ICH Good Clinical Practice E6(R3)

Preface: The evolution of Good Clinical Practice

The evolution of Good Clinical Practices (GCP) established by the International Council for Harmonisation (ICH)

has marked a milestone in the development of clinical studies and ethics in research. Since the publication of

the rst version (E6(R1)) in 1996, the objective has been to promote the guarantee of protection of the rights,

safety and well-being of participants in clinical studies and to improve the reliability of the data generated in

them. GCP has been adapted to technological and scienti c changes, as well as to the social and regulatory

demands of research.

The rst revision, E6(R2), published in 2016, addressed the challenges associated with the advancement of

technology in data collection and management, such as the use of electronic systems and quality risk

management. This update was signi cant because it introduced a more dynamic approach to quality, promoting

centralised monitoring and continuous risk assessment, allowing for greater exibility in data management and

improving e ciency in audit processes. In addition, it reinforced the need for clear policies on transparency and

information security, adapting to the context of globalization of clinical studies and their execution in multiple

countries and regions.

The latest revision, E6(R3), published in 2025 represents a response to the demands of an ever-changing

research environment, driven by advanced technologies, innovative quality designs, hybrid and decentralised

clinical studies, and a patient-centred vision. This version strengthens the principles of ethics and scienti c

integrity and encourages an active participation of patients in research. It also incorporates a risk-based

approach to quality, allowing for greater adaptability in the management and monitoring of clinical trials.

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 Module 1: Introduction to good clinical practices
applied to research

Introduction
This module introduces the updated Good Clinical Practice (GCP) Course, based on the ICH GCP E6(R3)
Guideline, and the WHO Guidance for best practices for clinical trials. It highlights the importance of these
guidelines in clinical research, emphasizing their role in safeguarding participant welfare and ensuring the
reliability of generated data.

Additionally, this module outlines the key stages of the research process, aligned with international
recommendations to promote research that adheres to ethical and methodological standards.

Good Clinical Practice

Good Clinical Practice (GCP) is an internationally recognized ethical, quality and scienti c standard for the
design, conduct, and reporting of clinical studies involving human participants. Its primary objective is to ensure
the protection of participants' rights, safety, and well-being, while also guaranteeing the reliability and credibility
of study data and results.

The principles of GCP are established in key international regulatory frameworks taking as a reference the ICH
GCP E6(R3) Guideline of the International Council for Harmonisation (ICH). The GCP sets a quality and ethical
standard for conducting Clinical Trials reinforcing compliance with fundamental ethical principles, such as those
outlined in the Declaration of Helsinki

The ICH GCP E6(R3) de ne Good Clinical Practice as "an international, ethical, scienti c, and quality standard
for the conduct of trials that involve human participants. Clinical trials conducted in accordance with this
standard will help to ensure that the rights, safety, and well-being of Trial Participants are protected; that the
conduct is consistent with the principles that originate in the Declaration of Helsinki; and that the clinical trial
results are reliable"

Additionally, the World Health Organization (WHO) Guidance for Best Practices for Clinical Trials (GCT) aligns
with the principles of ICH GCP E6(R3) and complements it by providing a broader global perspective. This is
particularly relevant for research conducted in diverse regulatory environments and low-resource regions, where
adapting to local contexts is essential. The WHO GCT emphasizes inclusivity, accessibility, and the
harmonisation of ethical research practices worldwide.

Both guidelines are governed by the Declaration of Helsinki and the ethical standards established by the Council
for International Organizations of Medical Sciences (CIOMS).

Declaration of Helsinki: Developed by the World Medical Association (WMA), the Declaration of Helsinki serves
as a global ethical framework for conducting research involving human participants, ensuring that participant
welfare takes precedence over scienti c and commercial interests.

ICH GCP E6(R3) applies to interventional clinical trials of Investigational Products that are intended to be
submitted to Regulatory Authorities The Principles of GCP in this guideline may also be applicable to other
interventional clinical trials of investigational products that are not intended to support marketing authorisation
applications in accordance with local requirements.

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 Principles of Good Clinical Practice and their Re ection of the
Ethics of the Belmont Report
The Belmont Report establishes the ethical basis for research involving human subjects, providing guidelines for
treating participants with dignity, ensuring their well-being, and promoting fairness in their selection. The GCP
principles operationalise these ethical ideals into speci c standards. The ICH GCP E6(R3) and WHO GCT further
emphasises the need for all Clinical Trials to comply with universal ethical standards.

Before proceeding, let's take a moment to recall the ethical pillars of all research: respect for people,
bene cence/non-male cence, and justice.

– Respect for people

Respect the rights, autonomy and well-being of participants: The well-being of the people involved in studies
should always come before scienti c and commercial interests. This means, among other things, that thorough
risk assessments should be conducted before starting a study and participants should be constantly monitored
to detect and address any problems.

Obtain Informed Consent: Participants must be fully informed about all aspects of the study, including its risks,
bene ts, rights, and the purpose of the research. This is especially important in vulnerable populations, where
obtaining consent may require the involvement of legal representatives or Impartial Witnesses.

– Bene cence

Risks, burdens and bene ts: Research involving human participants can only be conducted if the importance of
the objective outweighs the risks and burdens to study participants

Continuous ethical and scienti c Monitoring: Clinical trials must be reviewed and approved by a Research
Ethics Board (IRB or IEC) that evaluates the design, procedures, informational materials, and informed consent .
The review must be maintained throughout the study to ensure the safety and rights of participants.

– Justice

Equity in participant recruitment seeks to ensure that study design does not unfairly exclude certain population
groups and that research is relevant to all contexts. This includes the involvement of local communities and
minority populations to ensure that the evidence generated is applicable in di erent settings.

Stages of the Clinical Research Process

In all clinical research, the application of ethical principles, guidelines and recommendations are essential at
each stage of the process, ensuring both the protection of participants and the scienti c integrity of the study.
The 4 basic and general stages of the clinical research process are brie y reviewed below.

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 Although ICH E6(R3) primarily applies to interventional Clinical Trials, its principles may be applicable to other
types of research, particularly in areas related to ethics, participant protection, and data integrity and reliability.

Planning of the Study and Ethics Approval

This initial stage involves the preparation of documents that re ect that the ethical requirements applied to
human subjects' research are ensured in the planning of the study. ICH GCP E6(R3) promotes a proactive risk-
based approach, where study planning should identify critical-to-quality factors from the start.

