R-TF-015-010 Annex E UNE-EN ISO 14155:2021
Applicability and scope
This Annex E documents the UNE-EN ISO 14155:2021 applicability assessment and documentation status for the simulated-use multi-reader multi-case (MRMC) reader study performed under Clinical Investigation Plan R-TF-015-004 and Clinical Investigation Report R-TF-015-006 (investigation short-code bi-2024). It applies only to that investigation. The investigation is a simulated-use reader study on retrospective, fully anonymised images sourced from public dermatological atlases and from a de-identified image library provided by the sponsor (Boehringer Ingelheim); per MDCG 2020-6 Appendix III it generates Rank 11 evidence and per MDCG 2020-1 §4.4 contributes Pillar 3 Clinical Performance supporting evidence at Rank 11. Under MDR Article 2(48) it is distinct from clinical data on real patients, and it is conducted outside the material scope of the Spanish biomedical-research framework (see "Ethics Committee Non-Applicability Determination" below).
Pillar 2 (the algorithm's API-level analytical performance) 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 diagnostic accuracy to patient outcomes) is documented in R-TF-015-011 State of the Art.
UNE-EN ISO 14155:2021 Compliance Requirements
The table below documents, for each UNE-EN ISO 14155:2021 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) v1.1.0.0 of the device was provided to all reader-participants at investigation onboarding and served as the investigational-device orientation document. The IFU describes the device's intended purpose, indications, contraindications, principles of operation, warnings and precautions, and is the complete source of device information required for the reader-participants 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. | FALSE | The investigation uses only completely anonymised images from public dermatological atlases and from a de-identified sponsor image library; no patient is recruited, contacted, or consented, and the images constitute non-personal data under GDPR. Reader-participants do not receive medical intervention, diagnostic testing, or modification of care as a consequence of the investigation; accordingly, a formal ICF is not applicable to reader-participants. All reader-participants receive comprehensive written and oral information and sign a participation agreement with the sponsor. |
| Ethics Committee Approval | Official approval from the ethics committee to conduct the clinical investigation. | FALSE | See the "Ethics Committee Non-Applicability Determination" section below. The sponsor has determined and documented that this investigation does not fall within the material scope of the Spanish biomedical-research framework that would require ethics-committee review; it uses only completely anonymised images from public atlases and from a de-identified sponsor image library and recruits no patients. |
| Regulatory Authority Authorisation | Authorisation or notification from relevant regulatory bodies to proceed with the clinical investigation. | FALSE | The investigation is a simulated-use reader study on fully anonymised retrospective images under MDCG 2020-6 Appendix III Rank 11. It recruits no patients, performs no intervention on patients, processes no patient-identifiable data, and does not meet the definition of a "clinical investigation" under MDR Article 2(45). Accordingly, (i) MDR Article 62 authorisation is not applicable (the investigation is not a pre-market clinical investigation under Article 62); (ii) MDR Article 74 notification is not applicable (the investigation is not a post-market clinical follow-up investigation of a CE-marked device involving additional invasive or burdensome procedures); and (iii) MDR Article 82 does not apply (the investigation does not involve a non-CE-marked device undergoing clinical investigation in a member state). The trial registrations listed in the CIP (ClinicalTrials.gov and EMA RWD Catalogue / EUPAS) were performed as a transparency measure consistent with the MDCG 2020-6 evidence-transparency expectation for Rank 11 evidence; the registrations do not, of themselves, indicate that Article 62, 74 or 82 applicability was triggered. See also the "Ethics Committee Non-Applicability Determination" below. |
| 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 web-based platform served as the electronic Case Report Form (eCRF) for image presentation and response capture. All reader responses were captured electronically, time-stamped, and stored in the secure central database. The locked dataset was exported from the eCRF in a controlled, structured tabular format at database lock; full traceability from source data to exported records is maintained in accordance with Good Clinical Practice. 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. |
| Subject Recruitment Materials | Materials used to recruit subjects, ensuring they are ethically and appropriately informed. | FALSE | This is a simulated-use MRMC reader study using fully anonymised images from public dermatological atlases and from a de-identified sponsor image library. No patient recruitment, advertisement, or solicitation was performed; no direct contact with patients occurred. Reader-participants were identified through professional channels and signed a participation agreement with the sponsor; dedicated recruitment materials were not necessary and are not applicable. |
| Signed Agreements | Contracts between the sponsor, investigators, and institutions detailing roles and responsibilities. | TRUE | Signed participation agreements between the sponsor and each reader-participant, and the sponsor-investigator agreement between the Principal Investigator and the sponsor, are retained in the study essential documents under the custody of the Principal Investigator. |
| 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. |
| Training Records | Evidence of training provided to the investigation team on the CIP, investigational device, and GCP principles. | TRUE | Training was provided to all reader-participants and study staff on the CIP, the device (via IFU v1.1.0.0), the eCRF platform, data-entry procedures, and applicable compliance requirements. Attendance records and training materials are retained by the sponsor as part of the study essential documents. |
