R-TF-015-004 Clinical investigation plan
Scope
This Clinical Investigation Plan (CIP) sets out the rationale, objectives, design, methodology, conduct, implementation, record-keeping and method of analysis for the clinical investigation.
Nature and positioning of the evidence
This is a prospective, consecutive-case, cross-sectional clinical investigation on real patients with suspected malignant pigmented skin lesions, with biopsy-confirmed reference standard for the subset of lesions excised and multi-reader dermatologist consensus for the remainder. Under MDCG 2020-6 Appendix III the resulting evidence is Rank 2–4 (prospective observational study with reference standard). Per MDCG 2020-1 §4.4 it contributes primary Pillar 3 Clinical Performance evidence — measuring the diagnostic decision supported by the device's clinical output in the Top-5 prioritised differential and malignancy-gauge workflow — for the intended-purpose population of patients presenting with skin lesions of suspected malignancy. 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 the State of the Art (R-TF-015-011).
CIP Identification
| CIP | |
|---|---|
| Title of the clinical investigation | Clinical validation study of a CAD system with artificial intelligence algorithms for early noninvasive in vivo cutaneous melanoma detection |
| Device under investigation | Legit.Health Legacy Device |
| Protocol version | Version 3.0 |
| Date | 2021-10-28 |
| Protocol code | LEGIT_MC_EVCDAO_2019 |
| Sponsor | AI Labs Group S.L. |
| Coordinating Investigator | Dr. Jesus Gardeazabal Garcia and Dr. Rosa Ma Izu Belloso |
| Principal Investigator(s) | Dr. Jesus Gardeazabal Garcia and Dr. Rosa Ma Izu Belloso |
| Investigational site(s) | Hospital Universitario Cruces and Hospital Universitario Basurto |
| Ethics Committee | Comite de Etica de la Investigacion con Medicamentos de Euskadi |
Trial Registrations
- ClinicalTrials.gov (NCT): NCT06221397
- EMA RWD Catalogue (EUPAS): EUPAS108254
Table of contents
- Scope
- CIP Identification
- Compliance Statement
- Abbreviations and definitions
- CIP or protocol specifications
- Product Identification and Description
- Justification of the design
- Hypothesis
- Objectives
- Summary of the study
- Design and methods
- Ethical considerations
- CIP Modification
- CIP Deviations
- Start, follow-up and end reports
- Statements of compliance
- Informed Consent process
- Adverse events, adverse product reactions and product deficiencies
- Suspension or early termination of clinical research
- Annexes
Compliance Statement
The clinical investigation will be conducted according to the Clinical Investigation Plan (CIP) and other applicable guidances and regulations. This includes compliance with:
- The ethical principles originating from the
World Medical Association's Declaration of Helsinki - Harmonized standard
UNE-EN ISO 14155:2020 Regulation (EU) 2017/745 on medical devices (MDR), including the applicableGeneral Safety and Performance Requirements (GSPR)as outlined in Annex I, and the requirements ofAnnex XV(Chapter I and Chapter II, Section 3)- Harmonized standard
UNE-EN ISO 13485:2016 MDCG 2024-3for its structural and content expectations,MDCG 2021-8concerning application requirements, andMDCG 2020-10/1 Rev 1for safety reporting timelines and definitionsRegulation (EU) 2016/679(GDPR)- Spanish
Organic Law 3/2018on the Protection of Personal Data and guarantee of digital rights.
All data processing within the device is carried out in accordance with the highest standards of data protection and privacy. Patient information is managed in an encrypted manner to ensure confidentiality and security.
The research team assumes the role of Data Controller, responsible for the collection and management of study data. Legit.Health acts as the Data Processor and is not involved in the processing of patient data.
The storage and transfer of data comply with European data protection regulations. At the conclusion of the study, all information stored in the device will be permanently and securely deleted.
The device employs robust technical and organizational security measures to safeguard personal data against unauthorized access, alteration, loss, or processing.
