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.

Nature and positioning of the evidence

This is a prospective observational clinical investigation with real patients presenting with pigmented skin lesions or female androgenetic alopecia, conducted under a reference standard (histopathological confirmation for the pigmented-lesion malignancy analyses; investigator-scored Ludwig grading for the alopecia analyses). No diagnostic or therapeutic intervention is performed on any subject as a consequence of the investigation, and the device output does not modify the standard of care. Per MDCG 2020-6 Appendix III this investigation generates Rank 2–4 evidence (prospective observational study with reference standard); per MDCG 2020-1 §4.4 it contributes primary Pillar 3 Clinical Performance evidence — measuring the clinician's and the device's diagnostic decisions when the device's clinical outputs (the malignancy gauge and the Top-5 prioritised differential) are available.

Pillar 2 (the algorithm's API-level analytical performance across the ICD-11 categories) is evidenced independently through the device verification-and-validation records and is not the subject of this investigation; Pillar 1 (Valid Clinical Association literature anchoring accurate dermatological triage and severity assessment to improved patient outcomes) is documented in R-TF-015-011 State of the Art.

CIP Identification

	CIP
Title of the clinical investigation	Optimisation of clinical flow in patients with dermatological conditions using Artificial Intelligence
Device under investigation	Legit.Health Plus
Protocol version	Version 12.0
Date	2023-12-27
Protocol code	Legit.Health_IDEI_2023
Sponsor	AI Labs Group S.L.
Coordinating Investigator	Dr. Miguel Sánchez Viera
Principal Investigator(s)	Dr. Miguel Sánchez Viera
Investigational site(s)	Instituto de Dermatología Integral (IDEI)
Ethics Committee	Comité de Ética de la Investigación con Medicamentos de HM Hospitales (Reference: 24.12.2266-GHM)

Trial Registrations

• ClinicalTrials.gov (NCT): NCT05656709
• EMA RWD Catalogue (EUPAS): EUPAS1000000045

Table of contents

• Scope
  • Nature and positioning of the evidence
• CIP Identification
  • Trial Registrations
• Compliance Statement
• Abbreviations and definitions
• CIP or protocol specifications
  • Principal Investigator
  • Coordinating investigator
  • Collaborating Investigator(s)
  • 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 and exclusion criteria
    • Inclusion criteria
    • Exclusion criteria
  • Variables
    • Main variables
    • 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 the 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
  • Annex IV. Informed consent

Compliance Statement

• Harmonized standard UNE-EN ISO 14155:2021.
• Regulation (EU) 2017/745 on medical devices (MDR).
• Harmonized standard UNE-EN ISO 13485:2016s.
• Regulation (EU) 2016/679 (GDPR).
• Spanish Organic Law 3/2018 on the Protection of Personal Data and guarantee of digital rights.
• Spanish Organic Law 1090/2015 on regulating clinical trials with medicines, the Ethics Committees for Research with Medicines and the Spanish Registry of Clinical Studies.

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. Miguel Sánchez Viera (Instituto de Dermatología Integral - IDEI).

Coordinating investigator

• Dr. Miguel Sánchez Viera (Instituto de Dermatología Integral - IDEI).

Collaborating Investigator(s)

• Dr. Concetta D'Alessandro (Instituto de Dermatología Integral, IDEI)
• Dr. Alejandra Capote (Instituto de Dermatología Integral, IDEI)
• Dr. Pablo López Andina (Instituto de Dermatología Integral, IDEI)
• Dr. Allison Marie Bell-Smythe Sorg (Instituto de Dermatología Integral, IDEI)
• Dr. Alejandra Vallejos (Instituto de Dermatología Integral, IDEI)
• Dr. Isabel del Campo (Instituto de Dermatología Integral, IDEI)
• Dr. Juliana Machado (Instituto de Dermatología Integral, IDEI)
• Dr. Raúl Lucas Escobar (Instituto de Dermatología Integral, IDEI)
• Ms. Beatriz Torres (Instituto de Dermatología Integral, IDEI)

Technical Support (Manufacturer)

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

Investigational sites

• Instituto de Dermatología Integral (IDEI)

Funding

This research was co-financed under the framework of the 2021 Call for Grants for research and development projects in artificial intelligence and other digital technologies and their integration into value chains C005/21-ED. With file number 2021/C005/00154001. This grant was awarded to the Instituto de Dermatología Integral (IDEI).

