1 CHAPTER VI - Article 61 Clauses AVAILABILITY
Is the clinical data providing sufficient clinical evidence, including where applicable, relevant data as referred to in PMS (Annex III) are confirmed with relevant general safety and performance requirements set out in GSPR (Annex I)
Is the data evaluated for the undesirable side-effects and of the acceptability of the benefit-risk- ratio in the section 1 and 8 of GSPR (Annex 1)
Is the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements is specified and justified?
Is the device Class IIb that administer medicine or class III, then do they ask for the expert panel consultation on intended clinical development strategy and proposals for clinical investigation prior to the clinical evaluation and /or investigation?
If the consultation taken, then is the views expressed by the expert panel included in the CER.
Does Clinical evaluation follow a defined and methodological procedure and a clinical evaluation is planned?
Is critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, then following clauses has to be satisfied
Is the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relates is demonstrated as per Section 3 of Annex XIV
Is the data adequately demonstrate compliance with the relevant general safety and performance requirements
Is the critical evaluation of the results of all available clinical investigations, taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV
Are currently available alternative treatment options for that purpose considered?
In Case of the implantable devices and class III devices, clinical investigations shall be performed
Exceptions for above applicable if the device has been designed by modifications of a device already marketed by the same manufacturer,
Is the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body?
Is the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements
If the clinical investigation is excepted then, is the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device?
DOES the manufacturer demonstrate the device equivalence to an already marketed device of another manufacturer?
If above is yes, then can be excepted from clinical investigation then below points has to be fulfilled in addition to above point
Is the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis?
the original clinical evaluation of that manufacturer device has been performed in compliance with the requirements of this Regulation
Has the manufacturer of the second device given clear evidence thereof to the notified body?
If the devices implantable devices and the class III device with the following conditions? then the point no. 1. 7 and 1. 8 above is not applicable
Which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC (Medicine) or Directive 93/42/EEC (MDD) and for which the clinical evaluation is as below
Is the above based on sufficient clinical data?
is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available
Are the devices include 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 a CS is available?
If the device come under the point 1.9 and hence point 1.7 not applicable, then is it justified in the Clinical Evaluation report?
If the device come under the well-established technologies, similar to the exempted devices mentioned in point 1.9.2, or used in other device where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the commission may amend the above list with the power all applicable rules. Is the device come under the amended list (check the update in the EU website)
Is the product that does not have a medical purpose listed in Annex XVI of MDR, then must demonstrate the clinical benefit by means of demonstration of the performance
For above products is the Clinical evaluations based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation?
Is the clinical investigation performed, if not the reliance on existing clinical data from an analogous (equivalent)medical device is duly justified?
If the product not coming under point 1.7 and the clinical data not deemed to require for the demonstration of conformity with the GSPR, then is there adequate justification for any such exception provided below points has to be fulfilled
Is the above justification is based on the results of the risk management, the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer?
Also is the above point is substantiated in the Technical file that the conformity to the GSPR is based on the nonclinical testing method alone, including performance evaluation, bench testing and pre- clinical evaluation, to be adequate.
Is the clinical evaluation updated throughout the life cycle of the device concerned with clinical data obtained from the implementation of the manufacturer's PMCF plan and PMS plan?
Is the PMCF evaluation report and, if indicated, the summary of safety and clinical performance (Art. 32) updated at least annually with such data for class III and implantable devices?
Is the clinical Evaluation report is updated with the results and the clinical evidence derived from the clinical data evaluation and is the part of the technical file?
Is the Clinical Evaluation continuously conducted and documented with well-defined procedure addressing the planning, conduct, assessment, reporting and updating of the clinical evaluation?
is there post-market surveillance and PMCF procedures
The appraisal and analysis of the available data and its relevance regarding demonstrating conformity with the relevant requirements of the GSPR
Clinical Evaluation Report with the conclusions drawn with regard to the clinical evidence
The Clinical Evaluation documents cover the following requirements
Is the intended use specified by the manufacturer and claims for the device defined?
Is Clinical evaluation Plan prepared?
IS the methodology for the literature search established?
Is the relevant documentation from the literature search done?
the clinical investigation done?
Is the validity of equivalence claimed in relation to other devices, the demonstration of equivalence is done?
The suitability and conclusions data from equivalent and similar devices derived?
Are the documents related to the post-market surveillance and PMCF derived?
Is the Clinical Evaluation Report done?
If non-performance of clinical investigations or PMCF, justifications in relation to it given?
If in relation to clinical data from clinical investigations included within the clinical evaluation, is the conclusions drawn by the manufacturer are valid in the light of the approved clinical investigation plan?
