R-TF-015-004 Clinical investigation plan LEGIT.HEALTH_DAO_Derivación_PH_2022.

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	Project to enhance Dermatology E-Consultations in Primary Care centres using Artifical Intelligence Tools.
Device under investigation	Legit.Health
Protocol version	Version 1.0
Date	2022-06-29
Protocol code	LEGIT.HEALTH_DAO_Derivación_PH_2022
Sponsor	Instituto de Investigación Sanitaria Puerta de Hierro
Coordinating Investigator	Dr. Gastón Roustan Gullón
Principal Investigator(s)	Dr. Gastón Roustan Gullón
Investigational site(s)	Pozuelo and Majadahonda Health Centers and Puerta del Hierro Majadahonda University Hospital
Ethics Committee	Comité de Ética de la Investigación con Medicamentos del Hospital Universitario Puerta del Hierro de Majadahonda

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. Gastón Roustan Gullón (Hospital Universitario Puerta del Hierro de Majadahonda).

Coordinating investigator

• Dr. Gastón Roustan Gullón (Hospital Universitario Puerta del Hierro de Majadahonda).

Collaborating Investigator(s)

• Hospital Universitario Puerta del Hierro de Majadahonda
  • Dr. Ángel Rosell Díaz
• Centro de salud de Majadahonda
  • Dr. Esther Minguela
• Centro de salud de Pozuelo
  • Dr. Fernando León

Investigational sites

• Hospital Universitario Puerta de Hierro Majadahonda
• Centro de Salud de Majadahonda
• Centro de Salud de Pozuelo

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

Skin-related conditions are a frequent cause of primary care consultations, accounting for around 5% of visits, placing a significant demand on healthcare resources. Primary care physicians (PCPs) often lack specialized knowledge in dermatology, leading to discrepancies in diagnoses compared to dermatologists, with diagnostic agreement rates ranging between 57% and 65%. This diagnostic gap and the limited availability of dermatologists, especially in rural areas, make efficient management of skin conditions by PCPs essential to improve patient outcomes and reduce healthcare costs.

Additionally, the shortage of dermatologists (only 3 per 100,000 inhabitants) complicates access to specialists, leading to potential misdiagnoses and delays in care. Teledermatology, such as the teleDERMADRID project, has helped alleviate some of this burden by enabling remote consultations and reducing unnecessary referrals. However, further innovations are needed to enhance diagnostic accuracy at the primary care level and optimize patient referral processes.

This study aims to clinically validate an artificial intelligence (AI)-based tool designed to assist primary care physicians in improving the appropriateness of dermatology referrals. By leveraging AI, the tool can enhance diagnostic accuracy, facilitate timely patient triage, and reduce unnecessary referrals, ultimately improving the efficiency of healthcare delivery and patient outcomes in dermatology.

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 significantly improves the appropriateness of dermatology referrals. This is owing to the introduction of significant changes in the diagnostic process, such as greater sensitivity and specificity than a primary care physician in diagnosing skin conditions, especially in differentiating between malignant and benign lesions. And it also provides the reassurance of a second medical opinion, which has been clinically validated.

Objectives

Primary objective

To validate that the information provided by device increases the true accuracy of healthcare professionals (HCPs) in the diagnosis of multiple dermatological conditions.

Secondary objective(s)

• Reduce and correct the referral of patients with skin pathologies from primary care to dermatology.
• Individualize and improve the ongoing training of primary care physicians in the area of dermatology.
• Offer healthcare adapted to technological innovations.
• Measure the satisfaction of primary care physicians with the Legit.Health platform.
• Measure the satisfaction of dermatologists with the Legit.Health platform.

Summary of the study

This is a prospective, observational and analytical study designed to assess if Legit.Health is a valid tool to improve the accuracy of the healthcare professionals in the diagnosis of dermatological conditions. This investigation encompases a diverse cohort of 100 patients, which are pretended to represent the studied population with various dermatological conditions. Data collection will include questionnaires (Clinical Utility Questionnaire), photograph analysis, and the analysis of demographical and clinical data. 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

We will carry out an observational and analytical study with longitudinal character so as to assess the performance of Legit.Health improving the accuracy in the diagnosis of skin conditions and in a real-world environment. On one hand, in this investigation there will be a group of 100 patients with different skin conditions. On the other hand, there will be a group of HCPs, which consists of primary care practicioners and dermatologists. In this case there will not be control group, since the physicians themselves will be assessed using Legit.Health and without using it, after that we will assess if the use of Legit.Health improves the accuracy in the diagnosis.