Abbreviations and definitions
- AE: Adverse Event
- AEMPS: Spanish Agency of Medicines and Medical Devices
- AEP: Adverse Reaction to Product
- AUC: Area Under the ROC Curve
- CAD: Computer-Aided Diagnosis
- CMD: Data Monitoring Committee
- CIP: Clinical Investigation Plan
- CUS: Clinical Utility Questionnaire
- DLQI: Dermatology Quality of Life Index
- GCP: Standards of Good Clinical Practice
- ICH: International Conference of Harmonization
- IFU: Instructions For Use
- IRB: Institutional Review Board
- N/A: Not Applicable
- NCA: National Competent Authority
- PI: Principal Investigator
- PPV: Positive Predictive Value
- NPV: Negative Predictive Value
- SAE: Serious Adverse Events
- SAEP: Serious Adverse Event to Product
- SUAEP: Serious and Unexpected Adverse Event to the Product
- SUS: System Usability Scale
CIP or protocol specifications
Principal Investigator
- Dr. Jesús Gardeazabal García (Osakidetza, Hospital Universitario Cruces).
- Dr. Rosa Mª Izu Belloso (Osakidetza, Hospital Universitario Basurto).
Coordinating investigator
- Dr. Jesús Gardeazabal García (Osakidetza, Hospital Universitario Cruces).
- Dr. Rosa Mª Izu Belloso (Osakidetza, Hospital Universitario Basurto).
Collaborating Investigator(s)
- Dr. Juan Antonio Ratón Nieto (Hospital Universitario de Cruces)
- Dr. Ana Sánchez Diez (Hospital Universitario de Basurto)
Technical Support (Manufacturer)
- Mr. Alfonso Medela — Chief Technology Officer
- Mr. Taig Mac Carthy — Chief Executive Officer
- Mrs. Andy Aguilar — General Manager
- Mrs. Mireya Fernández — Clinical Operations
Investigational sites
- Hospital Universitario de Cruces
- Hospital Universitario de Basurto
Funding
This research was carried out without any funding or sponsorship.
Product Identification and Description
| Information | |
|---|---|
| Device name | Legit.Health Plus (hereinafter, the device) |
| Model and type | NA |
| Version | 1.1.0.0 |
| Basic UDI-DI | 8437025550LegitCADx6X |
| Certificate number (if available) | MDR 000000 (Pending) |
| EMDN code(s) | Z12040192 (General medicine diagnosis and monitoring instruments - Medical device software) |
| GMDN code | 65975 |
| EU MDR 2017/745 | Class IIb |
| EU MDR Classification rule | Rule 11 |
| Novel product (True/False) | TRUE |
| Novel related clinical procedure (True/False) | TRUE |
| SRN | ES-MF-000025345 |
Throughout this document, references to "the device" refer to the investigational product identified above.
Device version under investigation and bridging to the CE-marked release
The investigation was conducted using device version v1.1.0.0, which is the version placed on the market and the version to which the present technical documentation applies. The bridging between the investigation-version and the CE-marked release is therefore an identity bridge; no clinical-relevance assessment is required. The device-version statement has been reviewed and signed off by the PRRC.
Justification of the design
Background and rationale
The incidence of cutaneous melanoma (CM), the deadliest form of skin cancer, has been rising significantly, with a sharp increase in both new cases and mortality rates over the past decades. Melanoma metastasizes quickly to distant organs and becomes resistant to conventional therapies, making treatment difficult. However, when diagnosed early, it can be effectively treated through simple surgical excision. The main challenge in early detection lies in differentiating melanoma from benign pigmented skin lesions, as they often share visual similarities, especially during an initial visual examination. Limited access to dermatologists and a lack of public awareness further complicate timely diagnoses, frequently leading to delayed detection when tumours are already advanced.
Given these challenges, early melanoma diagnosis and prevention have become critical. Recent technological advancements in image recognition and artificial intelligence (AI) have shown promise in improving diagnostic accuracy. Studies have demonstrated that AI algorithms can classify skin lesion images, including melanomas, with a competency level comparable to that of dermatologists. These AI-driven computer-aided diagnosis (CAD) systems present a valuable opportunity for improving early detection and survival rates by assisting healthcare professionals and potentially empowering non-experts to detect melanomas earlier.
This study aims to clinically validate an AI-based system for diagnosing cutaneous melanoma, leveraging artificial vision and machine learning to differentiate between melanomas and benign skin lesions. By developing and validating this technology, the study seeks to improve diagnostic precision and contribute to earlier interventions, potentially enhancing patient outcomes and survival rates.