Is the clinical evaluation adequately addresses the relevant safety and performance requirements provided in GSPR?
Is the above point aligned with the risk management requirements, that it is conducted in accordance with Annex XIV of MDR and that it is appropriately reflected in the information provided relating to the device.
Is a Clinical evaluation plan established and updated?
Are the following details are entered in the CE Plan?
an identification of the general safety and performance requirements that require support from relevant clinical data?
a specification of the intended purpose of the device?
a clear specification of intended target groups with clear indications and contra-indications?
Is there detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters?
specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects
is there the list and specification of parameters to be used to determine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device
Above point with respect to State of Art considered?
Are there the components such as use of pharmaceutical, non- viable animal or human tissues, are to be addressed?
Are the indication based on how benefit-risk issues relating to specific components
clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF (Part B) with an indication of milestones and a description of potential acceptance criteria
Is there relevant clinical data available from the clinical investigation relevant to the device and its intended Purpose
Are there any gaps in clinical evidence, then through a systematic scientific literature review identified?
Are all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device appraised?
Any outstanding issues are addressed by new any new or additional clinical data through properly designed clinical investigation accordance to the clinical development Plan?
Whether through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues are generated?
Are all relevant clinical data analyzed in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits?
Is both favorable and unfavorable data evaluated?
The both data available depth and extent proportional to the to the nature, classification, intended purpose, risks and the manufacturer claim, if any of the device in question
Is the clinical evaluation is done on the basis of data of equivalent device?
If yes, the equivalence is demonstrated through technical, biological and clinical characteristics?
Technical characteristics include Similar design, Similar conditions of use, similar specifications,
physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms;
Similar operation principles, similar deployment methods and critical performance requirements
Biological: Is same raw materials for the equivalent device?
Are the same substances in contact with same human tissues or body fluids with same duration of contact?
Is similar release characteristics of substances, degradation products and leachable for the equivalent device
Clinical: Is the equivalent device use in same clinical condition or purpose, similar severity and stage of disease, same site in the body
Is the equivalent device used in the similar population (age, anatomy and physiology), same kind of user, similar relevant critical performance as expected clinical effect for a specific intended purpose.
Is the equivalence based on proper scientific justification
Is the characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device
It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence.
Are there sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence?
Does the Clinical evaluation report contain the clinical evaluation and clinical evidence to support the conformity of the medical device?
is the clinical evidence having the non-clinical data from the non-clinical testing methods demonstrate conformity with the general safety and performance requirements
Is the CER part of the technical documentation?
Is the CER contains the favorable and unfavorable data?
Is the stage 0 Procedure for the clinical evaluation Scoping and Planning done.
In the Scope of the Clinical evaluation, is the type of clinical evaluation planned?
Is the Evaluation done using the route of equivalent device data?
If the above point is yes, then is the equivalence demonstrated?
Is the clinical evaluation scope including the data from the risk management documents? Are residual risks addressed?
Is the current knowledge and the state of art established with the applicable standards and guidance documents?
Are there any data sources for the clinical evaluation held and generated by the manufacturer
Is the product being CE certified, If yes, then all the design changes, material and manufacturing process changes, changes in the information materials (IFU, Labels) and change in the equivalence claims
ARE there any specific clinical concerns to be addressed?
Are the PMS aspects like new clinical data for the equivalent device and device under evaluation, new risks, performance, benefits and claims to be updated in the CER has to be planned
PMS activities planned or the reference of the PMS plan.
If the device is developed or modified by increments, so they are not completely novels, then the clinical evidence established on the clinical experience and literature reports of the safety and performance of an equivalent device?
Does the device comply to the harmonized standards to satisfy the clinical evidence requirements for devices based on technologies with well-established safety and performance characteristics?
Is the Data generated and held by the manufacturer established as follows
premarket clinical investigations
Clinical data from risk management activities and PMS in the Europe and in other countries
the literature search and evaluation reports for PMS
complaints regarding performance and safety sent to the manufacturer
analysis of explanted devices
Relevant Pre-clinical studies (bench test reports including verification and validation data)
Literature Search and Review plan prepared?
Are the literature searches are done with clinical data related to the device under evaluation or relate to the equivalent device?
