R-TF-015-010 Annex E UNE-EN ISO 14155:2021

Applicability and scope

This Annex E documents the UNE-EN ISO 14155:2020 applicability assessment and documentation status for the prospective observational clinical investigation with a parallel retrospective case-series analysis performed under Clinical Investigation Plan R-TF-015-004 and Clinical Investigation Report R-TF-015-006 (investigation short-code IDEI_2023). It applies only to that investigation. The investigation is a non-interventional observational clinical validation of a medical device on adult patients presenting with pigmented skin lesions or female androgenetic alopecia; no diagnostic or therapeutic intervention is performed on any subject as a consequence of the investigation, and the device output does not modify the standard of care. Per MDCG 2020-6 Appendix III it generates Rank 2–4 evidence (prospective observational study with reference standard) and per MDCG 2020-1 §4.4 it contributes primary Pillar 3 Clinical Performance evidence.

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

UNE-EN ISO 14155:2020 Compliance Requirements

The table below documents, for each UNE-EN ISO 14155:2020 documentation item, whether the item is provided for this investigation and, where an item is not applicable or is provided through an equivalent record, the regulatory-level justification.

Document Title	Purpose	Included	Justification if not provided
Investigator's Brochure	Provides clinical and non-clinical data on the investigational device relevant to its study in human subjects.	TRUE	The Instructions for Use (IFU) together with the Device Description and Specifications record held within the technical file were supplied to all investigators at investigation onboarding and served as the investigational-device orientation document. Together they describe the device's intended purpose, indications, contraindications, principles of operation, warnings and precautions, and are the complete source of device information required for the investigators to operate the device under the investigation protocol.
Clinical Investigation Plan (CIP)	Describes the rationale, objectives, design, methodology, monitoring, and conduct of the clinical investigation.	TRUE	R-TF-015-004.
Subject Information Sheet and Informed Consent Form (ICF)	Ensures that potential study subjects are adequately informed about the investigation and provide voluntary consent.	TRUE	Patient Information Sheet and Informed Consent Form were provided to every prospectively enrolled subject prior to enrolment; written consent was obtained from each subject before any study-related activity. The templates are retained as essential study documents and are included as Annex III and Annex IV to the CIP.
Ethics Committee Approval	Official approval from the ethics committee to conduct the clinical investigation.	TRUE	Approved by the Comité de Ética en Investigación con Medicamentos (CEIm) of HM Hospitales, reference number 24.12.2266-GHM, issued on 25 January 2024. No subject was enrolled before the favourable opinion. The signed approval document is included as Annex II to the CIP.
Regulatory Authority Authorisation	Authorisation or notification from relevant regulatory bodies to proceed with the clinical investigation.	FALSE	The investigation is a non-interventional observational clinical validation of a medical device used within its intended purpose. No diagnostic or therapeutic intervention is performed on subjects as a consequence of the investigation, and the device output does not modify the standard of care. Under the Spanish biomedical-research framework applicable at the time of conduct, a non-interventional observational study of this type is subject to CEIm favourable opinion (obtained, as above) but does not trigger a pre-market clinical-investigation authorisation under MDR Article 62. The sponsor's non-interventional / intended-use determination is documented in the study essential documents and is retained by the sponsor.
Case Report Forms (CRFs)	Documents designed to record all protocol-required information to be reported to the sponsor on each trial subject.	TRUE	A secure, access-controlled electronic Case Report Form (eCRF) was used to capture all protocol-required information for each subject. All entries were captured electronically, time-stamped and stored in the study database. The eCRF template and data dictionary are retained by the sponsor as part of the study essential documents.
Monitoring Plan	Describes the strategy, methods, responsibilities, and requirements for monitoring the clinical investigation.	TRUE	Detailed in CIP §Monitoring plan (periodic, patient-based remote monitoring variant).
Subject Recruitment Materials	Materials used to recruit subjects, ensuring they are ethically and appropriately informed.	FALSE	Subjects were approached consecutively during routine dermatology visits at the investigator site; the Patient Information Sheet and Informed Consent Form served as the materials used to inform subjects about the investigation. Separate recruitment advertisements or promotional materials were not required and are not applicable to this consecutive-enrolment design.
Signed Agreements	Contracts between the sponsor, investigators, and institutions detailing roles and responsibilities.	TRUE	Signed sponsor-site and sponsor-investigator agreements are retained in the study essential documents under the custody of the Principal Investigator and the sponsor.
Delegation of Duties Log	Documents identifying the study-related duties and responsibilities assigned to each team member.	TRUE	Detailed in CIP §Research Team and in the delegation-of-duties log retained by the Principal Investigator as part of the study essential documents.
Training Records	Evidence of training provided to the investigation team on the CIP, investigational device, and GCP principles.	TRUE	A study initiation visit was conducted to train the investigators on the CIP, the device (via the IFU and the Device Description and Specifications record) and applicable GCP requirements. Attendance records and training materials are retained as essential study documents under the sponsor's training-record procedure.