Risks and benefits of the product in investigation and clinical research
Participants in this study did not undergo any procedures posing a risk to their safety. However, using the device could optimize patient diagnosis, save costs and time, and provide better treatment to patients.
Hypothesis
A CAD system powered by machine vision allows early and non-invasive diagnosis of cutaneous melanoma in vivo.
Objectives
Primary objective
To validate that the device's malignancy-estimation output — the signal the clinician observes in the Top-5 prioritised differential and malignancy-gauge workflow under the device's intended use — achieves the following values on images of lesions taken with a dermatoscopic camera from patients presenting with suspected malignancy:
- Area under the ROC curve (AUC) greater than 0.8.
- Sensitivity of 80% or higher at the operating threshold pre-specified in the Statistical Analysis Plan.
- Specificity of 70% or higher at the same operating threshold.
The malignancy-estimation endpoint is declared as primary because it corresponds to the device's clinical output used by the healthcare professional within the Pillar 3 Top-5 prioritised differential workflow for triage and referral decisions, in line with the device's intended purpose as a clinical decision-support tool.
Secondary objective(s)
- Melanoma detection as an additional (secondary) analysis, reporting Top-K precision, sensitivity, specificity and AUC for the melanoma-versus-non-melanoma task at K = 1, 3 and 5.
- Comparison of the device's performance with that of dermatologists on the subset of cases with biopsy-confirmed reference standard.
- Comparison with primary-care practitioners was planned for a subsequent phase of research and was not performed within the present investigation due to recruitment difficulties and the workload of practitioners at the participating centres; this limitation is documented in the Clinical Investigation Report.
- Evaluation of the practicality and reliability of the device in environments with technical constraints such as lack of instrumentation or lack of internet connection.
Summary of the study
This is a prospective observational analytical and cross-sectional study of a clinical case series. It is designed to validate the device as a valid tool to detect cutaneous melanoma in images from lesions early in the disease course. This research was planned to include 200 patients, representing a diverse population of patients with suspected malignancy and risk of melanoma. The data collection includes photographs and clinical and demographic data. The study adheres to strict ethical guidelines, ensuring patient confidentiality and compliance with international standards. Patients are provided with detailed information and informed consent. The robust methodology of the study is designed to assess the clinical utility and usability of the device.
Design and methods
Type of clinical research
This is an observational analytical and cross-sectional study for the performance of the device detecting melanoma in patients with high risk. In this study, there is one group of patients and there will be no control group since the study aims to assess the validity of the medical device for melanoma detection and whether it can detect it with the same effectiveness as an expert dermatologist, its detection capability is compared with that of the specialist.
Population
Adult patients (>18 years) with skin lesions of suspected malignancy seen at the Dermatology Department of the Hospital Universitario Cruces and Hospital Universitario Basurto.
Sample size
The sample size calculation targeted a prevalence of 20–25% positive melanoma cases among patients attending the dermatology department with suspected malignant pigmented skin lesions. Using G*Power 3.1.9, a z-test was performed for 95% power, 5% two-sided significance, an allocation ratio N2/N1 of 4, and pre-specified effect sizes corresponding to the acceptance thresholds (malignancy sensitivity ≥ 0.80 against a null of 0.70, malignancy specificity ≥ 0.70 against a null of 0.60). The resulting calculation yielded a minimum of 160 evaluable subjects (32 positive, 128 negative), inflated to 200 to account for attrition, image-quality loss and non-conclusive diagnoses. The recruitment was structured in two phases: an initial 40-subject phase to characterise enrolment feasibility and image acquisition, and an extension phase to reach the target N of 200.
The study was formally closed at N = 105 subjects (36 melanoma cases) in November 2023. The early closure is declared as a formal protocol deviation and assessed in the CIR (§Protocol Deviations), with post-hoc power recomputed at the achieved N against each acceptance threshold.
Duration
This study is estimated to have a recruitment period of 10 months for the inclusion of the first 40 patients. The recruitment period is extended by 12 months for the inclusion of patients up to a total of 200, with a minimum of 40 melanomas.
The total duration of the study is estimated at 36 months, including the time required after the recruitment of the last subject for the closing and editing of the database, the analysis of the data and the preparation of the final report of the study.
