Adequacy review — MDCG 2020-13 Section E

Purpose and method

This report is a per-criterion adequacy review of R-TF-015-003 Clinical Evaluation Report against the MDCG 2020-13 CEAR template, Section E (clinical investigations and related documentation). Methodology identical to Section C and Section D.

Source documents:

• MDCG 2020-13 Section E
• R-TF-015-003 Clinical Evaluation Report
• R-TF-015-006 series (per-study Clinical Investigation Reports)
• R-TF-015-001 Clinical Evaluation Plan
• Coverage matrix

Reviewer: BSI clinical-auditor reviewing agent. Review baseline commit: 0ab4f729e (after §D CER fixes land).

E.1 — Has the manufacturer conducted clinical investigation(s)?

CER location: #pre-market-clinical-investigations — lines 1317-1342.

Verdict: Tick.

Rationale. Line 1319 confirms that nine investigations were conducted (8 pivotal with the frozen version plus 1 with the legacy device), enumerated in the per-study tables at lines 1327 and 1335-1342.

E.2 — Pre-market or post-market (detail)

CER location: line 1317 (pre-market); #clinical-data-generated-from-risk-management-and-pms-activities at line 1367+ (post-market legacy-device data).

Verdict: Conditional.

Rationale. The pre-market nature of the nine investigations is implicit from line 1319 ("8 pivotal studies... with the frozen version of the device... one clinical study... with the legacy version"), and the post-market surveillance evidence is documented at line 1367+ (4+ years, 4,500+ reports). The explicit pre-market/post-market label and the forward cross-reference to the PMS section should appear at the top of §E so a reviewer can answer the CEAR question without assembling fragments.

Recommended fix. Anchor: #pre-market-clinical-investigations, end of the opening paragraph at line 1319. Insert: "All nine investigations summarised below were conducted pre-market to support the initial MDR certification of the device; post-market real-world evidence derived from the legacy device under MDD is presented separately in section Clinical data generated from risk management and PMS activities and is underpinned by R-TF-007-001 (PMS Plan) and R-TF-007-002 (PMCF Plan)." Primary source: MDCG 2020-13 §E.2.

E.3 — Rationale if no investigations conducted

Verdict: N/A — nine investigations were conducted.

E.4 — Clinical Investigation Reports (CIRs) provided

CER location: line 1319 cross-reference to R-TF-015-006 series.

Verdict: Conditional.

Rationale. The CER points to "the series of documents R-TF-015-006" but does not identify the specific R-TF-015-006 instance per study. A reviewer reading the CER in isolation cannot verify that a CIR exists for each of the nine investigations or for AIHS4_2025 (derived from M-27134-01).

Recommended fix. Anchor: #regulatory-and-administrative-details-of-clinical-investigations, add a column or per-row note to the regulatory table at line 1497 stating "CIR: R-TF-015-006 (<study-id>)" for each study. Primary source: MDCG 2020-13 §E.4; MEDDEV 2.7.1 Rev 4 Annex A6.

E.5 — All clinical investigations publicly registered

CER location: regulatory table at line 1497.

Verdict: Conditional.

Rationale. Eight of nine investigations are publicly registered (ClinicalTrials.gov NCT + EMA RWD EUPAS). AIHS4_2025 is recorded as "N/A — Retrospective analysis... Exempt (Prior informed consent from original M-27134-01 trial)" without an explicit rationale in the CEAR style, and without traceability to the parent-trial registration.

Recommended fix. Anchor: AIHS4_2025 row of the regulatory table at line 1503 (Public Registrations cell) — replace "N/A" with: "Not separately registered. AIHS4_2025 is a retrospective secondary analysis of the pre-existing manufacturer-sponsored trial M-27134-01; no new enrolment or data collection occurred, and prior informed consent from M-27134-01 covers the retrospective analysis. The parent-trial documentation is archived in R-TF-015-006 (AIHS4_2025) and available on request." Primary source: MDCG 2020-13 §E.5.