The studies’ documents will be rigorously evaluated by the local ethics committees and regulators for approval
of the study. The Protocol is the primary document, but other documents are also required for submission to the
ethics committee, as will be detailed in modules 4 to 7.

The protocol is the core document that de nes the study’s objective, methodology, and procedures. It must be
clear, operationally feasible, and designed to ensure both scienti c rigor and ethical integrity, aligning with Good
Clinical Practice principles to safeguard participant rights, safety, and data reliability.

All documents pertaining to a study proposal must be submitted for review and approval by a local Institutional
Review Board (IRB) when available and an Independent Ethics Committee (IEC).

Evaluation of the documents by Ethics committees and institutional review boards ensure that the study meets
standards of protection and respect for participants. As de ned in the ICH GCP E6(R3), from this point forward
in the course, the acronym IRB/IEC will be used to refer to them.

Important: A study should NOT be initiated without prior approval from the ethics committee and
Regulatory Authorities of the jurisdiction in which the research will be conducted.

Initiation of the Study (Setup)

The study setup follows a structured process that encompasses all phases, from identifying study sites to
enrolling the rst participant.

The formal start of a research is considered from the moment the Protocol receives ethical and regulatory
approval, which includes authorisation from the IRB/IEC and the competent Regulatory Authorities for each
jurisdiction where the study will be conducted. Before participant recruitment can commence, it is essential to
take practical measures to ensure that local site teams are adequately prepared to conduct the study at the
highest quality standards.

This involves study-speci c training to familiarise the team with the protocol’s requirements and their assigned
responsibilities, as well as broader preparatory steps, such as this course, which provides a foundational
understanding of the quality standards applicable to all clinical studies.

As will be detailed in Module 5: Principles applied in the initiation of the study, training should be conducted on
a regular basis to contribute to study implementation, maximising the quality and safety of clinical research.

The formal start of a clinical study is considered from the moment the protocol receives ethical and regulatory
approval, while the start of recruitment is the rst step of interaction with participants, seeking their enrolment in
the study according to the previously approved selection criteria.

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 Study conduct; recruitment data collection and Risk
Management
Conduct of the study is the stage where the research team carries out all the activities described in the Protocol,
such as recruitment of participants, data collection, safety Monitoring, and Adverse Events assessment,
ensuring adherence to the ethical principles of respect for persons, bene cence, and justice, as will be detailed
in Module 6: The principles applied in the Conduct of the Study focused on Risk Management.

An essential part of implementation is the conduction of the risk management plan. This plan includes
preventive and responsive measures to identify, assess and mitigate risks, such as adverse events and protocol
Compliance issues.

Conclusion, Closure and Post Study

This phase encompasses the nal procedures necessary to terminate a study in accordance with ethical and
scienti c guidelines.

Termination occurs when the interventions speci ed in the Protocol, the collection, consolidation, analysis of
data and interpretation of results are completed. The balance of risks and bene ts must be reassessed,
especially if new ndings about the safety or e ectiveness of the intervention emerge.

Study closure is a process involving a number of administrative and ethical activities. IRB/IEC, Regulatory
Authorities and funding organizations are noti ed of study completion, and a nal report is provided that
includes the results and any signi cant deviations from the protocol. Closure also involves archiving all essential
study documents in accordance with standardised procedures and local legislation, ensuring their accessibility
for future Audit or review.

Study completion is the end of the active phase of implementation while closure is the formal administrative
step that ensures the documented completion of the study in compliance with ethical and regulatory standards.

After formal closure, the post-study phase focuses on communicating the results to participants and the
scienti c community, following ethical principles of transparency and fairness. In addition, ethical guidelines
highlight the importance of continuity of care for participants after the closure of the Clinical Trials, which may
involve additional follow-up and the provision of free or accessible medication as part of an ethical commitment
to the health and well-being of those who have contributed to the research. These nal procedures will be
discussed in Module 7: Principles applied in the Conclusion, Closing and post-trial.

Practical Application of Good Clinical Practices in Di erent

Contexts
In some regions and countries, such as Europe and the USA, the requirements of ICH GCP E6(R3) guidelines
are embedded in their legislation. However, even though this requirement is limited to speci c studies, such as
Clinical Trials with investigational medicinal products, many other stakeholders (e.g. funding agencies, IRBs,
scienti c publishers) request that all studies are conducted according to GCP principles to ensure a similar
‘standard’.

It is important for investigators in low-and middle-income countries to clearly demonstrate that they are
adopting the principles of GCP and are therefore working to this same standard. This ensures that the
participants are protected, and the results are just as reliable as the results from research conducted in any
other GCP compliant study across the globe.

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 Summary and Key Points to Remember
Good Clinical Practice is a signi cant step towards promoting more inclusive, ethical and adaptive clinical
research, especially in resource-limited settings. By integrating fundamental ethical principles and de ning key
steps in the research process, they provide a framework to ensure that studies are conducted according to
standards of safety, ethics and scienti c rigor. This approach not only optimises the quality of research but also
reinforces the commitment to protecting the rights and well-being of participants, ensuring that clinical research
e ectively responds to the needs of diverse populations and contexts.

Key points to remember:

- Good Clinical Practices are international standards for participant protection and data integrity in clinical
research

- The ICH GCP E6(R3) emphasises a central role of the participant and justice and equity in Clinical Trial

- The WHO GCT is a global framework for conducting ethical and scienti cally sound clinical trials

- Ethical principles and good clinical practices are cross-cutting and must be adhered to at all stages of
research, from design, conduct, reporting of results and study closure

- Although Good Clinical Practice (GCP) was originally designed for interventional clinical trials, its principles
can and should be applied to non-interventional studies as well, particularly regarding ethical review (IRB/IEC
oversight), Informed Consent processes, data integrity, participant protection and Con dentiality

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 Module 2: The Principles of Good Clinical Practice

Introduction
This module provides a concise description of the 11 fundamental principles of Good Clinical Practice ICH
E6(R3), which set essential standards for ethics, quality and safety in clinical research.

The 11 principles of the ICH Good Clinical Practice E6(R3)

The principles of GCP are concerned with the safety, rights and well-being of participants and the validity and
quality of the research data.

The eleven principles of the ICH-GCP E6(R3) are set out below:

1 “Clinical Trial should be conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki and that are consistent with GCP and Applicable Regulatory Requirement(s). Clinical
trials should be designed and conducted in ways that ensure the rights, safety and well-being of participants.”

