GP-015 Clinical evaluation

Procedure flowchart

Purpose

To establish the methodology to collect, appraise and analyze clinical data related with the medical devices we manufacture to ensure that there is evidence of the accomplishment of the General Safety and Performance Requirements (GSPR) and any other applicable requirement.

Scope

All of our medical devices along their whole life cycle.

Responsibilities

JD-001

To consider the arguments provided by the JD-005 to decide the convenience of notifying the NCAs (National Competent Authorities) of the incident that occurred. To make the decision to proceed with the products' withdrawal from the market.

JD-005

To detect incidents or potential incidents and make the communications to the NCA. To perform and document the clinical evaluation of the products in the Technical File according to this procedure and to the T-015-001 Clinical evaluation plan (CEP).

JD-003

To provide to the JD-005 and JD-004 all existing information or documentation to include with each corresponding Technical File, and to review the documents created as a result of performing the activities described in this procedure within these Technical Files.

JD-004

To ensure that this procedure is performed and review when required and, together with the JD-003 and JD-005, to design, review and perform the T-015-001 Clinical evaluation plan (CEP), and elaborate and archive the corresponding associated report T-015-002 Preclinical and clinial evaluation record and T-015-003 Clinical evaluation report (CER).

Inputs

• Design and development process
• Clinical and preclinical data obtained from:
  • Literature.
  • Post-market surveillance.
  • Clinical investigations.

Outputs

• Evidence of compliance with the GSPR.
• T-007-001 Post-market surveillance (PMS) plan
• T-007-002 Post-market clinical follow-up (PMCF) plan
• T-007-003 PSUR
• T-015-001 Clinical evaluation plan (CEP)
• T-015-003 Clinical evaluation report (CER)
• T-015-004 Clinical Investigation Plan (CIP)
• T-015-005 Investigator's Brochure
• T-015-006 Clinical Investigation Report (CIR)
• T-015-007 Declaration of interest Clinical evaluation team
• T-015-008 Clinical development plan
• Review of the risk management policy, if applicable.

Development

Definitions

• CLINICAL EVALUATION: 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: any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device;
• INVESTIGATIONAL DEVICE: a device that is assessed in a clinical investigation;
• CLINICAL INVESTIGATION PLAN: a document that describes the rationale, objectives, design, methodology, monitoring, statistical considerations, organization and conduct of a clinical investigation;
• CLINICAL DATA: information concerning safety or performance that is generated from the use of a device and is sourced from the following:
  • clinical investigation(s) of the device concerned,
  • clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,
  • reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,
  • clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up;
• SPONSOR: any individual, company, institution or organization which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation;
• SUBJECT: an individual who participates in a clinical investigation;
• CLINICAL EVIDENCE: clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer;
• CLINICAL PERFORMANCE: the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer;
• CLINICAL BENEFIT: the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health;
• INVESTIGATOR: an individual responsible for the conduct of a clinical investigation at a clinical investigation site;
• INFORMED CONSENT: a subject's free and voluntary expression of his or her willingness to participate in a particular clinical investigation, after having been informed of all aspects of the clinical investigation that are relevant to the subject's decision to participate or, in the case of minors and of incapacitated subjects, an authorisation or agreement from their legally designated representative to include them in the clinical investigation;
• ETHICS COMMITTEE: an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organizations;
• ADVERSE EVENT: any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device;
• SERIOUS ADVERSE EVENT: any adverse event that led to any of the following:
  • death,
  • serious deterioration in the health of the subject, that resulted in any of the following:
  • life-threatening illness or injury,
  • permanent impairment of a body structure or a body function,
  • hospitalization or prolongation of patient hospitalization, medical or surgical intervention to prevent - life-threatening illness or injury or permanent impairment to a body structure or a body function,
  • chronic disease,
  • fetal distress, fetal death or a congenital physical or mental impairment or birth defect;
• DEVICE DEFICIENCY: any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer;
• POST-MARKET SURVEILLANCE: the activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions;

Procedure

Guidance and regulatory documents

• Royal Decree 192/2023 regarding the medical devices regulation.
• MDR 2017/745
• Royal Decree 1090/2015 regulating the clinical trials with medicines, the Ethics Committees and the Spanish Registry of Clinical Trials.
• MDCG 2020-1, 2020-5, 2020-6
• MDCG 2020-13: Quite helpful as it gives you an idea of the structure.
• MEDDEV 2.7/1 Rev. 4. (mostly for MDD, but still a good starting point; especially the list of proposed headings for a report at the end of the document).

