R-TF-015-004 Clinical investigation plan

Scope

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

Nature and positioning of the evidence

This is a simulated-use, multi-reader multi-case (MRMC) investigation performed on retrospective, fully anonymised dermatological images sourced from public dermatological atlases and from a de-identified image library provided by the sponsor (Boehringer Ingelheim). No patients are recruited, no patient-identifiable data are processed, and no diagnostic or therapeutic intervention is performed on any patient as a consequence of the investigation.

Under MDCG 2020-6 Appendix III the resulting evidence is Rank 11 (simulated-use reader study on retrospective images); it is distinct from clinical data on real patients within the meaning of MDR Article 2(48). Per MDCG 2020-1 §4.4 it contributes 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 that carry the primary Pillar 3 weight. Pillar 2 (the algorithm's API-level analytical performance across the 346 ICD-11 categories) is evidenced independently through the device verification-and-validation records and the published severity-validation manuscripts; it is not the subject of this investigation. Pillar 1 (Valid Clinical Association literature anchoring diagnostic accuracy to patient outcomes) is documented in the State of the Art (R-TF-015-011).

CIP Identification

	CIP
Title of the clinical investigation	Multi-Reader Multi-Case Study for Assessing the Impact of Legit.Health Plus on the Clinical Assessment of Generalised Pustular Psoriasis and Other Skin Conditions by Healthcare Professionals.
Device under investigation	Legit.Health Plus
Protocol version	Version 1.0
Date	2024-06-01
Protocol code	LEGIT.HEALTH_BI_2024
Sponsor	Boehringer Ingelheim
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 dermatologists.
Ethics Committee	This study did not require 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): NCT07428915
• EMA RWD Catalogue (EUPAS): EUPAS1000000910

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 Investigators (Clinical Staff)
  • 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
    • Justification for 1,500 paired observations
    • Selection of 15 reader-participants
    • Selection of 100 images per reader
  • Justification of acceptance thresholds
  • Duration
  • Acceptance criteria
  • Inclusion criteria
  • Exclusion criteria
  • Variables
    • Main variable
    • Secondary variables
  • Condition of interest
  • Limitations of clinical research
• Ethical considerations
  • Data confidentiality
  • Bias minimisation measures
  • Calendar
  • Monitoring plan
  • Completion of the investigation
  • Statistical analysis
  • Data management
    • Data collection
    • Access control and traceability
    • Data anonymity
    • Data export and analysis
    • Data security
• CIP Modification
• CIP Deviations
• Start, follow-up and end reports
• Statements of compliance
• Informed Consent process
  • For image subjects
  • For reader-participants (healthcare professionals)
• Adverse events, adverse product reactions and product deficiencies
  • Adverse Events (AE) and Adverse Events to the Product (AEP)
  • Product deficiencies
  • Serious Adverse Events, serious adverse events to product and serious and unexpected adverse events to the product
  • Foreseeable adverse events and adverse events to the product
  • Data Monitoring Committee (DMC)
• Suspension or early termination of clinical research

Compliance Statement

• Harmonised standard UNE-EN ISO 14155:2021.
• Regulation (EU) 2017/745 on medical devices (MDR).
• Harmonised standard UNE-EN ISO 13485:2016.
• Regulation (EU) 2016/679 (GDPR).
• Spanish Organic Law 3/2018 on the Protection of Personal Data and guarantee of digital rights.

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 Investigators (Clinical Staff)

• Dr. Mari Carmen Galindo
• Dr. Paco García Tolosa
• Dr. Laura Yuste Hidalgo
• Dr. Nuria Comabella
• Dr. Marta Vázquez
• Dr. David Palacios
• Dr. Norma Alejandra Doria Carlin
• Dr. Francisco José Esteban González
• Dr. Alfonso José Valcarce Leonisio
• Dr. José Antonio Arjona Sevilla
• Dr. Javier Melgosa
• Dr. Manuel Ballesteros Redondo
• Dr. Esmeralda Silva
• Dr. Ana Llull Ramos
• Dr. Angela Patricia Guzmán

Technical Support (Manufacturer)

• Mr. Alfonso Medela — Chief Technology Officer
• Dr. Alberto Sabater — Algorithm Lead
• Mrs. Alba Rodríguez — Clinical Operations

Investigational sites

This investigation was conducted remotely through a centralised, access-controlled web-based platform. Reader-participants (healthcare professionals) received individual authenticated credentials to securely access the platform. All images were presented through this platform, and reader-participant assessments were recorded on the same system. Access logs were maintained to ensure traceability of all reader-participant interactions with the platform.

