R-TF-015-004 Clinical investigation plan

Scope

This clinical Investigation Plan (CIP) sets out the rationale, objectives, design, methodology, conduct, implementation, record-keeping, and method of analysis for the clinical investigation.

CIP Identification

	CIP
Title of the clinical investigation	Pilot study for the clinical validation of an artificial intelligence algorithm to optimize the appropriateness of dermatology referrals.
Device under investigation	Legit.Health Plus
Protocol version	Version 1.0
Date	2022-04-07
Protocol code	LEGIT.HEALTH_DAO_Derivación_O_2022
Sponsor	AI Labs Group S.L.
Coordinating Investigator	Dr. Jesús Gardeazabal García and Dr. Rosa Mª Izu Belloso
Principal Investigator(s)	Dr. Jesús Gardeazabal García and Dr. Rosa Mª Izu Belloso
Investigational site(s)	Health Centre Sodupe-Güeñes, Health Centre Balmaseda, Health Centre Buruaga, and Health Centre Zurbaran
Ethics Committee	Comité de Ética de la Investigación con Medicamentos de Euskadi

Trial Registrations

• ClinicalTrials.gov (NCT): NCT06228014
• EMA RWD Catalogue (EUPAS): EUPAS108167

Table of contents

• Scope
• CIP Identification
  • Trial Registrations
• Compliance Statement
• Abbreviations and definitions
• CIP or protocol specifications
  • Principal Investigators
  • Coordinating investigators
  • Technical Support (Manufacturer)
  • Investigational sites
  • Funding
• Product Identification and Description
  • Device version under investigation and bridging to the CE-marked release
• Justification of the design
  • Background and rationale
  • Risks and benefits of the product in investigation and clinical research
• Hypothesis
• Objectives
  • Primary Objective
  • Secondary Objectives
• Summary of the study
• Design and methods
  • Type of clinical research
  • Population
  • Sample size
  • Duration
  • Acceptance 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 deficiencies
  • Serious Adverse Events, serious adverse events to product and serious and unexpected adverse events to the product
  • Foreseeable adverse events and adverse events to the product
  • Data Monitoring Committee (DMC)
• Suspension or early termination of clinical research
• Annexes
  • Annex I. Protocol of the study
  • Annex II. Ethics committee approval
  • Annex III Patient information sheet & 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 Investigators

• Dr. Jesús Gardeazabal García (Osakidetza, Hospital Universitario Cruces).
• Dr. Rosa Mª Izu Belloso (Osakidetza, Hospital Universitario Basurto).

Coordinating investigators

• Dr. Jesús Gardeazabal García (Osakidetza, Hospital Universitario Cruces).
• Dr. Rosa Mª Izu Belloso (Osakidetza, Hospital Universitario Basurto).

Technical Support (Manufacturer)

• Mr. Alfonso Medela — Chief Technology Officer
• Mr. Taig Mac Carthy — Chief Executive Officer

Investigational sites

• Health Centre Sodupe-Güeñes
• Health Centre Balmaseda
• Health Centre Buruaga
• Health Centre Zurbaran

Funding

This investigation was funded by the manufacturer. The manufacturer covered the costs of conducting the research and carrying out the clinical investigation.

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 000000 (Pending)
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

Throughout this document, references to "the device" refer to the investigational product identified above.

Device version under investigation and bridging to the CE-marked release

The investigational product under evaluation is the device at release version 1.1.0.0. The clinical-investigation window (2022-11-23 to 2025-05-06) spans development activities under the manufacturer's change-control process; the v1.1.0.0 release represents the frozen snapshot reported in this document. Device outputs used in the analysis were generated on the v1.1.0.0 artefact under configuration control. The identity bridge between the investigational version and the CE-marked v1.1.0.0 release is held within the technical file and signed off by the Person Responsible for Regulatory Compliance (PRRC) under the manufacturer's configuration-management procedure. Any future changes to the device that could materially affect the primary-endpoint results are subject to a formal bridging analysis recorded in the technical file.

Justification of the design

Background and rationale

Skin-related conditions are a significant reason for primary care visits. They represent about 5% of all consultations, predominantly among working-age populations.