Acceptance criteria
- top-1 accuracy equal to or greater than 50.00%.(User Group: Dermatologists)
- top-3 accuracy equal to or greater than 60.00%.(User Group: Dermatologists)
- top-5 accuracy equal to or greater than 80.00%.(User Group: Dermatologists)
- AUC (area under the ROC curve) equal to or greater than 80.00% detecting melanoma.(User Group: Dermatologists)
- top-1 accuracy equal to or greater than 80.00% detecting melanoma.(User Group: Dermatologists)
- sensitivity equal to or greater than 80.00% detecting melanoma.(User Group: Dermatologists)
- specificity equal to or greater than 70.00% detecting melanoma.(User Group: Dermatologists)
- AUC (area under the ROC curve) equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
- sensitivity equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
- specificity equal to or greater than 84.00% detecting malignancy.(User Group: Dermatologists)
- PPV (positive predictive value) equal to or greater than 80.00% detecting malignancy.(User Group: Dermatologists)
- NPV (negative predictive value) equal to or greater than 90.00% detecting malignancy.(User Group: Dermatologists)
Inclusion criteria
- Patients with skin lesions with suspected malignancy.
- Age over 18 years old.
- Patients who consent to participate in the study by signing the Informed Consent form.
Exclusion criteria
- Patients under 18 years of age.
Variables
Main variable
The main variable is the diagnostic performance of the device's malignancy-estimation output, with the gold standard being the pathological-anatomy result (biopsy) for the subset of lesions that were excised. For cases where biopsy was not clinically indicated, the gold standard is the consensus diagnosis of a panel of expert dermatologists with more than 10 years of experience in dermatology, assembled per the adjudication protocol defined in §Methods of the CIR. This mixed reference standard is consistent with common practice in clinical validation studies of dermatological diagnostic devices and is appraised as a limitation in the CIR.
Secondary variables
- Diagnoses that doctors make based on images of patients' skin lesions.
- System Usability Scale score.
Condition of interest
Patients with skin lesions and risk of cutaneous melanoma.
Limitations of clinical research
This investigation evaluates a frozen version of the device (v1.1.0.0); no algorithm training or model refinement is performed on the data collected during the study. The investigation is designed as a clinical validation of the device under its intended purpose.
The principal limitations foreseeable at the design stage are:
- Image-acquisition variability. Dermatoscopic images collected in routine clinical practice vary in illumination, colour, focus, framing, and number of acquisitions per lesion. Within-lesion variability and insufficient image coverage may reduce measured diagnostic accuracy relative to the device's intrinsic capability. Image-acquisition standardisation is addressed in §Methods of the CIR.
- Pilot-to-extended-sample progression. The initial 40-subject phase consisted predominantly of high-suspicion lesions that were referred for biopsy; this subset is not fully representative of the spectrum of lesions seen in daily dermatology practice. The sample was therefore planned to be extended to 200 subjects with inclusion of additional skin-lesion types (nevi and other common benign and malignant lesions) to better reflect the intended-use population. The extension and any associated threshold or endpoint adjustments are declared prospectively in the CIP and documented as protocol modifications where applicable.
- Class imbalance. Even at the extended sample, the image-level class distribution remains imbalanced across the ICD-11 categories present in the study, and some categories have low numbers. The primary and secondary analyses are pre-specified to operate on the malignancy-estimation and melanoma-detection tasks for which sufficient positive cases are available; per-category skin-lesion recognition metrics are reported as supporting information.
Ethical considerations
This study adhered to international Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki in its latest amendment, and applicable international and national regulations. As applicable, approval from the relevant Ethics Committee was obtained prior to the initiation of the study. When applicable, modifications to the protocol were reviewed and approved by the Principal Investigator (PI) and subsequently evaluated by the Ethics Committee before subjects were enrolled under a modified protocol.
This study was conducted in compliance with European Regulation 2016/679, of 27 April, concerning the protection of natural persons with regard to the processing of personal data and the free movement of such data (General Data Protection Regulation, GDPR), and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and the guarantee of digital rights. In accordance with these regulations, no data enabling the personal identification of participants was collected, and all information was managed securely in an encrypted format.