Optionally:

• IMDRF/SaMD WG/N41 FINAL:2017
• IMDRF MDCE WG/N55 FINAL:2019
• IMDRF MDCE WG/N56 FINAL:2019
• IMDRF MDCE WG/N57 FINAL:2019

Generalities

The clinical evaluation is carried out throughout the whole life cycle of each family of medical devices, being a continuous, iterative and planned process.

Initially, the clinical evaluation is established at the beginning of the design and development process of the medical devices to identify the necessary data that must be generated in order to fulfil the GSPR. This first evaluation is based on the preclinical evaluation and state of the art.

Therefore, the clinical evaluation is intended to obtain evidence of compliance with the GSPR in order to achieve the approval of the Notified Body and the corresponding CE certificate, as well as to evaluate the product undesirable side-effects and the acceptability of the benefit-risk ratio.

Clinical evaluation during the design & development phase

The clinical evaluation is based on a thorough and objective analysis of available pre- and post-market clinical data relevant to the intended purpose, including clinical performance data and safety data. The clinical evaluation shall consider both favorable and unfavorable data. Before a clinical evaluation is undertaken, the manufacturer defines its plan, based on the GSPR that need to be addressed from a clinical perspective and including:

• Whether there are any design features of the device or target treatment populations that require specific attention.
• Whether data from equivalent devices can be used to support the safety and/or performance of the device in question.

According to the Guideline MEDDEV 2.7-1 rev.4, the clinical evaluation will contain, at least:

• Plan: to define the scope, clinical evaluation strategy, search strategy and data introduction (also referred to as clinical evaluation plan).
• Identification of pertinent standards and clinical data.
• Appraisal of each individual data set, in terms of its relevance, applicability, quality and clinical significance.
• Analysis of the individual data sets, through which conclusions are reached about the compliance with the GSPR, the information provided by the manufacturer contents and the residual risks.
• Clinical Evaluation Report (CER).

Clinical evaluation for the CE marking

It is required:

• To document that there is sufficient clinical evidence to demonstrate compliance with the GSPR and other applicable requirements that ensure clinical safety and performance;
• To identify aspects that must be systematically addressed during the Post-Market Surveillance (PMS) and the Post-Market Clinical Follow-up (PMCF) included in the T-007-003 PSUR required under the regulation of medical devices.

Updating the clinical evaluation

We have defined an annual update of the clinical evaluation. The justification for this frequency will be included in the T-015-001 Clinical evaluation plan and/or in the T-015-003 Clinical evaluation report. It will also be updated by the JD-004 and JD-005 within one year if new post-market surveillance information is received that has the potential to change the current evaluation, in accordance with Procedure GP-007 Post-market surveillance. When updating the clinical evaluation, the following should be verified:

• Whether the risk/benefit, residual risks and risk mitigation measures still remain:
  • Effective to guarantee a high level of safety and performance in accordance with the current knowledge or the state of the art;
  • Consistent in relation to the documentation supplied by the manufacturer to the customer;
  • Properly addressed by our current post-market surveillance plan.
• That corresponds to the feedback obtained and analyzed by us.

With all this, the new data from the clinical evaluation may lead to changes in the risk management in accordance with the Procedure GP-013 Risk management.

Management of averse events

Due to the nature of the device, the investigation methods we use during our clinical investigation do not require any invasive procedure, and most importantly: do not involve a greater risk for the patient than would correspond to their care in normal clinical practice. As such, the investigation protocols typically do not need to consider adverse event handling.

If and when the investigation design allows for the possibility of any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, this will be regulated in the protocol of the invetigation, following Good Clinical Practices.

