Basak Erpolat, MDR consultant and freelance CER writer for Kolabtree, lists best practices to follow for a medical device clinical evaluation plan for EU MDR compliance. Basak has worked on over 80 MDD/MDR projects.
The new European Medical Device Regulation (MDR 2017/745) will soon replace the current Medical Device Directive MDD 93/42/EEC amended by 2007/47/EC. This new regulation comes with several considerable revisions of the regulatory aspects currently covered by the MDD and launches brand new requirements for the manufacturers who seek CE-mark approval for their products and the Competent Authority/Notified Body reviewers. From the moment MDR was published in 2017, the medical device sector has been working hard to understand the extent of the new requirements and their impact on their devices. There have been discussions regarding the grey areas and whether all the requirements would be applicable for all risk classes (Class I, IIa, IIb and III) devices.
Nonetheless, for sure, one of the hottest topics has been “clinical evaluation”. Manufacturers tried to process the actual requirements as well as “hidden tricks” to get their CE-mark approval under MDR as easy as possible before the deadline, May 26th, 2020.
This post gives manufacturers 5 DOs and DON’Ts when conducting a Clinical Evaluation to achieve best compliance with the MDR.
1. DO: Be proactive
Being proactive is the most critical point through MDR compliance and this sounds pretty self-explanatory, doesn’t it? However, most of the manufacturers—until the end of 2019—were waiting for a delay on MDR, hoping that the European Commission would see their struggle to align with the requirements of the regulation. Moreover, the United States had specifically asked European Union to delay both MDR and IVDR by three years to protect their current product portfolio within the EU market. That did not happen.
Now everyone has accepted that the MDR will replace MDD as of May 2020, and they know their Notified Bodies will not be as approachable or reachable as they used to be.
Because of the workload.
By 2019, it was (optimistically) projected that twenty Notified Bodies would be designated under MDR until 2020. However, by February 15, 2020 we have totally eleven (11) Notified Bodies, as follows:
- BSI Assurance (UK)
- BSI Assurance (Netherlands)
- DARE!! Services B.V. (Netherlands)
- Dekra Certification B.V (Netherlands)
- Dekra Certification GmbH (Germany)
- DNV GL Presafe AS
- IMQ ISTITUTO ITALIANO DEL MARCHIO DI QUALITÀ S.P.A. (Italy)
- MEDCERT ZERTIFIZIERUNGS- UND PRÜFUNGSGESELLSCHAFT FÜR DIE MEDIZIN GMBH (Germany)
- National Standards Authority of Ireland (NSAI)
- TÜV Rheinland LGA Products GmbH (Germany)
- TÜV SÜD Product Service GmbH Zertifizierstellen (Germany)
The following Notified Bodies are also under the assessment period for designation under MDR:
- Berlin Cert (Germany)
- DQS (Germany)
- ECM/ENTE (Italy)
- IMNB (Intertek)
- PCBC (Poland)
- SGS Belgium (Belgium)
- SGS Fimko (Switzerland)
- SGS UK (UK)
- TÜV NORD (Germany)
Beside of the limitations by number, there is also a limitation on the scope of designation. So far, a handful Notified Bodies provide full-scope (covering all Medical Device Nomenclatures) conformity assessment services.
Be aware of these limitations and adapt your strategy to save time and energy. Also bear in mind that even in the case you’ve found the chance to find an available Notified Body that agree on “reviewing” your documents including your clinical evaluation; the process may take significantly longer compared to MDD, because of the very reason of “workload”.
Be proactive and strategize your pathway according to the availability and applicability of the Notified Body you intend to work with. Bear in mind that, communication with Notified Body is the essence of everything and can save a lot of time, cost and effort if an aligned approach is employed. This is particularly true with clinical evaluation process which has now expected to cover “sufficient amount of clinical data generated with your own device” (please read below for more details).
You can check the designated Notified Bodies and their scope here.
Also read: How to hire a CER writer for your project
2. DO: Understand “applicable” requirements
The first thing you have to understand about the clinical evaluation as per MDR is it is not just a report anymore. The clinical evaluation report is the final output of the “ongoing clinical evaluation process” a compilation of “clinical evidence” to claim conformity to the applicable General Safety and Performance Requirements (GSPRs).
There are generic parts that have to be covered within the clinical evaluation process under MDR. These are:
- Clinical Development Plan
- Clinical Evaluation Plan
- Clinical Evaluation Report
- Clinical Investigations
- Summary of safety and clinical performance
- Common Specifications
- Post-market surveillance (PMS) / Product Safety Update Report activities
- Post-market Clinical Follow-Up (PMCF) activities
Clinical Evaluation Plan and Clinical Evaluation Report are already known components of the clinical evaluation process. Although, PMS and PMCF activities have been part of the clinical evaluation reports in the past as per MDD, the requirements on these activities are no longer optional (Please continue for more details for PMS and PMCF). PMS is now used for Class I products only, whereas Product Safety Update Report (PSUR) is the PMS activities for “Class IIa and higher-class products”.