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 device evaluated in this clinical investigation corresponds to the version currently released under technical file v1.1.0.0. No material change has been introduced to the diagnostic algorithms, the clinical outputs, the Instructions for Use or the integration requirements between the version tested in the investigation and the CE-marked release; the manufacturer's Person Responsible for Regulatory Compliance has confirmed that the investigation results apply to the CE-marked release on an identity basis. Any subsequent change that could materially affect the clinical performance evidenced here will be assessed under the change-control process and, where required, addressed by confirmatory post-market activities under the PMCF Plan.

Justification of the design

Background and rationale

The use of image-based artificial intelligence (AI) holds significant potential for improving diagnostic accuracy in medical visual assessments. The COVID-19 pandemic, which limited access to in-person healthcare, has accelerated the adoption of telemedicine, highlighting the importance of AI in triaging and supporting decision-making processes. In dermatology, conditions such as pigmented lesions and alopecia represent high-demand cases requiring significant in-person resources and specialist attention. AI tools can play a crucial role in optimizing these processes, reducing the workload, and improving efficiency in patient management.

Advancements in image recognition and AI technologies have led to innovations in diagnosing skin conditions, with Computer-Aided Diagnosis (CAD) systems proving their ability to classify lesion images at a level comparable to expert clinicians. This investigation evaluates the device, a clinical decision-support medical device, under its intended use in the dermatology clinical workflow. The device's clinical outputs under evaluation are the malignancy gauge (a calibrated 0–100 score indicating the estimated probability of malignancy for a given lesion) and the Top-5 prioritised differential view over ICD-11 categories, together with an objective Ludwig severity score for female androgenetic alopecia.

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. However, using the device could optimize patient diagnosis, save costs and time, and provide better treatment to patients.

Hypothesis

The device's malignancy gauge is an accurate estimator of lesion malignancy on adult patients presenting with pigmented skin lesions, and the device's Ludwig score is an accurate objective severity assessment for female androgenetic alopecia, when each is measured against an appropriate reference standard.

Objectives

Primary objective

• To estimate the diagnostic accuracy of the device's malignancy gauge for lesion malignancy on adult patients with pigmented skin lesions, against histopathology as the reference standard, measured by Area Under the ROC Curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value at the operating threshold pre-specified in the Statistical Analysis Plan.

Secondary objectives

• To estimate the Top-1, Top-3 and Top-5 diagnostic agreement between the device's prioritised ICD-11 differential and the investigator's clinical diagnosis on adult patients with pigmented skin lesions.
• To estimate the inter-rater agreement between the device's automated Ludwig score and the investigator's Ludwig score on female patients with androgenetic alopecia, measured by unweighted Kappa coefficient and Pearson correlation.
• To describe the benefit-risk profile of the device against GSPR 1 and GSPR 8, with particular reference to residual false-negative and false-positive rates for malignancy detection.

Summary of the study

This is a prospective observational clinical investigation with a parallel retrospective case-series analysis, designed to estimate the diagnostic performance of the device's malignancy gauge and Top-K prioritised differential on adult patients with pigmented skin lesions, and the accuracy of the device's automated Ludwig score on female patients with androgenetic alopecia. The investigation includes a minimum of 45 prospectively enrolled patients (30 with pigmented lesions and 15 with female androgenetic alopecia) and a parallel retrospective extraction of 60 pigmented-lesion patients and 15 female androgenetic alopecia patients from the IDEI patient database. Data collection comprises standardised image acquisition, investigator clinical assessment, histopathological reference standard (for pigmented-lesion biopsies performed under routine clinical care) and a specialist satisfaction questionnaire. The investigation is conducted in compliance with the principles of the Declaration of Helsinki, UNE-EN ISO 14155:2020 and Regulation (EU) 2017/745. Written informed consent is obtained from every prospectively enrolled participant; the retrospective analysis uses de-identified image and pathology data under the governance framework agreed with the Ethics Committee for Research with Medicines of HM Hospitales.

