R-TF-015-004 Clinical investigation plan LEGIT.HEALTH_PH_2024_NIPPLE
Scope
The purpose of this Clinical Investigation Plan (CIP) is to set out the rationale, objectives, design, methodology, conduct, implementation, record-keeping and the method of analysis for the clinical investigation. s
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_NIPPLE |
| 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 did not require an Ethics Committee approval due to its observational non-interventional and use of non-sensitive 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
- Record signature meaning
Compliance statement
- Harmonized standard UNE-EN ISO 14155:2021.
- Regulation (EU) 2017/745 on medical devices (MDR).
- Harmonized 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
- CAD: Computer-Aided Diagnosis
- CIP: Clinical Investigation Plan
- CUS: Clinical Utility Questionnaire
- SUS: System Usability Scale
- GCP: Standards of Good Clinical Practice
- ICH: International Conference of Harmonization
- PI: Principal Investigator
- DLQI: Dermatology Quality of Life Index
- ICH: International Conference of Harmonization
- AUC: Area Under the ROC Curve
CIP or protocol specifications
Principal Investigator
- Dr. Gastón Roustan Gullón
Coordinating investigator
- Dr. Gastón Roustan Gullón
Collaborating Investigator(s)
- Medical staff
- Dr. Adriana Vasconcelos
- Dr. María Porriño
- Dr. Gustavo
- Dr. Josefina Sanz
- Dr. Andrés
- Dr. Gerald Selda
- Dr. Helena Bahachille
- Dr. Mitchell Ignacio Leal Betancourt
- Dr. Marianela del Castillo
- Dr. María Pilar Martínez Marta
- Dr. Nadia Hayajneh Carrillo
- Dr. Carmen Arsuaga
- Dr. Elena Sánchez Largo
- Dr. María Gómez
- Dr. Pedro Ortega Lozano
- AI Labs Group S.L.
- Mr. Alfonso Medela
- Mr. Taig Mac Carthy
- Mrs. Alba Rodríguez
Investigational sites
- This study was conducted remotely and sending the images to the participating dermatologists.
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 | 1.0.0.0 |
| 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 |
| Class | Class IIb |
| Classification rule | Rule 11 |
| Novel product (True/False) | FALSE |
| Novel related clinical procedure (True/False) | FALSE |
| 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 primary care physicians 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 use of artificial intelligence (AI) presents a transformative opportunity to enhance the diagnostic capabilities of primary care physicians. Legit.Health, an AI-based medical device, has already been validated in the diagnosis of skin conditions and offers advanced tools, such as the automatic scoring of diverse patholohies. This pilot study aims to evaluate whether the use of the Legit.Health medical 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 patients recruitment, since the images used for it will be extracted from different sources such as dermatology atlases. However, using the device could optimize patient diagnosis, save costs and time, and provide better treatment to patients. The participating phyisicians will sign a contract with Legit.Health so as to participate in the study.
Hypothesis
The information provided by Legit.Health 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 device increases the true accuracy of primary care physicians in the diagnosis of multiple dermatological conditions.
Secondary objective(s)
- To validate what percentage of cases should be refered according the HCP with the information provided by the device.
- To validate what percentage of cases could be handled remotely with the information provided by the device.
Summary of the study
This is a prospective observational analytical and cross-sectional study. It is designed so as to assess if the use of the medical device Legit.Health by dermatologists and prymary care physicians can increase the accuracy in the diagnosis of multiple dermatological conditions, who will be presented with 29 images of patients with different skin conditions. In this case, the data collection will include the diagnosis accuracy for different dermatological pathologies. The study adhered to strict ethical guidelines, ensuring patient confidentiality and compliance with international standards. Patients were provided with detailed information and informed consent. The study's robust methodology aimed 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 to evaluate whether the use of the medical device by HCPs helps to increase the accuracy in the diagnosis of different skin conditions. In this study, there is just one group of participants, which consists of primary care physicians and dermatologists. There is no control group, since the same group of practicioners will be its own control group, using or not Legit.Health to diagnose the different images they see.
Population
In this study the population will consist of primary care physicians and dermatologists. A minimum of 15 physicians will be selected. Each participant will be presented with 29 images to review.
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
- An improvement of diagnostic accuracy on both primary care physicians and dermatologists.
- A positive view of Legit.Health regarding diagnosis support.
- A reduction of 30% of referral to dermatology (Warshaw et al. 2011).
- An improvement in remote consultations.
Inclusion criteria
- Board-certified primary care physicians and dermatologists, regardless of their professional experience.
- High quality images of patients different skin conditions.
Exclusion criteria
- Low quality images of patients which can not be properly analyzed.
Variables
Main variable
- The maing variable of this study is the accuracy of diagnosis of different skin pathologies using Legit.Health. In this case it will be the percentage of success with and without Legit.Health.
Secondary variables
- Percentage of cases should be refered according 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, color, 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.
Additionally, the consistency of investigators in using Legit.Health 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 behavior 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
The conduct of the study will conform to international Good Clinical Practice standards, to the Declaration of Helsinki in its latest active amendment, and to international and national rules and regulations. Any modification of this protocol will be reviewed and approved by the Principal Investigator and must be evaluated for approval before including subjects in a modified protocol.
The study will be conducted according to 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 the Protection of Personal Data and guarantee of digital rights with regard to data processing in which no data that allows the personal identification of subjects will be included, the information being managed in an encrypted manner.
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 used 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, each physician 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 physicians 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.
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 with regard to 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, physicians will be randomly selected to participate in this. Thus, outcomes will not be influence by pre-existing characteristics of the participants. Furthermore, we will use standarized 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 recruitment of the participating physicians and collection of all images and for closing and editing the database, data analysis and preparation of the final study report.
Monitoring plan
The Legit.Health team will hold a meeting with the participating investigators at the beginning of the study to address any potential questions and ensure that data is being collected properly.
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 (whether 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 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 percent 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
The management of the collection and processing of the study data will be carried out through the design of a Data Collection Notebook (CRD) in spreadsheet format, in which the researchers assigned to this task will enter the source data of each patient participating in the study.
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 the Protection of Personal Data and guarantee of digital rights). For this purpose, 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 center.
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 with regard to 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 participants will be included.
The transfer of data from the spreadsheet CRD to the electronic Database will be carried out using the double data entry technique. This will be done by the researchers collaborating in the project. 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 data discrepancies and errors. Any changes to the databases after closure can only be made after written agreement between the promoter and the technical coordinators of the project.
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 will be 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.
Modifications to the clinical investigation may only be implemented once favorable 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 emergency situations (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 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 in accordance with 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.
This clinical investigation will comply with any additional requirements imposed by the CREC and/or AEMPS.
Informed Consent process
For this study, Informed Consent will not be collected, due to its observational and non-interventional nature. In this case, we will not analyze personal identification data or sensitive health care data. Furthermore, all the data will be encryopted and anonymized, preventing direct or indirect identification of patients. Owing to these reasons, this study does not need to collect Informed Consent from patients or physicians.
Adverse events, adverse product reactions and product deficiencies
Adverse Events (AE) and Adverse Event 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.
A 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, serios adverse events to 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 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 center.
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.
Record signature meaning
- Author: JD-018 Jordi Barrachina
- Review: JD-003 Taig Mac Carthy
- Approval: JD-005 Alfonso Medela