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	Multi-Reader Multi-Case Study for Evaluating the Impact of Legit.Health Plus Device on the Healthcare Practitioners' Assessment of Skin Lesions
Device under investigation	Legit.Health Plus
Protocol version	Version 1.0
Date	2024-07-04
Protocol code	LEGIT.HEALTH_SAN_2024
Sponsor	Sanitas Hospitales SA
Coordinating Investigator	Dr. Antonio Martorell Calatayud
Principal Investigator(s)	Dr. Antonio Martorell Calatayud
Investigational site(s)	This study was conducted remotely by sending the images to the participating professionals.
Ethics Committee	This study did not require an Ethics Committee approval because it is observational and non-interventional. All data used consists of fully anonymized images sourced from public dermatology atlases and databases, containing no information permitting patient identification. As such, the research meets the criteria for exemption from ethics committee review under applicable regulatory frameworks.

Trial Registrations

• ClinicalTrials.gov (NCT): NCT07428954
• EMA RWD Catalogue (EUPAS): EUPAS1000000911

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
  • 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 objective(s)
• Summary of the study
• Design and methods
  • Type of clinical research
  • Population
  • Sample size
  • Duration
  • Acceptance criteria
    • Justification of acceptance thresholds
  • 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
    • Pre-specified analyses
    • Exploratory and hypothesis-generating analyses
    • Handling of incomplete reader data
    • Software
  • 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 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)
• Suspension or early termination of clinical research

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. Antonio Martorell Calatayud

Coordinating investigator

• Dr. Antonio Martorell Calatayud

Collaborating Investigator(s)

• Medical staff
  • Dr. Adriana De Vasconcelos Pereira
  • Dr. María Porriño
  • Dr. Gustavo Paredes
  • Dr. Josefina Sanz
  • Dr. Andrés Fernández
  • Dr. Gerald Selda
  • Dr. Helena Bahachille
  • Dr. Mitchell Ignacio Leal Betancourt
  • Dr. Marianela del Castillo
  • Dr. María Pilar Martínez Marta
  • Dr. Nadia Hayajneh Carrillo
  • Dr. Carmen Arsuaga
  • Dr. Elena Sánchez Largo
  • Dr. María Gómez
  • Dr. Pedro Ortega Lozano
• Manufacturer
  • Mr. Taig Mac Carthy (Regulatory and Quality, manufacturer)
  • Mr. Alfonso Medela (Chief Scientific Officer, manufacturer)

Investigational sites

This study was conducted remotely through a centralized web-based platform. Healthcare professionals (both primary care practitioners and dermatologists) were provided with individual user credentials (username and password) to securely access the platform. All images were presented through this platform, and practitioners' assessments were recorded on the same system. Access logs were maintained to ensure traceability of all practitioner interactions with the platform.

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 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 version active throughout the investigation period (1 June to 10 October 2024) was v1.1.0.0. The investigational device was not released commercially during or subsequent to the investigation window; no changes to the algorithm, model checkpoint, user interface, indications, or claims occurred between the version tested and the version submitted for CE marking. The clinical evidence generated by this investigation therefore bridges by identity to the CE-marked release, and no additional clinical-relevance assessment of inter-version differences is required.

Justification of the design

Background and rationale

Dermatological conditions represent a significant portion of primary care consultations, constituting approximately 5% of all visits. However, discrepancies between diagnoses made by general practitioners and dermatologists remain substantial, with concordance rates between 57% and 65.52%. This gap in expertise often leads to misdiagnoses, incorrect referrals, and delays in appropriate treatment, particularly in rare and severe conditions. The limited availability of dermatologists, especially in rural areas, further complicates patient care, underscoring the need for innovative solutions to optimize resource allocation and improve diagnostic accuracy.

Teledermatology has shown promise in reducing the pressure on in-person consultations by enabling remote assessments. However, the use of artificial intelligence (AI) presents a transformative opportunity to enhance the diagnostic capabilities of general practitioners. The device has already been validated for the diagnosis of skin conditions and offers advanced tools, such as the automatic scoring of diverse pathologies. This investigation evaluates whether the use of the device increases the top-1 diagnostic accuracy of healthcare professionals (HCPs) in the assessment of multiple dermatological conditions on a curated image set.