Funding

This research was carried out without any funding or sponsorship from the manufacturer; the sponsor (Boehringer Ingelheim) provided the de-identified internal image subset described below and took no role in the analysis or the conclusions.

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 investigation was conducted using device version v1.1.0.0, which is the only version placed on the market and the version to which the present technical documentation applies. No intermediate development build was used during the conduct of the investigation. The bridging between the investigation-version and the CE-marked release is therefore an identity bridge (no algorithm, model, UI or training-data changes); no clinical-relevance assessment is required. The device-version statement has been reviewed and signed off by the PRRC.

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 primary care physicians and dermatologists remain substantial, with concordance rates between 57% and 65.52%. This gap in expertise can lead to misdiagnoses, incorrect referrals, and delays in appropriate treatment, particularly in rare and severe conditions such as generalised pustular psoriasis (GPP) and hidradenitis suppurativa (HS). The limited availability of dermatologists, especially in rural areas, further complicates patient care, underscoring the need for decision-support tools that can assist primary care practitioners and dermatologists in the recognition of rare and complicated presentations.

Teledermatology has shown promise in reducing the pressure on in-person consultations by enabling remote assessments. The integration of artificial intelligence in the form of a clinical-decision-support device presents an opportunity to support the diagnostic capabilities of both primary care practitioners and dermatologists. This investigation evaluates, under simulated-use conditions on a curated anonymised image set containing rare-disease target pathologies (GPP, HS and related pustular dermatoses) alongside common confounders, whether the use of the device's Top-5 prioritised differential view increases the top-1 diagnostic accuracy of healthcare professionals relative to their unaided reads on the same image set. Diagnostic accuracy is a surrogate endpoint; the patient-benefit chain (earlier correct treatment, reduced disease progression, more efficient referral pathways) is anchored by published literature summarised in the State of the Art (R-TF-015-011) and assessed at Clinical Evaluation level in R-TF-015-003.

Risks and benefits of the product in investigation and clinical research

In this investigation, there is no patient recruitment or active patient involvement. The images used are sourced from public dermatological atlases and from a de-identified image library provided by the sponsor; all images are fully anonymised prior to analysis and no individual can be identified from them. The foreseeable risks of the investigation are: (i) data-protection residual risk on the handling of anonymised images and reader-participant session data, mitigated by GDPR-aligned technical and organisational controls; (ii) device-induced diagnostic error in either direction — a proportion of device-aided reads may improve an incorrect unaided decision and a proportion may switch a correct unaided decision to an incorrect one (automation-bias direction); both proportions are characterised in the Clinical Investigation Report and traced to the risk management record (R-TF-013-002); and (iii) over-extrapolation of simulated-use evidence to real-world performance, mitigated by the explicit Rank 11 / Pillar 3 §4.4 framing of this investigation and by cross-reference to higher-ranked real-patient evidence at Clinical Evaluation level. The foreseeable benefits of the investigation are: support for decision-making in rare-disease diagnosis, generation of Rank 11 supporting evidence for the device's Pillar 3 Clinical Performance claims, and characterisation of per-pathology directional trends that inform the PMCF Plan.

Hypothesis

When healthcare professionals use the device's Top-5 prioritised differential view, their top-1 diagnostic accuracy on a curated set of anonymised dermatological images — including the rare-disease target pathologies (GPP, HS, pustular dermatoses) and common confounders — increases, relative to their unaided diagnosis on the same image set.

Objectives

Primary Objective

• To demonstrate that the device, used in its Top-5 prioritised differential-view configuration, increases the top-1 diagnostic accuracy of healthcare professionals on a curated, anonymised image set representing multiple dermatological conditions, with the rare-disease target pathologies (GPP, HS, pustular dermatoses) included as part of the pooled endpoint.

