This document provides the process for management of Clinical Evidence
Version at end of page)
Signed V10 ML 15.10.2024
The process covers the requirements for clinical evidence however Principal involvement and documentation would be followed as the manufacturer
Approval: Author of the document, Monica Lucas
Changes: National Sales Manager/General Manager
‘clinical evaluation’ means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer;
‘clinical investigation’ means any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device;
‘investigational device’ means a device that is assessed in a clinical investigation;
SOP – Standard Operating Procedure
PSO – Post Market Surveillance Officer
MD – Managing Director
NCCAR – Non Conformance Corrective Action Report
CEv - Clinical Evaluation
CIv - Clinical Investigation
PMCF - Post Market Clinical Follow-up
ISO13485 Clause 7.3
SOP Adverse Incidents & Recall
SOP Non Conformance Corrective Action
Confirmation of conformity with relevant general safety and performance requirements under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in regulation.
The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. To that end, manufacturers shall plan, conduct and document a clinical evaluation .
For all class III devices and for the class IIb devices the manufacturer may, prior to its clinical evaluation and/or investigation, consult an expert panel as referred to in Article 106, with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation.
The manufacturer shall give due consideration to the views expressed by the expert panel. Such consideration shall be documented in the clinical evaluation report referred to in paragraph 12 of this Article. The manufacturer may not invoke any rights to the views expressed by the expert panel with regard to any future conformity assessment procedure.
Risk/Benefit Analysis in 3 Simple Steps:
1. Summarize all risk items from all risk analysis documents;
2. Summarize the traceability to risk mitigation actions;
3. Arrange a review with the project team, management, Regulatory, Quality and ideally an external expert on the device / use (e.g. a surgeon):
(a) Agree that the risks have been mitigated As Far As Possible and additional risk controls do not significantly reduce the risk.
(b) Agree that each residual risk is acceptable.
(c) Agree that the overall residual risk is acceptable.
(d) Agree that the benefit of using the device outweigh the residual risk
Benefit, as described by the potential benefit factors, may change over time.
Type of benefit(s) includes, but is not limited to, the medical device’s impact on patient health and clinical management. Examples include the effect of the device on patient treatment plans and quality of life; impact on survival and on ability to perform activities of daily living; and how much the medical device can aid in improving patient function, preventing loss of function, or providing relief from the symptoms of the disease or condition that the medical device is intended to treat.
Risk, as described by the potential risk factors, may change over time.
Severity of harm is categorized into three levels, each of which includes a duration component. The three levels are medical device-related deaths or serious injuries, medical device-related non-serious adverse events, and medical device-related events without reported harm.
Additional aspects:
Uncertainty any point in the total product life cycle, there is never 100% certainty regarding the safety, effectiveness, or quality of a device. The degree of certainty of the benefits and risks of a device is a factor REGULATOR considers when making benefit-risk assessments. Issues maybe due to the type of clinical information available (e.g., clinical trial data, real world evidence derived from registries or commercial experience), the degree to which the available information is representative (sample size, generalizability of the sample to the population exposed to the device), and the statistical inferences and limitations that can be drawn from the information.
Mitigations are actions taken by the manufacturer, by REGULATOR, or by other stakeholders to recover benefit or to limit harm. Mitigations could be clinical practice; use errors; unmet medical needs; the use environment; user population; user skill level; clinical understanding in assessing risk; current expectations in clinical use; any changes in medical practice, e.g., standard of care, that could increase risk; and use in emergency/crisis situations. Risk acceptability is assessed after any appropriate mitigation.
Detectability refers to whether nonconformity could be identified, either by the manufacturer or by the user.
Failure mode is the specific method or type of failure. The failure mode may be used to identify the cause of the nonconformance, including whether the nonconformance is related to manufacturing, design, use conditions, or environment.
Scope of the device issue should be evaluated to assess whether the risks identified are potentially inherent to similar devices of this type (i.e., whether the risk is specific to a single device, a single manufacturer, or is industry wide).
Patient impact is the impact on the health and quality of life of patients if a particular compliance or enforcement action is, or is not, taken or if the device relevant to the nonconformity or regulatory non-compliance is not available. REGULATOR and, where appropriate, industry should consider whether patients are better off if the device is or is not available.
Preference for availability relates to both the patient and the caregiver.
Nature of violations/Nonconforming product may include whether the violation was systemic or non-systemic in nature as well as the extent of any product nonconformity.
Firm compliance history may include the manufacturer’s regulatory history and initiative in identifying and correcting issues, the repetitiveness of such issues, and the manufacturer’s communication with REGULATOR.
Clinical evaluation shall follow a defined and methodologically sound procedure based on the following:
(a) a critical evaluation of the relevant scientific literature
- currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied: — it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate,
- the data adequately demonstrate compliance with the relevant general safety and performance requirements;
(b) a critical evaluation of the results of all available clinical investigations,
- taking duly into consideration whether the investigations were performed and
(c) a consideration of currently available alternative treatment options for that purpose, if any.