2 “Informed Consent is an integral feature of the ethical conduct of a trial. Clinical trial participation should be
voluntary and based on a consent process that ensures participants (or their Legally Acceptable
Representatives, where applicable) are well-informed.”

3 “Clinical trials should be subject to an independent review by an Institutional Review Board/Independent

Ethics Committee (IRB/IEC).”

4 “Clinical trials should be scienti cally sound for their intended purpose and based on robust and current
scienti c knowledge and approaches.”

5 “Clinical trials should be designed and conducted by quali ed individuals.”

6 “Quality should be built into the scienti c and operational design and conduct of clinical trials.”

7 “Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to
the risks to participants and to the importance of the data collected and that avoids unnecessary burden on
participants and investigators.”

8 “Clinical trials should be described in a clear, concise, scienti cally sound and operationally feasible Protocol.”

9 “Clinical trials should generate reliable results.”

10 “Roles and responsibilities in clinical trials should be clear and documented appropriately.”

11 “Investigational Products used in a clinical trial should be manufactured in accordance with applicable Good
Manufacturing Practice (GMP) standards and be managed in accordance with the product speci cations and
the trial protocol.”

Principle 1
1 “Clinical Trial should be conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki and that are consistent with GCP and applicable regulatory requirement(s). Clinical trials
should be designed and conducted in ways that ensure the rights, safety and well-being of participants.”

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 1.1 The rights, safety and well-being of the participants are the most important considerations and should
prevail over interests of science and society.

1.2 The safety of the participants should be reviewed in a timely manner as new safety information becomes
available, which could have an impact on participant safety, their willingness to continue in the trial or the
conduct of the trial.

1.3 Foreseeable risks and inconveniences should be weighed against the anticipated bene ts for the individual
participants and society. A trial should be initiated and continued only if the anticipated bene ts justify the
known and anticipated risks.

1.4 When designing a clinical trial, the scienti c goal and purpose should be carefully considered so as not to
unnecessarily exclude particular participant populations. The participant selection process should be
representative of the population groups that the investigational product is intended to bene t, once authorised,
to allow for generalising the results across the broader population. Certain trials (e.g., early phase, proof of
concept trials, bioequivalence studies) may not require such a heterogeneous population.

1.5 A quali ed physician or, when appropriate, a quali ed dentist (or other quali ed healthcare professionals in
accordance with local regulatory requirements) should have the overall responsibility for the trial-related medical
care given to and medical decisions made on behalf of participants; however, the practical interactions and the
delivery of medical care and decisions can be carried out by appropriately quali ed healthcare professionals in
accordance with applicable regulatory requirements.

1.6 The con dentiality of information that could identify participants should be protected in accordance with
applicable privacy and data protection requirements.

Comment: Principle 1 states that clinical trials should be conducted in accordance with ethical principles that
have their origin in the Declaration of Helsinki, ensuring the protection of the rights, safety and well-being of
participants. This ethical approach is not limited to clinical trials, but extends to all types of human studies,
regardless of their focus or design. Applying these universal ethical principles in human subjects' research
ensures that the integrity of participants is maintained across di erent methodologies, thus contributing to the
quality and validity of the research. This implies that both quantitative (e.g. observational, quasi-experimental)
and qualitative or mixed-method studies should adhere to these principles in order to safeguard research ethics
and foster con dence in the results obtained.

Principle 2
2 “Informed Consent is an integral feature of the ethical conduct of a trial. Clinical Trial participation should be
voluntary and based on a consent process that ensures participants (or their legally acceptable representatives,
where applicable) are well-informed following the regulatory requirements and the processes approved by the
IRB/IEC.”
2.1 Freely given informed consent should be obtained and documented from every participant prior to clinical
trial participation. For potential participants unable to provide informed consent, their legally acceptable
representatives, acting in the participants’ best interest, should provide consent prior to clinical trial
participation. These potential participants should be informed about the trial in a manner that facilitates their
understanding. In the event that a minor is a participant, assent should be collected from that minor, as
appropriate, and in accordance with local regulatory requirements (see ICH E11(R1) Clinical Investigation of
Medicinal Products in the Pediatric Population).

2.2 The process and information provided should be designed to achieve the primary objective of enabling
potential trial participants to evaluate the bene ts, risks and burden of participating in the trial and to make an
informed decision on whether or not to participate in the trial. The information provided during the informed
consent process should be clear and concise so as to be understandable by potential participants or legally
acceptable representatives.

2.3 The informed consent process should take into consideration relevant aspects of the trial, such as the
characteristics of the participants, the trial design, the anticipated bene ts and risks of the intervention(s), the
setting and context in which the trial will be conducted (e.g., trials in emergency situations), and the potential
use of technology to inform participants (or their legally acceptable representatives) and obtain informed
consent.

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 2.4 In emergency situations, where consent cannot be obtained prior to trial participation, consent should be
obtained from the participant or their legally acceptable representative as soon as possible in accordance with
applicable regulatory requirements and the processes approved by the institutional review board/independent
ethics committee (IRB/IEC).

Comment: Principle 2 states that free and informed consent is an essential component of respect for individual
autonomy. This ethical principle applies not only to clinical trials but can also be extended to all types of human
studies, regardless of their focus or design. Ensuring that all participants understand the risks, bene ts, and
nature of the study respects their autonomy and promotes an environment of trust. This ethical practice should
be a standard in biomedical research, contributing to the protection of subjects' rights and data integrity.

Principle 3
3 “Clinical Trials should be subject to an independent review by an Institutional Review Board/Independent
Ethics Committee (IRB/IEC)1.”

3.1 A trial should be conducted in Compliance with the Protocol that received prior IRB/IEC approval/favourable
opinion.

3.2 Periodic review of the trial by the IRB/IEC should also be conducted in accordance with Applicable
Regulatory Requirement.

Comment: Principle 3 states that clinical trials should be subject to independent review by IRB/IEC. This
principle, endorsed by both the Declaration of Helsinki and the Guidelines of the Council for International
Organizations of Medical Sciences (CIOMS)4, stresses the need for ethical and scienti c evaluation of studies
prior to their initiation. This review ensures that the rights and welfare of participants are protected and that the
study is adequately designed to ensure scienti c validity and social value. It is important to remark this is an
ethical requirement and apply to all type of studies involving human participants, by ensuring that all research
undergoes ethical review, researchers promote trust, transparency, and participant safety, aligning with broader
international ethical standards. It is recommended to consult local regulations to understand the speci c
requirements for the IRB/IEC review process, as these may vary by country or region.

