Clinical Evaluation Overview
Medical device Manufacturers of all risk classes and types must clinically evaluate the device’s safety and performance before applying for Notified Body for CE Marking. To conduct a clinical evaluation as per MDR Article 61, the manufacturer has to examine clinical data sourced from various sources to conclude the subjected medical device is safe and performing well for the intended purpose.
The clinical evaluation of a medical device extends throughout the entire life cycle of the device, and it’s becoming a tough challenge for the manufacturers to maintain and orderly arrange the documents.
Advantages of Outsourcing Clinical Evaluation Report
For early-stage NB approval or to ensure CE Certificate Validity, our expert writers will simplify and coordinate the Clinical Evaluation GSPR. All must recognize that medical device clinical evaluation is a recurring activity during product lifecycles, whether you are pursuing CE Certification or already have one. Manufacturers must establish and keep processes, as well as reports and supporting documentation, such as complete product details, post-market surveillance, risk management, and equivalent device data, readily accessible.
Looking beyond the enormity of their workload and the monumental challenge of developing and evaluating documentation for all of their medical devices, which is covered in each of the technical files by company staff, is not ideal. According to a recent survey, 68% of studies prepared and submitted in-house by medical device companies are either rejected by notified bodies or have several significant GAPA in their CERs and supporting evidence.
When it comes to conducting Clinical Evaluations, it is strongly recommended that manufacturers hire qualified consultants or clinical writers to streamline the process by documentation completed by skilled external practitioners. The cost of developing skills for in-house staff is significantly higher than recruiting external professionals.
Clinical Evaluation Consultants and Writers
We’ve heard hundreds of top officials and QA/RA regulatory managers speak about the revised MEDDEV 2.7/1 Rev 4 and the introduction of the new MDR and its effect and uncertainty on both the Notified Body surveillance audit and the new CE Application over the last two years.
In light of this puzzle, we believe it is critical for top officials and managers to have a strategic structure to use external consultants to resolve uncertainty in MDR 2017/745 & MEDDEV 2.7/1 Rev 4. As a result, we, as one of the best clinical evaluation consultants, like to propose a basic strategy: “handover the CER project to us, and we’ll take care of the rest.” While reviewing the features mentioned below, you can quickly see why manufacturers consider us a “real sourcing partner in medical device regulation.” It’s also important to note that this is not a one-time project for us; it’s a long-term commitment!!!
- Regardless of risk class or form, any unit will be taken on by our trained, effective, and experienced team in Bangalore, India, which will handle each project with utmost dedication and passion, under the supervision of team leaders and project heads. Day-to-day operations are carried out in the cloud, making it simple for clients worldwide to comprehend and direct missing data.
- We are not just consulting firm!!. We guide, create, review and submit documentation to Notified Body. Still not over. We manage, answer the notified body if any review comments, and resubmit if required. We will not ask or allow the client team to handle the documentation until we finish the job. We only need correct information from the client.
- We’re not just giving advice!! We develop the documents, review them, and submit documentation to the Notified Body if not done yet. We manage, reply and answer to notified bodies for any review feedback. We would not ask or encourage the client team to order the paperwork until the job is completed. We only want accurate information from the client.
- Last but not least, low prices and lightning-fast delivery. You are welcome to participate in a clinical evaluation project to see if we vary from the competition.
MEDDEV 2.7/1 Rev 4
Clinical data is information obtained by the use of medical devices on humans. Clinical data can be gathered in various ways (clinical trials, literature search, clinical Follow-Up, market surveillance, etc.) Clinical Evaluation is a systematic review and interpretation of clinical evidence relating to a particular device in order to validate clinical safety and results.
The manufacturer has the responsibility to justify the level of clinical evidence necessary to demonstrate conformity with MDR 2017/745. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose, so manufacturers shall plan, conduct and document a Clinical Evaluation in accordance with this Article 61, Part A and Annex XIV.
The European Commission’s MEDDEV 2.7/1 Rev 4 paper, published on July 1, 2016, is a guidance document, not a legal document. IT IS NOT A LEGALLY BINDING DOCUMENT. The current revision has 65 pages of text, compared to 46 in the previous edition, and is more comprehensive, with 12 chapters and 23 appendices. To validate MDR 2017/745, MEDDEV 2.7/1 Rev 4 guidelines detail how to perform Clinical Evaluation effectively and correctly over the entire life-cycle of a medical device, regardless of the device’s risk classification.
MDR 2017/745, Article 61.
