R-TF-015-004 Clinical investigation plan

Scope

This Clinical Investigation Plan (CIP) outlines the rationale, objectives, design, and methodology for the clinical investigation.

CIP Identification

	CIP
Title of the clinical investigation	Project to enhance Dermatology E-Consultations in Primary Care Centres using Artificial Intelligence Tools
Device under investigation	Legit.Health Plus
Protocol version	Version 1.0
Date	2022-06-29
Protocol code	LEGIT.HEALTH_DAO_Derivación_PH_2022
Sponsor	Instituto de Investigación Sanitaria Puerta de Hierro
Coordinating Investigator	Dr. Gastón Roustan Gullón
Principal Investigator(s)	Dr. Gastón Roustan Gullón
Investigational site(s)	Pozuelo and Majadahonda Health Centers and Puerta del Hierro Majadahonda University Hospital
Ethics Committee	Comité de Ética de la Investigación con Medicamentos del Hospital Universitario Puerta del Hierro de Majadahonda

Trial Registrations

• ClinicalTrials.gov (NCT): NCT07429123
• EMA RWD Catalogue (EUPAS): EUPAS108166

Table of contents

• Scope
• CIP Identification
  • Trial Registrations
• Compliance statement
• Abbreviations and definitions
• CIP or protocol specifications
  • Principal Investigator
  • Coordinating investigator
  • Collaborating Investigator(s)
  • Investigational sites
  • Funding
• Product Identification and Description
• Justification of the design
  • Background and rationale
  • Risks and benefits of the product in investigation and clinical research
• Hypothesis
• Objectives
  • Primary objective
  • Secondary objective(s)
• Summary of the study
• Design and methods
  • Type of clinical research
  • Population
  • Sample size
  • Duration
  • Acceptance criteria
  • Inclusion and exclusion criteria
    • Inclusion criteria
    • Exclusion criteria
  • Variables
    • Main variable
    • Secondary variables
  • Condition of interest
  • Limitations of clinical research
• Ethical considerations
  • Data confidentiality
  • Bias minimization measures
  • Calendar
  • Monitoring plan
  • Completion of the investigation
  • Statistical analysis
  • Data management
• CIP Modification
• CIP Deviations
• Start, follow-up and end reports
• Statements of compliance
• Informed Consent process
• Adverse events, adverse product reactions and product deficiencies
  • Adverse Events (AE) and Adverse Events to the Product (AEP)
  • Product deficencies
  • Serious Adverse Events, serious adverse events to the product and serious and unexpected adverse events to the product
  • Foreseeable adverse events and adverse events to the product
  • Data Monitoring Committee (DMC)
• Annexes
  • Annex I. Protocol of the study
  • Annex II. Ethics committee approval
  • Annex III. Patient information sheet
  • Annex IV. Informed consent

Compliance statement

The clinical investigation will be conducted according to the Clinical Investigation Plan (CIP) and other applicable guidances and regulations. This includes compliance with:

• The ethical principles originating from the World Medical Association's Declaration of Helsinki
• Harmonized standard UNE-EN ISO 14155:2020
• Regulation (EU) 2017/745 on medical devices (MDR), including the applicable General Safety and Performance Requirements (GSPR) as outlined in Annex I, and the requirements of Annex XV (Chapter I and Chapter II, Section 3)
• Harmonized standard UNE-EN ISO 13485:2016
• MDCG 2024-3 for its structural and content expectations, MDCG 2021-8 concerning application requirements, and MDCG 2020-10/1 Rev 1 for safety reporting timelines and definitions
• Regulation (EU) 2016/679 (GDPR)
• Spanish Organic Law 3/2018 on the Protection of Personal Data and guarantee of digital rights.

All data processing within the device is carried out in accordance with the highest standards of data protection and privacy. Patient information is managed in an encrypted manner to ensure confidentiality and security.

The research team assumes the role of Data Controller, responsible for the collection and management of study data. Legit.Health acts as the Data Processor and is not involved in the processing of patient data.

The storage and transfer of data comply with European data protection regulations. At the conclusion of the study, all information stored in the device will be permanently and securely deleted.

The device employs robust technical and organizational security measures to safeguard personal data against unauthorized access, alteration, loss, or processing.