However, there are notable discrepancies between general practitioners and dermatologists in diagnosing skin conditions. Diagnostic agreement typically ranges between 57% and 65%. Several factors contribute to this gap:

• Limited expertise: General practitioners lack specialized dermatological training
• Time constraints: Insufficient time for thorough skin condition assessment
• Limited specialist access: Scarce dermatologist availability, particularly in smaller communities

These challenges result in misdiagnoses and unnecessary referrals, reducing the efficiency of healthcare delivery.

Recent advances in artificial intelligence and image recognition show promise for improving diagnostic accuracy. Computer-Aided Diagnosis (CAD) systems combine AI with digital image processing to enable:

• More accurate interpretation of medical images
• Classification of skin lesions with accuracy comparable to expert dermatologists
• Improved clinical workflows
• Better patient assessments with reduced professional burden

This study aims to clinically validate an innovative AI tool for assessing skin condition severity. By improving diagnostic precision and referral decisions, this technology can:

• Enhance medical practice quality
• Improve early detection of skin cancer
• Enable new research on treatment effectiveness and disease subtypes

Risks and benefits of the product in investigation and clinical research

Participants in this study will not undergo any procedures posing a risk to their safety. However, using the device could optimize patient diagnosis, save costs and time, and provide better treatment to patients.

Hypothesis

The device will demonstrate the following capabilities:

1. Optimize referral appropriateness: The device improves the appropriateness of referrals to dermatology
2. Superior diagnostic performance: Provides greater sensitivity and specificity than general practitioners in diagnosing skin pathologies
3. Accurate malignancy detection: Effectively differentiates between malignant and benign lesions
4. Clinical validation: Provides the security of a second medical opinion, which has been clinically validated

Objectives

Primary Objective

To validate that the device is a valid tool for improving the adequacy of referrals to dermatology.

Secondary Objectives

To validate that the device:

• Reduces costs in secondary care
• Reduces dermatology waiting lists
• Optimizes clinical flow in Osakidetza

Summary of the study

This is a prospective observational analytical study of a longitudinal clinical case series, conducted as a non-interventional clinical investigation under Article 82 of Regulation (EU) 2017/745 (MDR) and the Spanish biomedical-research framework applicable at the time of conduct (Ley 14/2007 and Real Decreto 1090/2015). The investigation evaluates whether the device is a valid tool to improve the appropriateness of dermatology referrals from primary care. A target sample of 400 referred lesions from approximately 380 patients treated at their primary care centres and referred to the dermatology services of the University Hospital of Cruces and the University Hospital of Basurto was pre-specified. Data collection includes photograph analysis, data on clinical flow, and a cost-reduction analysis. The investigation adhered to the ethical principles of the Declaration of Helsinki, maintained patient confidentiality under Regulation (EU) 2016/679 (GDPR) and Ley Orgánica 3/2018, and operated under informed consent recorded on the Patient Information Sheet and Informed Consent form (Annex III).

Design and methods

Type of clinical research

This is a non-interventional, prospective observational clinical investigation of a CE-marked medical device used within its intended purpose. The primary care practitioner's referral decision was made without the device being visible at the point of care; device outputs were generated on the collected images under configuration control and compared retrospectively against the dermatologist reference standard. Under MDCG 2020-6 Appendix III the resulting evidence is ranked 2–4 for the device-versus-reference-standard diagnostic-accuracy analysis and supports the Pillar 3 Clinical Performance claim under MDCG 2020-1 §4.4 — the clinician, using the device's output in the referral workflow, makes measurably better referral decisions than without it. Adult patients with different skin conditions were included. The investigation follows a single-arm design against the dermatologist reference standard; a target sample of 400 referred lesions (approximately 380 patients, with some patients contributing more than one lesion) was pre-specified.

Population

Adult patients (>18 years) with dermatological conditions that meet the inclusion criteria. These patients are attended at their Health Centers and referred to the Dermatology Departments of the Hospital Universitario Cruces and Hospital Universitario de Basurto.

Sample size

Considering a concordance rate of 55% between primary care and dermatology for referred lesions, a consensus agreed that a 15% reduction in inappropriate referrals from primary care to dermatology would represent the minimum clinically important difference (MCID) to justify a significant change in practice. To detect a 15% reduction in inappropriate referrals with 80% power at a two-sided 5% significance level under these assumptions, a sample size of 400 referred lesions from approximately 380 patients (some patients contributing more than one lesion) was pre-specified. The referral-decision threshold to be applied to the device's malignancy output in the primary analysis is pre-specified as the threshold documented in the IFU for referral output; any deviation from this pre-specified threshold is recorded in the CIP Deviations section and handled in the Statistical Analysis Plan.