Medical Device EU Regulation 2017/745, Chapter VI annexe 61 mandates conducting Clinical Evaluation in order to confirm safety and performance based on intended use claimed by the manufacturer set out in Annex I.
MDR 2017/745 substantially tightens the Clinical Evaluation requirements for equivalence justification compared even to MEDDEV 2.7/1 Rev 4 expectation. Information on competitors’ clinical data, specifications, and other data is almost impossible, making the level of MDR compliance tougher.
MDR Article 61 paragraph 4 states; In the case of implantable devices and class III medical devices, clinical investigations shall be performed, except if…
- The device has been designed by modifications of a device already marketed by the same manufacturer.
- The modified device has been demonstrated equivalent by way of technical, biological, and clinical characteristics to the equivalent device.
- The data adequately demonstrate compliance with the relevant general safety and performance requirements.
For Class III devices, the body should check that the Post Market Clinical Follow (PMCF Plan) is appropriate and includes post-market studies to demonstrate the safety and performance of the device in the case no clinical investigation is opted by the manufacturer.
MDR Article 61 paragraph 6 states; Clinical Investigations need not be performed if previously CE Certified and marketed following Directive 90/385/EEC or Directive 93/42/EEC with sufficient clinical data and devices such as 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 CS, where such CS is available.
MDR Article 61 paragraph 11; states class III implants PMCF report along with the summary of safety and clinical performance referred to in Article 32 shall be updated at least annually with relevant data. MDR Article 61 paragraph 12; states clinical Evaluation, its results, and the clinical evidence derived from it shall be documented as Clinical Evaluation Report (CER) as referred to in Section 4 of Annex XIV. The clinical Evaluation Report shall be part of the Technical Documentation (Technical File) for each device covered in the scope as referred to in MDR Annex II.
MEDDEV 2.7/1 Rev 4 special emphasis on Evaluation
Medical device manufacturers that are already certified or are in the process of being CE certified must rethink how the CER is delivered to the Notified Bodies. CERs are an essential part of the Technical File.
- For all Implantable devices and class III devices, the outcome of the Evaluation will become public.
- In particular, the Technical File will be critically evaluated and assessed by the Notified Body.
- For Implantable Class IIb and Class III devices, Notified Body may ask an expert panel to review the report.
- MEDDEV recommendations are incorporated into the MDR in article 61 and annexe XIV, including requirements related to equivalent devices.
Clinical Evaluation should be a standalone document with all clinical data evidence on the Medical Device following the expected statements, residual risks, etc., summarized into the technical documentation, according to new MDR article 61. MDR Clinical Evaluation should also back up all manufacturer claims with details from the IFU, user manual, or other promotional materials where the device’s argument is made to ensure it’s correct.
The CER should also be thoroughly prepared concerning any therapeutic alternatives, surgical practices, and equivalent devices to establish the solid State Of Art, pre-requisite to any device development. When completing the Medical Device Inspection for the first time, a CER must be completed. CE Manufacturers can use the marking conformity assessment process to determine if an inquiry is required or find a different approach to obtaining data to support a claim or address risk, such as additional preclinical studies, risk analysis, or even re-designing the medical device.
Clinical Evaluation Plan
A clinical Evaluation Plan is a road map for conducting the clinical evaluation process since it contains the scope, methodological and systematic approach of proceeding and reaching a conclusion on the clinical evaluation. It is the first and foremost document to be prepared. It gives the stepwise planning for the activities to be carried out. This plan helps to conduct and document a clinical evaluation continuously. Chapter VI, Article 61 of the MDR details the relevant aspects to the critical assessment of the clinical data that support the general safety and performance requirements. Towards the end of clause no. 1 has indicated planning, conducting, and documenting the clinical evaluation.
Annex XIV, Part A explains the details explicitly to be covered in the clinical evaluation plan.
Clinical Evaluation Plan Contents
- Identification of general safety and performance requirements (Annex I of MDR) that require clinical data support.
- The intended purpose of the device.
- Intended target groups with indications and contraindications.
- Different aspects are required for the analysis and the conformity assessment of the clinical data.
- Intended clinical benefits with relevant and specified clinical outcome parameters.
- Methods to be used to examine qualitative and quantitative aspects of clinical safety concerning residual risks and side effects.
- Identify and specify the parameters to be used to determine the acceptability of the benefit-risk ratio for various indications and the device’s intended purpose, based on state –of –art.
- If any specific components such as pharmaceuticals, non-viable animal or human tissues are incorporated in the medical device, then how to address the related benefit-risk has to be identified.