Principle 4
4 “Clinical Trials should be scienti cally sound for their intended purpose and based on robust and current
scienti c knowledge and approaches.”

4.1 The available nonclinical and clinical information on an investigational product(s) should be adequate to
support the proposed clinical trial.

4.2 Clinical trials should be scienti cally sound and re ect the state of knowledge and experience with the
investigational product(s), including, if applicable, the condition to be treated, diagnosed or prevented; the
current understanding of the underlying biological mechanism (of both the condition and the investigational
product); and the population for which the investigational product is intended.

4.3 There should be periodic review of current scienti c knowledge and approaches to determine whether
modi cations to the trial are needed, since new or unanticipated information may arise once the trial has begun.

Comment: Principle 4 states that clinical trials should be scienti cally sound for their intended purpose and
based on robust and current scienti c knowledge. Relying on sound science and appropriate methodologies is
an ethical principle emphasised for human studies, regardless of their focus or design. Applying this principle to
human subjects' research ensures that the results are valid and reliable, which in turn protects the safety and
well-being of participants. This scienti c approach is not only crucial for the credibility of ndings but also
promotes the advancement of knowledge in the eld of health by encouraging ethical and responsible practices
in all areas of research.

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Principle 5
5 “Clinical Trials should be designed and conducted by quali ed individuals1.”

5.1 Individuals with di erent expertise and training may be needed across all phases of a clinical trial, such as
health care professionals, scientists, ethicists, technology experts, trial coordinators, monitors, auditors and
statisticians. Individuals involved in a trial should be quali ed by education, training and experience to perform
their respective task(s).

Comment: Principle 5 states that clinical trials should be designed and conducted by quali ed individuals. This
principle, endorsed by the Declaration of Helsinki and the Guidelines of the Council for International
Organizations of Medical Sciences (CIOMS)4 , stresses the importance of having competent and adequately
trained personnel who are quali ed by virtue of their training and experience to perform competently and with
integrity in the planning and conduct of research involving human subjects. This principle applies not only to
clinical trials but should be extended to all types of human studies, regardless of their focus or design. In this
way, the integrity of the research is ensured, and the safety and well-being of participants is protected,
contributing to the validity and con dence in the results obtained.

Principle 6
6 “Quality should be built into the scienti c and operational design and conduct of Clinical Trials1.”

6.1 Quality of a clinical trial is considered in this guideline as tness for purpose.

6.2 Factors critical to the quality of the trial should be identi ed prospectively. These factors are attributes of a
trial that are fundamental to the protection of participants, the reliability and interpretability of the trial results and
the decisions made based on those trial results. Quality by design involves focusing on critical to quality factors
of the trial in order to maximise the likelihood of the trial meeting its objectives.

6.3 Strategies should be implemented to avoid, detect, address and prevent recurrence of serious
noncompliance with GCP, the trial Protocol and Applicable Regulatory Requirement.

Comment: Principle 6 states that quality should be integrated into the di erent stages of clinical trials. This
recommendation extends to all types of human studies, regardless of their approach or design, ensuring
Compliance with the ethical principles set out in the Declaration of Helsinki and the guidelines of the Council for
International Organizations of Medical Sciences (CIOMS). By incorporating quality from the earliest stages of
research, the validity and reliability of the data collected is promoted, as well as the protection of participants'
well-being.

Principle 7
7 “Clinical Trial processes, measures and approaches should be implemented in a way that is proportionate to
the risks to participants and to the importance of the data collected and that avoids unnecessary burden on
participants and investigators1.”

7.1 Trial processes should be proportionate to the risks inherent in the trial and the importance of the
information collected. Risks in this context include risks to the rights, safety and well-being of trial participants
as well as risks to the reliability of the trial results.

7.2 The focus should be on the risks associated with trial participation. For clinical trials involving patients, the
focus should be on risks that go beyond those associated with usual medical care. The risks relating to
investigational products that have a marketing authorisation when used in the clinical trial context may di er
from the usual care of patients and should be taken into consideration.

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 7.3 Risks to critical to quality factors should be managed proactively and adjusted when new or unanticipated
issues arise once the trial has begun.

7.4 Trial processes should be operationally feasible and avoid unnecessary complexity, procedures and data
collection. Trial processes should support the ICH E6(R3) Guideline key trial objectives. The sponsor should not
place unnecessary burden on participants and investigators.

Comment: Principle 7 states that clinical trial processes, measures, and approaches should be implemented in a
manner that is proportionate to the risks faced by participants and the relevance of the data collected.
Unnecessary complexity or excessive data collection can increase participant risk, prolong study timelines, and
compromise the ethical integrity of the research. Ethically, this aligns with the principles of bene cence and non-
male cence, ensuring that trials are designed e ciently to minimize undue burden on participants and
researchers, and this ethical requirement apply to all type of studies involving human participants. This principle
is essential to ensure that an appropriate balance is maintained between the protection of participants and the
scienti c validity of the research. In this way, it not only protects the integrity and well-being of participants but
also contributes to con dence in the validity of the ndings.

Principle 8
8 “Clinical Trials should be described in a clear, concise, scienti cally sound and operationally feasible protocol.”

8.1 A well-designed trial Protocol is fundamental to the protection of participants and for the generation of
reliable results.

8.2 The scienti c objectives of any trial should be clear and explicitly stated in the protocol.

8.3 The clinical trial protocol as well as the plans or documents for the protocol execution (e.g., statistical
analysis plan, data management plan, Monitoring Plan) should be clear, concise and operationally feasible.

Comment: Principle 8 states that clinical trials should be described in a clear, concise and operationally feasible
protocol. This principle should be extended to all types of human studies, regardless of their design, to comply
with the ethical principles set out in the Declaration of Helsinki and the guidelines of the Council for International
Organizations of Medical Sciences (CIOMS). The clarity and operational feasibility described in the protocol are
essential to ensure that all aspects of the study are understandable and applicable, facilitating proper
implementation and Monitoring. Ensuring that protocols are accessible and understandable to all involved
promotes transparency in research and protects the welfare of participants. According to the CIOMS, the
principles of clarity, operational feasibility, and proportionality in research design apply to all types of studies
involving human participants, not just clinical trials. Ethically, this approach contributes to the integrity of the
data collected and con dence in the results, encouraging responsible research practices.

Principle 9
9 “Clinical Trials should generate reliable results1.”