Duration

This study estimates a recruitment period of 2 months.

Specialist HCPs will have 1 month to label the photographs.

Researchers will have 1 month to close and edit the database, analyze the data, and prepare the final report of the study.

The total duration of the study is estimated at 4 months.

Acceptance criteria

• AUC (area under the ROC curve) equal to or greater than 80.00% detecting malignancy.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 80.00% detecting malignancy.(User Group: Primary care practitioners)
• specificity equal to or greater than 84.00% detecting malignancy.(User Group: Primary care practitioners)
• PPV (positive predictive value) equal to or greater than 40.00% detecting malignancy.(User Group: Primary care practitioners)
• NPV (negative predictive value) equal to or greater than 80.00% detecting malignancy.(User Group: Primary care practitioners)
• equal to or greater than 15.00%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 72.93%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 45.00%.(User Group: Primary care practitioners)
• specificity equal to or greater than 66.11%.(User Group: Primary care practitioners)
• specificity equal to or greater than 47.00%.(User Group: Primary care practitioners)
• adequacy of referrals during in-person care equal to or greater than 50.00%.(User Group: Primary care practitioners)
• adequacy of referrals during in-person care equal to or greater than 38.90%.(User Group: Primary care practitioners)
• adequacy of referrals during remote care equal to or greater than 0.00%.(User Group: Primary care practitioners)
• adequacy of referrals during remote care equal to or greater than 67.00%.(User Group: Primary care practitioners)
• reduction in the number of days greater than 78.10%.(User Group: Primary care practitioners)
• reduction in the number of days equal to or greater than 30.00%.(User Group: Primary care practitioners)
• reduction in the number of days lower than 10.35.(User Group: Primary care practitioners)

Inclusion criteria

• Patients with skin pathologies.
• Patients aged 18 years or older.
• Patients who have signed the informed consent for the study.

Exclusion criteria

• Patient who at the investigator's discretion will not comply with the study procedures.

Variables

Main variable

The main variable aims to determine the efficiency of the device when optimizing the appropriateness of referrals to dermatology.

To do this, we will identify inappropriate referrals. We define an inappropriate referral as one that, according to the criteria of the specialists consulted in the study, does not require the attention of a dermatologist to be treated, as may be the case of seborrheic keratosis.

Secondary variables

• Patient demographic data: Sex and age.
• Data on the general practitioner: Age, years practising and centre.
• Cost reduction: Calculated as the product of the cost of a dermatological consultation by the number of consultations that the device would have avoided.
• Waiting list reduction: Calculated as the difference between the mean number of patients on the dermatology waiting list during the duration of the study minus the mean number of referrals avoided during the duration of the study.
• Clinical data: A photograph, to be taken with a dermatoscope whenever relevant, taken by the general practitioner at the time of the first consultation, whether the referral has occurred and the referral criteria.

Condition of interest

Patients with dermatological pathologies are treated at their health centres and referred to the dermatology service of Cruces and Basurto University Hospitals.

Limitations of clinical research

The performance of image-based algorithms depends on the quantity and quality of the images collected. Variability in illumination, colour, shape, size and focus, together with the number of images per patient, affect diagnostic output. Substantial within-patient variability combined with an insufficient number of images to represent that variability may result in reduced diagnostic accuracy.

All participants are recruited from primary care centres in the Basque Country (Spain); the generalisability of results to other European healthcare systems, primary-care workflows and patient populations is to be established via the PMCF activities identified in the PMCF Plan (R-TF-007-002). The cohort is anticipated to include a limited number of Fitzpatrick V participants and no Fitzpatrick VI participants; performance on Fitzpatrick V–VI skin tones is therefore not, on its own, supported by this investigation and is addressed by dedicated phototype-bridging evidence at Clinical Evaluation level (R-TF-015-003) and by the PMCF Plan.

