the quality management system and the technical file must be updated accordingly.

Don't be caught unprepared! RPN is at your disposal to offer you support to better manage the transition from the current directive to the new regulation.

In about one year the new European regulation on medical devices, European Regulation 745/2017, will be reality and the new requirements will become mandatory and applicable to all medical devices and to all companies operating in the medical device field.

Although 1 year may sound like a very long time, the truth is that the time is short, and you need to know what are the main changes and what impact they may have on products and company activities.

A brief list of the main news of the European Regulation 745/2017 is reported below:

• New obligations for manufacturers, importers, distributors
• New rules and requirements for clinical evaluation
• Additional information to be provided on substance-based devices in the technical file
• New classification rules for
  • devices containing substances
  • softwares
  • nano-materials
  • active medical devices
• New definitions of “incidents” with medical device
• Introduction of the “Person responsible for regulatory compliance”
• New requirements on traceability (i.e. UDI system)
• New vigilance and post-marketing surveillance activities and duties, such as:
  • Preparation of PSURs for class II and class III MDs
  • Implementation of a Post-Marketing Clinical Follow Up Plan (PMCF Plan)
  • Implementation of a Post-Marketing Surveillance Plan (PMS Plan)
• New Essential Requirements List
• New requirements for clinical investigations with Medical Devices
• New traceability requirements

On the basis of these points, each company should make an internal evaluation of its quality system and the technical files of its medical devices, to check if, how, when and where apply changes in order to be ready for the entry into force of the new regulation, avoiding any unpleasant surprises.

Don't get caught unprepared!

Regulatory Pharma Net is available to offer support to better manage the transition from the current directive to the new regulation.

According to Article 26 of Regulation 745/2017 on medical devices, a European Medical Device Nomenclature will be available to support the functioning of the future EUDAMED database, as well as to further harmonize the medical devices field in Europe.

The activities to define the European medical device nomenclature started more than a year ago and involved several experts (the MDCG group, experts from EU Commission, experts from each member state). The process has now come to completion and the CND nomenclature, the nomenclature currently used in Italy, has been officially chosen as the new European Medical Device Nomenclature.

The CND nomenclature was initially published in 2007 for the registration of Medical Devices in the Italian national database hosted by the Italian Ministry of Health.

The CND classification categorizes the devices by intended use and/or anatomical-functional location. An alphanumeric code is assigned to each device. The alphanumeric code consists of a letter, identifying the category of the device, a pair of identification numbers of the group to which it belongs, and from a series of other pairs of numbers (stating the level of depth of that part of the classification - max 7), which as a whole identifies the type of homogeneous products.

Further details will be provided by the EU in the next months and manufactures should become familiar with this nomenclature.

Regulatory Pharma Net is at your disposal to offer you support to better manage the transition from the current directive to the new regulation.

Currently, many over-the-counter medical devices are substances or combinations of substances.

Medical devices containing substances are the medical devices that will closely be affected by the changes of the new regulation on medical device, coming into force next May 2020.

This type of medical devices will be more strictly regulated than the current directive provisions.

Presently, according to the Medical Device Directive, the only classification rule that directly mentions substances (in this case only of animal origin) is rule 17 according to which a medical device containing an animal origin substance is classified as class III, unless the substance comes in contact only with not-injured skin (in this case the device is a class I device). Additionally, it should be noted that the Medical Device Directive does not foresee any additional technical and clinical information for substance based devices.

This approach has been completely changed by the new Medical Device Regulation.

Classification rule number 21 has been introduced specifically for medical devices containing substances. According to rule number 21 devices that are composed of substances to be introduced in the body or applied on skin and are absorbed or locally dispersed in the human body must be classified as class IIa, class IIb or class III depending on their intended use.

Rule 21 implies that as of May 26th 2020 substance-based medical devices can no longer be classified as Class I. This point has a great impact in particular on all those products containing substances that today are classified as class I; these products must be classified into a higher risk class and must be evaluated by a Notified Body.

In addition, Annex II of the regulation lists the additional information that must be provided in the technical documentation for substance-based products. A challenging requirement is the additional data that must be provided concerning absorption, distribution, metabolism, toxicology and excretion.

For manufacturers of substance-based devices, meeting these new requirements might be a great challenge: stronger clinical evidence to support the safety and performance, new classification rules, the needs of be evaluated by a Notified Body and manage a CE certificate. It might also lead to additional resources being required and significant investments in pre-clinical testing and clinical investigations, to keep these products on the market under the new legislation.

The date of application of the new requirements is approaching rapidly and it is time to take decisions and act in order to be in compliance with the new regulation.

Regulatory Pharma Net is at your disposal to offer you support to better manage the transition from the current directive to the new regulation.

Regulation EU 2017/745 introduced a new requirement for the manufacturer of implantable medical device. The manufacturers of implantable devices must prepare and provide to the patients an implant card (IC) containing some information on the implanted device; the aim of the IC is to enable the patient to identify the implanted devices and to get access to other information related to it but also to enable emergency clinical staff or first responder to be informed about special care/needs for relevant patients in case of emergency situations. Medical devices such as staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors are exempted from these obligations.