Risks and benefits of the product in investigation and clinical research

In this study, there will be no patient recruitment, since the images used for it will be extracted from different sources such as dermatology atlases. However, using the device could optimize patient diagnosis, save costs and time, and provide better treatment to patients. The participating HCPs will sign a contract with the manufacturer so as to participate in the study.

Hypothesis

The information provided by the device increases the top-1 diagnostic accuracy of healthcare professionals (HCPs) in the assessment of multiple dermatological conditions on a curated image set.

Objectives

Primary objective

To validate that the information provided by the device increases the top-1 diagnostic accuracy of healthcare professionals (HCPs) in the assessment of multiple dermatological conditions on a curated image set.

Secondary objective(s)

• To validate what percentage of cases should be referred according to the HCP with the information provided by the device.
• To validate what percentage of cases could be handled remotely with the information provided by the device.
• Confirm that the use of the medical device is perceived by specialists as being of great clinical utility.

Summary of the study

This is a prospective observational multi-reader, multi-case (MRMC) study designed to assess whether the use of the device by dermatologists and general practitioners increases diagnostic accuracy in the assessment of multiple dermatological conditions on a curated set of 29 anonymised images sourced from public dermatological atlases. The data collection captured the diagnostic accuracy for different dermatological pathologies as scored against the ground-truth diagnosis established for each image. The investigation was conducted in accordance with the applicable ethical principles for retrospective studies of anonymised material (see Ethical considerations, below); because no patients were recruited or contacted, patient-level informed consent was not applicable. The methodology was designed to assess the clinical utility and usability of the device as perceived by healthcare professionals acting as expert readers.

Design and methods

Type of clinical research

This is a prospective, observational multi-reader, multi-case (MRMC) self-controlled study to evaluate whether the use of the medical device by healthcare professionals helps to increase the accuracy in the diagnosis of different skin conditions. In this self-controlled design, each healthcare professional serves as their own comparator, first providing diagnoses without the use of the device, and subsequently providing diagnoses with the support of the device on the same set of images.

Population

In this study, the population will consist of general practitioners and dermatologists. A total of 16 HCPs participated in the study. Each participant was presented with 29 images to review.

Sample size

This study aims to evaluate whether the use of the device improves diagnostic accuracy by at least 10% among healthcare professionals, providing evidence to support its integration into clinical practice. To achieve this, 16 HCPs will participate in the study, a sample size determined through statistical power analysis to achieve 80% power at an alpha level of 0.05 for detecting a minimum 10% improvement in diagnostic accuracy. This design balances practical feasibility with robust statistical sensitivity.

Each HCP will review 29 dermatological images representing a diverse range of skin pathologies. These images will be carefully selected to encompass varying severity levels and types of conditions, ensuring that the device's performance is tested across a wide spectrum of clinical scenarios. The decision to use 29 images per HCP reflects a balance between ensuring sufficient variability in case profiles and minimizing cognitive fatigue, thereby maintaining the quality of the evaluations.

Limiting the study to 16 HCPs allows for a focused and manageable cohort, reducing inter-observer variability and enhancing the consistency of results. This approach also enables precise estimates of diagnostic accuracy while ensuring that each HCP gains substantial practical experience with the device. The smaller, well-defined group of experienced healthcare professionals ensures high-quality data collection, providing reliable insights into the device's impact on clinical decision-making.

By combining a smaller HCP cohort with a robust volume of cases, this study design ensures statistically reliable and clinically relevant findings. The combination of diverse patient profiles and concentrated HCP evaluations strengthens the validity of the conclusions, supporting a meaningful assessment of the device's potential to improve diagnostic accuracy.

Duration

The total duration of the study is estimated at 4 months, including the time required after the collection of the corresponding images for the closing and editing of the database, the analysis of the data and the preparation of the final report of the study.