9.1 The quality and amount of the information generated in a clinical trial should be su cient to provide
con dence in the trial’s results and support good decision making.

9.2 Systems and processes that aid in data capture, management and analyses, as well as those that help
ensure the quality of the information generated from the trial, should be t for purpose, should capture the data
required by the protocol and should be implemented in a way that is proportionate to the risks to participants
and the importance of acquired data.

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9.3 Computerised systems used in clinical trials should be t for purpose (e.g., through risk-based validation, if
appropriate), and factors critical to their quality should be addressed in their design or adaptation for clinical trial
purposes to ensure the integrity of relevant trial data.

9.4 Clinical trials should incorporate e cient and robust processes for managing records (including data) to help
ensure that record integrity and traceability are maintained and that personal information is protected, thereby
allowing the accurate reporting, interpretation and veri cation of the relevant clinical trial related information.

9.5 Essential records should be retained securely by sponsors and investigators for the required period in
accordance with applicable regulatory requirements. These essential records should be available to regulatory
authorities, monitors, auditors and IRBs/IECs (as appropriate) upon request to enable appropriate evaluation of
the trial conduct in order to ensure the reliability of trial results.

9.6 The transparency of clinical trials includes timely registration on publicly accessible and recognised
databases and the public posting of clinical trial results. Communicating trial results to participants should be
considered. Such communication should be objective and non-promotional.

Comment: Principle 9 states that clinical trials should generate reliable results. This principle is fundamental to
the validity of clinical trials. The ethical principles outlined in Principle 9 of ICH E6(R3) extend beyond clinical
trials and apply to all studies involving human participants. Research must generate reliable and ethically sound
results, proportionally manage risks, ensure data security, and promote transparency through public registration
and responsible reporting. Generating reliable results implies the use of rigorous and appropriate research
methods that ensure the integrity and accuracy of the data collected. By focusing on the reliability of the results,
not only is the well-being of the participants protected, but also the credibility of the research as a whole is
promoted. This ethical and scienti c approach is essential to foster con dence in the ndings and in the
application of these results in clinical practice and health policy, thus contributing to responsible and e ective
research.

Principle 10
10 “Roles and responsibilities in Clinical Trials should be clear and documented appropriately.”

10.1 The Sponsor may transfer or the Investigator may delegate their tasks, duties or functions (hereafter
referred to as activities), but they retain overall responsibility for their respective activities.

10.2 Agreements should clearly de ne the roles, activities and responsibilities for the clinical trial and be
documented appropriately. Where activities have been transferred or delegated to Service Providers service
providers, the responsibility for the conduct of the trial, including quality and integrity of the trial data, resides
with the sponsor or investigator, respectively.

10.3 The sponsor or investigator should maintain appropriate oversight of the aforementioned activities.

Comment: Principle 10 states that roles and responsibilities in clinical trials should be clear and adequately
documented. Set out in the Declaration of Helsinki and the guidelines of the CIOMS this principle applies to all
types of studies involving human participants, regardless of their focus or design, to comply with ethical
principles. Clarity in the assignment of roles and responsibilities is essential to ensure e cient and ethical
conduct of research, while keeping in mind that the responsibility for the conduct of the study and its quality
and data integrity remains with the sponsor or investigator, as appropriate. By properly documenting these
roles, confusion is minimised and accountability among researchers and sta involved is strengthened. This
approach not only protects the well-being of participants by ensuring that established protocols are followed but
also enhances the integrity and validity of the results obtained. It is recommended to consult local regulations to
understand the speci c additional responsibilities and requirements, as these may vary by country or region.

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 Principle 11
11 “Investigational Products used in a Clinical Trial should be manufactured in accordance with applicable Good
Manufacturing Practice (GMP) standards and be managed in accordance with the product speci cations and
the trial Protocol1.”

11.1 Investigational products used in a clinical trial should be manufactured in accordance with applicable GMP
standards.

11.2 Measures should be in place to ensure that the investigational product provided to Trial Participants retains
its quality.

11.3 Investigational products should be used in accordance with the protocol and relevant trial documents.

11.4 Manufacturing, handling and labelling of investigational products should be undertaken in a manner that
aligns with treatment assignment and maintains Blinding, where applicable.

11.5 Investigational product labelling should follow Applicable Regulatory Requirement.

11.6 Appropriate processes should be implemented for the handling, shipping, storage, dispensing, returning
and destroying or alternatively disposing of the investigational product.

Comment: Principle 11 states that investigational products used in a clinical trial should be manufactured in
accordance with applicable Good Manufacturing Practice (GMP) standards, and should be stored, shipped,
handled, and disposed of in accordance with product speci cations and the trial protocol. This principle is
fundamental not only for clinical trials on pharmacological products but should be extended to all types of
health technologies evaluated (i.e. devices or other products). Ensuring that investigational products are handled
according to quality and safety standards is essential to protect the health and well-being of participants as well
as to guarantee the integrity of the data collected.

The GCP Principles as a Framework for Research Integrity

The eleven fundamental principles of GCP provide a clear and structured framework for guiding Clinical Trials
towards integrity and ethics. Each principle plays a critical role in creating an environment of trust, not only
between researchers and participants, but also with the scienti c community and society at large. By adhering
to these principles, researchers not only comply with regulations, but also demonstrate a genuine commitment
to scienti c excellence and social justice.

As mentioned before, most principles of ICH E6(R3) are closely aligned with internationally recognized ethical
guidelines for human research, such as the CIOMS Ethical Guidelines and the Declaration of Helsinki. These
frameworks establish core requirements for scienti c validity, risk minimization, data integrity, and participant
protection, which apply to various types of research beyond clinical trials. Since these principles re ect
fundamental ethical and methodological standards, they can be e ectively applied to di erent research designs,
ensuring that studies maintain high ethical and scienti c standards regardless of intervention type.

The next few modules will explore in detail how each of these principles is applied in practice and their
importance in promoting ethical and comprehensive clinical research.

Summary and key points to remember

The principles of Good Clinical Practice guide ethical and regulatory compliance, strengthen the trustworthiness
and value of research. By applying them, they promote respect and transparency in the research process, which
is essential for high-quality results that improve the health and well-being of individuals and communities. The
following few modules will discuss how these principles are applied at each stage of the research process.