Design and methods

Type of clinical research

This is a prospective observational clinical investigation with a parallel retrospective case-series analysis. It is a non-interventional, diagnostic-accuracy investigation at a single investigator site: no diagnostic or therapeutic intervention is performed on any subject as a consequence of the investigation, and the device output does not modify the standard of care. Two patient populations are evaluated in parallel: adult patients with pigmented skin lesions, and adult female patients with androgenetic alopecia. The investigation does not include a randomised control arm; the comparator is the reference standard (histopathology for pigmented-lesion malignancy; investigator Ludwig score for female androgenetic alopecia severity).

Population

Adult patients (>18 years) diagnosed with pigmented lesions, or adult female patients diagnosed with androgenetic alopecia, who meet the inclusion criteria. These patients are attended at the Instituto de Dermatología Integral (IDEI).

Sample size

The initial sample-size target was set as a feasibility sample based on the subject throughput of the IDEI Dermatology Unit over the planned recruitment window: a minimum of 30 prospective and 60 retrospective pigmented-lesion cases, and 15 prospective and 15 retrospective female androgenetic alopecia cases. This target was selected to provide adequate case-mix diversity for descriptive estimates of diagnostic accuracy and inter-rater agreement, and for the generation of confidence intervals sufficient to support a Pillar 3 §4.4 exploratory-confirmatory Clinical Performance evaluation at Rank 2–4 under MDCG 2020-6 Appendix III. The investigation is not powered for formal hypothesis testing against a single pre-specified effect size; confirmatory independent-sample validation of the primary diagnostic-accuracy endpoint is committed to the PMCF Plan.

The inclusion of both retrospective and prospective data for pigmented lesions ensures diversity in lesion presentation, from benign to malignant cases, and is consistent with the real-world case mix reported at dermatology consultations (Moreno et al., 2005, approximately 20–30%).

Duration

The total duration of the study is approximately 7 months, comprising a prospective-recruitment window of 3 months and the time required after recruitment of the last subject for closure of the data collection, data cleaning, statistical analysis and preparation of the final Clinical Investigation Report.

The total duration for each participant with pigmented lesions is 1–3 months (single-visit image acquisition followed by histopathology follow-up where a biopsy is indicated by routine clinical care). The duration for participants with androgenetic alopecia is 1 day (single-visit image acquisition).

Acceptance criteria

The pre-specified acceptance criteria for this investigation are rendered below from the Clinical Validation master data. Each row states the indication, user group, metric, valence and pre-specified threshold that define pass/fail, together with the state-of-the-art benchmark from R-TF-015-011 where applicable.

• top-1 accuracy equal to or greater than 61.80%.(User Group: Dermatologists)
• top-1 accuracy equal to or greater than 50.00%.(User Group: Dermatologists)
• top-3 accuracy equal to or greater than 60.00%.(User Group: Dermatologists)
• top-5 accuracy equal to or greater than 80.00%.(User Group: Dermatologists)
• AUC (area under the ROC curve) equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
• sensitivity equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
• specificity equal to or greater than 84.00% detecting malignancy.(User Group: Dermatologists)
• PPV (positive predictive value) equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
• NPV (negative predictive value) equal to or greater than 95.00% detecting malignancy.(User Group: Dermatologists)
• correlation equal to or greater than 50.00%.(User Group: Dermatologists)
• unweighted Kappa equal to or greater than 60.00%.(User Group: Dermatologists)

Each acceptance criterion is pre-specified by indication (pigmented-lesion malignancy detection, pigmented-lesion Top-K diagnostic agreement, and objective Ludwig severity assessment for female androgenetic alopecia), by user group (dermatologist aided by the device, or the device alone), and by dataset (retrospective, prospective). The primary confirmatory endpoint is the malignancy-detection AUC with the operating threshold set in the Statistical Analysis Plan; all other criteria are pre-specified as secondary. Independent-sample validation of criteria that depend on in-sample operating-point selection is committed to the PMCF Plan.

