Response

Response to BSI Item 3a - Clinical Data Analysis

Following the BSI auditor's observations, a comprehensive review and update of the Clinical Evaluation Report (CER) and the supporting Clinical Investigation documentation have been completed to ensure all relevant clinical data is identified and sufficient analysis is provided.

1. Overall Analysis and Traceability The CER (R-TF-015-003) has been significantly enhanced to provide a clear, integrated analysis of how all clinical benefit, safety, and performance claims have been met:

A new "Acceptance criteria reconciliation" section (within Section 15) has been added. This section explicitly maps every performance and safety metric from each clinical investigation against the predefined acceptance targets derived from the State of the Art (SotA). This provides direct, unambiguous traceability and a clear discussion of whether each criterion was met, along with clinical justifications for any minor deviations.
A "Methodological justifications and statistical adequacy" section was added to transparently justify the analysis methodology. This includes the rationale for the sample sizes (e.g., explaining that the MC_EVCDAO_2019 study concluded at 105 patients because the high prevalence of malignant cases provided sufficient statistical power to validate the primary safety endpoint), the rationale for data exclusion (justifying the use of the integrated Deep Image Quality Assessment algorithm to mirror real-world use), and the coverage of both clinical and dermatoscopic imaging modalities.

2. Clinical Investigations (CIs) Documentation The regulatory and administrative details for all pivotal studies, including MC_EVCDAO_2019 and IDEI_2023, have been explicitly documented in a new "Regulatory and Administrative Details of Clinical Investigations" table in the CER. This includes:

Competent Authority & Ethics Committee: Confirmation of AEMPS notification (observational) and specific CEIm approval reference numbers and dates.
Public Registration: All studies have been publicly registered; their ClinicalTrials.gov (NCT) and EMA RWD Catalogue (EUPAS) numbers are now explicitly listed.
Publication Status: The publication status in peer-reviewed journals is now tracked (e.g., BI_2024 published in JMIR Dermatology, IDEI_2023 published with DOI 10.1101/2025.03.11.25323753).
Protocol Deviations: All protocol deviations for the pivotal studies (including the sample size adjustment in MC_EVCDAO_2019 and the expanded cohort in IDEI_2023) are now fully documented and justified within their respective Clinical Investigation Reports (R-TF-015-006). The critical deviations have also been integrated into the methodological justifications of the CER.

3. Representativeness of Patient Populations and Indications To demonstrate sufficient coverage of representative patient populations, a "Representativeness of the Study Populations (Demographics & Skin Phototypes)" table was added to the CER. This provides a comprehensive breakdown of Gender, Age distribution across life stages, and Fitzpatrick skin phototypes (I-VI) across the 800+ patients in the pivotal studies. Furthermore, the "Coverage of Indications and Conditions" analysis justifies the strategy of evaluating the Vision Transformer architecture against "anchor conditions" representing the highest clinical risk (e.g., Malignancy) and most common diagnostic challenges, ensuring robust validation across the intended use.

4. Demonstration of Equivalence & Software Changes The Equivalence assessment (CER Section 16.1.4) has been thoroughly expanded. Detailed comparative tables now explicitly justify the Technical, Clinical, and Biological equivalence between the device and the legacy version.

To address the observed inconsistency between the CEP and CER regarding software changes, the documentation has been unified. The CEP and CER now explicitly list the exact improvements introduced in Legit.Health Plus compared to the legacy version (1.0.0.0). These are limited strictly to software stabilization and feature consolidation required for MDR compliance:

Migration to a microservices architecture.
Implementation of the HL7 FHIR standard.
Database encryption and cybersecurity upgrades.
Enhanced user interface (UI) feedback for image quality (DIQA algorithm).

A robust justification is provided explaining that none of these changes affect the core Artificial Intelligence models, the Vision Transformer architecture, the clinical indications, or the fundamental principles of operation. Therefore, these software stabilization updates structurally cannot negatively impact the clinical safety, performance, or diagnostic accuracy of the device. The new clinical data collection was primarily mandated by the regulatory shift from an MDD Class I device to an MDR Class IIb device, which requires a significantly higher level of clinical evidence.

5. Clinical Literature Search The documentation has been updated to address the clinical literature search protocol and the presentation of SotA clinical data:

To address the confusion in Section 3.1 of the SotA, the section headers have been corrected from "Clinical data collected on..." to "State of the art data collected on...". This clarifies that these tables present the baseline performance of alternative/similar devices and standard clinical practice, rather than clinical data on the subject device itself. The formatting of the tables has also been reviewed to ensure they are not cut off.
The CER (Section 16.1.5) has been updated to clarify the nature of the identified clinical literature. It explicitly states that the 12 articles identified pertained to preclinical (in-silico) algorithmic testing and benchmarking, and thus do not constitute "clinical data" under MDR Article 2(48).
To address the search protocol clarity, the CER documentation now explicitly confirms: "The literature search for the device under evaluation followed the same rigorous PICO protocol and appraisal methodology as the State of the Art (SotA) search, with the only difference being the addition of the specific keywords 'Legit.Health' and 'AI Labs Group' to specifically target publications related to the subject device. This ensures that no relevant peer-reviewed clinical studies were missed."

6. Post-Market Surveillance (PMS) Data The CER Executive Summary and the PMS analysis sections have been updated to explicitly incorporate and discuss the extensive data from the market. It is now formally documented that the equivalent legacy device has generated over 4,500 clinical reports across 21 active contracts since 2020, with zero reported serious incidents, CAPAs, or Field Safety Corrective Actions (FSCAs), providing strong real-world confirmation of the device's long-term safety and performance profile.

7. AIHS4 Study Limitations and PMCF Mitigation: A limitation regarding the AIHS4 2025 study was formally acknowledged in the CER. While the study produced promising results for the severity assessment of Hidradenitis Suppurativa, the sample size was small. To address this, the PMCF Plan (R-TF-007-002) has been updated to include Activity B.5: Confirmatory validation... for severity assessment of Hidradenitis Suppurativa (target sample: 100 patients) to provide the necessary confirmatory clinical evidence.

8. Justification of Sufficiency of Clinical Evidence A new dedicated section, "Justification of sufficiency of clinical evidence" (Section 15.3.3.3), has been added to the CER. This section provides an explicit justification that sufficient data in quantity and quality has been analyzed:

It details how the aggregated data from 8 pivotal studies (involving over 800 patients and diverse HCP tiers) provides high-quality (Level 1-2) evidence.
It justifies that the data is representative of the target population across genders, age groups, and relevant phototypes.
It provides a rationale for how validating against "anchor conditions" representing the highest clinical risk (e.g., Malignancy) and common diagnostic challenges ensures robust validation across the device's intended use.
It synthesizes how the flawless safety record from PMS data, combined with empirical performance data meeting SotA acceptance criteria, conclusively supports the clinical benefit, safety, and performance of the device.