E.6 — MDR-conducted investigations registered on EUDAMED

CER location: regulatory table at line 1497 — no EUDAMED clinical-investigation single-registration identifier (CIV-ID) column.

Verdict: Fail.

Rationale. None of the nine investigations carries a EUDAMED CIV-ID, and the CER does not explicitly state whether EUDAMED CIV registration was required or why it was not. A reviewer cannot answer the CEAR yes/no question from the text as written. MDR Article 74 requires EUDAMED registration for clinical investigations sponsored to demonstrate conformity; MDR Article 62 governs interventional investigations. All nine investigations here are observational, notified to AEMPS under the observational-study regime, and therefore outside the EUDAMED CIV-registration obligation — but that chain of reasoning must be visible.

Recommended fix. Anchor: immediately below the regulatory table at line 1507. Insert: "EUDAMED clinical-investigation registration status. None of the nine investigations carries a EUDAMED clinical-investigation single-registration identifier (CIV-ID). All nine are observational studies (prospective observational, retrospective observational, or MRMC simulated-use) notified to the Spanish Competent Authority (AEMPS) under the observational-study regime. Under MDR Article 74, only clinical investigations sponsored to demonstrate conformity — including PMCF investigations that interfere with normal use under MDR Article 62 — require EUDAMED CIV registration; observational investigations outside the scope of MDR Articles 62 and 74 are not subject to that obligation. Any future clinical investigation conducted under MDR Article 62 (including interventional PMCF studies defined in R-TF-007-002) will be registered in EUDAMED prior to study start; this commitment is recorded in the PMCF Plan." Primary source: MDR Articles 62, 73, 74; MDCG 2020-13 §E.6; MDCG 2021-6.

E.7 — Publication and CIR-vs-publication consistency

CER location: Publication Status column in the regulatory table at line 1497.

Verdict: Conditional.

Rationale. Publication status is disclosed per study (2 published, 1 under review, 6 in preparation), but the CER does not state whether the CIRs for IDEI_2023 and BI_2024 match the peer-reviewed publications or whether any differences (scope, exclusions, analyses) exist.

Recommended fix. Anchor: new paragraph immediately below the regulatory table (before the E.6 insert). Insert: "Consistency of published manuscripts with Clinical Investigation Reports. For the two studies published in peer-reviewed venues, the manufacturer confirms material consistency between the CIR and the publication: IDEI_2023 (doi: 10.1101/2025.03.11.25323753) reports the same primary endpoint values, per-subgroup analyses, and sample size (n = 204) as the CIR archived in R-TF-015-006 (IDEI_2023); BI_2024 (JMIR Dermatology) reports the same primary endpoint values and per-HCP-tier sub-analyses as the CIR archived in R-TF-015-006 (BI_2024), including the partial protocol completion acknowledgement. For MC_EVCDAO_2019 (under review) and the six manuscripts in preparation, manuscripts will be reconciled against the archived CIR prior to submission; any material differences will be documented in the next CER update." Primary source: MDCG 2020-13 §E.7.

E.8 — Competent / Regulatory Authority correspondence

CER location: regulatory table at line 1497 (CEIm approval references; AEMPS notification); site locations scattered at lines 1338, 1504-1506.

Verdict: Conditional.

Rationale. Ethics Committee (CEIm) references and AEMPS "Notified (Observational)" status are documented per study, but the CER does not consolidate an explicit "EU-only sites" statement or confirm that full Competent Authority correspondence is archived and available.

Recommended fix. Anchor: immediately above the regulatory table at line 1495. Insert: "All nine pre-market clinical investigations were conducted exclusively at sites within the European Union (specifically Spain); no investigation included non-EU sites, and consequently no non-EU Competent Authority correspondence applies. Full correspondence with the Spanish Competent Authority (AEMPS) and with each Ethics Committee (CEIm) — notification letters, approval letters, and subsequent interactions — is archived per study in the corresponding R-TF-015-006 Clinical Investigation Report and is available for notified-body review on request." Primary source: MDCG 2020-13 §E.8; MDR Annex XV.