Abbreviations and definitions

• AE: Adverse Event
• AEMPS: Spanish Agency of Medicines and Medical Devices
• AEP: Adverse Reaction to Product
• AUC: Area Under the ROC Curve
• CAD: Computer-Aided Diagnosis
• CMD: Data Monitoring Committee
• CIP: Clinical Investigation Plan
• CUS: Clinical Utility Questionnaire
• DLQI: Dermatology Quality of Life Index
• GCP: Standards of Good Clinical Practice
• ICH: International Conference of Harmonization
• IFU: Instructions For Use
• IRB: Institutional Review Board
• N/A: Not Applicable
• NCA: National Competent Authority
• PI: Principal Investigator
• PPV: Positive Predictive Value
• NPV: Negative Predictive Value
• SAE: Serious Adverse Events
• SAEP: Serious Adverse Event to Product
• SUAEP: Serious and Unexpected Adverse Event to the Product
• SUS: System Usability Scale

CIP or protocol specifications

Principal Investigator

• Dr. Gastón Roustan Gullón (Hospital Universitario Puerta del Hierro de Majadahonda).

Coordinating investigator

• Dr. Gastón Roustan Gullón (Hospital Universitario Puerta del Hierro de Majadahonda).

Collaborating Investigator(s)

• Hospital Universitario Puerta de Hierro de Majadahonda
  • Dr. Ángel Rosell Díaz
• Centro de salud de Majadahonda
  • Dr. Esther Minguela
• Centro de salud de Pozuelo
  • Dr. Fernando León

Investigational sites

• Hospital Universitario Puerta de Hierro Majadahonda
• Centro de Salud de Majadahonda
• Centro de Salud de Pozuelo

Funding

This research was carried out without any funding or sponsorship.

Product Identification and Description

	Information
Device name	Legit.Health Plus (hereinafter, the device)
Model and type	NA
Version	1.1.0.0
Basic UDI-DI	8437025550LegitCADx6X
Certificate number (if available)	MDR 792790
EMDN code(s)	Z12040192 (General medicine diagnosis and monitoring instruments - Medical device software)
GMDN code	65975
EU MDR 2017/745	Class IIb
EU MDR Classification rule	Rule 11
Novel product (True/False)	TRUE
Novel related clinical procedure (True/False)	TRUE
SRN	ES-MF-000025345

Justification of the design

Background and rationale

Skin-related conditions are a frequent cause of primary care consultations, accounting for around 5% of visits, placing a significant demand on healthcare resources. Primary care practitioners (PCPs) often lack specialized knowledge in dermatology, leading to discrepancies in diagnoses compared to dermatologists, with diagnostic agreement rates ranging between 57% and 65%. This diagnostic gap and the limited availability of dermatologists, especially in rural areas, make efficient management of skin conditions by PCPs essential to improve patient outcomes and reduce healthcare costs.

Additionally, the shortage of dermatologists (only 3 per 100,000 inhabitants) complicates access to specialists, leading to potential misdiagnoses and delays in care. Teledermatology, such as the teleDERMADRID project, has helped alleviate some of this burden by enabling remote consultations and reducing unnecessary referrals. However, further innovations are needed to enhance diagnostic accuracy at the primary care level and optimize patient referral processes.

This study aims to clinically validate an artificial intelligence (AI)-based tool designed to assist primary care practitioners in improving the appropriateness of dermatology referrals. By leveraging AI, the tool can enhance diagnostic accuracy, facilitate timely patient triage, and reduce unnecessary referrals, ultimately improving the efficiency of healthcare delivery and patient outcomes in dermatology.

Risks and benefits of the product in investigation and clinical research

Participants in this study did not undergo any procedures posing a risk to their safety. Using the device could optimize patient diagnosis, reduce healthcare costs and consultation time, and enable better treatment.

Hypothesis

The device significantly improves the appropriateness of dermatology referrals by providing greater sensitivity and specificity than primary care practitioners (PCPs) in diagnosing skin conditions, particularly in differentiating between malignant and benign lesions. Additionally, it provides the clinical reassurance of a second medical opinion with validated diagnostic support.

Objectives

Primary objective

To validate that the information provided by the device increases the true accuracy of healthcare professionals (HCPs) in the diagnosis of multiple dermatological conditions.

Secondary objective(s)

• Reduce and correct the referral of patients with skin pathologies from primary care to dermatology.
• Individualize and improve the ongoing training of primary care practitioners in the area of dermatology.
• Offer healthcare adapted to technological innovations.
• Measure the satisfaction of primary care practitioners with the device.
• Measure the satisfaction of dermatologists with the device.