What is new is the Clinical Development Plan. While this is extensively used in pharmaceutical industry when planning all pre-market and post-market clinical and non-clinical investigations; because the very requirement of conducting a clinical study for medical devices has been recently introduced, the “Clinical Development Plan” is a novel component for manufacturers.
Summary of safety and clinical performance (SSCP) is required for “implantable devices and for class III devices, other than custom-made or investigational devices”; this is compiled entirely from Technical File/Design Dossier through design verification/validation reports, the risk management report/file, the clinical evaluation report, and post-market surveillance (PMS) and post-market clinical follow-up (PMCF) plans and reports. The critical part of SSCP is they will be publicly available for intended users –both healthcare professionals and if relevant for patients. The specifications on SSCP content was given in Article 32 of MDR.
Clinical investigations (pre-market) are also expected to be conducted, particularly for implantable and Class III devices. However, Article 61 gives some “flexibility” to waive this requirement:
“— the device has been designed by modifications of a device already marketed by the same manufacturer,
— the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, and
— the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements.”
“The requirement to perform clinical investigations […] shall not apply to implantable devices and class III devices:
- which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation:
— is based on sufficient clinical data, and
— is in compliance with the relevant product-specific Common Specifications for the clinical evaluation of that kind of device, where such a Common Specifications is available; or
- that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific Common Specifications, where such a Common Specifications is available.”
As given above, the other term introduced through MDR is “Common Specifications”. This means “a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system”. These Common Specifications are particularly compelling for manufacturers as for years they have been claiming that their device complies with the “harmonized standards”. However, Common Specifications bring more stringent requirements to comply with and the worse situation is, they are not ready yet either. The EU proposed a “draft” of Common Specifications for “reprocessing single-use medical devices”, in 2019, and it is not approved yet.
Another new thing is the MEDDEVs are now expected to be replaced by guidance documents issued by Medical Device Coordination Group (MDCG) and although so far (as of February 15, 2020) only one MDCG guidance was issued specific to the Clinical Investigation and evaluation; these guidance documents are required to be followed ongoing basis to achieve precise compliance.
By following MDCG-endorsed documents you may find useful guidance and more clear understanding for the requirements on clinical evaluation and investigation processes.
The guidance documents may be accessed here.
3. DO: Be systematic and structured
This continues to be a requirement on the clinical evaluation part as in MEDDEV 2.7.1 Rev. . A clinical evaluation needs to be methodologically sound and well-structured to facilitate conformity claims.
A clinical evaluation can be systematic where a very spot-on data is retrieved and summarized through well-constructed search combinations to demonstrate the clinical safety and performance when the device used intended. Or, it can be a nightmare with thousands of irrelevant hits obtained via using too broad search terms with no- or poorly-constructed combinations. If you’re manufacturing a syringe or coronary stent, using generic terms without any other combinations (device characteristics, Boolean operators, trademark names etc) will get you thousands of articles, with no use and certainly with this tight deadline for MDR, no time either. MEDDEV 2.7.1 Rev. 4 suggests a number of search strategies to get the optimum results to overcome this challenge.
Furthermore, a clinical evaluation should be well-structured. This means it should be clearly demonstrated how retrieved and included scientific data aligns with the product literature, risk management documentation and post-market surveillance as well as post-market clinical follow-up.
This approach will also help you to prepare auditor-friendly documentation.
4. DO: Make your clinical evaluation a “living process”
As stated before, clinical evaluation is not just a Clinical Evaluation Plan and Report, anymore. It is a “living process” based on (ideally) a Clinical Development Plan and continuously fed by post-market surveillance and post-market clinical follow-up activities in line with this plan.
Writing a Clinical Evaluation Report and set an update term of 5 years cannot be practical under MDR. In fact, Article 61, Paragraph 11 and 12 explicitly says that: “The clinical evaluation and its documentation shall be updated throughout the life cycle of the device concerned with clinical data obtained from the implementation of the manufacturer’s PMCF plan[…]and the post-market surveillance plan […]. For class III devices and implantable devices, the PMCF evaluation report and, if indicated, the summary of safety and clinical performance […] shall be updated at least annually with such data.”.
So, you are expected to provide continuous PMCF data to continue to claim adequate safety and performance.
The whole process should be continuously interactive between different components including Risk Management Documentation, PMS and PMCF activities as well as the product literature (if necessary).
5. DO: Collaborate with experts
Whether you’re outsourcing or hiring someone to perform clinical evaluation for EU MDR compliance of your medical devices, be aware that, the requirements on qualifications of the authors and medical reviewers apply.
The challenge within the medical device industry right now is, due to the stringer requirements on clinical evaluation, most of the expert clinical evaluation report writers were already hired by Notified Bodies, as assessors. However, the growing demand also led new people to get into the business.
6. DON’T: Rely on Grandfathering
As the MDR has come on stage, t claims of manufacturers such as “Look, my device has been around for decades and it complied with MDD perfectly, so please CE-mark me under MDR, too” has been defeated. Because, MDR brings more stringent and brand-new rules and requirements and, thus, new conformity assessment routes, which are hardly covered by the MDD. Therefore, all devices (and products without intended medical purpose as listed in Annex XVI of MDR) are required to undergo a new conformity assessment to be CE-marked under MDR.
