R-TF-015-004 Clinical investigation plan
Scope
This Clinical Investigation Plan (CIP) outlines the rationale, objectives, design, and methodology for the clinical investigation.
CIP Identification
| CIP | |
|---|---|
| Title of the clinical investigation | Non-invasive prospective Pilot in a Live Environment for the Improvement of the diagnosis of skin pathologies in Primary Care |
| Device under investigation | Legit.Health Plus |
| Protocol version | Version 1.0 |
| Date | 2024-07-04 |
| Protocol code | LEGIT.HEALTH_PH_2024 |
| Sponsor | Instituto de Investigación Sanitaria Puerta de Hierro |
| Coordinating Investigator | Dr. Gastón Roustán Gullon |
| Principal Investigator(s) | Dr. Gastón Roustán Gullon |
| Investigational site(s) | This study was conducted remotely by sending the images to the participating professionals. |
| Ethics Committee | This study does not require an Ethics Committee approval due to the nature of the images used. The images employed in this study are completely anonymized medical images sourced from public dermatological atlases and freely available public sources. These images are not derived from identifiable patients, and their anonymization makes patient recognition impossible. As these images constitute non-personal data, they do not fall under the scope of regulations requiring ethics committee approval for studies based on fully anonymized, publicly available data. |
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
Compliance Statement
- Harmonised standard UNE-EN ISO 14155:2021.
- Regulation (EU) 2017/745 on medical devices (MDR).
- Harmonised standard UNE-EN ISO 13485:2016s.
- Regulation (EU) 2016/679 (GDPR).
- Spanish Organic Law 3/2018 on the Protection of Personal Data and guarantee of digital rights.
- Spanish Organic Law 1090/2015 on regulating clinical trials with medicines, the Ethics Committees for Research with Medicines and the Spanish Registry of Clinical Studies.
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. Gastón Roustan Gullón
Coordinating investigator
- Dr. Gastón Roustan Gullón
Collaborating Investigators (Clinical Staff - Primary Care Practitioners)
- Dra. Esther Minguela
- Dr. Fernando León
- Dr. Ángel Rossell Díaz
Technical Support (AI Labs Group S.L.)
- Mr. Alfonso Medela
- Mr. Taig Mac Carthy
- Mrs. Alba Rodríguez
Investigational sites
This study will be conducted remotely through a centralized web-based platform. Primary care practitioners will receive individual user credentials (username and password) to securely access the platform. All images will be presented through this platform, and practitioners' assessments and annotations will be recorded on the same system. Access logs will be maintained to ensure traceability of all practitioner interactions with the platform.
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 792790 |
| 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 |
Justification of the design
Background and rationale
Dermatological conditions represent a significant portion of primary care consultations, constituting approximately 5% of all visits. However, discrepancies between diagnoses made by general practitioners and dermatologists remain substantial, with concordance rates between 57% and 65.52%. This gap in expertise often leads to misdiagnoses, incorrect referrals, and delays in appropriate treatment, particularly in rare and severe conditions. The limited availability of dermatologists, especially in rural areas, further complicates patient care, underscoring the need for innovative solutions to optimize resource allocation and improve diagnostic accuracy.
Teledermatology has shown promise in reducing the pressure on in-person consultations by enabling remote assessments. However, the adoption of artificial intelligence (AI) presents a transformative opportunity to enhance the diagnostic capabilities of general practitioners. The device has already been validated in the diagnosis of skin conditions and offers advanced tools, such as the automatic scoring of diverse pathologies. This pilot study aims to evaluate whether the use of the device can increase the true accuracy of healthcare professionals (HCPs) in the diagnosis of multiple dermatological conditions.
Risks and benefits of the product in investigation and clinical research
In this study, there will be no patient recruitment or active patient involvement. The images used will be extracted from public dermatological atlases and openly accessible public sources with confirmed diagnoses. These completely anonymized images will be presented to participating primary care practitioners through a secure centralized platform. Primary care practitioners will receive a user account to access the platform and review these images. Using the device could optimize diagnostic accuracy in clinical practice, potentially save consultation time and costs, and support better clinical decision-making for patients with skin pathologies. The participating primary care practitioners will sign a contract with the sponsor to regulate their participation in the study.