Secondary Objectives

• To characterise, as a pre-specified secondary endpoint, the paired change in top-1 diagnostic accuracy within the rare-disease subgroup (GPP, Acne Conglobata, Palmoplantar Pustulosis, Subcorneal Pustular Dermatosis, AGEP, Pemphigus Vulgaris).
• To characterise the paired change in top-1 diagnostic accuracy stratified by reader specialty (primary care physicians versus dermatologists).

Per-pathology and per-age-band analyses are pre-specified as exploratory / hypothesis-generating (see §Statistical analysis).

Summary of the study

This is a prospective, simulated-use, multi-reader multi-case (MRMC) self-controlled reader study. Each healthcare professional reviews the same curated set of 100 anonymised dermatological images, first unaided and then with the device's Top-5 prioritised differential view. The primary endpoint is the paired change in pooled top-1 diagnostic accuracy; secondary endpoints are the paired change in accuracy within the pre-specified rare-disease subgroup and stratified by reader specialty. The investigation generates Rank 11 supporting Pillar 3 §4.4 Clinical Performance evidence (per MDCG 2020-6 Appendix III and MDCG 2020-1 §4.4) and does not, by itself, demonstrate clinical performance on real patients; the primary Pillar 3 evidence is supplied by the prospective real-patient investigations at Ranks 2–4.

Design and methods

Type of clinical research

This is a prospective, observational, multi-reader multi-case self-controlled study to evaluate whether the use of the device by healthcare professionals helps to increase the accuracy in the diagnosis of different skin conditions, with particular attention to rare pustular dermatoses and hidradenitis suppurativa. In this self-controlled design, each reader-participant 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 investigation, the reader population consists of healthcare professionals. A target of 15 reader-participants is planned, comprising 11 primary care physicians and 4 dermatologists, reflecting the mixed-specialty user population at deployment. Each participant reviews the 100-image set.

Sample size

The investigation is designed to detect a pre-specified absolute improvement of at least 10 percentage points (pp) in pooled top-1 diagnostic accuracy between unaided and device-aided reads on the same image set, using McNemar's test for paired proportions at a two-sided significance level of 0.05. The target sample is 15 reader-participants each reviewing 100 anonymised dermatological images, yielding 1,500 paired observations (per-observation analysis population). For a paired-binary design with an expected baseline accuracy of approximately 50% and a discordant-pair rate consistent with state-of-the-art aided-HCP performance (R-TF-015-011), 1,500 paired observations provide power ≥ 80% to detect the pre-specified 10 pp absolute improvement on the pooled endpoint.

Justification for 1,500 paired observations

• Primary-endpoint power: 1,500 paired observations provide ≥ 80% power to detect the pre-specified 10 pp absolute improvement in pooled top-1 accuracy via McNemar's test at α = 0.05 (two-sided).
• Multiple reads per image: each of the 100 images is evaluated by 15 readers, yielding 15 paired observations per image and allowing assessment of inter-reader agreement and consistency of the device effect.
• Per-pathology subgroup scope: with 100 images distributed across 15 pathology categories (2–10 images per category), per-pathology subgroup analyses are pre-specified as exploratory / hypothesis-generating; the investigation is not powered for confirmatory per-pathology conclusions.
• Rare-disease secondary endpoint: the six rare-disease pathologies together account for 40 images and 600 paired observations, which supports the rare-disease pooled secondary endpoint at reduced-but-usable power.
• Per-specialty secondary endpoint: 11 primary care physicians (1,100 paired observations) and 4 dermatologists (400 paired observations) support per-specialty exploratory comparisons; the dermatologist stratum in particular is acknowledged as under-powered.

Selection of 15 reader-participants

The reader cohort size of 15 (11 PCPs + 4 dermatologists) is chosen to contain inter-reader variability while remaining practically feasible for a simulated-use MRMC design. Recruitment targets board-certified primary care physicians and dermatologists without prior regular exposure to the device, reflecting the target user population at deployment. The primary-care over-weighting (11 vs 4) reflects the primary-care-first intended-use position of the device.

Selection of 100 images per reader

One hundred images per reader provide a representative range of the dermatological conditions of interest, including the rare-disease target pathologies and common confounders. The image set represents 15 dermatological conditions sampled from public dermatological atlases and from a de-identified image library provided by the sponsor.