Participants were informed both orally and in writing about all relevant aspects of the study, with the information being tailored to their level of understanding. They were provided with a copy of the informed consent form and the accompanying patient information sheet. Adequate time was given to patients to ask questions and fully comprehend the details of the study before providing their consent.
The PI was responsible for the preparation of the informed consent form, ensuring it included all elements required by the International Conference on Harmonisation (ICH), adhered to current regulatory guidelines, and complied with the ethical principles of GCP and the Declaration of Helsinki.
The original signed informed consent forms were securely stored in a restricted access area under the custody of the PI. These documents remained at the research site at all times. Participants were provided with a copy of their signed consent form for their records.
Data confidentiality
Current legislation will be complied with in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons with regard to the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on Personal Data Protection and guarantee of digital rights). For this purpose, when applicable, each participant will receive an alphanumeric identification code in the study that will not include any data allowing personal identification (coded CRD). The Principal Investigator will have an independent list that will allow the connection of the identification codes of the patients participating in the study with their clinical and personal data. This document will be filed in a secure area with restricted access, under the custody of the Principal Investigator and will never leave the centre.
Once the paper CRDs are completed and closed by the Principal Investigator, the data will be transferred to a database.
As in the CRDs, the Database will comply with current legislation in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons about the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and guarantee of digital rights) in which no data allowing personal identification of patients will be included.
Bias minimization measures
Bias-control measures in this investigation are:
- Consecutive enrolment. Patients meeting the inclusion criteria were approached consecutively during routine dermatology visits at the participating centres, avoiding selective recruitment.
- Standardised image acquisition. Images were collected according to the acquisition protocol described in §Methods of the CIR (dermatoscope model, smartphone specifications, acquisition settings, disabled post-processing) to minimise operator- and device-related variability.
- Pre-specified primary and secondary endpoints. Acceptance criteria and analysis populations are defined prospectively in this CIP and in the Statistical Analysis Plan to prevent selective reporting of favourable endpoints.
- Blinded reference standard. For lesions with biopsy, the pathological-anatomy result is established independently of the device output; for non-biopsied lesions, the consensus diagnosis is established by a panel of expert dermatologists adjudicating independently of the device output, per the adjudication protocol described in §Methods of the CIR.
- Prospective data capture. All study data are captured prospectively in the electronic Case Report Form, avoiding recall bias inherent to retrospective chart review.
Calendar
This study was planned in two phases. The initial phase was designed to recruit 40 patients over a 10-month period. The recruitment period was then extended for the inclusion of patients up to a total of 200, with a minimum of 40 melanomas, planned over an additional 12 months.
The total estimated duration of the study was 36 months, including the time required after recruitment of the last subject for closing and editing the database, data analysis, and preparation of the final study report.
Monitoring plan
The team will hold a meeting with the investigative team every 3 months to address any potential questions and ensure that data is being collected properly.
The clinical investigation will be monitored by a designated clinical monitor, who is independent of the investigational site and appointed by the sponsor. The purpose of monitoring is to ensure that:
- The rights, safety, and well-being of the subjects are protected.
- The data reported are accurate, complete, and verifiable from source documents.
- The clinical investigation is conducted in compliance with the Clinical Investigation Plan (CIP), applicable regulatory requirements (including Regulation (EU) 2017/745), and ISO14155:2020.
In this way, monitoring will be performed through:
- Remote monitoring activities: Including scheduled video or telephone meetings depending on the availability of the investigators to review study progress, discuss challenges, and ensure ongoing compliance.
- On-site visits: If deemed necessary based on data review, protocol deviations, or issues raised during remote monitoring.
- Source data verification (SDV): The sponsor in this case has secure access to anonymised source documents (e.g., image files, clinical assessment records) via encrypted digital platforms or controlled site systems to verify data accuracy and consistency with Case Report Forms (CRFs).
- Risk-based monitoring approach: The extent and frequency of monitoring activities will be adapted to the complexity and risk level of the investigation. Given that this study does not involve significant deviation from routine care, the monitoring will be primarily remote unless specific issues arise.
All monitoring activities will be documented in monitoring visit reports. Any protocol deviations or non-compliance identified will be documented, assessed for impact, and communicated promptly to the sponsor. Corrective actions will be tracked and followed up by the monitor or the sponsor.