Investigational Device Accountability Records	Tracks the receipt, use, and disposition of the investigational device to ensure traceability.	TRUE	The device is a software-only medical device accessed via a validated, access-controlled web-based platform provided by the manufacturer. The research team was granted controlled access to the investigational device via individual authenticated user accounts. Session logs, access logs and activity timestamps maintained by the platform provide complete traceability of device access and annotation activity; these logs constitute the device-accountability record for software-only devices and are retained under the sponsor's information-security and records-retention procedures.
Subject Identification Code List	Confidential list linking subjects' codes to their identities, maintained by the investigator.	TRUE	A subject identification code list linking study codes to subject identities is maintained confidentially at the investigator site under the custody of the Principal Investigator in accordance with GDPR and Spanish data-protection law, and is available on audit request subject to the applicable confidentiality controls.
Screening and Enrollment Logs	Documents tracking the screening and enrollment status of potential and actual study subjects.	TRUE	Screening and enrolment logs are maintained confidentially at the investigator site under the custody of the Principal Investigator.
Investigational Device Dossier (IDD)	Comprehensive technical and clinical data on the investigational device, including design, manufacturing, and performance information.	TRUE	The Investigational Device Dossier is constituted by the device's Technical File under MDR Annex II, comprising the Device Description and Specifications record, the design-and-development records (R-TF-012 series), the Risk Management Record (R-TF-013-002), the verification-and-validation records, the cybersecurity documentation, and the IFU. These records are cross-referenced from the CIP (§Product Identification and Description) and are held by the manufacturer.
Insurance Statement	Proof of insurance coverage for participants in case of study-related injuries.	TRUE	The manufacturer's civil liability insurance covered possible damages to participants throughout the investigation duration, consistent with MDR Article 69 and Spanish Ley 14/2007 on biomedical research. The investigation is non-interventional in nature; nevertheless, comprehensive insurance coverage was maintained for the duration of the investigation.
Financial Disclosure Records	Documentation of any financial interests of investigators that could affect the study's integrity.	TRUE	Financial-disclosure and declaration-of-interests forms were completed by each investigator and are retained in the study essential documents under the custody of the sponsor. Funding sources for the investigation are disclosed in CIP §Funding.
Audit Certificates	Reports from independent audits assessing compliance with the CIP and GCP.	FALSE	No independent audit was conducted for this investigation. The risk-based rationale is as follows: (i) the investigation is non-interventional with no subject-level risk beyond standard of care; (ii) subject-count is modest (204 subjects) at a single investigator site with periodic remote sponsor monitoring; (iii) essential study documents are retained under the sponsor's quality-assurance procedure and are available for audit on request. A retrospective quality review of essential study records can be commissioned if required by the notified body.
Statistical Analysis Plan (SAP)	Pre-specified statistical methods, analysis populations, and primary / secondary endpoint definitions.	TRUE	The statistical analysis plan is embedded in the CIP (§Statistical analysis) and further detailed in the CIR (§Statistical analysis). The in-sample operating-threshold selection for the malignancy-estimation endpoint and the retrospective-arm Ludwig-tuning dependency are declared in CIR §Protocol Deviations and will be addressed by a pre-specified SAP with a pre-specified operating threshold in the PMCF confirmatory study.
Deviations Log	Record of CIP deviations and their impact assessment.	TRUE	Six protocol deviations are documented in CIR §Protocol Deviations: (i) retrospective-cohort extension; (ii) reference-standard statement reconciliation (paper-questionnaire → histopathology); (iii) aided-reader design in the prospective arm; (iv) in-sample Youden-J operating-threshold selection for the malignancy gauge; (v) pooled retrospective+prospective metrics for the Ludwig-agreement endpoint are not used as confirmatory evidence (prospective Kappa 0.33 does not meet the pre-specified threshold); (vi) missing histopathological confirmation in the prospective arm handled via pre-specified sensitivity analysis. Each deviation is classified and its impact assessed. No CAPA was required at investigation level.
Adverse-event reporting procedure and timelines	Procedure and timelines for the reporting of AEs, ADEs, SAEs and SADEs.	TRUE	The AE / ADE / SAE / SADE reporting procedure and timelines are defined in CIP §Adverse events, adverse product reactions and product deficiencies and follow UNE-EN ISO 14155:2020. No AE, ADE, SAE or SADE attributable to the investigational device was observed during the investigation, as reported in CIR §Adverse events and adverse reactions to the product.
Device-deficiency reporting procedure	Procedure for the reporting and management of device deficiencies.	TRUE	The device-deficiency reporting procedure is defined in CIP §Product deficiencies and is aligned with the sponsor's non-conforming product control procedure. No device deficiency was observed during the investigation, as reported in CIR §Product deficiencies.
Annual safety / progress report to Ethics Committee	Periodic safety and progress report to the Ethics Committee.	TRUE	Follow-up reports to the CEIm of HM Hospitales were submitted in accordance with CIP §Start, follow-up and end reports. The correspondence with the CEIm is retained as an essential study document under the custody of the Principal Investigator.
Final Clinical Investigation Report	A comprehensive report summarising the clinical investigation's methodology and results.	TRUE	R-TF-015-006.

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