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

Bias is controlled through the following pre-specified measures:

• Consecutive eligible-patient enrolment at each participating primary care centre, avoiding selective inclusion.
• Standardised image-acquisition procedures across centres, with each image collected under the same protocol.
• Pre-specified primary and secondary endpoints with pre-specified acceptance criteria recorded in the Acceptance Criteria table.
• Blinded dermatologist reference-standard adjudication: the dermatologist's diagnosis is recorded without access to the device output, and the device output is generated without access to the dermatologist diagnosis.
• Second-dermatologist adjudication procedure for cases in which the initial dermatologist diagnosis is inconclusive between conditions of differing malignancy, with the final reference diagnosis established through consensus.
• Prospective data capture, reducing recall bias inherent to retrospective review.

Residual sources of bias that cannot be eliminated by design (operator-dependent image-acquisition variability at the primary care site; referral-decision-threshold tuning if performed on the present sample) are declared in the CIR Limitations section.

Calendar

The duration of this study was estimated at 4 months, including 2 months for the recruitment time, 1 month for the specialist to review photos, and 1 month for data analysis. However, the study will be extended if deemed necessary to achieve adequate sample size or for quality assurance purposes. Any extension to this timeline will be formally requested and approved by the Ethics Committee prior to implementation.

The study will remain active as long as it has not reached the specified number of recruited patients.

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. The first review will take place after data from 3 patients have been collected. Subsequently, a review will be conducted every 5 additional patients.
• 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: R-TF-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, where applicable, to the Spanish Agency for Medicines and Medical Devices (AEMPS). The results obtained (whether positive, inconclusive, or negative) will be made available through the trial-registration entries listed under §Trial Registrations.

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 characterised using frequency distributions for qualitative variables and statistics of central tendency (mean, median) and variability (standard deviation, interquartile range) for quantitative variables according to their distributional characteristics.

Diagnostic performance metrics — sensitivity, specificity, positive and negative predictive values (PPV and NPV) and likelihood ratios (LR+ and LR−) — will be calculated for the device and for the primary care practitioner using the dermatologist diagnosis as the reference standard. Confidence intervals for sensitivity, specificity, PPV, NPV and accuracy will be computed using the Wilson score method. Confidence intervals for LR+ and LR− will be computed by the log-transformation (delta-method) approach. Confidence intervals for AUC will be computed via bootstrap with 2000 iterations. All confidence intervals will be reported at a 95% confidence level. The primary comparison of inappropriate-referral rates between the primary care practitioner and the device is tested at two-sided α = 0.05.

The primary confirmatory endpoint is the reduction in the inappropriate-referral rate produced by the device compared with the primary care practitioner, referenced against the pre-specified 15% minimum clinically important difference (MCID). Secondary endpoints (cost reduction, waiting-list reduction, clinical-flow metrics) are pre-specified as supporting; per-subgroup analyses (teledermatology vs. in-person, per-pathology, per-image-quality stratum) are pre-specified as exploratory and hypothesis-generating. Operating thresholds applied to continuous model outputs for the primary analysis are pre-specified in the Statistical Analysis Plan; any threshold selected post-hoc on the present sample is declared as a methodological deviation and the primary analysis is additionally reported at the pre-specified threshold.

All analyses are implemented in a deterministic, version-controlled statistical analytics environment maintained by the manufacturer; p-values below 0.05 are considered statistically significant for the primary endpoint.

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 start of the study will be notified to the ethics committee. Annual follow-up reports will be submitted thereafter.

Upon obtaining the study conclusions, a final report (R-TF-015-006 Clinical Investigation Report, CIR) will be prepared and submitted 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 deficiencies

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 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 R-TF-013-002 Risk Management Record for the product under study.

Data Monitoring Committee (DMC)

No Data Monitoring Committee was established for this clinical investigation. Justification: the investigation is a non-interventional observational study in which subjects do not receive any procedure or intervention as part of the research and the device is used within its intended purpose under the CE mark; the safety risk to subjects is negligible. Safety events, product deficiencies and any corrective actions are managed by the sponsor in accordance with the applicable risk-management and post-market surveillance procedures identified in the technical file.

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 Euskadi on 2022-11-23, reference number PS2022074.

Annex III Patient information sheet & 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-018 Clinical Research Coordinator
• Approver: JD-022 Medical Manager