Inclusion and exclusion criteria

Inclusion criteria

• Adult patients (>18 years).
• Patients with pigmented lesions who meet any of the following conditions:
  • They consult for the first time for a pigmented lesion.
  • Patients already scheduled for a dermatoscopy consultation for the first time or a review of pigmented lesions.
• Women with androgenic alopecia.

Exclusion criteria

• Patients for whom, in the judgement of the investigator, participation is contraindicated on clinical or compliance grounds.
• Patients whose images fail the device's built-in Dermatology Image Quality Assessment (DIQA) threshold and who cannot provide a repeat image meeting the IFU image-acquisition requirements.
• Fitzpatrick V or VI skin phototypes are eligible for inclusion; however, the investigator site population during the investigation window is expected to under-represent these phototypes, and generalisability to Fitzpatrick V or VI is addressed separately in the Clinical Evaluation (R-TF-015-003) and in the PMCF Plan rather than on the basis of this investigation.
• Paediatric patients (under 18 years of age) are excluded; paediatric generalisability is addressed in the PMCF Plan and not on the basis of this investigation.

Variables

Main variables

• Diagnostic agreement between the dermatologist's clinical diagnosis and the device's prioritised ICD-11 differential, measured at Top-1, Top-3 and Top-5.
• The probability of malignancy estimated by the device (malignancy gauge, 0–100 scale) and the dermatologist's clinical suspicion of malignancy (0–10 scale), each compared against histopathological confirmation as the reference standard for every lesion for which a biopsy is performed under routine clinical care.

The device's malignancy gauge (0–100) and the dermatologist's suspicion score (0–10) are each reported and analysed on their native scales; binarisation against the histopathology reference standard is performed at the operating threshold pre-specified in the Statistical Analysis Plan for the device, and at a clinically customary cut-off for the dermatologist's 0–10 suspicion score. Operating thresholds derived from in-sample Youden-J optimisation, if reported, are labelled exploratory and do not substitute for the pre-specified threshold.

Secondary variables

• Female androgenetic alopecia: severity according to the Ludwig scale — scored by the investigator and computed automatically by the device.
• Pigmented lesions (retrospective arm): investigator's diagnosis, device's malignancy gauge, and histopathological confirmation where a biopsy was indicated.
• Pigmented lesions (prospective arm): number of lesions of concern to the patient (maximum three); number of lesions identified by the investigator as clinically relevant, with note of coincidence with the patient-identified set; investigator's clinical diagnosis; device malignancy gauge; investigator malignancy suspicion score (0–10); histopathological result for lesions for which a biopsy was indicated under routine clinical care.
• Specialist satisfaction with the device, collected via the Clinical Utility Questionnaire.

Condition of interest

Patients with any of the following dermatological pathologies: pigmented lesions and women with androgenic alopecia.

Limitations of clinical research

This investigation has the following pre-identified limitations:

1. Single-centre convenience sample. The investigation is conducted at a single investigator site (IDEI) with consecutive enrolment during a 3-month recruitment window. Demographic coverage therefore reflects the patient population of this site; Fitzpatrick V and VI phototypes are expected to be under-represented and paediatric patients are excluded by design. Generalisability to under-represented populations is addressed in the Clinical Evaluation (R-TF-015-003) and in the PMCF Plan, not on the basis of this investigation alone.
2. Image quality and image-acquisition variability. Device performance depends on adherence to the IFU image-acquisition requirements; variability in lighting, focus, lesion centring and hair coverage — particularly in the retrospective arm, where images predate the device's DIQA image-quality gating — may reduce measured performance relative to the prospective arm.
3. Small malignant subset in the prospective arm. The number of histopathologically confirmed malignant cases in the prospective arm is expected to be small, producing wide confidence intervals on malignancy-detection estimates. Confirmatory independent-sample validation at a pre-specified operating threshold is committed to the PMCF Plan.
4. In-sample threshold selection. Any operating threshold for the device's malignancy gauge that is selected by in-sample Youden-J optimisation is reported as exploratory; the pre-specified operating threshold is the reference point for acceptance-criterion evaluation.
5. Aided-reader design in the prospective arm. In the prospective arm, the investigator's clinical diagnosis is recorded after the device output is available to the clinician; consequently, any prospective "dermatologist" estimate reflects the aided reader and is not an independent-reader comparator. An unaided-reader comparator is not produced by this investigation and is addressed in 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

