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, consecutive-case, cross-sectional clinical investigation performed under Clinical Investigation Plan R-TF-015-004 and Clinical Investigation Report R-TF-015-006 (investigation short-code MC_EVCDAO_2019). It applies only to that investigation. The investigation is a non-interventional observational clinical validation on patients presenting with skin lesions of suspected malignancy; 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 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 early melanoma detection and accurate malignancy triage 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 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 to the CIP.
Ethics Committee Approval	Official approval from the ethics committee to conduct the clinical investigation.	TRUE	Approved by the Comité de Ética de la Investigación con medicamentos (CEIm) of Euskadi under reference number PI2019216. Two approvals are on file: the initial CEIm favourable opinion issued on 2020-02-10 for the original 40-subject pilot phase, and the subsequent CEIm favourable opinion issued on 2022-01-13 for the substantial amendment extending the cohort. No subject was enrolled before the initial favourable opinion. The signed approval documents are 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 CE-marked medical device used within its intended purpose. No 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 on a CE-marked device 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 / CE-marked / 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 participating centres; 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 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 each study centre 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 each study centre 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 study duration. In accordance with Article 2(2) of the MDR and the provisions of ISO 14155:2020, the investigation was non-interventional in nature; nevertheless, comprehensive insurance coverage was maintained for the duration of the study.
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.
Audit Certificates	Reports from independent audits assessing compliance with the CIP and GCP.	TRUE	An independent audit of the clinical investigation was conducted by the Biocruces Bizkaia Health Research Institute study coordinator responsible for the conduct of the study. The audit verified compliance with the Clinical Investigation Plan and Good Clinical Practice principles. Audit date, scope and disposition of findings are recorded in the audit documentation retained as essential study documents under the sponsor's quality-assurance procedure.
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 primary-endpoint re-framing under the MDCG 2020-1 §4.4 Pillar 3 alignment and the in-sample operating-threshold selection for the malignancy-estimation endpoint 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	Five protocol deviations are documented in CIR §Protocol Deviations: (i) early closure of recruitment at N = 105; (ii) primary-endpoint re-framing under MDCG 2020-1 §4.4 Pillar 3 alignment; (iii) primary-care practitioner comparison not performed; (iv) malignancy operating threshold selected in-sample; (v) DIQA < 5 exclusion rule defined post-hoc. Each deviation is classified and its impact on the primary and secondary endpoints assessed. No CAPA was required.
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 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	Annual follow-up reports to the CEIm of Euskadi were submitted in accordance with CIP §Start, follow-up and end reports. The correspondence with the CEIm is retained as essential study documents 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