In the case of implantable devices and class III 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 by the manufacturer to be equivalent to the marketed device and this demonstration has been endorsed by the notified body, and
- the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device.
A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph:
— 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, and
— the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body.
The requirement to perform clinical investigations shall not apply to implantable devices and class III devices:
(a) 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 CS for the clinical evaluation of that kind of device, where such a Common Specification/ Standard (CS) e.g ISO/IEC; is available; or
(b) 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 CS, where such a CS is available.
Cases above to be justified in the clinical evaluation report by the manufacturer and in the clinical evaluation assessment report by the notified body.
· Where justified in view of well-established technologies,
· similar to those used in the exempted devices listed in point (b) of paragraph 6 of this Article, being used in other devices, or
· where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health,
CIv shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified.
Where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on:
· the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body,
· the clinical performance intended and
· the claims of the manufacturer.
In such a case, the manufacturer shall duly substantiate in the technical documentation why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre- clinical evaluation, to be adequate.
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
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.
1. To plan, continuously conduct and document a clinical evaluation, manufacturers shall:
(a) establish and update a clinical evaluation plan, which shall include at least:
— 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;
— a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters;
— a 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;
— an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device;
— an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non- viable animal or human tissues, are to be addressed; and
— a 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 to record an indication of milestones and a description of potential acceptance criteria;
(b) identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review;
(c) appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device;
(d) generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues; and
(e) analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits.
2. The clinical evaluation shall be thorough and objective, and take into account both favourable and unfavourable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer's claims in respect of the device.
3. A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence:
— Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements;
— Biological: the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables;
— Clinical: the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. 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.
Considerations of equivalence shall be based on proper scientific justification. 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.
The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device. The clinical evidence together with non-clinical data generated from non-clinical testing methods and other relevant documentation shall allow the manufacturer to demonstrate conformity with the general safety and performance requirements and shall be part of the technical documentation for the device in question. Both favourable and unfavourable data considered in the clinical evaluation shall be included in the technical documentation.
PMCF shall be understood to be a continuous process that updates the clinical evaluation 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.
PMCF shall be performed pursuant to a documented method laid down in a PMCF plan.
The PMCF plan shall specify the methods and procedures for proactively collecting and evaluating clinical data with the aim of:
(a) confirming the safety and performance of the device throughout its expected lifetime,
(b) identifying previously unknown side-effects and monitoring the identified side-effects and contraindications,
(c) identifying and analysing emergent risks on the basis of factual evidence,
(d) ensuring the continued acceptability of the benefit-risk ratio referred to in Sections 1 and 9 of Annex I, and
(e) identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct.
The PMCF plan shall include at least:
(a) the general methods and procedures of the PMCF to be applied, such as gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of clinical data;
(b) the specific methods and procedures of PMCF to be applied, such as evaluation of suitable registers or PMCF studies;
(c) a rationale for the appropriateness of the methods and procedures referred to in points (a) and (b);
(d) a reference to the relevant parts of the clinical evaluation report referred to in Section 4 and to the risk management ;
(e) the specific objectives to be addressed by the PMCF;
(f) an evaluation of the clinical data relating to equivalent or similar devices;
(g) reference to any relevant CS, harmonised standards when used by the manufacturer, and relevant guidance on PMCF; and
(h) a detailed and adequately justified time schedule for PMCF activities (e.g. analysis of PMCF data and reporting) to be undertaken by the manufacturer.
The manufacturer shall analyse the findings of the PMCF and document the results in a PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation.
The conclusions of the PMCF evaluation report shall be taken into account for the clinical evaluation and in the risk management. If, through the PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer shall implement them.
In the event of non compliance follow SOP NON CONFORMANCE CORRECTIVE ACTION
The Risk Assessment to is found in SOP PREVENTIVE ACTION RISK ASSESSMENT refer Document
The analytical reviews of supplier performance, and any other quality related matters, are reported to management and as part of the input to management review refer Data Analysis
The Trend analysis may identify any potential and recurring incidents, where corrective action must be reported at the management review to facilitate continual improvement.
Revision 10; 15.10.2024 - ML - Checked and Confirmed. Digitally signed by ML
Revision 9; 20.11.2023 - ML - Checked and Confirmed. Digitally signed by ML
Revision 8; 17.10.2022 - ML - Checked and Confirmed. Digitally signed by ML
Revision 7; 07.10.2021 - ML - Formatting. Digitally signed by ML
Revision 6; 10.05.2021 - ML - Digitally signed by ML
Revision 5, 30.04.2021 Updating the SOP to the new format. Approval / Scope / Risk Based Approach / Records and Revision History / numbering
Revision 4, Digitally signed on 08.01.2020 by TNA
Revision 1-3, unknown due to googlesite change to new googlesite
Name Retained by/ in Retention period Hard copies Destroyed by
Clinical Evidence Report Google Drive 5 years Management Representative deletion
Post Market Clinical
follow up Plan and Report Google Drive 5 years Authorised Representative deletion