Completion of the investigation
After the final closure of the clinical investigation, a Clinical Investigation Report (R-TF-015-006) will be drafted, even in the event of early termination or suspension. The CIR will be provided to the Ethics Committee and, where applicable under the study's regulatory status, to the Spanish Agency for Medicines and Medical Devices (AEMPS). The results obtained (whether positive, inconclusive, or negative) will be included in the public-access database identified in the Trial Registrations section.
Additionally, if deemed appropriate, the results may be published in scientific journals. The Ethics Committee that approved this clinical investigation will be acknowledged, and any funds received by the author for the study and its source of funding will be disclosed. The anonymity of participants in the clinical investigation will be maintained at all times.
Upon completion of the study, the results of the clinical utility and satisfaction surveys, as per the annexed models, may be presented at conferences and scientific meetings, subject to prior authorization by both parties. Press releases and other communications may also be issued to share the study's results. All publications and communications must be reviewed and approved by the parties involved.
Statistical analysis
Each variable will be characterized using frequency distributions for qualitative variables and central tendency statistics such as mean and median and variability statistics such as standard deviation (S.D.) or interquartile range for quantitative variables according to their distributional characteristics.
Between-group and within-group comparisons will be made using parametric tests whenever the distributional characteristics of the data allow it. For intergroup comparisons, one- and two-factor Analysis of Variance techniques will be used with post-hoc comparisons if significant overall differences are detected. To evaluate intra-group changes, Student's t-test for related samples or Analysis of Variance/ANOVA with repeated measures will be used if the theoretical assumptions of the model are supported by the data. Otherwise, more flexible models (GEE) that allow incorporating different autocorrelation structures of the data will be fitted.
Comparisons between groups with respect to qualitative variables will be carried out by means of contingency tables and Fisher's exact or Chi-square tests. The probability of type I error will not be adjusted for multiple comparisons. The level of statistical significance in the contrasts (alpha) will be 5 per cent with bilateral contrasts.
Comparisons between two continuous variables will be made using Pearson's or Spearman's correlation, depending on the distributional characteristics.
All the analyses described thus far will be conducted based on the requirements for obtaining descriptive results from the sample. Interobserver concordance analyses will also be performed by estimating the kappa coefficient.
A study of diagnostic tests will be performed being the main measures in the results: sensitivity, specificity, positive and negative predictive values (PPV and NPV) and likelihood ratios (LR+ and LR-). The diagnosis of the lesion will be made according to the clinical judgment of expert dermatologists, such as the Principal Investigators, (considered the Gold Standard).
Analyses will be performed using appropriate statistical software, SPSS version 23.0 and STATA 13.0. Values of p lower than 0.05 will be considered significant.
Data management
The data will be managed and tabulated with consistency rules and logical ranges to control inconsistencies during data tabulation. A validation process of the clinical data will be carried out by running computer filters based on validation rules, which will automatically identify missing values or inconsistencies of clinical data according to the protocol. Additionally, manual editing and validation will be performed using descriptive and exploratory statistical techniques to complement the detection of logical errors and inconsistent values.
The database will be considered closed upon completion of all data management processes and satisfactory resolution of discrepancies and errors in the data. Any changes in the database after its closure can only be made after written agreement between the Principal Investigator and the technical coordinators of the project.
AI Labs Group, S.L. (hereinafter, the manufacturer) is the owner of the device. During the period of validity of this study, the manufacturer will grant a license to use the device by the research team free of charge. The research team will be the administrator of the account. Both patients and members of the medical team will have login credentials. The manufacturer will not have access to the account or patient information.
According to the definitions and roles set out in Regulation (EU) 2016/679 (GDPR), the Data Controller is the research team and the manufacturer is the Data Processor.
The storage of data and photographs will be in line with the European Regulation 2016/679 (GDPR) and the Organic Law 3/2018 of 5 December on the Protection of Personal Data and guarantee of digital rights. At the end of the study, all information stored in the device will be totally and permanently deleted.
The device complies with current legislation on the protection and confidentiality of personal data European Regulation 2016/679 (GDPR). Appropriate technical and organizational security measures are adopted to ensure the security of personal data and prevent its alteration, loss, unauthorized processing or access, given the state of technology, the nature of the data and the risks to which they are exposed, whether from human action or the natural physical environment.