Justification of acceptance thresholds

The acceptance thresholds rendered by <AcceptanceCriteriaTable studyCode="BI_2024" /> are derived from the State of the Art synthesis documented in R-TF-015-011 (Clinical Evaluation — State of the Art). Absolute-value thresholds match or exceed the meta-analytic baseline for aided-HCP performance reported in that record; relative-change thresholds are set at approximately +10 pp above the state-of-the-art AI-aided improvement baseline (per R-TF-015-011 §"Methodology for Establishing Acceptance Criteria"), in order to demonstrate substantial clinical benefit in the sense of MDCG 2020-1 §4.4.

The primary confirmatory endpoint is the paired absolute improvement of ≥ 10 pp in pooled top-1 diagnostic accuracy across the full image set, tested across the full reader cohort (all specialties pooled).

The following secondary confirmatory endpoints are pre-specified:

• Per-specialty paired absolute improvement in pooled top-1 diagnostic accuracy, with thresholds PCP ≥ 10 pp and dermatologist ≥ 5 pp (the lower dermatologist threshold reflects the higher specialist baseline accuracy; the dermatologist stratum is acknowledged as under-powered for confirmatory per-pathology claims and the per-specialty pass/fail call on the dermatologist stratum is supportive only).
• Rare-disease pooled paired absolute improvement in top-1 diagnostic accuracy using the same PCP ≥ 10 pp / dermatologist ≥ 5 pp structure.

All stratum-level comparisons below the per-specialty pooled level (per-pathology, per-age-band) are pre-specified as exploratory / hypothesis-generating.

Duration

The total duration of the investigation is estimated at approximately 3–4 months, including the time required for reader recruitment, data collection, database lock, data analysis, and preparation of the Clinical Investigation Report.

Acceptance criteria

• top-1 accuracy equal to or greater than 7.00%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy greater than 47.94%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 53.96%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity greater than 6.93%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity greater than 70.00%.(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 equal to or greater than 70.00%.(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 47.91%.(User Group: Primary care practitioners)
• top-1 accuracy equal to or greater than 46.12%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 14.30%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 66.30%.(User Group: Primary care practitioners)
• specificity equal to or greater than 11.88%.(User Group: Primary care practitioners)
• specificity equal to or greater than 70.10%.(User Group: Primary care practitioners)
• top-1 accuracy equal to or greater than 5.83%.(User Group: Dermatologists)
• top-1 accuracy equal to or greater than 57.25%.(User Group: Dermatologists)
• top-1 accuracy equal to or greater than 61.80%.(User Group: Dermatologists)
• sensitivity equal to or greater than 6.93%.(User Group: Dermatologists)
• sensitivity equal to or greater than 70.00%.(User Group: Dermatologists)
• sensitivity greater than 61.64%.(User Group: Dermatologists)
• specificity equal to or greater than 77.60%.(User Group: Dermatologists)
• specificity greater than 62.47%.(User Group: Dermatologists)
• top-1 accuracy equal to or greater than 6.93%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 30.90%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity equal to or greater than 6.93%.(User Group: Dermatologists, Primary care practitioners)
• sensitivity greater than 21.04%.(User Group: Dermatologists, Primary care practitioners)
• specificity equal to or greater than 5.06%.(User Group: Dermatologists, Primary care practitioners)
• specificity greater than 38.69%.(User Group: Dermatologists, Primary care practitioners)
• top-1 accuracy equal to or greater than 24.34%.(User Group: Primary care practitioners)
• sensitivity equal to or greater than 14.30%.(User Group: Primary care practitioners)
• sensitivity greater than 19.33%.(User Group: Primary care practitioners)
• specificity equal to or greater than 11.88%.(User Group: Primary care practitioners)
• specificity greater than 36.64%.(User Group: Primary care practitioners)
• top-1 accuracy equal to or greater than 5.83%.(User Group: Dermatologists)
• top-1 accuracy equal to or greater than 48.15%.(User Group: Dermatologists)
• sensitivity greater than 35.89%.(User Group: Dermatologists)
• specificity greater than 55.67%.(User Group: Dermatologists)

Inclusion criteria

• Board-certified primary care physicians and dermatologists, regardless of years of professional experience, without prior regular exposure to the device.
• Dermatological images with confirmed reference diagnosis, meeting pre-specified technical quality criteria (sufficient resolution, adequate focus, lesion clearly framed).