Current Knowledge or state of art identified with the appropriate standards and guidance documents
data that relate to benchmark devices, other devices, critical components and medical alternatives or to the specific medical conditions and patient populations intended to be managed with the device
Data describe the clinical background
identify potential clinical hazards (including hazards due to substances and technologies, manufacturing procedures and impurity profiles),
Is the data justify the validity of criteria used for the demonstration of equivalence
Is the data justify the validity of surrogate endpoints
Is the plan for the literature search contain the strategy to identify the favorable and unfavorable data
Is the comprehensive search planned for the literature, if not justify with appropriate reason
Is appropriate literature search and review plan prepared?
Is the clinical data identified in the literature of relevant, scientifically valid, demonstrate adequate clinical performance and /or clinical safety?
Are any abstracts only added to the literature search? Then not acceptable
Are full texts available for the appraisal of the data?
Is the literature search and review report with the full text of the literatures is made part of the Technical file documentation?
6 Stage 3 Appraisal of Data
Is an appraisal plan prepared as part of CER with levels for each criteria?
Are individual documents appraised for the clinical performance and safety?
Is appraisal done on the below criteria’s- and the relevance of data to the evaluation of the device relation to the different aspects of its intended purpose?
on the methodological quality and the scientific validity of each data
the relevance to the clinical evaluation (relevance to the device
and to the different aspects of its intended purpose
weighting the contribution of each data set to the overall clinical evaluation.
Are criteria for adequate weighting of both to favorable and unfavorable contents of each document given?
If the device is well established and lower-risk devices, then is a qualitative data available may be adequate to fulfil the requirements?
Conduct of the appraisal
Based on the plan, is each document including the investigation, literature, PMCF data appraised for the criteria’s set in the plan?
Is the review of all of the contents, the methodology employed, the reporting of results, the validity of conclusions drawn from the investigation or report, and evaluate any limitations and potential sources of error in the data done?
Is a decision derived on the data set based on the criteria’s above?
Is the methodological quality and scientific validity for each type of data like pre-market and post-market clinical investigations, vigilance data, device registry data, case series, patient dossiers, and
other use data assessed?
Is the pivotal data and other data determined?
Are all the aspects in the MEDDEV considered for the relevance determination?
Is the weighting of the contribution of the data set done?
For clinical data generated through a well-designed and monitored randomized controlled clinical investigation (also called randomized
controlled trial), conducted with the device under evaluation in its intended purpose, with patients and users that are representative of the target population, is given highest weighting?
if randomized clinical investigations not always be feasible and/or
appropriate, alternative study designs may provide relevant clinical information of adequate weighting is justified?
If data rejected, is the reason documented?
Demonstration of Equivalence
Is the Clinical, biological and Technical characteristics is compared for equivalence? Please check those characteristics in MEDDEV 2.7.1 rev4 Appendix 1
Is equivalence based on a single device?
If wish to refer to several devices that are equivalent, is the equivalence of every single device to the device under evaluation should be fully investigated, demonstrated, and described in the clinical evaluation report?
When the equivalent device is not a CE-marked
device following information to be included
Is information concerning the regulatory status of the equivalent device given?
Is a justification for the use of its data included in the clinical evaluation report?
Does the justification explain if the clinical data is transferrable to the European population?
Is an analysis of any gaps to good clinical practices (such as ISO 14155) and relevant harmonized standards?
Is the clinical data appraised available for the analysis?
Is sound method used for the analysis?
Is a comprehensive analysis done?
If additional clinical investigations or other measures are necessary are determined?
Is any PMCF needs determined?
Is the qualitative or quantitative method used for the analysis with proper justification depending on the device and the circumstances?
In quantitative analysis is the available clinical data such as numbers of incidents in the post market phase should be assessed quantitatively in relation to current knowledge/ the state of the art?
Is a rationale given for the lack of value of a data set to the evaluation?
If the different pivotal datasets report particular device performance characteristics and identified risks similar outcomes? then robustness increases
If different results are observed across the datasets, then is the reason for such differences determined?
if the data that are not methodologically sound (such as single patient reports) it should not be used for demonstration of adequate clinical performance and clinical safety of a device?
In exceptional situations, when an evaluation is based on limited data, is it described and justified in the clinical evaluation report? As below
8 Appendix 8 Of MEDDEV
Is it a breakthrough device? i.e. medical conditions that are life threatening, or cause permanent impairment of a body
function, and for which current medical alternatives are insufficient or carry significant risks.
For above is the clinical evidence limited to experience available from compassionate use/ humanitarian exemption programs, use of
custom-made devices, results of feasibility studies; limited long-term data are available?
If the above point satisfied then the exact intended purpose, including the medical indication (if applicable to the device), the product was developed for and whether residual risks and uncertainties or unanswered questions are considered acceptable in this indication (often a niche indication) is addressed in the CER?