Population

Adult patients (>18 years) diagnosed with skin conditions that meet the inclusion criteria. These patients will be treated in their health centers (Pozuelo and Majadahonda Health Centers) and referred to the dermatology service of the Puerta del Hierro Majadahonda University Hospital.

Duration

This study estimates a recruitment period of 4 months.

The total duration of the study is estimated at 5 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. We estimate a period of 1 month for the data analysis.

The total duration of the study for each participant will be 1 day from the date of inclusion.

Acceptance criteria

• An improvement of diagnostic accuracy of 10% (Ferri et al. 2020) in primary care physicians and dermatologists.

Inclusion and exclusion criteria

Inclusion criteria

Patients suspected of having the following conditions in Primary Care:

• Tumor pathology:
  • Benign:
    • Histiocytoma
    • Seborrheic keratosis
    • Angiomas
  • Precancerous:
    • Actinic keratosis
  • Suspected malignancy:
    • Basal cell carcinoma
    • Squamous cell carcinoma
  • Pigmented lesions:
    • Melanocytic nevus
    • Malignant melanoma
• Inflammatory pathology:
  • Psoriasis
  • Atopic dermatitis
  • Urticaria
  • Hidradenitis suppurativa
  • Lichen planus
• Infectious pathology:
  • Viral warts
  • Molluscs
  • Herpes simplex
• Patients aged 18 years or older.
• Patients who have signed the informed consent for the study.

Exclusion criteria

• Patients under 18 years of age.
• Pregnant patients.
• Patients who, in the opinion of the researcher, will not comply with the study procedures.

Variables

Main variable

• The accuracy on the diagnosis of skin pathologies by primary care physicians using and without using Legit.Health to make their diagnosis.

Secondary variables

• Patient demographics: Sex and age.
• Teleconsultation data: Response time, Response label (PC follow-up, shared follow-up, dermatology follow-up, insufficient or inadequate information).
• In-person consultation data: Duration of in-person dermatology consultation to respond to the PC e-consultation, Waiting time until being seen in a monographic consultation.
• Diagnoses: Diagnostic correlation between primary care and dermatology, Number of patients referred for pathology, Diagnostic correlation between primary care, dermatology and dermatopathology (if required), Time elapsed from the day seen in primary care and the day of the anatomopathological diagnosis (if required).
• Satisfaction of primary care physicians using the Clinical Utility and Satisfaction Questionnaire.
• Satisfaction of dermatologists using the Clinical Utility and Satisfaction Questionnaire.

Condition of interest

Patients with any of the following dermatological pathologies: Histiocytoma, Seborrheic keratosis, Angiomas, Actinic keratosis, Basal cell carcinoma, Squamous cell carcinoma, Melanocytic nevus, Malignant melanoma, Psoriasis, Atopic dermatitis, Urticaria, Hidradenitis suppurativa, Lichen planus, Viral warts, Molluscs and Herpes simplex.

Limitations of clinical research

The main limitation of machine learning is the quantity and quality of the images collected. Variability in lighting, colour, shape, size and focus are key factors, as well as the number of images per patient. This means that high variability within the same patient and an insufficient number of images to reflect this variability can result in lower than expected accuracy.

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 Puerta del Hierro Majadahonda University Hospital 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 will be randomly selected to participate in this. 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 1 month. The total duration of the study is estimated at 5 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 will be just 1 day from the date of inclusion.

Monitoring plan

The Legit.Health team 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.

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

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 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.

Analyses will be performed using appropriate statistical software, SPSS version 23.0 and STATA 13.0. Values of p less 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 XX 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 ethics committee will be notified of the start of the study. Annual monitoring reports will be sent subsequently.

After obtaining the conclusions of the study, a final report will be prepared and presented 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