Be prepared for new requirements, particularly for Clinical Evaluation, as Notified Bodies or Competent Authorities will not rely on your MDD-compliance history.
7. DON’T: Fall for the “simplicity, old technology or low-risk class” of your device(s)
You may be a manufacturer of a Class I tongue depressor, syringe, band-aid, infusion tube or similar device which have been used for decades and readily available through all the clinics worldwide. However, that does not mean you don’t have to provide a clinical evaluation based on “clinical data” to continue your sales within EU.
But what type of “clinical data” you can provide for this type of devices? While this discussion partly belongs to the PMCF strategies (see below), one thing you have to understand that there are different options, that can be tailored as per device characteristics to generate clinical data. The keyword is “tailoring”; however, as stated in the first item of Dos; be proactive and have a discussion on the strategy that you intend to adopt.
8. DON’T: Claim equivalence if you don’t have a “certain amount of data” belongs to your competitor
The latest clinical evaluation report that you stated that “My product is the same with the product manufactured by this global firm” and summarized all the published data to demonstrate performance and safety of “your device” was probably “the last” clinical evaluation report.
Because, until the (un)official guidance on Clinical Evaluation, MEDDEV 2.7.1 Rev. 4 (2016), was published, the requirements on presenting clinical data or proofs were not that stringent. By June 2016, MEDDEV 2.7.1 Rev. 4 brought more stringent rules on equivalence claims and laid down conditions to meet three-dimensional characteristics (clinical, technical and biological) to extend clinical data generated with the competitor device. Furthermore, it explicitly stated that manufacturers who claim equivalence with a competitor device should have access to the Technical File or Design Dossier of the device in order to prove the similarity between both devices. This new requirement really affected the structure and the length and contents of the clinical evaluation reports for most of manufacturers.
However, even with these requirements, some Notified Bodies still accepted equivalence claims when manufacturers basically gave the IFU or website as a “source” of the information extracted for equivalence claims. But with MDR, this became impossible. Specifically, in Article 61, Paragraph 5; MDR states that (1) the two manufacturers shall have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and (2) the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and (3) the manufacturer of the second device provides clear evidence thereof to the Notified Body.
This requirement which was referred in a “guidance” document (MEDDEV 2.7.1 Rev.4), has now become a mandatory under an “EU Regulation”. This means, manufacturers who relied on published clinical data generated with their competitors for years, now have to generate their own clinical data, by means of PMCF activities (See more details for PMCF below).
9. DON’T: Underestimate the power of post-market clinical follow-up
Post-market clinical follow-up or “PMCF” has become the “thing” of MDR. Once upon a time, PMCF studies were rarely conducted in medical device sectors.
With MDR, PMCF has now become an “ongoing part” of the clinical evaluation process. Manufacturers are required to conduct ongoing PMCF studies, specifically if their device(s) is implantable and/or Class III.
So, a PMCF just means clinical investigation, right? Well, partly.
MDR defines PMCF in Annex XIV Part B as “a continuous process that updates the clinical evaluation referred to in Article 61 and Part A of this Annex and shall be addressed in the manufacturer’s post-market surveillance plan. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data from the use in or on humans of a device which bears the CE marking and is placed on the market or put into service within its intended purpose as referred to in the relevant conformity assessment procedure, with the aim of confirming the safety and performance throughout the expected lifetime of the device, of ensuring the continued acceptability of identified risks and of detecting emerging risks on the basis of factual evidence.”
You will be expected to present a PMCF plan to define your rationale for your strategy. However, that does not mean you will be immediately required to conduct clinical investigation (well, unless your device is not high-risk; implantable or Class III device).
MDR further describes the possible routes of PMCF studies as “[…] gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of clinical data[…]”.
So, to be more clear, you may adopt user surveys, screening of scientific literature and other sources of clinical data, if these are more precise routes to collect clinical evidence on PMCF aspects.
PMCF is one of the most tender topics within the clinical evaluation, and if a clinical investigation is required, it would be very expensive, so to be more cautious, it is recommended to align with your Notified Body before conducting any of these activities and be sure that both of you are on same page.
10. DON’T: Forget that “Medical Device Regulation” now covers more than “Medical Devices”
Yes. The “Medical Device” Regulation covers more than medical devices which are now called “PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE” as referred in Article 1 and listed in Annex XVI. And these products also require a clinical evaluation.
This applies to manufacturers of:
- Contact lenses or other items intended to be introduced into or onto the eye
- Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings
- Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing
- Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty
- High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment
- Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain
You should prove your products’ clinical benefit (as referred in Article 61 of MDR) in terms of “performance”. MDR further states that “Clinical evaluations of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified.”
MDR also states that, GSPRs relevant to the “performance” requirements of these products cover from GSPR1 through GSPR8.
Basically a clinical evaluation for these products aims to demonstrate that when used under the conditions and for the purposes intended, does not present a risk at all or presents a risk that is no more than the maximum acceptable risk related to the product’s use which is consistent with a high level of protection for the safety and health of persons.
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