Hypothesis
The information provided by the device increases the true accuracy of healthcare professionals (HCPs) in the diagnosis of multiple dermatological conditions.
Objectives
Primary objective
To validate that the information provided by the device increases the true accuracy of primary care practitioners in the diagnosis of multiple dermatological conditions.
Secondary objective(s)
- To validate the percentage of cases that should be referred according to the HCP with the information provided by the device.
- To validate the percentage of cases that could be handled remotely with the information provided by the device.
Summary of the study
This is a prospective observational analytical and cross-sectional self-controlled study. It is designed to assess if the use of the medical device by primary care practitioners can increase the accuracy in the diagnosis of multiple dermatological conditions, who will be presented with 30 images of different skin conditions sourced from public dermatological atlases. In this case, the data collection will include the diagnosis accuracy for different dermatological pathologies. The study adheres to strict ethical guidelines, ensuring data confidentiality and compliance with international standards. The study's robust methodology is designed to assess the clinical utility and potential diagnostic support value of the device.
Design and methods
Type of clinical research
This is a prospective observational analytical and cross-sectional self-controlled study to evaluate whether the use of the medical device by primary care practitioners helps to increase the accuracy in the diagnosis of different skin conditions. In this self-controlled design, each primary care practitioner serves as their own comparator, first providing diagnoses without the use of the device, and subsequently providing diagnoses with the support of the device on the same set of images.
Population
In this study, the population will consist of primary care practitioners. A minimum of 8 primary care practitioners will be selected. Each participant will be presented with 30 images to review.
Sample size
The objective of this study is to evaluate whether the use of Legit.Health Plus improves diagnostic accuracy by at least 10% among primary care practitioners, providing evidence to support its integration into clinical practice. To achieve this, the study will recruit a minimum of 8 primary care practitioners, each reviewing 30 dermatological images, resulting in a total of 270 diagnostic evaluations (8-9 practitioners × 30 images per practitioner).
Justification for 270 Observations:
A sample of 270 observations (image-based diagnostic evaluations) is considered a robust number for this type of study. Each of the 30 images will be evaluated by multiple practitioners, providing multiple independent observations of device impact for each clinical case. This design allows for:
- Adequate Statistical Power: 270 paired observations provide sufficient power to detect clinically meaningful improvements (e.g., 10% relative improvement in diagnostic accuracy) using paired statistical tests such as McNemar's test for binary outcomes
- Condition-Specific Analysis: With 30 images representing 9 different dermatological conditions (2-5 images per condition), the 270 observations allow for preliminary subgroup analysis by pathology, though with the caveat that individual condition subgroups will have smaller sample sizes
- Multiple Perspectives: Each image evaluated by 8-9 independent practitioners provides 8-9 observations per image, enabling assessment of inter-observer agreement and consistency of device impact across different clinical perspectives
- Practical Feasibility: This sample size balances the need for adequate statistical power with practical constraints of recruitment and resource availability in a pilot setting
Selection of 8-9 Primary Care Practitioners:
The recruitment of 8-9 primary care practitioners aims to minimize inter-observer variability while maintaining a manageable and representative cohort. This focused group of practitioners ensures high-quality data collection and allows for detailed review of each practitioner's performance patterns and consistency in using the device.
Selection of 30 Images per Practitioner:
Thirty images per practitioner provides a robust set of diverse clinical scenarios while remaining feasible to complete within the study timeline. The 30 images are specifically selected to represent:
- Real-world diagnostic diversity (9 different dermatological conditions)
- Varying severity and complexity levels
- Cases with different diagnostic certainty levels
- A representative distribution of malignant and benign conditions
This design ensures that each practitioner's evaluations are both practical and highly relevant to real-world primary care scenarios, providing valid evidence for the device's utility in clinical practice.