The investigation uses the following pre-specified bias-control measures:

• Consecutive enrolment of eligible patients presenting at the investigator site during the recruitment window; no selection by the investigator other than the documented inclusion/exclusion criteria.
• Retrospective-cohort extraction from the IDEI patient database using a pre-specified, documented query with inclusion-window, pathology and image-quality criteria.
• Standardised image-acquisition protocols consistent with the device's Instructions for Use, including image-quality gating via the device's Dermatology Image Quality Assessment (DIQA) algorithm.
• Histopathological confirmation as the reference standard for pigmented-lesion malignancy analyses, performed under routine clinical care and independently of the device output.
• Pre-specified endpoints, analysis populations, and operating thresholds documented in the Statistical Analysis Plan; any in-sample operating-threshold optimisation is reported as exploratory and does not replace the pre-specified threshold.

Residual sources of bias (convenience-sampling window; investigator access to device output at the time of prospective clinical assessment; under-representation of Fitzpatrick V/VI phototypes) are declared in the Limitations section of the Clinical Investigation Report and are addressed in the PMCF Plan.

Calendar

The investigation is conducted in a single recruitment window of approximately 3 months, followed by a data-cleaning, analysis and reporting window that brings the total investigation duration to approximately 7 months. The total duration per participant is 1–3 months for pigmented-lesion cases (to allow for histopathology follow-up where a biopsy is indicated by routine clinical care) and 1 day for alopecia cases (single-visit image acquisition).

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 (R-TF-015-006) 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 (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

The reference standard for the pigmented-lesion malignancy analyses is histopathological confirmation, performed under routine clinical care for every lesion for which a biopsy is indicated. Lesions without histopathological confirmation are excluded from the pigmented-lesion malignancy analyses; an intention-to-treat sensitivity analysis (best-case and worst-case imputation of missing histopathology) is pre-specified to assess the impact of this exclusion on the primary estimate.

Diagnostic accuracy for lesion malignancy is estimated by Area Under the ROC Curve (AUC), and — at the operating threshold pre-specified in the Statistical Analysis Plan for the device's malignancy gauge — by sensitivity, specificity, positive predictive value and negative predictive value. Ninety-five-percent confidence intervals are reported for each estimate using the Wilson method for proportions and bootstrap resampling for AUC. Any operating threshold reported in addition to the pre-specified threshold (for example, the in-sample Youden-J optimum) is labelled exploratory.

Diagnostic agreement between the device's prioritised ICD-11 differential and the investigator's clinical diagnosis is estimated by Top-1, Top-3 and Top-5 accuracy, with Wilson 95% confidence intervals.

For female androgenetic alopecia, inter-rater agreement between the device's automated Ludwig score and the investigator's Ludwig score is estimated by unweighted Cohen's Kappa coefficient and Pearson correlation, each with 95% confidence intervals. The prospective arm is the pre-specified validation set; the retrospective arm is used for hyperparameter selection and is reported separately. Pooled estimates across retrospective and prospective data are not used as confirmatory evidence of the pre-specified Ludwig-agreement threshold.

The primary confirmatory endpoint is the malignancy-detection AUC against histopathology; secondary endpoints are exploratory-confirmatory and are not formally controlled for multiplicity, consistent with the investigation's Rank 2–4 exploratory-confirmatory positioning under MDCG 2020-6 Appendix III. Confirmatory independent-sample validation at a pre-specified operating threshold is committed to the PMCF Plan.

All analyses are implemented in a deterministic, version-controlled analytics environment maintained by the manufacturer; the analysis-script package is retained as an essential study document.

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 Clinical Investigation Report (R-TF-015-006) 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 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 Risk Management Record (R-TF-013-002) 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 HM Hospitals on 2024-01-25, reference number 24.12.2266-GHM.

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-018 Clinical Research Coordinator
• Approver: JD-022 Medical Manager