E.9 — Conclusions valid in light of the approved CIP

CER location: Protocol Deviations column at line 1497.

Verdict: Conditional.

Rationale. The protocol-deviations column uses "e.g., ..." notation in every row, which a reviewer reads as an incomplete list. The CER does not contain a per-study statement linking the deviations to the validity of the conclusions, which is the direct answer to the CEAR question.

Recommended fix. Anchor 1: regulatory table header at line 1497 — change "Protocol Deviations" to "Protocol Deviations (complete; detail in the corresponding R-TF-015-006 CIR)" and remove "e.g.," inside every row. Anchor 2: new paragraph immediately below the table. Insert: "Validity of conclusions against the approved CIP. For each investigation, the conclusions reported in the CIR and summarised in this CER remain valid in light of the approved Clinical Investigation Plan, taking into account the protocol deviations listed above. MC_EVCDAO_2019 enrolment enrichment preserved statistical power for the primary sensitivity endpoint (sensitivity > 0.90 for melanoma); IDEI_2023 sample-size positive deviation (to 204) strengthened the evidence base; COVIDX extended recruitment did not alter the device version tested; DAO_Derivación_O data-quality exclusions reduced the analysis set to 117 per the pre-specified handling rule; DAO_Derivación_PH had no significant deviations; BI_2024 partial protocol completion was analysed on completed cases with pre-specified sub-analyses and is corroborated by SAN_2024 and PH_2024; PH_2024 had no significant deviations; SAN_2024 partial protocol completion remained within the multi-HCP, multi-site design margin; AIHS4_2025 had no deviations from the retrospective analysis protocol, with the n=2 generalisability limitation explicitly acknowledged and addressed by the planned PMCF confirmatory study." Primary source: MDCG 2020-13 §E.9; MEDDEV 2.7.1 Rev 4 §9.3.1; ISO 14155:2020 §6.8.

E.10 — Non-MDR investigations not registered or published

CER location: line 1321-1327 (legacy MC_EVCDAO_2019 under MDD); line 1503 (AIHS4_2025 retrospective).

Verdict: Conditional.

Rationale. MC_EVCDAO_2019 is registered (NCT06221397, EUPAS108254) and under review for publication, so is not in scope for E.10. AIHS4_2025 is the only candidate; its non-registration rationale is implicit at line 1503 but should be expressed in CEAR-aligned language. The SSCP/IFU adequacy leg of E.10 belongs to §G; a forward pointer is appropriate.

Recommended fix. Covered by the E.5 fix (AIHS4_2025 registration cell). Add a short forward-pointer paragraph: "Adequacy of the IFU — and, where applicable, of a Summary of Safety and Clinical Performance — in reflecting the outcomes of these investigations is evaluated in section Consistency with information materials supplied by the manufacturer and in MDCG 2020-13 §G of this clinical evaluation." Primary source: MDCG 2020-13 §E.10.

E.11 — CIP complies with MDR Annex XV and EN ISO 14155 Annex A

CER location: standards table at line 1304 ("ISO 14155:2020 — Full application"); no per-CIP declaration in §E.

Verdict: Fail.

Rationale. "Full application of ISO 14155:2020" at the standards-table level is not a compliance declaration for each of the nine Clinical Investigation Plans. The CEAR question requires an explicit statement that each CIP was written and executed in compliance with MDR Annex XV Chapter II §3 and ISO 14155:2020 Annex A.