CIP Modification
As indicated in the UNE-EN ISO 14155:2021 standard, the Clinical Investigation Plan (CIP) may be modified as necessary during the clinical investigation. The changes made must be described, along with their justification, potential impact on clinical performance, efficacy, safety, or other evaluation criteria, and identification of other affected documents.
CIP modifications will be prepared by the sponsor and agreed upon and accepted between the sponsor and the principal investigator. The modifications will be recorded with a justification for each one in the form of an amendment or addendum.
The required regulatory authority (AEMPS) and the Ethics Committee or Institutional Review Board (IRB) will be notified, if necessary. Modifications to the clinical investigation may only be implemented once favourable feedback and the corresponding approval have been obtained.
In accordance with Article 75 of Regulation (EU) 2017/745, substantial modifications to the clinical investigation must be approved by both the Ethics Committee for investigation with medicines (CEIm) and the Competent Authority (AEMPS) prior to their implementation.
- In the case of substantial modifications to authorized clinical investigations, a request must be submitted to the AEMPS and the CEIm.
- For non-substantial modifications to authorized clinical investigations, until the corresponding module is available in the EUDAMED database, the updated documentation will be sent to the AEMPS for inclusion in their file.
CIP Deviations
As indicated in the UNE-EN ISO 14155:2021 standard, the investigator may not deviate from the Clinical Investigation Plan (CIP), except in emergencies (section 4.5.4.b of the standard). In such cases, the investigator may proceed without prior approval from the sponsor and the Ethics Committee to protect the rights, safety, and well-being of human subjects. The use of waivers from the Clinical Investigation Plan is strictly prohibited.
These deviations must be documented by the principal investigator and notified to the sponsor and the IRB as soon as possible, and always within a maximum of 15 days. Immediately after receiving the notification, the sponsor will record and analyze the deviations carried out and their potential impact. Depending on the findings, the sponsor will take the necessary corrective and/or preventive measures.
In other circumstances, when deviations affect the rights, safety, and well-being of the subject or the scientific integrity of the clinical investigation, deviation requests and reports must be provided to the IRB if required.
Start, follow-up and end reports
The start of the study will be notified to the ethics committee. Annual follow-up reports will be submitted thereafter.
Upon obtaining the study conclusions, a final report (R-TF-015-006 Clinical Investigation Report) will be prepared and submitted to the Ethics Committee.
Statements of compliance
The present clinical investigation will be conducted following the ethical principles originating from the Declaration of Helsinki.
Additionally, the clinical investigation will comply with the harmonized standard UNE-EN ISO 14155:2021 and the European Regulation MDR 2017/745. The statement specifying compliance with the general safety and performance requirements in accordance with MDR can be found in the document Manufacturer's Declaration of Compliance with Requirements.
As appropiate, clinical investigation will not commence until approval/favourable opinion has been obtained from the Clinical Research Ethics Committee (CREC) and the required regulatory authority (Spanish Agency for Medicines and Medical Devices, AEMPS), and it must comply with any additional requirements imposed by the CREC and/or AEMPS.
Informed Consent process
The patient, or in their absence, the family member or legally authorized representative, must provide written consent before their inclusion in the clinical investigation. This will occur after they have understood, through a prior interview with the principal investigator or a member of the research team, the objectives of the investigation, its risks, inconveniences, and benefits, as well as the conditions under which it will be conducted, and after being informed of their right to withdraw from the investigation at any time without explanation and without incurring any responsibility or prejudice.
The principal investigator will discuss the study with the subject and provide the information objectively, without coercion or influence, and without offering any inappropriate or undue incentive. The principal investigator will use non-technical language in the subject's native language (or that of the spouse/closest relative or legally authorized representative) for better understanding and will allow sufficient time for reading and comprehending the information.
Each participant will document their informed consent by signing and dating the informed consent form. Each signed and dated consent will be kept by the principal investigator, and a copy of the informed consent will be provided to the subject.
If new important information arises that could affect the subject's willingness to continue participating in the clinical investigation, it will be provided in any case. If necessary, their continued informed consent will be confirmed in writing.