Article 18 of the Regulation describes the main information to be reported on the IC:

• device name, serial number, lot number, the UDI, the device model, the name and the address of the manufacturer;
• warnings, precautions or measures to be taken by the patient or a healthcare professional about reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions;
• information about the expected lifetime of the device and any necessary follow-up

Article 18, lays down that Member States shall require health institutions (or healthcare providers) inter alia to make available the IC to the relevant patient. The IC should bear their identity. For this purpose, the IC provided together with the device should contain blank fields which shall be filled out by the health institution or healthcare provider, respectively.

Considering the high impact of Article 18 requirements, in particular as concerns the aspect related to the information to be provided by health institution or healthcare provider, that may have a great impact from the economic and logistic stand point, a specific guidance document has been issued on June 2019 by the Medical Device Coordination Group (MDCG) (MDCG 2019-8 Medical Devices: Guidance document Implant Card relating to the application of Article 18 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices).

The guidance document defines the fields to be completed by the implanting healthcare institutions or healthcare providers, that is:

• Name of the patient or patient ID;
• Name and address of the health institution or healthcare provider who performed the implantation;
• Date of implantation.

This means that in the development of the IC the manufacturer must foresee blank fields for this information. Furthermore, the guideline reports a list of symbols that may be used in the implant cards as well as designs examples of Implant Cards.

Don't get caught unprepared!

Regulatory Pharma Net is at your disposal to offer you support to better manage the transition from the current directive to the new regulation.

26 May 2020, the date of entry into force of Regulation (EU) 2017/475 on Medical Devices (the MDR), it is getting closer, yet at the date of entry into force most medical devices will still be on the market thanks to a CE certificate obtained with the "old" Directive 93/42/ECC. Article 120(2) of the MDR reports what will happen to the CE certificates granted according to Directive 93/42/ECC and still valid at the date of application of MDR.

According to article 120(2) of Regulation (EU) 2017/475 on Medical Devices (the MDR), certificates issued in accordance with Directive 93/42/EEC will remain valid until 27 May 2024 at the latest. However, article 120(3) establishes specific conditions that such certificates, and the related devices, have to comply with.

In short, after 26 May 2020 it will be possible placing on the market a device CE marked according to the Directive 93/42/EEC provided that:

• All certificates necessary for the placing on the market of the device in question need to be valid, e.g. a class III device needs to have a valid QMS as well as product specific certificate;
• The manufacturer assures a continuous compliance of the device with the Directives;
• No significant changes in the design and intended purpose of the device occur; if there is a significant change in either the design or the intended purpose, art. 120(3) of MDR cannot be claimed. Qualification of a change as “significant” according to art. 120(3) of MDR shall be determined on a case by case basis by the Notified Body.

In any case, even if the “old” CE Certificate is valid, manufacturer shall comply with the following requirements of the MDR:

• Registration of economic operators and of devices (see Art. 31 MDR and Art. 29 MDR);
• Post market surveillance (PMS) (see Art. 83-86, 92 MDR including Annex III but without the PMS having to be an integral part of the QMS);
• Market surveillance (see Art. 93 – 100 MDR, but device standards to be met = Directives);
• Vigilance (see Art- 87-92 MDR).

To be noted that exceptions are possible in the case that EUDAMED is not fully functional in time (then see Art. 123 para 3 d and e MDR) and that the notified body responsible of the issue of the Directive 93/42/ECC Certificate will continue to be responsible for the appropriate surveillance of all the applicable requirements relating to the devices it has certified.

Regulatory Pharma Net offers regulatory support to the Medical Devices companies to be compliance with the requirements of the new MDR 2017/745. We are available for any clarification, do not hesitate to contact us!

The EUROPEAN REGULATION 2017/745 (MDR) will formally introduce the role of the “importer” defined as any natural or legal person established within the Union that places a device from a third country on the Union market.

The obligations of the importers have been defined in article 13 of the MDR.

According to article 13, importers, before placing the device on the market, have the responsibility to verify that:

• the device has been CE marked,
• that the declaration of conformity of the device has been drawn up (they have also the duty to keep a copy of the EU declaration of conformity)
• that the manufacturer/authorized representative is identified. Importers shall also verify that the labelling of the device is compliant to the requirements of the MDR (including the UDI requirements when they will be applicable).

Additionally, importers shall indicate on the device, on its package or in a supporting document their name, registered trade name or registered trademark, their registered place of business and the address at which they can be contacted, so that their location can be established. This aspect is crucial, considering also that the additional label must not obscure any information on the label provided by the manufacturer.

As concerns storage and distribution, importers must assure under their responsibility that the storage and distribution conditions set for the device are respected. Importers are also required to have an adequate system to manage complaints and reports of suspected incidents and to promptly communicate them to the legal manufacturer. Importers should keep a register of complaints, of non-conforming devices and of recalls and withdrawals, as well.

Regulatory Pharma Net offers regulatory support to Medical Devices companies to be compliant with the requirements of the new MDR 2017/745. We are available for any clarification, do not hesitate to contact us!