| Investigational Device Accountability Records | Tracks the receipt, use, and disposition of the investigational device to ensure traceability. | FALSE | The device is a software-only medical device accessed via a validated, access-controlled web-based platform provided by the manufacturer. Reader-participants were granted controlled access to the platform through individual authenticated credentials; session logs, access logs and activity timestamps maintained by the platform provide complete traceability of device access and use in lieu of physical device-accountability records, which are not applicable to software-only devices. |
| Subject Identification Code List | Confidential list linking subjects' codes to their identities, maintained by the investigator. | FALSE | The investigation is a simulated-use MRMC reader study on fully anonymised retrospective images; no patients are recruited and no patient-identification code list is applicable. A separate investigator identification-code list, linking reader-participant pseudonymised codes to reader identities, is retained under the custody of the Principal Investigator and is available on audit request. |
| Screening and Enrollment Logs | Documents tracking the screening and enrollment status of potential and actual study subjects. | FALSE | The investigation is a simulated-use MRMC reader study on fully anonymised retrospective images; no patients are screened or enrolled. Reader-participant screening and onboarding records are retained by the sponsor as part of the study essential documents. |
| 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 specification 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 Instructions for Use v1.1.0.0. 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. | FALSE | The investigation performs no intervention on patients, recruits no patients, and presents no patient-level risk; reader-participants do not receive medical intervention, diagnostic testing, or modification of care as a consequence of the investigation. Accordingly, study-specific participant insurance is not applicable. |
| 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 have been 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. | FALSE | An independent external audit was not conducted for this investigation. Given the simulated-use, non-interventional nature of the study (review of anonymised images by trained healthcare professionals on a secure platform), internal compliance verification and monitoring by the sponsor in accordance with the sponsor's internal-audit procedure were determined to be sufficient. Internal monitoring-execution records and data-verification records, governed by the sponsor's internal-audit and quality-assurance procedures (cross-referenced from GP-004 Internal Audits within the manufacturer's QMS), are retained under the custody of the sponsor as part of the study essential documents. |
| Deviations Log | Record of CIP deviations and their impact assessment. | TRUE | Two minor CIP deviations are documented in CIR §Clinical Investigation Plan (CIP) Compliance: (i) partial completion by 6 of 15 reader-participants with a pre-specified sensitivity-analysis mitigation, and (ii) a source-record metadata reconciliation (101→100) performed prior to analysis. Neither deviation impacted data integrity, analysis population or pre-specified endpoints; no CAPA was required. |
| Final Clinical Investigation Report | A comprehensive report summarising the clinical investigation's methodology and results. | TRUE | R-TF-015-006. |
Ethics Committee Non-Applicability Determination
This clinical investigation is a simulated-use multi-reader multi-case (MRMC) study performed entirely on retrospective, fully anonymised dermatological images obtained from public dermatology atlases and other freely available public sources. The investigation does not involve the recruitment of patients, direct contact with patients, or the collection or processing of patient-identifiable data; no therapeutic or diagnostic intervention is performed on any patient as a consequence of the study. Healthcare professionals acting as readers participate in their professional capacity as expert evaluators of device performance; they are not enrolled as research subjects within the meaning of biomedical-research law.
Accordingly, the sponsor has determined, and documents herein, that this investigation does not fall within the material scope of:
- Ley 14/2007, de 3 de julio, de Investigación Biomédica, which governs biomedical research involving human subjects, human biological samples and personal health data in Spain.
- Real Decreto 957/2020, de 3 de noviembre, por el que se regulan los estudios observacionales con medicamentos de uso humano and, by analogy for medical-device performance studies, the Spanish framework transposing the requirements of Regulation (EU) 2017/745 Article 62 and Annex XV for clinical investigations of medical devices involving human subjects.
The sponsor further confirms that the study is conducted in accordance with the ethical principles of the Declaration of Helsinki to the extent applicable to retrospective studies of anonymised material; complies with Regulation (EU) 2016/679 (GDPR) and with Ley Orgánica 3/2018, de 5 de diciembre, de Protección de Datos Personales y garantía de los derechos digitales for the handling of any personal data collected from reader-participants; and is registered in the public trial registries identified in the corresponding Clinical Investigation Plan and Clinical Investigation Report.
This determination of non-applicability is signed off by the sponsor and retained in the technical file. Where a participating site or competent authority requires a formal ethics-committee opinion or waiver for local conduct, such opinion is obtained and attached separately; otherwise this determination applies.
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