Adverse events, adverse product reactions and product deficiencies
Adverse Events (AE) and Adverse Events to Product (AEP)
An AE is any unintended medical event, unanticipated illness or injury, or unintended clinical signs (including abnormal laboratory findings) in subjects, users, or other persons, whether or not related to the investigational product and whether intended or unintended.
An AEP is an adverse event related to the use of an investigational medical device.
Given these definitions, potential AEPs or AEs are documented in the product's IFU.
Product deficiencies
Possible inadequacies of a medical device may relate to its identity, quality, durability, reliability, safety, or performance.
Product deficiencies in the investigation will be managed by the sponsor according to non-conforming product control procedures. When appropriate, corrective and/or preventive actions will be taken to protect the safety of subjects, users, and other individuals.
Serious Adverse Events, serious adverse events to the product and serious and unexpected adverse event to the product
According to UNE-EN ISO 14155:2021:
- A Serious Adverse Product Reaction (SAEP) is a SAE that has produced any consequence characteristic of a serious adverse event.
- A Serious Adverse Event (SAE) is an AE that resulted in any of the following events: death, serious deterioration of the health status of the subject, users or other persons, or fetal distress, fetal death, congenital anomaly or birth defect.
- A Serious Unexpected Adverse Event to the Product (SUAEP) is a SAE that, due to its nature, incidence, intensity or consequences, has not been identified in the updated risk assessment.
Taking into account these definitions, there are no SAEP, SAEs or SUAEPs related to the use of the product.
Foreseeable adverse events and adverse events to the product
The foreseeable adverse events and expected adverse reactions to the product, as well as their incidence, mitigation and treatment, are documented in R-TF-013-002 Risk Management Record for the product under study.
Data Monitoring Committee (DMC)
Information on the DMC (Data Monitoring Committee), if established. This is an independent committee that the sponsor may establish to evaluate, at indicated intervals, the progress of the clinical investigation, the safety data or the critical clinical performance or efficacy endpoints and to recommend to the sponsor whether to continue, suspend, modify, or stop the clinical investigation.
Suspension or early termination of clinical research
As indicated in the UNE-EN ISO 14155:2021 regulation, the sponsor may suspend or terminate the clinical research early for significant and documented reasons. These are:
- If during the clinical research the suspicion of an unacceptable risk arises, including a serious threat to the health of the subjects. It must be suspended while the risk is determined.
- If an unacceptable risk that cannot be controlled is confirmed.
- Due to the impossibility of including a minimum number of subjects that allows the final assessment of the study within a reasonable period according to the characteristics of the study.
- When instructed by the IRB or the required regulatory authority (AEMPS).
- Due to non-compliance with the obligations assumed in the contract by any of the contracting parties.
- By mutual agreement between the parties, expressed in writing.
- By the will of one of the parties, expressed in writing at least one month in advance.
In the event of a suspension or early termination of the clinical research, the sponsor will inform the AEMPS. The sponsor must provide the resources to comply with the obligations of the CIP and with the existing agreements. The principal investigator must inform the subjects if so stipulated in the agreement between the sponsor and the research centre.
If the clinical investigation is resumed, the sponsor must inform the principal investigator and, where appropriate, the AEMPS. Approval from the IRB and, where appropriate, from the AEMPS will be required for such resumption. The principal investigator must inform the subjects.
In accordance with Article 77 of Regulation (EU) 2017/745, the sponsor must notify the Member States in which the clinical investigation is being conducted of the end of the clinical investigation, its temporary halt, or its early termination, within the deadlines specified by the regulation (within 15 days of the end, or within 24 hours in case of early termination or temporary halt for safety reasons). This notification must be accompanied by a justification in case of early termination or temporary halt.
Annexes
Annex I. Protocol of the study
Annex II. Ethics committee approval
The study was approved by the Comité de Ética de la Investigación con medicamentos (CEIm) of Euskadi under reference number PI2019216. Two approvals are on file:
- Initial CEIm favourable opinion issued on 2020-02-10, authorising the original 40-subject pilot phase under the protocol submitted to the Committee.
- Subsequent CEIm favourable opinion issued on 2022-01-13, approving the substantial amendment that extended the sample to up to 200 subjects and incorporated additional skin-lesion categories (nevi and other common benign and malignant lesions).
No subject was enrolled before the initial favourable opinion of 2020-02-10.
Annex III. Patient information sheet & Informed consent
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