Acceptance criteria

• top-1 accuracy equal to or greater than 7.00%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 53.96%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 68.08%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity equal to or greater than 6.93%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity greater than 75.99%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity greater than 52.61%.(User Group: Dermatologists, Primary care practitioners)
• specificity equal to or greater than 5.06%.(User Group: Dermatologists, Primary care practitioners)
• specificity greater than 84.12%.(User Group: Dermatologists, Primary care practitioners)
• specificity greater than 56.45%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 46.12%.(User Group: Primary care practitioners)
• top-1 accuracy equal to or greater than 62.90%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 14.30%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 72.93%.(User Group: Primary care practitioners)
• sensitivity greater than 51.58%.(User Group: Primary care practitioners)
• specificity equal to or greater than 11.88%.(User Group: Primary care practitioners)
• specificity equal to or greater than 77.11%.(User Group: Primary care practitioners)
• specificity greater than 54.35%.(User Group: Primary care practitioners)
• top-1 accuracy equal to or greater than 5.00%.(User Group: Dermatologists)
• top-1 accuracy greater than 61.80%.(User Group: Dermatologists)
• top-1 accuracy greater than 76.47%.(User Group: Dermatologists)
• sensitivity equal to or greater than 82.80%.(User Group: Dermatologists)
• sensitivity greater than 70.38%.(User Group: Dermatologists)
• specificity equal to or greater than 85.36%.(User Group: Dermatologists)
• specificity greater than 82.35%.(User Group: Dermatologists)
• reduction in the number of days lower than 76.00%.(User Group: Dermatologists)
• increase in patients that can be managed remotely equal to or greater than 40.00%.(User Group: Dermatologists)
• Expert consensus lower than 75.00%.(User Group: Dermatologists)
• Expert consensus equal to or greater than 75.00%.(User Group: Dermatologists)

Justification of acceptance thresholds

The acceptance thresholds listed in the table above are not set ad hoc; each is derived from the formal State-of-the-Art record R-TF-015-011 State of the Art, which constitutes the authoritative source of the state-of-the-art benchmarks referenced in this investigation. That record documents the systematic review, selection criteria, and meta-analytic synthesis of the SotA literature from which the thresholds are derived, and explains the choice of metrics (Top-1 diagnostic accuracy, sensitivity, specificity, referral and remote-management proportions, and inter-observer agreement) for the device's intended use. The relationship between each threshold and the SotA record is as follows:

• Absolute-value ("absoluteValue") thresholds — for example, the pooled "with-device" top-1 diagnostic-accuracy target for combined primary-care practitioners and dermatologists, and the corresponding sensitivity and specificity targets — are set to match or exceed the SotA meta-analytic baselines for aided-HCP performance reported in R-TF-015-011, so that the device's post-intervention metric is competitive with the current clinical state of the art.
• Relative-change ("relativeChange") thresholds — for example, the paired improvement in HCP top-1 diagnostic accuracy attributable to the use of the device — are set at approximately a minimum of +10 percentage points on the curated image set, consistent with the methodology documented in R-TF-015-011 §"Methodology for Establishing Acceptance Criteria", which sets the device's acceptance target approximately ten percentage points higher than the SotA-averaged AI-aided improvement baseline (overall HCP +6.36%; PCP +9.30%; dermatologist +5.30%). Setting the acceptance criterion above the SotA AI-aided baseline is the mechanism by which the investigation tests the "substantial clinical benefit" positioning required under MDCG 2020-1.
• Primary vs secondary designation. The primary confirmatory endpoint is the paired +10% improvement in pooled top-1 diagnostic accuracy tested using McNemar's test for paired proportions on the curated image set; the sample size in this investigation is powered only for this pooled-accuracy comparison. All remaining thresholds in the table above are pre-specified as secondary or supporting; statistical comparisons against these thresholds at the per-pathology or per-specialty stratum level are exploratory, hypothesis-generating and are not used to support confirmatory claims (see §Statistical analysis).

For the full systematic review, literature inclusion criteria, meta-analytic synthesis and per-metric derivations, refer to R-TF-015-011 (held by the manufacturer within the technical file).

Inclusion criteria

• Board-certified general practitioners and dermatologists, with at least 5 years of experience in clinical practice, and currently seeing patients.
• High-quality images of patients with different skin conditions.

Exclusion criteria

• Low-quality images of patients which can not be properly analyzed.

Variables

Main variable

• The main variable of this study is the accuracy of diagnosis of different skin pathologies using the device. In this case, it will be the percentage of success with and without the device.