Exclusion criteria

• Images of insufficient technical quality (blurred, poorly framed, or with insufficient lesion coverage) that cannot be properly analysed.

Variables

Main variable

• Paired change in pooled top-1 diagnostic accuracy across the full image set, calculated both with and without the use of the device.

Secondary variables

• Paired change in pooled top-1 diagnostic accuracy within the pre-specified rare-disease subgroup.
• Paired change in top-1 diagnostic accuracy stratified by reader specialty (primary care physicians versus dermatologists).
• Diagnostic sensitivity and specificity for each pathology, reported descriptively with Wilson 95% CIs.

Condition of interest

Dermatological conditions including rare pustular dermatoses (GPP, Palmoplantar Pustulosis, Subcorneal Pustular Dermatosis, AGEP, Pemphigus Vulgaris), Acne Conglobata, Hidradenitis Suppurativa, and common confounders (eczematous dermatitis, seborrheic keratosis, seborrheic dermatitis, plaque psoriasis, impetigo, tinea corporis, acne, severe inflammatory acne).

Limitations of clinical research

The investigation is subject to the following structural limitations, pre-specified here and to be restated and assessed in the Clinical Investigation Report:

1. Rank 11 simulated-use evidence. Under MDCG 2020-6 Appendix III this investigation produces Rank 11 evidence (simulated-use reader study on retrospective images) and is distinct from clinical data on real patients within the meaning of MDR Article 2(48). It contributes Pillar 3 §4.4 supporting evidence only; primary Pillar 3 Clinical Performance evidence is supplied by the prospective real-patient investigations at Ranks 2–4.
2. Curated image set vs real-world imaging. The image set is sourced from public dermatological atlases and from a de-identified sponsor image library, with confirmed reference diagnoses; atlas-grade image quality over-represents optimal acquisition conditions relative to typical real-world captures, and this is expected to bias observed accuracy upward relative to real-world deployment.
3. Fitzpatrick phototype coverage. The image set under-represents darker phototypes; performance claims on Fitzpatrick V and VI cannot be supported by this investigation alone and are addressed by dedicated phototype-bridging evidence at Clinical Evaluation level (see R-TF-015-003 and related MRMC investigations).
4. Paediatric subgroup scope. Paediatric representation is limited, and per-age-band subgroup analyses are pre-specified as exploratory / hypothesis-generating only; the investigation is not powered to detect age-stratified effects.
5. Recall bias in a within-subject design. Because the unaided and device-aided reads evaluate the same image set sequentially without a washout period, the observed difference reflects device impact plus any recall-assisted improvement across reads; the net bias is expected to be upward on accuracy.
6. Per-pathology statistical power. With 2–10 images per pathology category, per-pathology analyses are exploratory and under-powered; no per-pathology confirmatory benefit claim is made on the basis of this investigation.
7. Per-specialty imbalance. With 11 primary care physicians and 4 dermatologists, the dermatologist stratum is under-powered for per-specialty confirmatory claims; per-specialty analyses below the pooled level are treated as exploratory.
8. Device-influenced decision-change direction. A proportion of device-aided reads will correctly change an incorrect prior answer (improvement) and a proportion will incorrectly change a correct prior answer (automation-bias harm); both proportions are reported and the latter is traced to the risk management record.
9. Hawthorne effect under simulated use. Readers are aware that they are being observed; this may modulate their behaviour relative to routine practice.
10. User trust and consistency. Variation between readers in how readily they incorporate the device's output affects observed inter-reader variability; this is reported rather than suppressed.
11. Image-source heterogeneity. The image set combines public atlases with a de-identified sponsor image library; reference-diagnosis confirmation was performed per-source and pooled for analysis.

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.