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 Key points to remember:

- Each GCP principle underscores the importance of protecting the rights, safety and well-being of participants.
The principles are aligned with international ethical standards set out in the Declaration of Helsinki

- Voluntary and well-informed consent ensures respect for participants' autonomy. All studies, regardless of
design, must ensure that participants understand the aims, risks and bene ts to make free and informed
decisions

- Review by an IRB/IEC protects the safety of participants and validates the scienti c value of studies, providing
an external check to ensure compliance with ethical standards

- The scienti c soundness and quality of studies is essential for reliable and applicable results

- Researchers must be adequately trained and experienced and carry out their responsibilities in an ethical and
professional manner

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 Module 3: Key Stakeholders in Clinical Research:
Roles and Skills for the Application of Good Clinical
Practice Principles

Introduction

DESCRIPTION

This module introduces the fundamental roles and responsibilities of key stakeholders in the context of clinical
research, with a particular focus on the skills and competencies needed to e ectively apply the principles set
out in Good Clinical Practice ICH E6(R3) Annex 1 and World Health Organization Guidance for Best Practices
for Clinical Trials (WHO GCT)

Key stakeholders in the research process

The research process is inherently collaborative and multifaceted, involving a variety of stakeholders who play
critical roles in each phase of the study.

In this module, the roles and responsibilities of four key stakeholders in the research process will be discussed:
(IRB/IEC), Investigator, Sponsor, and Data Governance, based on ICH GCP E6(R3)1 and WHO GCT2 , with an
emphasis on the context of Clinical Trials.

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 Institutional Review Board (IRB)/Independent Ethics Committee
(IEC)
“An independent body (a review board or a committee, institutional, regional, national or supranational)
constituted of health professionals and non-medical members whose responsibility is to ensure the protection of
the rights, safety and well-being of human participants involved in a trial and to provide public assurance of that
protection by, among other things, reviewing and approving/providing favourable opinion on the trial Protocol,
the suitability of the Investigator(s), the facilities, and the methods and material to be used in obtaining and
documenting Informed Consent of the Trial Participants1.”

The legal status, composition, function, operations and regulatory requirements pertaining to IRBs/IECs may
di er among countries but should allow the IRB/IEC to act in agreement with GCP.”

Important: The requirements for IRB/IEC in GCP should be read in conjunction with local regulatory
requirements.

Role of IRB/IEC
IRBs/IECs play a key role in reviewing, Monitoring and supervising human studies to ensure that they are
conducted ethically and in accordance with international principles for the protection of participants. Their work
is guided by national and international regulations, including the Declaration of Helsinki , the Ethical Guidelines
of the Council for International Organizations of Medical Sciences (CIOMS) , and WHO recommendations.

ICH E6(R3) recommends that the IRB/IEC should consist of at least ve members with experience in science,
medicine and ethics. It should include one member with experience outside the medical eld and one member
independent of the Institution/Investigator. It should operate under documented procedures, the GCP, such as
making decisions in announced meetings with a minimum quorum, allowing the investigator or Sponsor to
provide information, but without participating in the review and approval decision of the study, and may invite
non-member experts for advice in specialized areas. It should be noted that WHO GCT indicates that IRBs/IECs
should operate in accordance with the laws and regulations of each country, ensuring that the review of the
studies complies with local requirements.

General responsibilities of IRB/IEC

1. Protect study participants: Safeguard the rights, safety, and well-being of all study participants, with special
attention to the inclusion of vulnerable populations

2. Ethical and Scienti c Review

- Conduct ethical and scienti c evaluation of the study Protocol and approve key documents before the start
of research
- Ensure the safety, rights and well-being of Trial Participants
- Give appropriate consideration to trials with Vulnerable Participants
3. Presentation, Communication with Regulatory Authorities
- Responsibility for submission may lie with the researcher/Institution or the Sponsor, depending on local
regulations
- In some regions, submission to the IRB/IEC may be combined with submission to the regulatory authority
4. Guarantee of rigorous review

- Evaluate key information, including:

- Protocol and amendments

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 - Informed Consent and Assent material
- Researcher's Brochure or Product Information
- Recruitment documentation (advertising, processes)
- Compensation plans for participants
- Security updates
- Researcher's CV and quali cations
- Any other document requested based on local regulations necessary for review
- Review Clinical Trials within a reasonable time frame and document the results
- Record dates of approval, modi cations, rejection or suspension
- Periodically evaluate studies based on risk to participants
- Request additional information to improve the protection of participants
- Evaluate whether a protocol justi es the lack of prior consent in emergency cases
- Ensure that studies with under aged participants take into account their maturity and psychological state
- Approve proportional eventual payments not conditioned on completing the study
- Review payment information in informed consent
5. Evaluate information on the consent process:
- Ensure that the informed consent process is clear and transparent
- Con rm that participants receive all relevant information about the study, risks and bene ts
- Evaluate compensation to participants to avoid coercion or undue in uence
- Evaluate protocols that include minors, people with limited cognitive abilities or populations in vulnerable
conditions
- Ensure that assent and legal consent procedures are appropriate to the age and capacity of the participant
6. Standardization of operating procedures

- Document composition, quali cations, and authority

- Schedule meetings and notify members

- Conduct initial and ongoing reviews of clinical trials

- Establish the frequency of reviews based on the risk of the study

- Apply expedited reviews for minor changes to ongoing studies

- Do not allow registration of participants without documented approval

- Do not allow changes to the protocol without prior approval, except to eliminate immediate hazard

- The researcher/institution must immediately inform:

- Deviations from protocol to eliminate urgent risks.

- Changes that increase the risk to participants.

- Suspected Unexpected Serious Adverse Reactions (SUSARs).

- New information that may a ect the safety of participants and the study.

- Inform in writing (paper or electronic) to researchers or sponsors about:

- IRB/IEC opinions and decisions.

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 - Reasons for approval, rejection or request for modi cations.

- Procedures for appealing decisions.

7. Records Management

- Keep records such as:

- Procedures performed.

- List of members and quali cations.

- Reviewed documents and decisions.

- Results of continuous Monitoring of studies including periodic assessments of the risk-bene t balance, review
of adverse e ects and safety measures, veri cation of Compliance with the protocol and regulations.

- Minutes of meetings and correspondence.

- Make records accessible to regulatory authorities upon request.

- Make your procedure manuals and membership lists accessible to researchers, sponsors or authorities.

8. Adapt your processes for rapid reviews of clinical trials in the context of emergencies or health crises :

- Implement rapid review processes, ensuring and maintaining the rigor of assessments

- Coordinate with other entities and/or regulatory agencies to optimize deadlines and avoid unnecessary delays
in emergencies.