Secondary variables

• Percentage of cases should be referred according to the HCP with the information provided by the device.
• Percentage of cases could be handled remotely with the information provided by the device.

Condition of interest

Patients with different skin pathologies.

Limitations of clinical research

The main limitations of the investigation include several factors that may influence the perception and effectiveness of the AI-based device. Firstly, the acceptance and trust of healthcare professionals in these emerging technologies can vary significantly. The device's effectiveness may be compromised if users are not fully convinced of its accuracy or usefulness, thereby affecting the overall perception of its performance.

Additionally, image quality is crucial for the device's performance. Issues such as low-quality photographs, errors in cropping lesions, or variations in lighting and focus can deteriorate the quality of the data received by the system, which may negatively influence the evaluation and perception of its effectiveness by the researchers.

Variability in image conditions is also an important aspect to consider. Differences in lighting, colour, shape, size, and focus of the images, along with the number of images available for each patient, can affect the accuracy of the results. High variability in images of the same patient or an insufficient number of representative images can lead to a decrease in the expected diagnostic accuracy of the device.

Additionally, the consistency of investigators in using the device is crucial. Variations in how diligently investigators use the device can impact the investigation's findings. If the investigators are not consistent in their use of the device, it can lead to unreliable results and affect the overall assessment of its efficacy.

Another limitation is the Hawthorne effect, where investigation participants may change their behaviour simply because they know they are being observed. This awareness can influence their decisions and actions within the investigation, potentially skewing the results and not accurately reflecting how the device would be used in a non-study environment.

The image set is drawn from public dermatology atlases and is not intended to be epidemiologically representative of any target population. In particular, Fitzpatrick phototypes V and VI are under-represented in the image set (1 image and 0 images respectively); the investigation therefore does not support claims of equivalent performance in Fitzpatrick V and VI skin. Evidence for darker-skin performance is provided by the MAN_2025 PMCF investigation and is evaluated at CER level.

Under MDCG 2020-6 Appendix III, simulated-use multi-reader multi-case (MRMC) studies conducted on retrospective anonymised images constitute Rank 11 evidence and are distinct from clinical data generated on real patients within the meaning of MDR Article 2(48); per MDCG 2020-1 §4.4 they contribute Pillar 3 Clinical Performance supporting evidence — measuring the clinician's diagnostic decision-making when using the device's Top-5 prioritised differential view — at a lower rank than the prospective real-patient studies. The positioning of this investigation within the overall body of clinical evidence is documented in the Clinical Evaluation Plan and Clinical Evaluation Report.

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

Minimising bias is essential to ensure the validity and reliability of the investigation's results. Participating HCPs were invited directly on the basis of professional qualification (board-certified primary care practitioners or dermatologists); random selection of HCPs from a larger pool was not performed and is not claimed. Bias controls implemented by design include the following:

• Standardised data-collection protocols, applied uniformly to every participating HCP, so that the conditions under which each HCP is exposed to the device are identical.
• Prospective pre-specification of primary and secondary outcomes before the investigation begins, which prevents selective reporting of only favourable outcomes and ensures that all relevant data (positive, neutral or negative) are considered.
• A self-controlled design in which each HCP serves as their own comparator: the same HCP first diagnoses each case without the device and subsequently re-diagnoses the same case with the device's output available, eliminating between-subject confounding as a source of bias.
• Case-order randomisation across HCPs to limit systematic order effects.
• Separation of the unaided ("without device") and aided ("with device") reading phases for each case, to mitigate immediate recall carry-over between reads.
• Prospective data capture on a timestamped secure platform with access logs, which reduces the chance of inaccurate recall of past events relative to retrospective designs.

Known residual sources of bias that cannot be fully controlled by design in this kind of MRMC investigation (immediate-recall carry-over within a reader, reader expectation effects in simulated environments, Hawthorne effect) are acknowledged in the Limitations section.

Calendar

The total duration of the study is estimated at 4 months, including the time required after recruitment of the participating HCPs and collection of all images and for closing and editing the database, data analysis and preparation of the final study report.