No informed consent is collected from patients because the investigation does not recruit patients, does not interfere with any clinical care, and uses only completely anonymised images sourced from public dermatological atlases and from a de-identified sponsor image library (images in these sources do not constitute personal data under GDPR as no individual is identifiable). No active patient involvement takes place. The sponsor's determination of non-applicability of biomedical-research law and ethics-committee review for this investigation is recorded in Annex E (R-TF-015-010) under "Ethics Committee Non-Applicability Determination".

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 minimisation measures

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

• Self-controlled design. Each reader serves as their own comparator (unaided vs device-aided reads on the same image set), removing between-reader confounding on the primary endpoint.
• Standardised platform and session protocol. All readers access the same access-controlled web-based reader platform through individual credentials, are presented with the same image set in a standardised layout, and answer the same pre-specified question set for each image.
• Pre-specified primary and secondary outcomes. All endpoints, thresholds and analysis populations are defined prior to data collection; per-pathology, per-age-band and per-specialty analyses below the pooled level are pre-declared as exploratory / hypothesis-generating to prevent selective reporting.
• Prospective data capture. All reader responses are electronically captured in real time in the eCRF and time-stamped, removing recall bias at the per-read level.
• Acknowledged residual bias — carry-over between reads. The unaided and device-aided reads evaluate the same 100 images sequentially. There is no washout period between the two reads and readers are not blinded to their prior answer. This is a known residual source of carry-over / recall-assisted improvement and is documented as a structural limitation of the design; the expected net bias direction is upward on observed accuracy.
• Acknowledged residual bias — image-set curation. The image set is curated from public atlases and a de-identified sponsor image library with confirmed reference diagnoses, which over-represents optimal imaging conditions relative to typical real-world captures and is expected to bias observed accuracy upward relative to real-world deployment.

Calendar

The total duration of the investigation is estimated at approximately 3–4 months, including the time required after the recruitment of the participating healthcare professionals 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) will be drafted, even in the event of early termination or suspension. The results obtained (whether positive, inconclusive, or negative) will be included in the trial registrations identified above.

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 investigation, 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 authorisation by both parties. Press releases and other communications may also be issued to share the investigation's results. All publications and communications must be reviewed and approved by the parties involved.

Statistical analysis

The pre-specified statistical analysis plan is as follows.

Primary analysis — confirmatory. The primary endpoint is the paired change in pooled top-1 diagnostic accuracy across the full image set (1,500 paired per-observation reads), tested with McNemar's test for paired proportions at a two-sided significance level of 0.05. The accompanying 95% confidence interval for each proportion is reported using the Wilson score method; the 95% confidence interval for the paired difference in proportions is reported using the Newcombe method. The pre-specified primary analysis population is the per-observation paired set (each image-reader pair is one observation).

Secondary analyses — supporting. Paired change in pooled top-1 accuracy within the pre-specified rare-disease subgroup and stratified by reader specialty (PCP vs dermatologist) is reported with Wilson 95% CIs for each proportion and Newcombe 95% CIs for the paired difference. Diagnostic sensitivity and specificity by pathology are reported descriptively with Wilson 95% CIs.

Exploratory / hypothesis-generating analyses. Per-pathology analyses (15 pathology categories), per-age-band analyses (newborn, infant, child, adolescent, adult, elderly), and the qualitative decomposition of device-attributable decision changes (reinforce / improve / no-change / switch-to-incorrect) are pre-specified as exploratory / hypothesis-generating only. P-values and CIs reported for these strata are labelled exploratory and are not used as the basis for any confirmatory benefit claim. No multiplicity correction is applied across exploratory analyses, consistent with their hypothesis-generating purpose.

Inter-reader agreement. Inter-reader agreement on the primary endpoint is characterised by Cohen's kappa (or a weighted kappa where appropriate), reported with its 95% CI.

Missing-data handling. The pre-specified primary analysis is complete-case at the per-observation level. Any missing response is excluded from the paired analysis for that reader-image pair; no imputation is applied. A sensitivity analysis at the ≥ 50%-completer and 100%-completer reader level is pre-specified.

Zero-cell handling. For strata where either the unaided or the device-aided read yields a zero-cell (e.g., single-case subgroups), exact confidence intervals are used and the stratum is explicitly flagged as non-evaluable for confirmatory purposes.