Stages of the clinical evaluation

Definition of the Clinical Evaluation Plan (CEP) (Stage 0)

Before the clinical evaluation is undertaken, we define its scope and establish and update a T-015-001 Clinical evaluation plan that includes, at least:

• The device description
• An identification of the GSPR that require support from relevant clinical data;
• A specification of the intended purpose of the product;
• A clear specification of the intended target groups with clear indications and contraindications;
• A detailed description of the intended clinical benefits to patients with relevant and specified clinical outcome parameters;
• Information needed for evaluation of equivalence, if equivalence may possibly be claimed;
• A specification of the methods to be used for the examination of the 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 the 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 product;
• An indication how the risk-benefit issues relating to specific components, such as the use of pharmaceuticals, non-viable animal or human tissues, are to be addressed; and
• A clinical development plan indicating progression from exploratory investigations (for example, first-in-man studies, feasibility and pilot studies) to confirmatory investigations (for example, pivotal clinical investigations) and post-market clinical follow-up, with an indication of the milestones and a description of potential acceptance criteria.

Identification of pertinent data (Stage 1)

The justification of the used source of the clinical data is established in the technical documentation, and may come from information from other established procedures as GP-014 Feedback and complaints, GP-007 Post-market surveillance and GP-013 Risk management, from the study of bibliographic information, from all pre market clinical investigations or from a clinical investigation carried out for this purpose.

All these data will be identified, disclosed and made available to the evaluators, and properly documented.

Data retrieved from literature search

This type of data includes, at least, applicable standards, data that relates to reference products, critical components of other devices, and specific medical conditions and patient populations to which the product is intended to target in order to establishing:

• Clinical data relevant to the device under evaluation
• Current State of the art (SOTA): clinical background, potential clinical hazards, equivalence.

The literature search protocol (designed according to MedDev 2.7/1 rev 4 guide) should be objective and include:

• The data sources to be used and a justification for their choice;
• The scope of any search in scientific literature databases (the database search strategy);
• The selection/criteria to be applied to the published literature and the rationale for their choice;
• Strategies to address the potential for data duplication in multiple publications.

Data generated through clinical experience

This type of data is generated through clinical use that is outside of the performance of clinical investigations and may be related to the product in question, and include at least:

• Reports, records or post-market surveillance studies generated by us;
• Databases of adverse events;
• Data for the device in question generated from individual patients under compassionate use programs prior to the device commercialization;
• Details of clinically relevant field corrective actions.

Data generated from clinical investigations

All the clinical investigations ruled out by us will be performed in accordance with the MDR 2017/745 regulation Annex XV and ISO 14155:2020 standard:

Main aspects to consider

• Clinical research should be conducted in accordance with the ethical principles originating in the Declaration of Helsinki.
• Before initiating a clinical investigation, foreseeable risks and inconveniences should be considered in relation to the expected benefit, both for the individual research subject and for society. A clinical investigation should be initiated and continued only if the anticipated benefits justify the risk.
• The rights, safety, and welfare of human subjects are the most important considerations and override the interests of science and society. The sponsor of the clinical investigation shall be responsible for ensuring that an insurance or financial guarantee has been taken out to cover damages suffered as a result of the clinical investigation.
• Available clinical and non-clinical information on an investigational product should be sufficient to support the proposed clinical investigation.
• Clinical investigations should be scientifically justified and described in a clear and detailed T-015-004 Clinical Investigation Plan (CIP) or Clinical study protocol containing the information related at this mentioned template. Amendments to the clinical research plan and the justification for these changes will be recorded.
• A clinical investigation should be conducted in accordance with the CIP or protocol that has previously received a favorable opinion from an Ethics Committee and, where appropriate, approval/no objection from the National Competent Authorities, and the documentation, opinions and comments of the ethics committees relevant to each one will be properly archived.
• The medical care received by subjects and the medical decisions made on their behalf should always be the responsibility of a qualified physician.
• Each individual involved in the design, conduct, recording and reporting of a clinical investigation should be qualified, by degree, training and experience, to perform his or her respective task.
• Freely given informed consent should be obtained from each subject prior to participation in the clinical investigation.
• All information related to clinical research should be recorded, managed and archived in a secure manner that allows for accurate reporting, interpretation, monitoring, auditing and verification.
• The confidentiality of records that could identify subjects should be protected while respecting privacy and confidentiality standards.
• Investigational products should be designed, manufactured, handled, and stored in accordance with the essential principles. Investigational products should be used in accordance with the approved CIP, the T-015-005 Investigator's Brochure, and the manufacturer's instructions for use.
• Systems with procedures that ensure the quality of every aspect of the clinical investigation should be implemented.
• The record should be submitted and keep updated in the EUDAMED database, in accordance with Article 70(2) of the MDR.