Monitoring plan

The sponsor will hold a meeting with the investigative team at the beginning of the study 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 every 3 months with 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. In this study, this will be carried out online.
• 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 Clinical Investigation Report) will be drafted, even in the event of early termination or suspension. A results summary (whether positive, inconclusive, or negative) will be uploaded to the public trial registries identified in the CIP Identification section (ClinicalTrials.gov NCT07428954 and EMA RWD Catalogue EUPAS1000000911); the underlying image dataset and reader-level raw data are not publicly shared due to privacy and confidentiality considerations.

Additionally, if deemed appropriate, the results may be published in scientific journals. All the investigators who 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

Pre-specified analyses

The primary endpoint is the paired difference in top-1 diagnostic accuracy (per reader, per case, correct vs. incorrect against the established ground truth) before and after exposure to the device's output, pooled across all participating HCPs. This paired binary outcome is analysed using the McNemar test for paired proportions, with a two-sided alpha of 0.05. Ninety-five per cent confidence intervals for each proportion are reported using the Wilson score method; differences in paired proportions are reported with their Newcombe 95% confidence intervals.

The secondary endpoints pre-specified for confirmatory analysis are:

• The proportion of cases for which the HCP, with the device's output available, considers that specialist referral is not required.
• The proportion of cases for which the HCP, with the device's output available, considers that the case can be handled remotely.

Association between the "referral" and "remote-management" secondary outcomes is assessed using Pearson's chi-squared test of independence; proportions are reported with Wilson 95% confidence intervals.

Exploratory and hypothesis-generating analyses

Per-pathology analyses (comparing accuracy before and after device exposure, stratified by each of the thirteen condition categories present in the image set) and per-specialty analyses (primary-care practitioners vs. dermatologists) are pre-specified as exploratory, hypothesis-generating analyses. Because the sample size is powered only for the primary pooled-accuracy comparison and not for per-stratum comparisons, and because no adjustment for multiple comparisons is applied at this stratification level, p-values from these per-pathology and per-specialty contrasts are reported for descriptive purposes and are not used to support confirmatory claims. Where a per-pathology cell contains fewer than 20 observations, the cell is flagged as having limited interpretability.

Reader-level completion rates, self-reported consultation time and the Clinical Utility Questionnaire responses are summarised descriptively (frequencies for categorical variables; mean, median and interquartile range for continuous variables) and are not used to support confirmatory performance claims.

Handling of incomplete reader data

The pre-specified primary analysis population comprises all cases reviewed by any enrolled HCP under the "without device" then "with device" paired protocol (analysis at the paired-observation level, not at the reader level). Readers who completed only a partial number of cases contribute the observations they did complete. A sensitivity analysis restricted to HCPs who completed at least 50% of the 29 cases, and a further sensitivity analysis restricted to HCPs who completed all 29 cases, are performed and reported; the primary result is considered robust if the direction and magnitude of the estimated effect are preserved across both sensitivity analyses.

Software

Analyses are performed using a deterministic, version-controlled statistical analytics environment maintained by the manufacturer, applying the pre-specified statistical methods to the de-identified exported dataset. All analytical code is held under version control and is available for audit on request.

Data management

The management of data collection and processing was carried out through a centralized web-based platform that served as the Case Report Form (CRF). Healthcare professionals logged into the platform using individual credentials and recorded their diagnostic assessments directly on the system. All data entries were timestamped and tracked to ensure traceability. After data collection was completed, the data were exported from the platform to a CSV (Comma-Separated Values) file for analysis.

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 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). For this purpose, 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.

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 principal investigator and all the participant investigators.

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

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

In this study, informed consent from patients was not collected. The images used in this study are completely anonymized medical images sourced from public dermatological atlases and freely available public sources. These images are not derived from identifiable patients, and their anonymization makes patient recognition impossible. As these images constitute non-personal data, they do not fall under the scope of regulations requiring patient informed consent.

However, for healthcare professionals participating in the study, a different approach was used. Participating healthcare professionals received oral information about the aims, design, and methods of the study, and subsequently signed a participation contract with the study sponsor to formalize their involvement and ensure they understood the study procedures and their responsibilities.

Adverse events, adverse product reactions and product deficiencies

Adverse Events (AE) and Adverse Events to 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 resulted 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 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.

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