R-TF-015-004 Clinical investigation plan Legit.Health_IDEI_2023.

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.

CIP Identification

	CIP
Title of the clinical investigation	Optimization of clinical flow in patients with dermatological conditions using Artificial Intelligence.
Device under investigation	Legit.Health
Protocol version	Version 12.0
Date	2023-12-27
Protocol code	Legit.Health_IDEI_2023
Sponsor	AI Labs Group S.L.
Coordinating Investigator	Dra. Miguel Sánchez Viera
Principal Investigator(s)	Dra. Miguel Sánchez Viera
Investigational site(s)	Instituto de Dermatología Integral (IDEI)
Ethics Committee	Comité de Ética de la Investigación con Medicamentos de HM Hospitales

Table of contents

• Scope
• CIP Identification
• Compliance statement
• Abbreviations and definitions
• CIP or protocol specifications
  • Principal Investigator
  • Coordinating investigator
  • Collaborating Investigator(s)
  • Investigational sites
  • Funding
• Product Identification and Description
• Justification of the design
  • Background and rationale
  • Risks and benefits of the product in investigation and clinical research
• Hypothesis
• Objectives
  • Primary objective
  • Secondary objective(s)
• Summary of the study
• Design and methods
  • Type of clinical research
  • Population
  • Duration
  • Acceptance criteria
  • Inclusion and exclusion criteria
  • Variables
  • Condition of interest
  • Limitations of clinical research
• Ethical considerations
  • Data confidentiality
  • Bias minimization measures
  • Calendar
  • Monitoring plan
  • Completition of the investigation
  • Statistical analysis
  • Data management
• CIP Modification
• CIP Deviations
• Start, follow-up and end reports
• Statements of compliance
• Informed Consent process
• Adverse events, adverse product reactions and product deficiencies
  • Adverse Events (AE) and Adverse Event to Product (AEP)
  • Product deficencies
  • Serious Adverse Events, serios adverse events to product and serious and unexpected adverse event to the product
  • Foreseeable adverse events and adverse events to product
  • Data Monitoring Committee (DMC)
• Annexes
  • Annex I. Protocol of the study
  • Annex II. Ethics committee approval
• 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. Miguel Sánchez Viera (Instituto de Dermatología Integral - IDEI).

Coordinating investigator

• Dr. Miguel Sánchez Viera (Instituto de Dermatología Integral - IDEI).

Collaborating Investigator(s)

• Instituto de Dermatología Integral (IDEI)
  • Dr. Concetta D'Alessandro
  • Dr. Alejandra Capote
  • Dr. Pablo López Andina
  • Dr. Allison Marie Bell-Smythe Sorg
  • Dr. Alejandra Vallejos
  • Dr. Isabel del Campo
  • Dr. Juliana Machado
  • Dr. Raúl Lucas Escobar
  • Ms. Beatriz Torres
• AI Labs Group S.L.
  • Mr. Alfonso Medela
  • Mr. Taig Mac Carthy

Investigational sites

• Instituto de Dermatología Integral (IDEI)

Funding

This research was co-financed under the framework of the 2021 Call for Grants for research and development projects in artificial intelligence and other digital technologies and their integration into value chains C005/21-ED. With file number 2021/C005/00154001. This grant was awarded to the Instituto de Dermatología Integral (IDEI).

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

The use of image-based artificial intelligence (AI) holds significant potential for improving diagnostic accuracy in medical visual assessments. The COVID-19 pandemic, which limited access to in-person healthcare, has accelerated the adoption of telemedicine, highlighting the importance of AI in triaging and supporting decision-making processes. In dermatology, conditions such as pigmented lesions, acne, and alopecia represent high-demand cases requiring significant in-person resources and specialist attention. AI tools can play a crucial role in optimizing these processes, reducing the workload, and improving efficiency in patient management.

Advancements in image recognition and AI technologies have led to innovations in diagnosing skin conditions, with Computer-Aided Diagnosis (CAD) systems proving their ability to classify lesion images at a level comparable to expert clinicians. This study aims to evaluate the Legit.Health tool, developed by AI LABS GROUP S.L., which utilizes AI to enhance clinical workflow and patient care for dermatological conditions. The tool seeks to automatically prioritize patients based on urgency, assign appropriate consultations (dermatological or aesthetic), improve diagnostic capabilities in non-specialist staff, and provide a visual record for expert review.

The primary goal of this study is to validate that the AI-based Legit.Health tool improves clinical workflow efficiency and patient care processes by diagnosing and determining the severity of skin lesions. This would result in reduced in-person consultation time and healthcare costs per patient, while assigning the correct type of consultation from the outset. Secondary objectives include decreasing patient wait times based on medical urgency, reducing the number of initial dermatology consultations, and improving both specialist satisfaction and patient usability, ultimately benefiting the clinic's economic outcomes.