- Please nd the responsibilities of IRBs/IECs, in detail, in Annex I, section 1 of the ICH GCP E6(R3) guideline.

Important: IRBs/IECs not only review documentation for approval of studies, but also provide ongoing oversight
to ensure that the studies are conducted in an ethical manner. They operate within the legal framework of each
jurisdiction, ensuring that their ethical assessment complies with local, national, and international regulations. In
the event of unforeseen risks to participants, the IRB/IEC has the authority to request modi cations or suspend
the research to protect the safety of participants

Example of the role of the IRB/IEC

A multicentre, phase III Clinical Trial has been approved and is being conducted to evaluate the e cacy and
safety of a new antibiotic (intervention) for the treatment of severe lung infections caused by a bacteria resistant
to multiple antibiotics in people who have not responded to standard treatments (control).

After four months of study, the Ethics Committee (IRB/IEC) reviewed a periodic safety report sent by the
principal Investigator, where serious adverse e ects were reported in the intervention group: 12% of participants
presented severe hepatotoxicity (signi cant liver damage) and 8% unexpected cardiac arrhythmias. These
e ects had not been observed in preclinical studies or in previous phases of the trial.

Based on these ndings, the IRB/IEC conducted a review of the study and took the following actions:

- Stop the inclusion of new participants until the risks are thoroughly analyzed.

- Ask researchers to stop treatment with the experimental drug in participants who experienced serious adverse
e ects.

- Request immediate analysis of safety data to determine whether the events are directly related to the drug.

Based on the safety assessment, a modi cation is made to the Protocol, where the antibiotic dose is reduced
by 30% to assess whether liver toxicity decreases without compromising e cacy. Mandatory cardiac
Monitoring is implemented in all participants to detect possible arrhythmias before they become a serious risk.
Exclusion criteria are modi ed to avoid including patients with pre-existing liver disease.

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 Informed Consent is also updated to include information on the new risks identi ed. All documents are
submitted as amendments for further IRB/IEC review.

The IRB/IEC requires all participants to sign a new consent form after being informed of the observed Adverse
Events and allows the trial to continue after the amendment is approved, under more stringent monitoring. After
two months, the new safety report shows a signi cant reduction in cases of liver toxicity and arrhythmias,
con rming that the dose modi cation was e ective in improving the safety of the drug.

Investigator
ICH E6(R3) de nes the Investigator as:

“A person responsible for the conduct of the Clinical Trial, including the Trial Participants for whom that person
has responsibility during the conduct of the trial. If a trial is conducted by a team of individuals, the investigator
is the responsible leader of the team and may be called the principal investigator."

- Where an investigator/Institution is referenced in this guideline, it describes expectations that may be

applicable to the investigator and/or the institution in some regions4.

- Where required by the Applicable Regulatory Requirements, the “investigator” should be read as “investigator
and/or the institution1.”

The WHO de nes the investigator as:

“The person who leads and manages the clinical study, being responsible for its design, implementation,
supervision and Compliance with established ethical and scienti c principles."

The US Food and Drug Administration (FDA) de nes the investigator as:

"The person responsible for the conduct of the clinical trial at a speci c site. If the study involves a team of
investigators, one of them should be designated as the Principal Investigator (PI) and assume overall
responsibility ."

The European Medicines Agency (EMA) does not provide a speci c de nition of "investigator" in its public
guidelines. However, in the context of clinical trials it adopts and applies the international GCP ICH E6(R3)
standards in the assessment and supervision of clinical trials in the European Union.

Roles of an Investigator
Lead and manage the study, being responsible for its design, implementation, supervision and Compliance with
established ethical and scienti c principles. The researcher is primarily responsible for the planning and conduct
of the study, ensuring compliance with the Protocol, the safety of participants and the integrity of the data.

General responsibilities of an Investigator

1. Quali cations and Training

- Must be quali ed by education, training and experience to assume responsibility for the trial.

- Provide evidence of quali cations.

2. Available Resources

- Demonstrate the potential to recruit eligible participants within the agreed timeframe.

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 - Ensure su cient time, quali ed personnel and adequate facilities for the safe conduct of the trial.

3. Responsibilities and Delegation

- May delegate activities but retain ultimate responsibility and oversight of delegates. This will depend on the
importance of the data and the risks to participants.

- Ensure that delegates are trained in the Protocol and the Investigational Product.

- Maintain a documented record of delegated activities.

- Document agreements with Service Providers involved in the study.

- Allow audits and Monitoring by the Sponsor and Regulatory Authorities.

4. Communication with the Ethics Committee (IRB/IEC)

- Obtain documented approval before starting the study.

- Inform the IRB/IEC of relevant modi cations or new ndings.

- Submit study progress reports as required.

5. Compliance with the Protocol

- Sign the Protocol and/or alternative contract with the Sponsor.

- Record and explain signi cant deviations from Protocol.

- Implement measures to prevent recurrences.

- Modify the Protocol only in case of immediate danger to participants and report it to the Sponsor and IRB/IEC.

6. Premature Termination or Suspension

- Notify participants and provide appropriate medical follow-up.

- Inform the Sponsor, IRB/IEC and Regulatory Authorities with a detailed explanation.

7. Medical Care and Safety Reporting

- Ensure that a quali ed physician is in charge of the medical care of participants.

- Ensure adequate medical care for study-related Adverse Events.

- Immediately report Serious Adverse Events (SAEs) to the Sponsor with an assessment of causality.

- If required, provide additional reports, such as autopsies in the event of death.

8. Obtaining Informed Consent

- Comply with GCP and applicable regulations.

- Use clear and concise language, including images or videos if necessary.

- Obtain IRB/IEC approval before using consent forms.

- Allow electronic methods of consent where appropriate and approved by IRB/IEC.

- Explain the purpose of the study, procedures, risks, bene ts, alternatives, Con dentiality and voluntariness.

- Obtain consent from the legal representative when applicable and approved by IRB/IEC and inform the
participant and obtain their consent if feasible.

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 - Allow participants to withdraw without penalty and ensure proper handling of their data.

9. Completion of Participation in the Study

- Document the reason for withdrawal when possible, respecting the participant's decision.

- Evaluate whether there are ways to minimise withdrawal without unduly in uencing the participant.

- Inform participants about the results of the study and the treatment received if they request it.