Are the explanations of why current medical alternatives are considered to be insufficient or to carry significant risks are added in the CER?
are the explanations of the benefits delivered by the device under evaluation is added to the CER?
Whether the IFU clearly describe the exact intended purpose (including medical indications) and any limitations, the limited clinical experience,
and uncertainties or unanswered questions about residual risks and benefits to patients?
Is the need to set up a stringent PMCF plan is identified with information
on the type and quality of data that needs to be generated,
how to generate data in a timely manner and aspects thereof, including projections on the numbers of patients that will be managed with the device per year?
For a device that carries significant risks (i.e. expected to cause serious adverse events), or a device for rare diseases, is the PMCF study aimed at including all patients
Is the CER actively updated when new significant information
Is it a Subsequent product ie that enter the market subsequent to a therapeutic/ diagnostic breakthrough? Then below should be considered
Is the clinical evidence being likely to have evolved rapidly since the first breakthrough device became available?
if the PMCF data are required, is the PMCF Studies is foreseen for devices that enter the market subsequent to a therapeutic/ therapeutic breakthrough?
Are the uncertainties no longer legitimate?
Does the Comprehensive analysis include the compliance to the conformity assessment of safety, performance, acceptability of risk benefit and undesirable side effects to each of the GSPR points that require the clinical data?
Are the following points evaluated
Adequacy of the pre-clinical testing verified for the safety/
Risks to the patients, users or other persons associated with the intended purpose of the device?
Benefits to patients reported?
Confirmation that the device achieves the performance(s) intended by the manufacturer, including all claims made by the manufacturer?
Confirmation of usability, that the design adequately reduces the risk of use error as far as possible, and that the design is adequate for the intended users?
adequacy of the information materials supplied by the manufacturer, including if risk mitigation measures are correctly addressed in the IFU
Are all products covered by the clinical evaluation and all aspects of
their intended purpose?
Are any gaps in evidence identified, including in respect to
information relevant to the interaction between the device and the body?
The comprehensiveness of the available data, considering - the entire range of products/ models/ sizes/ settings, the entire range of conditions of use and of the intended purpose, the estimated number of patients exposed to the device?
The type and adequacy of patient monitoring
The number and severity of adverse events
The adequacy of the estimation of associated risk for each identified hazard
The severity and natural history of the condition being diagnosed or treated
Current standards of care, including the availability and the benefit/risk profiles of other devices and medical alternatives
Is all the hazards and other clinically relevant information have being
identified and analyzed appropriately and linked to the risk management
Is all the data as above considering all current knowledge/ the state of the art
Is any gap in the data for the below evaluations? then additional clinical investigation is required
Is the evaluation of the safety, performance and the benefit/risk profile in the CER?
Is the compatibility with a high level of protection of health and safety noted in the CER?
the acceptability of any undesirable side-effects noted in the CER?
Is the risk of use error and the adequacy of the IFU to the intended users noted
Is the consistency between available information?
Is residual risks and any uncertainties or unanswered questions described, then PMCF need is determined?
Are the aspects such as rare complications, uncertainties regarding medium- and long-term performance, or safety under wide-spread use then PMCF need is determined?
If the conformity with GSPR based on clinical data is not deemed appropriate, then is the adequate justification for any such exclusion given as below
based on the output of the risk management process, include an evaluation of background clinical data identified from the literature, and an appraisal of their relevance to the device under evaluation
Is the device/body interaction, the clinical performances intended, and the claims of the manufacturer specifically considered?
Is Conformity based on the performance evaluation, bench testing and pre-clinical evaluation in the absence of clinical data duly substantiated?
Even the clinical data not required, the clinical evaluation is performed and an evidence-based justification is included in the CER?
Is the CER compiled to document the clinical evaluation and its output?
Does the report contain sufficient detail for understanding the search criteria adopted by the evaluators, data that are available, all assumptions made, and all conclusions reached?
Are the statements are substantiated with the data and the conclusions or opinions of the evaluators?
Does the report include the references of the literature-based data and the titles and investigational codes (if relevant and available) of any clinical investigation reports, with cross-references to the location in the manufacturer’s technical documentation?
If the new device or technology has been developed, then does the report include an overview of the developmental process and the points in the development cycle at which all clinical data have been generated?
Is all the above information pertained to each stage mentioned above included in the CER?
Is the CER include accurate statement of evaluators analysis and opinions, and sign the report with their verification?
Is the evaluator CV and their declaration of interests to the manufacturer are included?
Is the CER dated and version controlled?
Is the CER format according to the proposed checklist in Appendix A 10 in MEDDEV?