- Indication of the method followed for collecting clinical data for the clinical evaluation( equivalent device data or the device under evaluation data or the scientific literature.
- A clinical development plan indicates the progress from an exploratory investigation to a confirmatory study and a PMCF with a clear indication of the milestone and description of potential acceptance criteria for each progression.
- Level of clinical evidence required to demonstrate the conformity assessment of the general safety and performance requirement.
MEDDEV 2.7.1 Rev. 4 is the guideline for performing the clinical evaluation of a medical device before CE marking and after the CE marked stage. It has a stage-wise explanation for the clinical assessment. Stage 0 contains the Scoping and the planning of the Clinical evaluation, which specifies the contents as below:
- Device description.
- Intended purpose, Target group, an indication that requires any specific attention for safety and performance.
- The specific application of the device target the treatment group and disease proposed warnings, contraindications, precautions, and application method.
- Specific claims were made by the manufacturer about clinical safety & performance.
- Residual risk has clinical significance.
- Applicable standards and guidelines available for the current knowledge and state of the art, available medical alternatives for the target population.
- Data source & types of data to be used in clinical evaluation.
All the above aspects must be covered for both (a) before CE Marking and (b) already CE Marked medical devices. Information needed to evaluate equivalence, if it is claimed, has also been considered the before CE-marking devices.
Aspects of being considered for CE Marked Devices during Planning
- Relevant changes in the design, materials, manufacturing processes, information materials supplied by the manufacturer or other claims, and any claims related to the equivalence.
- Any specific clinical concerns that have newly emerged and that need to be addressed.
- PMS aspects to be updated with the new clinical data, new knowledge about potential hazards, risks, performance, benefits, claims, and any other elements identified in the PMS.
- Any need for planning PMS activities.
The clinical evaluation literature search protocol results are related to the critical information needed to establish the subject device’s or an equivalent device’s safety and performance. This will assist in determining current knowledge and state-of-the-art (SOA). It is required by MEDDEV 2.7.1 Rev 4 and MDR article 61. Scientific Literature supports the clinical safety and performance of medical devices by combining data from various sources that are relevant to the device under review.
Purpose of Literature Search Protocol?
The purpose of the Clinical Evaluation Literature search Protocol is to prove the medical device’s clinical safety and performance through data obtained from various Literature relevant to the device under evaluation for establishing its clinical safety and performance. (Clinical Performance: Behavior of a medical device or response of the subject(s) to that medical device concerning its intended use, when correctly applied to the relevant issue (s).)
Sources of Literature
Among the different sources of clinical Literature, must follow a comprehensive search strategy in multiple databases. Should use an appropriate and a maximum number of relevant keywords on the various sources of search.
- Scientific Literature Database
- Citations referenced in the Scientific Literature
The search strategy should be documented and justified.
Scientific Literature Databases
- Shall search additional databases such as European PMC to ensure the adequate coverage of devices and therapies in use in Europe, to identify relevant clinical trials and publications of user experience.
- Progress the searches by device name and manufacturer (e.g. EMBASE (biomedical literature database) /Excerpta Medica, the Cochrane CENTRAL trials register, etc.).
- Due to frequent changes in information coverage and search features available in scientific databases, the criteria for selecting adequate databases must be defined and re-evaluated regularly.
Effectively way to conduct a Literature search
The selection of Literature should be objective and justified, i.e. the selected Literature should include all relevant data, both favorable and unfavorable. With respect to the clinical evaluation, the clinical evaluators must assess the degree to which the selected papers reflect the intended application/ use of the device.
- Develop a Clinical Evaluation literature search protocol based on subject
- Literature search planning based on the available resources and subject device
- The keywords/strings used for the search should not be too broad or too narrow.
- List all databases used for search, e.g. Medline/ PubMed, EMBASE, the Cochrane register, etc.)
- To review the abstracts of the studies carefully to save time
- The Literature should be direct to the device or the equivalent device, a similar device having the same intended use, inclusion/exclusion criteria, etc.
The output of the Literature search
- The relevant literature abstract should describe the purpose, method, and results.
- Should provide the data relevancy in terms of intended use, user population, use environment, patient population, safety, and performance of the literature data to the device under evaluation.
- The current knowledge/state of the art must be provided for the proper conduct of the appraisal and analysis of the clinical data of the device under evaluation and the equivalent.
- The Literature collected should be related directly to the device in question (e.g. publications of clinical investigations of the device in question that third parties have performed, its side effects or complications, incidence reports) and/or to the equivalent device, benchmark devices, other devices, and medical alternatives available to the intended patient population.