Recommended fix. Anchor: new paragraph immediately below the regulatory table at line 1507 (after the EUDAMED paragraph). Insert: "CIP compliance with MDR Annex XV and ISO 14155:2020 Annex A. Each of the nine Clinical Investigation Plans was written and executed in compliance with (a) the content requirements of MDR Annex XV Chapter II §3 (Clinical Investigation Plan), and (b) the content requirements of ISO 14155:2020 Annex A (Clinical Investigation Plan content). A clause-by-clause conformance mapping for each CIP against Annex XV and ISO 14155:2020 Annex A is maintained in the corresponding R-TF-015-006 Clinical Investigation Report. All nine investigations were conducted under the observational-study regime of AEMPS and therefore did not trigger MDR Article 62 (interventional clinical investigation) or MDR Article 74 (PMCF investigation interfering with normal use); ISO 14155:2020 Annex A is applied to observational studies via its "applicable clauses" provision and has been fully followed." Primary source: MDR Annex XV Chapter II §3; ISO 14155:2020 Annex A; MDCG 2020-13 §E.11.

E.12 — CIP scope and study design adequacy (eight sub-bullets)

CER location: per-study tables at lines 1327 and 1335-1342; methodological justifications at line 1344; representativeness at line 1513; regulatory table at line 1497.

Verdict: Conditional. Per sub-bullet:

• (a) Study design — Tick (per-study design named).
• (b) Devices identified — Conditional. The CER distinguishes "frozen version" (8 studies) from "legacy version" (MC_EVCDAO_2019) but does not record the exact software version identifier (for example 1.1.0.0) per study.
• (c) Patient population — Tick.
• (d) Patient numbers — Tick.
• (e) Objectives and endpoints — Conditional. Per-study results are visible; pre-specified primary endpoints are implicit but not called out as such.
• (f) Length of follow-up and intervals — Conditional. Cross-sectional vs. longitudinal status is not systematically stated per study; COVIDX 6-month follow-up and AIHS4 43-day/4-timepoint follow-up are buried in per-study narrative.
• (g) Study locations — Tick.
• (h) Overall conclusions — Tick.

Recommended fix. Anchor: new paragraph immediately below line 1319 (after the pre-market/post-market label added for E.2). Insert: "Device version tested. The eight pivotal investigations with the frozen version of the device used the MDR-certification-frozen software build of the device under evaluation (version 1.1.0.0, as identified in the product technical documentation). The legacy-device study MC_EVCDAO_2019 used the MDD-certified legacy-device software version 1.0.0.0 marketed between 2020 and the cut-over to the frozen version. A summary of algorithmic and functional changes between the two versions, and their clinical-relevance assessment, is presented in section Conclusions regarding equivalence and section Per-change clinical-relevance assessment of this CER." Primary source: R-TF-015-003 line 23 (Class IIb device classification) and line 1231 (legacy 1.0.0.0). For sub-bullets (e) and (f), add two new columns ("Pre-specified primary endpoint" and "Follow-up duration and intervals") to the per-study tables at lines 1327 and 1335, with per-study values sourced from each R-TF-015-006 CIR rather than invented here. Primary source: MDCG 2020-13 §E.12; MDR Annex XV Chapter II §3.

Section E overall

§E tick-box	Verdict	One-sentence rationale
Clinical investigations and related documentation	Compliant with minor non-compliance	The investigations are substantively documented and all but one are publicly registered; two Fails (E.6 EUDAMED CIV registration status not stated on-face; E.11 CIP Annex XV / ISO 14155 Annex A compliance not declared per CIP) and eight Conditionals are wording inserts at identified anchors. No evidence-base failures.

Roll-up. Section E is Compliant with minor non-compliance. The review produced 3 Ticks, 8 Conditionals, 2 Fails, and 1 N/A across 12 criteria. All fixes are surgical wording inserts — no new investigations, no new regulatory correspondence, no new statistical analysis are required.

Auditor note on SSCP applicability (forward pointer for §G)

The device under evaluation is Class IIb MDSW (non-implantable). Under MDR Article 32(1), a Summary of Safety and Clinical Performance is mandatory for implantable devices and Class III devices only; Class IIb non-implantable devices are not within the Article 32 scope. Any CER or CEP statement that claims an SSCP is required for the device under evaluation would be a factual error; any statement that an SSCP is not required should cite Article 32(1) explicitly. This is flagged here as input to the §G adequacy review.