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

Legit.Health enhances the efficiency of clinical workflows and patient care processes, streamlining care and reducing the need for in-person consultations per patient.This is based on the following processes: - It facilitates the prioritization of patients with greater urgency based on the suspicion of malignancy and severity of the process or lesion, automatically optimizing the flow and time of care for these patients. - It allows the type of consultation appropriate for the patient to be automatically assigned, reducing the need for an initial assessment consultation (triage). - It increases the capacity for assessment and detection of pigmented lesions by auxiliary personnel, freeing up the specialist's time in the process of carrying out the examination and determining the lesions to be studied in more detail. - It increases the precision and speed in measuring the degree of severity of female androgenic alopecia. - It increases the precision and speed in measuring the severity and number of acne lesions. - It provides a visual record (photograph) of the condition at the time the patient reports the pathology, allowing its subsequent review by an external expert.

Objectives

Primary objective

To validate that Legit.Health optimizes clinical flow and patient care processes, reducing the time and cost of care per patient, through greater precision in medical diagnosis and determination of the degree of malignancy or severity.

Secondary objective(s)

• To demonstrate that the device improves the ability of healthcare professionals in detecting malignant or suspected malignant pigmented lesions.
• Demonstrate that the device improves the ability and accuracy of healthcare professionals in measuring the degree of involvement of patients with female androgenic alopecia.
• To demonstrate that the device improves the ability and accuracy of healthcare professionals in measuring the degree of involvement of patients with acne.
• Automate the initial triage/assessment process in patients consulting for pigmented lesions.
• To evaluate the reduction in the use of healthcare resources by the center by reducing the number of triage consultations and direct referral of the patient to the appropriate consultation (aesthetic or dermatological).
• Evaluate the degree of usability of the device by the patient.
• Demonstrate that the device increases specialist satisfaction.
• Evaluate the reduction in the use of healthcare resources by reducing the number of triage consultations and directing the patient directly to the appropriate consultation, whether in the aesthetic or dermatological field.

Summary of the study

This is a prospective observational study with both longitudinal and retrospective case series to assess if Legit.Health is a validate tool to improve the clinical flow and patients care process. This investigation encompasses a diverse cohort of patients with different pathologies. On one hand, prospectively, a minimum of 60 cases will be included: 30 with pigmented lesions, 15 with androgenic alopecia and 15 with inflammatory acne. On the other hand, retrospectively, 60 patients with pigmented lesions, 15 with androgenic alopecia and 15 with inflammatory acne will be included. Data collection will include questionnaires, photograph analysis, and patient satisfaction surveys. 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 a prospective observational study with both longitudinal and retrospective case series. It is designed to evaluate if Legit.Health is a valid tool to improve clinical flow and and the care process of patients with different skin pathologies. On one hand in this study there are three different groups of patients with different pathologies: pigmented lesions, androgenetic alopecia and acne. On the other hand, in this investigation there will not be control group, as we pretend to assess if Legit.Health can improve the clinical flow and if it can improve he ability of healthcare professionals in detecting malignant or suspected malignant pigmented lesions or measuring he degree of involvement of patients with female androgenic alopecia or patients with acne.

Population

Adult patients (>18 years) diagnosed with pigmented lesions, andregenetic alopecia or acne that meet the inclusion criteria. These patients are attended at the Instituto de Dermatología Integral (IDEI).

Duration

This study estimates a recruitment period of 3 months.

The total duration of the study is estimated at 6 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.

The total duration of the study for each participant with pigmented lesions will be 1-3 months. The duration for patients with acne and alopecia will be 1 day.

Acceptance criteria

• An improvement of diagnostic accuracy of 10% (Ferri et al. 2020).
• Scores equal or greater than 70 on the System Usability Scale (SUS).
• An AUC equal or greater than 0.8 detecting malignancy.

Inclusion and exclusion criteria

Inclusion criteria

• Adult patients (>18 years) 16 years in the case of acne.
• Patients with pigmented lesions who meet any of the following conditions:
  • They consult for the first time for a pigmented lesion.
  • Patients already scheduled for a dermatoscopy consultation for the first time or for a review of pigmented lesions.
• Patients with active inflammatory acne.
• Women with androgenic alopecia.

Exclusion criteria

• Patient who, in the opinion of the researcher, cannot or will not comply with the study procedures.

Variables

Main variable

• The main variable in this study will be, on the one hand, the analysis of concordance between the diagnosis issued by the dermatologist and the one determined by the Legit.Health tool.
• On the other hand, the correlation between the possibility of malignancy determined by the dermatologist and the one determined by the Legit.Health tool.