- In the overall conclusion of the Literature, the output should be mentioned, and it should satisfy the clinical safety and performance of the device under evaluation following its intended purpose.
Clinical Evaluation Report
New EU MDR Regulation 2017/745, Chapter VI annexe 61 mandates a Clinical Evaluation Report to be submitted along with Technical File to demonstrate the safety and performance of the medical device based on the intended use claimed by the manufacturer.
European Commission released MEDDEV 2.7/4 Revision 4 guidelines explaining in detail the process of clinical evaluation and development of the Clinical Evaluation Report (CER). EU commission released to MEDDEV 2.7/1 Rev 4 and IMRF N41 guidance document before the arrival of EU MDR article 61. Both guidance documents are legally not binding.
Clinical Evaluation Report must document important aspects such as the scope of the clinical evaluation, description of the medical device, state-of-the-art science and technology, clinical background, and route of clinical evaluation for the device under evaluation. The clinical Evaluation Report must be updated on routine intervals. The manufacturer has the right to monitor PMS, PMCF, and PSUR activities, and the status of the risk management strategy to determine when to update the Clinical Evaluation Report.
Notified Bodies during routine surveillance reviewing clinical evaluation reports do not require a set schedule for Clinical Evaluation Report updates. Still, they require manufacturers to have their own processes in place for when and how the Clinical Evaluation Report will be updated.
Clinical Evaluation Report Writer (CER Writing)
(Clinical Evaluation Report Writer, Consulting, Document & CER Writing Services with PMS, PMCF, PSUR)
Are they worried or confused about MDR Article 61 or MEDDEV 2.7/1 Revision 4 Clinical Evaluation Report? No worries. Our expert writers review your current clinical evaluation report and CER writing process from top to bottom.
Is it essential for the makeover to Article 61 to send you a formal offer for your approval? Before sending the request, we take you to the cockpit and explain what we do and what you must do in due course.
Essential things about CER Writing:
- Availability of equivalent device 25% fees discount
- Drug-Device combination products 40% additional fees
- Active Implantable Device 40% additional fees
- Additional Fees for paid scientific Literature. The prices may vary between 150-350 USD
- Complete activities are done in the cloud. Consultants/Clinical writers travel to clients located limited to emergency only.
- The above fees are for each clinical significance (Clinical Indication) of the medical device.
- We practice completing a Class IIb CER writing for a single clinical indication in less than 120 days.
In (Definition 60) Article 2 of the EU Medical Devices Regulation (MDR 2017/745), the scope and goal of post-market surveillance in the European Union are clearly stated:
In 2017/745, the European Commission lays out highly detailed rules for how the post-market surveillance system, as part of the quality management system, should be utilised to collect feedback from device users. This system should be thorough, proactive, and systematic, enabling collaboration on market surveillance and vigilance. It should also interact with corrective or preventative action procedures and be appropriate to the risk and kind of device. The PMS system will create key inputs for technical documentation, product benefit-risk, clinical evaluation procedure, and Clinical Evaluation Report (CER).
Frequently Asked Questions
How many scientific Literatures must be added to the CER documenatation?
Depending on the device; 10 - 15 numbers of articles discuss Intended use, patient population, user environment, Contraindication, Warning, Material suitability, Device Safety & Residual Risks.
Is it necessary to attach the full text of the selected article? Does this violate copyright laws?
Yes, the full text of the selected articles must be attached to the CER documentation. Since we are not modifying the content of the article, it does not violate copyright law.
Do we need to have an information scientist / Doctor assist in developing the search strategy?
Yes, experts in the field can do in-depth literature searches using relevant keywords and analyze the data. Consultants and medical writers with previous experience were also suggested.
What are keywords / Key phrases/ Key Sentences? How should I derive that?
Keywords are defined as words that searchers enter the search engine. Keywords are selected from various factors mainly from indication of use, device material characteristics, safety aspects, usage significance, State of art Technology used and residual risks etc.
Why can't I simply search on a keyword in google string and see if I like and attach what I get?
Yes, it can be done, if it is relevant to the medical device under the scope.
What is the average length, in number of pages for CER, or what is the range in pages?
Generally, a good CER with all consolidated supporting documents will be around 300-600 pages, CER alone will be around 15 to 20 pages.
How CER is related to PMS & PMCF? How important is this in Report?
Post Market Surveillance provides the data post-sales through various sources on the similar type of device and the device under the scope.
PMCF provide the data only on the device under the scope.