Summary of the study

This is a prospective, observational and analytical study designed to assess if the device is a valid tool to improve the accuracy of healthcare professionals in the diagnosis of dermatological conditions. This investigation encompasses a diverse cohort of 100 patients, which intend to represent the studied population with various dermatological conditions. Data collection will include questionnaires (Clinical Utility Questionnaire), photograph analysis, and the analysis of demographical and clinical data. The study adhered to strict ethical guidelines, ensuring patient confidentiality and compliance with international standards. Patients were provided with detailed information and informed consent. The study's robust methodology aimed to assess the clinical utility and usability of the device.

Design and methods

Type of clinical research

We will carry out an observational and analytical study with longitudinal character to assess the performance of the device improves the accuracy in the diagnosis of skin conditions and in a real-world environment. On one hand, in this investigation, there will be a group of 100 patients with different skin conditions. On the other hand, there will be a group of HCPs, which consists of primary care practitioners and dermatologists. In this case, there will not be a control group, since the HCPs themselves will be assessed using the device and without using it, after that, we will assess if the use of the device improves the accuracy of the diagnosis.

Population

Adult patients (>18 years) diagnosed with skin conditions that meet the inclusion criteria. These patients will be treated in their health centres (Pozuelo and Majadahonda Health Centres) and referred to the dermatology service of the Puerta del Hierro Majadahonda University Hospital.

Sample size

The goal of this study is to evaluate whether the use of the device by HCPs can improve the diagnostic accuracy of skin pathologies by at least 10%. The 10% improvement refers to an increase in the proportion of correct diagnoses compared to baseline performance. This level of improvement would provide a strong justification for a meaningful change in clinical practice. Consequently, 15 HCPs will participate in this study, which provides a strong basis and ensures sufficient statistical power. For this reason, assuming the diagnostic accuracy is measured as a proportion (e.g., correct diagnoses), a sample size of 100 patients can provide a 95% confidence level with a margin of error of around 9-10% for the accuracy rate and 80% of power.

The sample size is sufficient for evaluating qualitative assessments, such as evaluating usability, satisfaction, and clinical utility, using validated scales and descriptive statistics. Each HCP will interact with 6-7 patients on average (100 patients distributed across 15 doctors), ensuring a manageable workload and thorough evaluation of each case. However, subgroup analysis may be limited by the small number of participants per group. The design provides a solid foundation for detecting meaningful improvements in diagnostic accuracy, HCP satisfaction and exploring the usability of the device in clinical settings.

Duration

This study estimates a recruitment period of approximately 4-6 months.

The total duration of the study is estimated at 5-6 months, including the time required after the recruitment of the last subject for closing and editing the database, data analysis, and preparation of the final study report. We estimate a period of 1 month for the data analysis.

The total duration of the study for each participant will be 1 day from the date of inclusion.

Acceptance criteria

• AUC (area under the ROC curve) equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
• increase in the adequacy of referrals equal to or greater than 15.00%.(User Group: Dermatologists)
• Expert consensus equal to or greater than 70.00%.(User Group: Dermatologists)

Inclusion and exclusion criteria

Inclusion criteria

Patients suspected of having the following conditions in Primary Care:

• Tumor pathology:
  • Benign:
    • Histiocytoma
    • Seborrheic keratosis
    • Angiomas
  • Precancerous:
    • Actinic keratosis
  • Suspected malignancy:
    • Basal cell carcinoma
    • Squamous cell carcinoma
  • Pigmented lesions:
    • Melanocytic nevus
    • Malignant melanoma
• Inflammatory pathology:
  • Psoriasis
  • Atopic dermatitis
  • Urticaria
  • Hidradenitis suppurativa
  • Lichen planus
• Infectious pathology:
  • Viral warts
  • Molluscs
  • Herpes simplex
• Patients aged 18 years or older.
• Patients who have signed the informed consent for the study.

Exclusion criteria

• Patients under 18 years of age.
• Pregnant patients.
• Patients who, in the opinion of the researcher, will not comply with the study procedures.

Variables

Main variable

• The accuracy of the diagnosis of skin pathologies by primary care practitioners using and without using the device to make their diagnosis.