Secondary variables

• In the case of alopecia and acne:
  • Severity measurement given by the researcher.
    • For acne: severity according to the IGA and lesion count.
    • For female androgenic alopecia: severity according to the Ludwig scale.
  • Severity measurement given by the tool.
    • For acne: severity according to the number of lesions and the density of inflammatory lesions.
    • For female androgenic alopecia: severity according to the Ludwig scale.
• In the case of pigmented lesions:
  • In the retrospective analysis:
    • Pathology diagnosed by the researcher.
    • Malignancy detected by the tool.
    • Confirmatory result of the pathological anatomy.
  • In the prospective analysis:
    • Number of pigmented lesions that concern the patient (a maximum of 3).
    • Number of lesions quickly explored by the researcher that he considers relevant. Indicate whether any of them coincide with the 1-3 indicated by the patient.
    • Clinical diagnosis by the researcher of the lesions indicated by the patient.
    • Malignancy detected by the tool for the lesions indicated by the patient.
    • Degree of malignancy given by the researcher (from 0 to 10) for the lesions indicated by the patient.
    • Degree of malignancy given by the tool for these same lesions (from 0 to 100). Pathological anatomy result of the lesions evaluated by this process in which a biopsy was necessary.
• As for satisfaction, the variables are:
  • Degree of satisfaction of the specialist using the Clinical Utility Questionnaire.

Condition of interest

Patients with any of the following dermatological pathologies: pigmented lesions, women with androgenic alopecia, and acne.

Limitations of clinical research

The main limitation in relation to machine learning lies in the quantity and quality of the images collected. Factors such as variability in lighting, colour, shape, size and focus are determining factors, in addition to the number of images available per patient. This implies that high intra-patient variability and an insufficient number of images to represent said variability can lead to lower than expected accuracy.

A crucial aspect to consider is the adequate delimitation of the lesion, given that a photograph in which the lesion occupies a very small proportion of the image can confuse the algorithm and lead it to detect erroneous patterns in the image. Appropriate cropping around the lesion helps to avoid such inconveniences.

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 and will not be initiated until approval has been obtained from the HM Hospitals Ethics Committee. Any modification of this protocol will be reviewed and approved by the Principal Investigator and must be evaluated by the Ethics Committee 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.

Patients will be informed orally and in writing about all the information related to the study and adapted to their level of understanding. A copy of the consent form and information sheet should be provided to the patient. The investigator should allow the patient the necessary time to ask questions about the details of the study.

Preparation of the informed consent form is the responsibility of the Principal Investigator. This form should include all the elements required by the International Conference of Harmonization (ICH), current regulatory guidelines, and comply with the Standards of Good Clinical Practice (GCP) and ethical principles that originate from the Declaration of Helsinki.

The investigator or the Principal Investigator's designee will keep the original signed informed consent form in a secure restricted access area under the custody of the Principal Investigator and will never leave the center and will give a copy of the original signed consent form to the patient.

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 patient 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 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, patients with the target pathologies 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.

Calendar

This study estimates a recruitment period of 3 months. The total duration of the study is estimated at 12 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. The total duration of the study for each participant with pigmented lesions will be 1-3 months. The duration for patients with acne and alopecia will be 1 day.

Monitoring plan

The Legit.Health 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.

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 CIR will be provided to the Ethics Committee and the Spanish Agency for Medicines and Medical Devices (AEMPS). 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. 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

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 assess 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. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and likelihood ratios (LR+ and LR-) will be calculated by comparing the results obtained using the Legit.Health tool and the paper questionnaire system used as the gold standard.

Analyses will be performed using appropriate statistical software, SPSS version 23.0 and STATA 13.0. Values of p-value 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 databases 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 Legit.Health) is the owner of the software named "Legit.Health Plus". During the period of validity of this study, Legit.Health will grant a license to use the Legit.Health Plus device to the research team free of charge. The research team will be the administrator of the account created on the Legit.Health platform. Both patients and members of the medical team will have login credentials. The Legit.Health team will not have access to the account or patient information.

The Data Controller is the research team. Legit.Health is the Data Processor and is not responsible for the processing of the data included in the Software or its users. The storage of data and photographs will be in line with the 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 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 Legit.Health platform complies with current legislation on the protection and confidentiality of personal data (European Regulation 2016/679 of 27 April on the protection of natural persons with regard to the processing of personal data and on 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). 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 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.

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 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 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 (T-015-006 Clinical Investigation Report (CIR)) will be prepared and submitted to the ethics committee.

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 not commence until approval/favorable 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 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. Likewise, the sponsor or principal investigator will notify the IRB. 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, the IRB 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.

Annexes

Annex I. Protocol of the study

Annex II. Ethics committee approval

Record signature meaning

• Author: JD-018 Jordi Barrachina
• Review: JD-003 Taig Mac Carthy
• Approval: JD-005 Alfonso Medela