Study Completion

• The monitor(s) will perform final closeout activities, including documentation of monitoring activities.
• After final closure of the clinical investigation, a T-015-006 Clinical Investigation Report (CIR), or an equivalent document containing the information related at this mentioned template, should be written, even if the clinical investigation was suspended or terminated early.
• A formal review of the risk information should be conducted after the clinical investigation is completed, including, in the risk analysis and clinical evaluation, an update of the benefit-risk conclusions.

Appraisal of pertinent data (Stage 2)

Each piece of data identified in the previous stage is appraised to determine its suitability to address questions about the device, and its contribution to demonstrate the safety and performance of the device.

Therefore, the evaluators should:

• Identify information contained in each document;
• Evaluate the methodological quality of work done by the authors and, from that, the scientific validity of the information;
• Determine the relevance of the information to the clinical evaluation; and
• Systematically weight the contribution of each data set to the clinical evaluation.

The appraisal plan

The evaluators should set up an appraisal plan and document it within the T-015-003 Clinical evaluation report that describes the procedure and the criteria to be used for the appraisal. It should include criteria for determining the methodological quality and the scientific validity of each data set, the relevance to the clinical evaluation and criteria for weighting the contribution of each data set to the overall clinical evaluation.

• The appraisal should be thorough and objective.
• The criteria adopted for the appraisal should reflect the nature, the history and the intended clinical use of the device.
• The appraisal will be performed for each document, in relation to the similarity with the device developed. It cannot be possible to base on standard techniques because the clinical evaluation process is analysed as global, with small contributions from accepted publications. There is no valid source of information to evaluate the whole device.

Finally, we develop a systematic procedure that relates the methodological quality (Q), the relevance (R) and the contribution (C) of the data to assess it against the objectives of the clinical evaluation:

Data characteristics	Methodological quality Q	Relevance, R	Contribution, C	Weighted value, W (W=Q+R+C)	Appraisal data	Notes
Very relevant information in relation with the product and its intended use	Up tp 40	Up to 30	Up to 30	W ≥ 70	Accepted	Pivotal data
Relevant information in relation with the product and its intended use	Up to 40	Up to 30	Up to 30	30 < W < 70	Accepted	Other data
Little relevant information in relation with the product and its intended use	Up to 40	Up to 30	Up to 30	W ≤ 30	Rejected	No contribution, rejected

The rejection of any data source must be justified. Only the data sets with the highest weight pass on to the next analysis stage, rejecting the other sources. The aspects considered when determining the relevance are documented as part of the assessment of each piece of data.

Device equivalence

Clinical data related to more than one equivalent device can also be used in the clinical evaluation. The manufacturer of the product may demonstrate to be equivalent to an already marketed device. Technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence. The characteristics shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. In addition, these considerations shall be based on proper scientific justification, and the manufacturer shall demonstrate that he/she has sufficient levels of access to the data relating to devices with which he/she is claiming equivalence. We will use the equivalence table from the Annex I of the Guideline MDCG 2020-5 (see below). The items in the first column of the table are examples only and are to be considered as such.

1. Technical Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Device is of similar design			1.1
Used under similar conditions of use			1.2
Similar specifications and properties including software algorithms			1.3
Uses similar deployment methods where relevant			1.4
Has similar principles of operation and critical performance requirements			1.5

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
1.1
1.2

2. Biological Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Uses the same materials or substances in contact with the same human tissues or body fluids			(The characteristic must be the same for the demonstration of equivalence) 2.1

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
2.1

3. Clinical Characteristics (add a separate row for each of the assessed characteristics)	Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents	Device 2 (marketed device) Description of characteristics and reference to specifying documents	Identified differences or conclusion that there are no differences in the characteristic
Same clinical condition or purpose, including similar severity and stage of disease			3.1
Same site in the body			(The characteristic must be the same for the demonstration of equivalence) 3.2
Similar population, including as regards age, anatomy and physiology			3.3
Same kind of user			(The characteristic must be the same for the demonstration of equivalence) 3.4
Similar relevant critical performance in view of the expected clinical effect for a specific intended purpose			3.5

Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable)	Clinically significant difference Yes / No
3.1
3.2

Summary

In the circumstance that more than one non-significant difference is identified, provide a jsutification whether the sum of differences may affect the safety and clinical performance of the device.