Secondary variables

• Patient demographics: Sex and age.
• Teleconsultation data: Response time, Response label (PC follow-up, shared follow-up, dermatology follow-up, insufficient or inadequate information).
• In-person consultation data: Duration of in-person dermatology consultation to respond to the PC e-consultation, Waiting time until being seen in a monographic consultation.
• Diagnoses: Diagnostic correlation between primary care and dermatology, Number of patients referred for pathology, Diagnostic correlation between primary care, dermatology and dermatopathology (if required), Time elapsed from the day seen in primary care and the day of the anatomopathological diagnosis (if required).
• Satisfaction of primary care practitioners using the Clinical Utility and Satisfaction Questionnaire.
• Satisfaction of dermatologists using the Clinical Utility and Satisfaction Questionnaire.

Condition of interest

Patients with any of the following dermatological pathologies: Histiocytoma, Seborrheic keratosis, Angiomas, Actinic keratosis, Basal cell carcinoma, Squamous cell carcinoma, Melanocytic nevus, Malignant melanoma, Psoriasis, Atopic dermatitis, Urticaria, Hidradenitis suppurativa, Lichen planus, Viral warts, Molluscs and Herpes simplex.

Limitations of clinical research

The main limitation of machine learning is the quantity and quality of the images collected. Variability in lighting, colour, shape, size and focus are key factors, as well as the number of images per patient. This means that high variability within the same patient and an insufficient number of images to reflect this variability can result in lower-than-expected accuracy.

Ethical considerations

This study adhered to international Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki in its latest amendment, and applicable international and national regulations. As applicable, approval from the relevant Ethics Committee was obtained prior to the initiation of the study. When applicable, modifications to the protocol were reviewed and approved by the Principal Investigator (PI) and subsequently evaluated by the Ethics Committee before subjects were enrolled under a modified protocol.

This study was conducted in compliance with European Regulation 2016/679, of 27 April, concerning the protection of natural persons with regard to the processing of personal data and the free movement of such data (General Data Protection Regulation, GDPR), and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and the guarantee of digital rights. In accordance with these regulations, no data enabling the personal identification of participants was collected, and all information was managed securely in an encrypted format.

Participants were informed both orally and in writing about all relevant aspects of the study, with the information being tailored to their level of understanding. They were provided with a copy of the informed consent form and the accompanying patient information sheet. Adequate time was given to patients to ask questions and fully comprehend the details of the study before providing their consent.

The PI was responsible for the preparation of the informed consent form, ensuring it included all elements required by the International Conference on Harmonisation (ICH), adhered to current regulatory guidelines, and complied with the ethical principles of GCP and the Declaration of Helsinki.

The original signed informed consent forms were securely stored in a restricted access area under the custody of the PI. These documents remained at the research site at all times. Participants were provided with a copy of their signed consent form for their records.

Data confidentiality

Current legislation will be complied with in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons with regard to the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on Personal Data Protection and guarantee of digital rights). For this purpose, when applicable, each participant will receive an alphanumeric identification code in the study that will not include any data allowing personal identification (coded CRD). The Principal Investigator will have an independent list that will allow the connection of the identification codes of the patients participating in the study with their clinical and personal data. This document will be filed in a secure area with restricted access, under the custody of the Principal Investigator and will never leave the centre.

Once the paper CRDs are completed and closed by the Principal Investigator, the data will be transferred to a database.

As in the CRDs, the Database will comply with current legislation in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons about the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and guarantee of digital rights) in which no data allowing personal identification of patients will be included.

Bias minimization measures

In clinical research, minimizing bias is essential to ensure the validity and reliability of the study's results. In this study, patients will be randomly selected to participate in this. Furthermore, we will use standarised protocols, Using standardized procedures for conducting the study and measuring outcomes ensures that all participants are treated and evaluated in the same way, reducing variability due to differences in how the intervention is applied or how outcomes are assessed. Finally, Collecting data prospectively reduces the chance that participants or investigators will inaccurately recall past events, which is common in retrospective studies.

Calendar

This study estimates a recruitment period of approximately 4-6 months. The total duration of the study is estimated at 5-6 months, including the time required after the recruitment of the last subject for closing and editing the database, data analysis, and preparation of the final study report. The total duration of the study for each participant will be just 1 day from the date of inclusion.

Monitoring plan

The team will hold a meeting with the investigative team every 3 months to address any potential questions and ensure that data is being collected properly.