Clinical evaluation is a continuous process that requires updation depending on the risk classification of the device. While updating PMS and PMCF is one of the bases, if during the process any incident observe with the subjected device or any similar device-related risk and literature steps taken to avoid such incident need to be analyzed and appraise using evaluation..
How Clinical Evaluation Report is related to Equivalent Device? How important is this in CER?
It is practically not possible to conduct an investigation considering cost and legal requirements, but at the same time, it is important that the device should be clinically proven safe and effective. If an equivalent US FDA or EU approved device in the market helps to prove device safety and effectiveness with respect to technical, clinical and biological parameters.
Equivalent device data are also appraised and analyzed and recorded give more value edition to CERs.
How can I get equivalent Device data? If so not avliable in public domain. What is the solution?
Published data such as IFU, Product Brochures and Specifications, CE Certificate, 510(k) details are easily available on public domains or manufacturer websites. If the device has undergone any trial that can be found on https://clinicaltrials.gov/ website.
If no data of equivalent device, appropriate justification with the PMS covering PMCF obtained for the device under the scope.
What are the most common deficiencies in reports that a Notified Body can found out in CER?
- Medical Device variants and construction features not covered in the Evaluation.
- Equivalent device data not sufficient or no justification provided
- No data covering state of art and current knowledge and technology
- No enough and robust justification for any deviation from Meddev 2.7.1/ Rev.4 concepts
How good the search obtained from EMBASE? Is MEDLINE, PUBMED or NCBI data is enough?
All sources of appropriate data are ok. Among these PUBMED provides the maximum literature search relevant to the medical device under the question.
Is it necessery to have a statistician appraise each article for statistical validity, or can I do this myself?
It can be done by the individual who is doing CER.
My device is already FDA 510k, can I send 510k letter instead of writing a new CER?
CER is a part of the EU Medical Device Regulation(MDD) whereas 510k is that of the US FDA. Ideally, that is not acceptable, however, data from 510(k) can be added in the CER.
Can I use videos to demonstrate and argue that device is safe and effective for the intended use?
No. They will not assure the safety and efficacy of the device for a large population. Only the data obtained from PMS and PMCF can assure that the device is safe for use, as per MEDDEV 2.7/1 guideline, the literature evaluation is accepted by the notified body.
How Clinical Evaluation is related to Risk analysis as per EN ISO 14971?
The residual risk of the medical device is considered while conducting PMS and PMCF studies. In another way, it is directly related to risk analysis as with the help of clinical evaluation manufacturer should prove device safety and effectiveness which should develop literature to be analyzed and appraised for residual risk identified after a risk analysis. Warnings, indications, side effects, biocompatibility issues- the overall safety of the devices are assessed from the Risk analysis.
How Clinical Evaluation related with IFU / User Manual?
Contraindication and warning of the medical device mentioned in IFU or User Manual must be considered while performing data research. In another way around IFU or user manual must be modified based on the outcome of the Evaluation.
Will a Notified Body would ever inform a company that CER is not adequate, and need data from clinical trial?
Yes. The Notified Body will inform if they require a clinical trial in the below situations. data are insufficient to prove the medical device safety and performance
where the clinical evidences and clinical data not relevant and accurate to the device in question.
If the device is new with respect to technology,
If the device is new with respect to use, material of Construction and application
No similar device is available in the market
Multiple recalls on similar device is reported.
What will happen if a company does not update an existing CER during Surveillance audit?
The Notified Body may suspend the CE Certificate Valid if they failed to submit the Clinical Evaluation Report (CER) within the timeline allocated.
Reports to be submitted to the Notified Body? or only for class III devices?
All classes of Medical devices should submit Clinical Evaluation Report (CER) to Notified Body.
How long does a Notified Body takes generally to review the Clinical Evaluation Report CER?
Clinical Evaluation Report (CER) review is a part of Technical Documentation ( Technical File / Design Dossier).
The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated. Why
Clinical risks and residual risk from risk management should be considered for clinical evaluation to prove the safety, and similarly, any new risk or adverse effect is obtained in clinical evaluation it should be reflected in risk management considering the design or material change if required. They are updated regularly to prove the continuing clinical safety and performance of the device or for the need for modification /rejection of the device from the market based on the adverse event or new risk observed.
External clinical experts - Who are they? What is there role?
External Clinical Experts are clinical professionals' expertise in the subject device, chosen and trained by a Notified Body (NB) for the assessment of Clinical Evaluation and provide advice to NB with respect to the regulations, guidance, common specifications and harmonized standards.