Duration
The total duration of the study is estimated at 4 months, including the time required after the collection of the corresponding images 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 7.00%.(User Group: Primary care practitioners)
- top-1 accuracy equal to or greater than 63.70%.(User Group: Primary care practitioners)
- top-1 accuracy equal to or greater than 46.12%.(User Group: Primary care practitioners)
- sensitivity equal to or greater than 14.30%.(User Group: Primary care practitioners)
- sensitivity equal to or greater than 72.93%.(User Group: Primary care practitioners)
- sensitivity equal to or greater than 68.55%.(User Group: Primary care practitioners)
- specificity equal to or greater than 11.88%.(User Group: Primary care practitioners)
- specificity equal to or greater than 77.11%.(User Group: Primary care practitioners)
- specificity equal to or greater than 78.01%.(User Group: Primary care practitioners)
- top-1 accuracy equal to or greater than 6.93%.(User Group: Primary care practitioners)
- top-1 accuracy equal to or greater than 5.56%.(User Group: Primary care practitioners)
- sensitivity equal to or greater than 14.30%.(User Group: Primary care practitioners)
- sensitivity greater than 22.22%.(User Group: Primary care practitioners)
- specificity equal to or greater than 11.88%.(User Group: Primary care practitioners)
- specificity greater than 22.22%.(User Group: Primary care practitioners)
- reduction in the number of days equal to or greater than 40.00%.(User Group: Primary care practitioners)
- increase in patients that can be managed remotely equal to or greater than 40.00%.(User Group: Primary care practitioners)
Inclusion criteria
- Board-certified primary care physicians, regardless of their professional experience.
- High-quality images of patients with different skin conditions.
Exclusion criteria
- Low-quality images of patients which can not be properly analysed.
Variables
Main variable
- The main variable of this study is the diagnostic performance (accuracy, sensitivity, and specificity) in different skin pathologies using the device. Performance will be calculated both with and without the use of the device.
Secondary variables
- Percentage of cases should be referred according to the HCP with the information provided by the device.
- Percentage of cases could be handled remotely with the information provided by the device.
Condition of interest
Patients with different skin pathologies.
Limitations of clinical research
The main limitations of the pilot include several factors that may influence the perception and effectiveness of the AI-based device. Firstly, the acceptance and trust of healthcare professionals in these emerging technologies can vary significantly. The device's effectiveness may be compromised if users are not fully convinced of its accuracy or usefulness, thereby affecting the overall perception of its performance.
Additionally, image quality is crucial for the device's performance. Issues such as low-quality photographs, errors in cropping lesions, or variations in lighting and focus can deteriorate the quality of the data received by the system, which may negatively influence the evaluation and perception of its effectiveness by the researchers.
Variability in image conditions is also an important aspect to consider. Differences in lighting, colour, shape, size, and focus of the images, along with the number of images available for each patient, can affect the accuracy of the results. High variability in images of the same patient or an insufficient number of representative images can lead to a decrease in the expected diagnostic accuracy of the device.
Furthermore, the consistency of researchers in using the device is crucial. Variations in how diligently investigators use the device can impact the pilot's findings. If the investigators are not consistent in their use of the device, it can lead to unreliable results and affect the overall assessment of its efficacy.
Another limitation is the Hawthorne effect, where pilot subjects may change their behaviour simply because they know they are being observed. This awareness can influence their decisions and actions within the pilot, potentially skewing the results and not accurately reflecting how the device would be used in a non-study environment.
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.
In this study, informed consent from patients will not be collected, as the study will not interfere with the medical routine of doctors or patients. Furthermore, the data will not be sensitive and will be anonymized to prevent patient identification. Additionally, the images used will come from dermatological atlases.
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
In clinical research, minimizing bias is essential to ensure the validity and reliability of the study's results. In this study, HCPs will be randomly selected to participate in this. Thus, outcomes will not be influenced by pre-existing characteristics of the participants. Furthermore, we will use standarised protocols, Using standardized procedures for conducting the study and measuring outcomes ensures that all participants are treated and evaluated in the same way, reducing variability due to differences in how the intervention is applied or how outcomes are assessed. Finally, Collecting data prospectively reduces the chance that participants or investigators will inaccurately recall past events, which is common in retrospective studies. Along with this, before the study begins we define primary and secondary outcomes, which prevents selective reporting of only favorable outcomes. This ensures that all relevant data, whether positive or negative, are considered.
Calendar
The total duration of the study is estimated at 4 months, including the time required after the recruitment of the participating HCPs and collection of all images and for closing and editing the database, data analysis and preparation of the final study report.
Monitoring plan
The sponsor will hold a meeting with the investigative team at the beginning of the study 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 every 3 months with 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. In this study, this will be carried out online.
- 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.