The clinical investigation will be monitored by a designated clinical monitor, who is independent of the investigational site and appointed by the sponsor. The purpose of monitoring is to ensure that:

• The rights, safety, and well-being of the subjects are protected.
• The data reported are accurate, complete, and verifiable from source documents.
• The clinical investigation is conducted in compliance with the Clinical Investigation Plan (CIP), applicable regulatory requirements (including Regulation (EU) 2017/745), and ISO14155:2020.

In this way, monitoring will be performed through:

• Remote monitoring activities: Including scheduled video or telephone meetings depending on the availability of the investigators to review study progress, discuss challenges, and ensure ongoing compliance.
• On-site visits: If deemed necessary based on data review, protocol deviations, or issues raised during remote monitoring.
• Source data verification (SDV): The sponsor in this case has secure access to anonymised source documents (e.g., image files, clinical assessment records) via encrypted digital platforms or controlled site systems to verify data accuracy and consistency with Case Report Forms (CRFs).
• Risk-based monitoring approach: The extent and frequency of monitoring activities will be adapted to the complexity and risk level of the investigation. Given that this study does not involve significant deviation from routine care, the monitoring will be primarily remote unless specific issues arise.

All monitoring activities will be documented in monitoring visit reports. Any protocol deviations or non-compliance identified will be documented, assessed for impact, and communicated promptly to the sponsor. Corrective actions will be tracked and followed up by the monitor or the sponsor.

Completion of the investigation

After the final closure of the clinical investigation, a Clinical Investigation Report (CIR: T-015-006 Clinical Investigation Report) will be drafted, even in the event of early termination or suspension. The CIR will be provided to the Ethics Committee and the Spanish Agency for Medicines and Medical Devices (AEMPS). The results obtained (whether positive, inconclusive, or negative) will be included in the previously mentioned public access database.

Additionally, if deemed appropriate, the results may be published in scientific journals. The Ethics Committee that approved this clinical investigation will be acknowledged, and any funds received by the author for the study and its source of funding will be disclosed. The anonymity of participants in the clinical investigation will be maintained at all times.

Upon completion of the study, the results of the clinical utility and satisfaction surveys, as per the annexed models, may be presented at conferences and scientific meetings, subject to prior authorization by both parties. Press releases and other communications may also be issued to share the study's results. All publications and communications must be reviewed and approved by the parties involved.

Statistical analysis

Each variable will be characterized using frequency distributions for qualitative variables and central tendency statistics such as mean and median and variability statistics such as standard deviation (S.D.) or interquartile range for quantitative variables according to their distributional characteristics.

Between-group and within-group comparisons will be made using parametric tests whenever the distributional characteristics of the data allow it. For intergroup comparisons, one- and two-factor Analysis of Variance techniques will be used with post-hoc comparisons if significant overall differences are detected. To assess intra-group changes, Student's t-test for related samples or Analysis of Variance/ANOVA with repeated measures will be used if the theoretical assumptions of the model are supported by the data. Otherwise, more flexible models (GEE) that allow incorporating different autocorrelation structures of the data will be fitted.

Comparisons between groups with respect to qualitative variables will be carried out by means of contingency tables and Fisher's exact or Chi-square tests. The probability of type I error will not be adjusted for multiple comparisons. The level of statistical significance in the contrasts (alpha) will be 5 per cent with bilateral contrasts.

Analyses will be performed using appropriate statistical software, SPSS version 23.0 and STATA 13.0. Values of p less than 0.05 will be considered significant.

Data management

The data will be managed and tabulated with consistency rules and logical ranges to control inconsistencies during data tabulation. A validation process of the clinical data will be carried out by running computer filters based on validation rules, which will automatically identify missing values or inconsistencies of clinical data according to the protocol. Additionally, manual editing and validation will be performed using descriptive and exploratory statistical techniques to complement the detection of logical errors and inconsistent values.

The database will be considered closed upon completion of all data management processes and satisfactory resolution of discrepancies and errors in the data. Any changes in the database after its closure can only be made after written agreement between the Principal Investigator and the technical coordinators of the project.

AI Labs Group, S.L. (hereinafter, the manufacturer) is the owner of the device. During the period of validity of this study, the manufacturer will grant a license to use the device by the research team free of charge. The research team will be the administrator of the account. Both patients and members of the medical team will have login credentials. The manufacturer will not have access to the account or patient information.