Analysis of the clinical data (Stage 3)

The objective of this analysis is to determine if the evaluated data demonstrates compliance with the GSPR. For it, the evaluators must demonstrate, at least, that:

• The product works according to the intended purpose described by the manufacturer;
• The product does not pose undue security problems to the final user or other people;
• Any risk associated with the usage of the product is acceptable when compared to the benefits to the patient;
• The aduquacy of the information material supplied.

In addition, we will determine with this analysis if additional clinical investigations or other measures are necessary, and the PMCF needs.

Elaboration of the Clinical Evaluation Report (CER)

We elaborate a T-015-003 Clinical evaluation report (CER) to document the clinical evaluation, its results and the clinical evidence derived from it. This report should contain sufficient information to be read and understood by an independent party (e.g. regulatory authority or notified body). Therefore, it should provide sufficient detail to understand the search criteria adopted by the evaluators, the data that is available, all the assumptions and all the conclusions reached.

The content of the T-015-003 Clinical evaluation report (CER) shall be cross-referenced to the relevant documents that support it. It should be clear which statements are supported by which data, and which ones reflect the conclusions of the evaluators.

The report should include references to 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 corresponding technical documentation (file name and chapter of the evidence).

The amount of information may differ according to the history of the device or technology. Where a new device or technology has been developed, the report would need to include an overview of the development process and the points in the development cycle at which all the data have been generated.

According to the Guideline MEDDEV 2.7-1 rev.4, the T-015-003 Clinical evaluation report (CER) should contain, at least:

• General details (name of the product and of the manufacturer);
• Description of the device (materials, components, accessories, mechanical characteristics…) and its intended purpose;
• Intended therapeutic and/or diagnostic indications and claims;
• Context of the evaluation and choice of the clinical data types;
• Summary of the clinical data and appraisal;
• Data analysis
  • Performance
  • Safety
  • Product literature and instructions for use
• Conclusions.

Additionally, we compile an overview of the process by which we provide evidence of the performance of each device in the T-015-008 Clinical development plan record within each product technical file.

Qualification and experience

The evidence of the qualification of the personnel participating in the clinical evaluation is documented in the T-005-002 Personnel cards.

The criteria established regarding the knowledge that the personnel participating in the clinical evaluation should have are, at least, the following:

• Knowledge of the product technology.
• Specialized clinical experience in the clinical conditions for which the product will be used.
• University degree and 5 years of documented professional experience in the field or sector, or 10 years of experience in the absence of academic requirements.
• Experience with scientific databases and in the systematic and critical review of clinical data.

Additionally, each evaluator signs their Declaration of interests (T-015-007 Declaration of interest Clinical evaluation team) and CV, that are also archived at the corresponding clinical evaluation folder within each product technical file.

Associated documents

• T-005-002 Personnel cards
• GP-007 Post-market surveillance
• T-007-001 Post-market surveillance (PMS) plan
• T-007-002 Post-market clinical follow-up (PMCF) plan
• T-007-003 PSUR
• GP-013 Risk management
• GP-014 Feedback and complaints
• T-015-001 Clinical evaluation plan (CEP)
• T-015-002 Preclinical and clinial evaluation record
• T-015-003 Clinical evaluation report (CER)
• T-015-004 Clinical Investigation Plan (CIP)
• T-015-005 Investigator's Brochure
• T-015-006 Clinical Investigation Report (CIR)
• T-015-007 Declaration of interest Clinical evaluation team
• T-015-008 Clinical development plan

Signature meaning

The signatures for the approval process of this document can be found in the verified commits at the repository for the QMS. As a reference, the team members who are expected to participate in this document and their roles in the approval process, as defined in Annex I Responsibility Matrix of the GP-001, are:

• Author: Team members involved
• Reviewer: JD-003
• Approver: JD-004