Completition of the investigation
After the final closure of the clinical investigation, a Clinical Investigation Report (CIR: T-015-006 Clinical Investigation Report) will be drafted, even in the event of early termination or suspension. The results obtained (positive, inconclusive, or negative) will be included in the previously mentioned public access database.
Additionally, if deemed appropriate, the results may be published in scientific journals. All the investigators who approved this clinical investigation will be acknowledged, and any funds received by the author for the study and its financing source 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.
The analysis will focus on calculating diagnostic accuracy, sensitivity, and specificity for primary care practitioners, both with and without the use of the Legit.Health Plus medical device. For each of these metrics, two types of results will be analyzed:
- The percentage of variation in the metric attributable to the use of the device.
- The absolute value of the metric, which will be compared against the state of the art and the values obtained by the practitioners during the study.
Additionally, a subgroup analysis will be performed specifically for rare diseases, which in the context of this study focuses on Pustular Psoriasis. This analysis will evaluate the same diagnostic performance metrics (accuracy, sensitivity, and specificity) to assess the device's utility in conditions with lower clinical incidence but high diagnostic complexity for primary care.
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 so far will be performed based on the needs of descriptive results of the sample. Interobserver concordance analyses will also be performed by estimating the kappa coefficient.
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
All study data will be collected and managed through a centralized, secure web-based platform that serves as the Case Report Form (CRF). Each participating primary care practitioner will receive individual login credentials (username and password) to access the platform. The platform will present the standardized set of 30 images to each practitioner and capture their diagnostic assessments and clinical decisions in response to structured questions.
Data Collection: Diagnostic assessments, referral decisions, and remote consultation feasibility evaluations will be electronically captured directly in the platform when practitioners provide their responses. All data entries are time-stamped and automatically stored in a secure central database.
Access Control and Traceability: Access to the platform is restricted to authorized practitioners through individual user credentials. Complete access logs are maintained for each practitioner, documenting login times, data entry activities, and timestamps of all interactions. This audit trail ensures full traceability of who accessed what data and when.
Data Anonymity: Study images are completely anonymized and bear no patient identifiers. Each practitioner receives a unique study identification code that is not linked to their personal identity in the analysis dataset. The Principal Investigator maintains a confidential list linking practitioner identification codes to their identities, stored separately in a secure area with restricted access.
Data Export and Analysis: Once all data collection is completed and the database is closed and locked by the Principal Investigator, data are exported to CSV format for statistical analysis. The exported dataset contains only anonymized image data and practitioner responses, with no personal identifying information.
Data Security: All data transmitted to and stored on the platform are encrypted using industry-standard security protocols. Access to the central database is restricted to authorized personnel only, and the system implements appropriate technical and organizational measures to prevent unauthorized access, alteration, or loss of data.
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 the case of substantial modifications to authorized clinical investigations, a request must be submitted to the AEMPS.
- 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.
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 principal investigator and all the participant investigators.
Upon obtaining the study conclusions, a final report (T-015-006 Clinical Investigation Report (CIR)) will be prepared and submitted to the sponsor of the study.
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
For Patients/Image Subjects: Informed Consent from patients whose images might appear in the atlases or public sources is not required for this study because: (1) the study utilizes completely anonymized images from public dermatological atlases and publicly available sources where individuals cannot be identified; (2) there is no active patient recruitment or direct involvement of patients in this study; (3) the images used constitute non-personal data under GDPR as they contain no information allowing identification of data subjects; and (4) the study does not involve any intervention, modification of care, or processing of sensitive personal health data.
For Healthcare Practitioners (Primary Care Physicians): While formal Informed Consent Forms are not required for practitioners (as this study is observational and non-interventional with respect to their clinical practice), all participating primary care practitioners will receive comprehensive written and oral information about the study, including the objectives, procedures, their roles and responsibilities, data handling practices, and confidentiality protections. Each practitioner will sign a contract with the sponsor that regulates their participation in the study, outlines their obligations, and confirms their understanding and voluntary agreement to participate.
Adverse events, adverse product reactions and product deficiencies
Adverse Events (AE) and Adverse Events to the 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 deficencies
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 events 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 results in any of the following events: death, serious deterioration of the health status of the subject, users or other persons, 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 the T-013-002 Risk management record of 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.
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-003 Design & Development Manager, JD-004 Quality Manager & PRRC
- Approver: JD-001 General Manager