According to the definitions and roles set out in Regulation (EU) 2016/679 (GDPR), the Data Controller is the research team and the manufacturer is the Data Processor.

The storage of data and photographs will be in line with the European Regulation 2016/679 (GDPR) and the Organic Law 3/2018 of 5 December on the Protection of Personal Data and guarantee of digital rights. At the end of the study, all information stored in the device will be totally and permanently deleted.

The device complies with current legislation on the protection and confidentiality of personal data European Regulation 2016/679 (GDPR). Appropriate technical and organizational security measures are adopted to ensure the security of personal data and prevent its alteration, loss, unauthorized processing or access, given the state of technology, the nature of the data and the risks to which they are exposed, whether from human action or the natural physical environment.

CIP Modification

As indicated in the UNE-EN ISO 14155:2021 standard, the Clinical Investigation Plan (CIP) may be modified as necessary during the clinical investigation. The changes made must be described, along with their justification, potential impact on clinical performance, efficacy, safety, or other evaluation criteria, and identification of other affected documents.

CIP modifications will be prepared by the sponsor and agreed upon and accepted between the sponsor and the principal investigator. The modifications will be recorded with a justification for each one in the form of an amendment or addendum.

The required regulatory authority (AEMPS) and the Ethics Committee or Institutional Review Board (IRB) will be notified, if necessary. Modifications to the clinical investigation may only be implemented once favourable feedback and the corresponding approval have been obtained.

In accordance with Article 75 of Regulation (EU) 2017/745, substantial modifications to the clinical investigation must be approved by both the Ethics Committee for investigation with medicines (CEIm) and the Competent Authority (AEMPS) prior to their implementation.

• In the case of substantial modifications to authorized clinical investigations, a request must be submitted to the AEMPS and the CEIm.
• For non-substantial modifications to authorized clinical investigations, until the corresponding module is available in the EUDAMED database, the updated documentation will be sent to the AEMPS for inclusion in their file.

CIP Deviations

As indicated in the UNE-EN ISO 14155:2021 standard, the investigator may not deviate from the Clinical Investigation Plan (CIP), except in emergencies (section 4.5.4.b of the standard). In such cases, the investigator may proceed without prior approval from the sponsor and the Ethics Committee to protect the rights, safety, and well-being of human subjects. The use of waivers from the Clinical Investigation Plan is strictly prohibited.

These deviations must be documented by the principal investigator and notified to the sponsor and the IRB as soon as possible, and always within a maximum of 15 days. Immediately after receiving the notification, the sponsor will record and analyze the deviations carried out and their potential impact. Depending on the findings, the sponsor will take the necessary corrective and/or preventive measures.

In other circumstances, when deviations affect the rights, safety, and well-being of the subject or the scientific integrity of the clinical investigation, deviation requests and reports must be provided to the IRB if required.

Start, follow-up and end reports

The ethics committee will be notified of the start of the study. Annual monitoring reports will be sent subsequently.

After obtaining the conclusions of the study, a final report will be prepared and presented to the ethics committee.

Statements of compliance

The present clinical investigation will be conducted following the ethical principles originating from the Declaration of Helsinki.

Additionally, the clinical investigation will comply with the harmonized standard UNE-EN ISO 14155:2021 and the European Regulation MDR 2017/745. The statement specifying compliance with the general safety and performance requirements in accordance with MDR can be found in the document Manufacturer's Declaration of Compliance with Requirements.

As appropiate, clinical investigation will not commence until approval/favourable opinion has been obtained from the Clinical Research Ethics Committee (CREC) and the required regulatory authority (Spanish Agency for Medicines and Medical Devices, AEMPS), and it must comply with any additional requirements imposed by the CREC and/or AEMPS.

Informed Consent process

The patient, or in their absence, the family member or legally authorized representative, must provide written consent before their inclusion in the clinical investigation. This will occur after they have understood, through a prior interview with the principal investigator or a member of the research team, the objectives of the investigation, its risks, inconveniences, and benefits, as well as the conditions under which it will be conducted, and after being informed of their right to withdraw from the investigation at any time without explanation and without incurring any responsibility or prejudice.

The principal investigator will discuss the study with the subject and provide the information objectively, without coercion or influence, and without offering any inappropriate or undue incentive. The principal investigator will use non-technical language in the subject's native language (or that of the spouse/closest relative or legally authorized representative) for better understanding and will allow sufficient time for reading and comprehending the information.