Analytics environment. All pre-specified analyses are implemented in a deterministic, version-controlled analytics environment maintained by the manufacturer. The analytics module is unit-tested against known inputs to ensure reproducibility from the locked source dataset to the published results tables.

Data management

All investigation data will be collected and managed through a centralised, access-controlled web-based platform that serves as the electronic Case Report Form (eCRF). Each reader-participant will receive individual authenticated credentials to access the platform. The platform will present the standardised set of 100 images to each reader-participant and capture their diagnostic assessments in response to structured questions.

Data collection

Diagnostic assessments are electronically captured directly in the eCRF platform as readers provide their responses. All entries are time-stamped and automatically stored in a secure central database.

Access control and traceability

Access to the platform is restricted to authorised readers through individual authenticated credentials. Complete access logs are maintained for each reader, documenting login times, data-entry activities, and timestamps of all interactions. This audit trail ensures full traceability of who accessed what data and when.

Data anonymity

Study images are completely anonymised and bear no patient identifiers. Each reader is assigned a pseudonymised identification code that is not linked to the reader's identity in the analysis dataset. The Principal Investigator maintains a confidential identification-code list linking reader codes to identities, stored separately in a secure area with restricted access.

Data export and analysis

Once data collection is completed and the database is locked by the Principal Investigator, the locked dataset is exported for statistical analysis in a controlled, structured tabular format. The exported dataset contains only anonymised image-level data and reader responses under pseudonymised codes, with no personal identifying information.

Data security

All data transmitted to and stored on the platform are encrypted using industry-standard security protocols. Access to the central database is restricted to authorised personnel, and the platform implements appropriate technical and organisational measures to prevent unauthorised access, alteration, or loss of data.

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 investigation will be notified to the principal investigator and all the participant investigators.

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

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

For image subjects

Informed consent from patients whose images may appear in the atlases or in the de-identified sponsor image library is not required for this investigation because: (i) only completely anonymised images are used and no individual can be identified; (ii) there is no active patient recruitment or direct involvement of patients; (iii) the images constitute non-personal data under GDPR as they contain no information allowing identification of data subjects — the anonymisation assessment is documented in the sponsor's data-protection file and follows the criteria set out in Article 29 Working Party Opinion 05/2014 on anonymisation techniques; and (iv) the investigation involves no intervention, no modification of care, and no processing of sensitive personal health data.

For reader-participants (healthcare professionals)

Formal informed consent is not required for reader-participants because the investigation is observational and non-interventional with respect to their clinical practice; no medical intervention, diagnostic testing, or modification of care is performed on the reader-participants as a consequence of the investigation. All reader-participants receive comprehensive written and oral information about the investigation, including its objectives, procedures, their roles and responsibilities, data-handling practices, and confidentiality protections, and sign a participation agreement with the sponsor that regulates their participation, outlines their obligations, and confirms their voluntary agreement to participate. The sponsor's determination of non-applicability of biomedical-research law and ethics-committee review for this investigation is recorded in Annex E (R-TF-015-010) under "Ethics Committee Non-Applicability Determination".

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, and because the investigation recruits no patients and performs no intervention on patients, patient-level adverse events are not applicable. Reader-participant-level events (if any) are logged through the platform feedback field and feed the post-market surveillance procedure (GP-009 Post-Market Surveillance). Potential AEPs or AEs foreseen for the device 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 arising during the investigation will be managed by the sponsor according to non-conforming product control procedures. When appropriate, corrective and/or preventive actions will be taken to protect the safety of subjects, users, and other individuals.

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

According to UNE-EN ISO 14155:2021:

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

Because the investigation recruits no patients and performs no intervention on patients, SAEP, SAEs and SUAEPs related to the use of the product are not foreseen in the conduct of this investigation; the Clinical Investigation Report will confirm the outcome.

Foreseeable adverse events and adverse events to the product

The foreseeable adverse events and expected adverse reactions to the product, as well as their incidence, mitigation and treatment, are documented in R-TF-013-002 Risk management record for the device under investigation.

Data Monitoring Committee (DMC)

No Data Monitoring Committee is established for this investigation because the investigation does not recruit patients, does not perform any intervention on patients, and presents no direct safety risk to any subject. The Clinical Investigation Report will confirm, consistent with this plan, that no DMC was constituted.

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