Each participant will document their informed consent by signing and dating the informed consent form. Each signed and dated consent will be kept by the principal investigator, and a copy of the informed consent will be provided to the subject.

If new important information arises that could affect the subject's willingness to continue participating in the clinical investigation, it will be provided in any case. If necessary, their continued informed consent will be confirmed in writing.

Adverse events, adverse product reactions and product deficiencies

Adverse Events (AE) and Adverse Events to the Product (AEP)

An AE is any unintended medical event, unanticipated illness or injury, or unintended clinical signs (including abnormal laboratory findings) in subjects, users, or other persons, whether or not related to the investigational product and whether intended or unintended.

An AEP is an adverse event related to the use of an investigational medical device.

Given these definitions, potential AEPs or AEs are documented in the product's IFU.

Product deficencies

Possible inadequacies of a medical device may relate to its identity, quality, durability, reliability, safety, or performance.

Product deficiencies in the investigation will be managed by the sponsor according to non-conforming product control procedures. When appropriate, corrective and/or preventive actions will be taken to protect the safety of subjects, users, and other individuals.

Serious Adverse Events, serious adverse events to the product and serious and unexpected adverse events to the product

According to UNE-EN ISO 14155:2021:

• A Serious Adverse Product Reaction (SAEP) is a SAE that has produced any consequence characteristic of a serious adverse event.
• A Serious Adverse Event (SAE) is an AE that results in any of the following events: death, serious deterioration of the health status of the subject, users or other persons, fetal distress, fetal death, congenital anomaly or birth defect.
• A Serious Unexpected Adverse Event to the Product (SUAEP) is a SAE that, due to its nature, incidence, intensity or consequences, has not been identified in the updated risk assessment.

Taking into account these definitions, there are no SAEP, SAEs or SUAEPs related to the use of the product.

Foreseeable adverse events and adverse events to the product

The foreseeable adverse events and expected adverse reactions to the product, as well as their incidence, mitigation and treatment are documented in the T-013-002 Risk management record of the product under study.

Data Monitoring Committee (DMC)

Information on the DMC (Data Monitoring Committee), if established. This is an independent committee that the sponsor may establish to evaluate, at indicated intervals, the progress of the clinical investigation, the safety data or the critical clinical performance or efficacy endpoints and to recommend to the sponsor whether to continue, suspend, modify, or stop the clinical investigation.

Suspension or early termination of clinical research

As indicated in the UNE-EN ISO 14155:2021 regulation, the sponsor may suspend or terminate the clinical research early for significant and documented reasons. These are:

• If during the clinical research the suspicion of an unacceptable risk arises, including a serious threat to the health of the subjects. It must be suspended while the risk is determined.
• If an unacceptable risk that cannot be controlled is confirmed.
• Due to the impossibility of including a minimum number of subjects that allows the final assessment of the study within a reasonable period according to the characteristics of the study.
• When instructed by the IRB or the required regulatory authority (AEMPS).
• Due to non-compliance with the obligations assumed in the contract by any of the contracting parties.
• By mutual agreement between the parties, expressed in writing.
• By the will of one of the parties, expressed in writing at least one month in advance.

In the event of a suspension or early termination of the clinical research, the sponsor will inform the AEMPS. The sponsor must provide the resources to comply with the obligations of the CIP and with the existing agreements. The principal investigator must inform the subjects if so stipulated in the agreement between the sponsor and the research centre.

If the clinical investigation is resumed, the sponsor must inform the principal investigator and, where appropriate, the AEMPS. Approval from the IRB and, where appropriate, from the AEMPS will be required for such resumption. The principal investigator must inform the subjects.

In accordance with Article 77 of Regulation (EU) 2017/745, the sponsor must notify the Member States in which the clinical investigation is being conducted of the end of the clinical investigation, its temporary halt, or its early termination, within the deadlines specified by the regulation (within 15 days of the end, or within 24 hours in case of early termination or temporary halt for safety reasons). This notification must be accompanied by a justification in case of early termination or temporary halt.

Annexes

Annex I. Protocol of the study

Annex II. Ethics committee approval

Approved by CEIm of Puerta de Hierro University Hospital on 2022-06-24, reference number 47/395984.9/22.

Annex III. Patient information sheet

Annex IV. Informed consent

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 Design & Development Manager, JD-004 Quality Manager & PRRC
• Approver: JD-001 General Manager

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