10. Management of the Product in Investigation

- Correctly manage, store, record and dispose of the Investigational Product.

- May delegate management of the Investigational Product to a pharmacist or other quali ed personnel.

- Maintain detailed records of product batches, quantities and distribution.

- Ensure it is stored and used according to the Sponsor's speci cations.

11. Randomisation and Unblinding Procedures

- Follow Randomisation procedures according to Protocol.

- Ensure that the treatment code can be broken in emergency situations.

- Document any premature unmasking.

12. Records and Data Management

- Ensure that data is accurate, complete and well documented.

- Review data in a timely manner and ensure that it is consistent with the Source Records.

- Any corrections must be traceable without altering the original record.

- Implement data privacy and security measures in accordance with applicable regulations.

- Control and monitor access to electronic systems used in the study.

- Retain records as required by regulatory requirements and until authorized by the Sponsor.

13. Final Reports and Communications

- Inform the Institution and the IRB/IEC about the results of the study.

- Submit required reports to Regulatory Authorities.

- Facilitate access to records for audits, Monitoring or regulatory inspections.

IMPORTANT: The Investigator must ensure the safety, rights and well-being of participants in research involving
human subjects. To do so, he or she must ensure that the study is conducted in accordance with the approved
Protocol, complying with regulatory standards and ethical principles. In addition, it is his or her duty to directly
supervise the research team, ensuring that all delegated activities are carried out by quali ed personnel. He or
she must also maintain accurate and complete records, reporting any Adverse Events or deviations from the
Protocol to the Sponsor, IRB/IEC and Regulatory Authorities, when appropriate. Ful lling these responsibilities is
key to the scienti c validity of the study, the integrity of the data and the protection of research subjects.

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 Example of the role of an Investigator
A phase III Clinical Trials is being conducted to evaluate the e cacy and safety of a new antibiotic for treating
complicated urinary tract infections in hospitalized patients. The experimental group receives the new antibiotic
intravenously for 7 days. The control group receives the standard of care (usual care with conventional
antibiotics) to compare the cure rate and Adverse Event in both groups. The study follows the principles of
Good Clinical Practice (GCP) and has been approved by the IRB/IEC. One patient in the experimental group
develops severe acute kidney failure after 5 days of treatment with the new antibiotic. His medical history shows
that he had no history of kidney disease prior to the study.

In previous studies, no serious kidney problems have been reported with the new antibiotic, and no similar
events have occurred in the usual care group.

Faced with such an adverse event, the researcher immediately suspends the administration of the new
antibiotic, refers the patient for evaluation and treatment, and records all symptoms and examinations in the
patient's medical history.

Within the rst 24 hours, the Investigator has sent a report to the Sponsor about the Serious Adverse Event
(SAE), reported the details of the case to the IRB/IEC, and completed the Serious Adverse Event (SAE) reporting
form. The investigator follows up on the event and reports the results of the renal studies.

Based on the results of the report, the sponsor and the IRB/IEC may make decisions such as: continuing with
the study without changes, modifying the protocol to include mandatory renal monitoring, updating the Informed
Consent to warn participants about the renal risk, temporarily suspending the recruitment of new participants
while the event is investigated.

Sponsor
An individual, company, Institution or organization that takes responsibility for the initiation, management and
arrangement of the nancing of a Clinical Trials. A clinical trial may have one or several sponsors where
permitted under regulatory requirements. All sponsors have the responsibilities set out in this guideline. In
accordance with Applicable Regulatory Requirements, sponsors may decide in a documented Agreement
setting out their respective responsibilities. Where the documented agreement does not specify to which
sponsor a given responsibility is attributed, that responsibility lies with all Sponsor.”

Roles of a Sponsor
The Sponsor leads the planning, nancing and supervision of the study, ensuring Compliance with the Protocol,
safety of participants and data integrity, through the selection and Monitoring of clinical sites, risk management,
pharmacovigilance (when applicable) and regulatory compliance.

General Responsibilities of a Sponsor

1. Proportional approach to risk

- Implement risk-proportionate approaches to ensure the safety, rights and well-being of participants and the
reliability of results throughout the study cycle.

2. Trial Design

- Ensuring quality in study design

- Securing data to analyse safety and e cacy

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 - Ensure that su cient data exist on the Investigational Products before exposing it to human studies.

- Identify and mitigate risks in critical quality factors.

- Include perspectives from healthcare professionals and patients in Protocol development and participant
information.

- Ensure the operational viability of the study.

- Avoid complex procedures and unnecessary burden on participants and researchers.

3. Availability of Resources and Assignment of Activities

- Ensure the availability of su cient resources for the execution of the trial.

- Assign study activities or tasks in a structured way before they begin.

- Employ quali ed personnel in speci c functions (biostatisticians, pharmacologists, physicians, data managers,
etc.).

- Rely on medical experts to resolve medical issues related to the study.

4. Financing and Agreements

- Document nancial aspects in an Agreement with the researcher/Institution.

- Formalize agreements with researchers, Service Providers and other stakeholders before starting the study.

- Ensure Compliance with protocol and regulations by all parties involved.

- Maintain oversight and ultimate responsibility for outsourced activities.

5. Selection of Researchers and Communication with Authorities

- Select quali ed researchers/institutions with adequate resources.

- Ensure that researchers receive the necessary protocol and information.

- Notify Regulatory Authorities and ethics committees about study approval and reviews.

6. Study Supervision

- Ensure that the study and data generation are of su cient quality to guarantee reliable results.

- De ne criteria for signi cant deviations from protocol and manage the resulting risks.

- Implement Monitoring and control measures proportional to the risks and complexity of the study.

- Escalate and manage issues appropriately and in a timely manner.

- Consider establishing an Independent Data Monitoring Committee (IMDC) to assess safety and e cacy at
speci c intervals.

7. Quality and Risk Management

- Implement a risk-based quality system to protect participants and ensure the reliability of results.

- Identify risks before and during the study.

- Assess the likelihood of impact on data security and reliability.

- Implement measures to minimize signi cant risks (risk mitigation plan).

- Document and communicate identi ed risks.

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 - Periodically review Quality Controls and make adjustments as necessary.

- Report quality issues and corrective actions taken in the nal trial report.

8. Quality Assurance and Control

- Implement audits proportional to the risks of the study to assess compliance with the protocol and regulations.

- Ensure ongoing monitoring to protect participants and validate data quality.

- Establish Monitoring Plans tailored to trial risks.

9. Regulatory Compliance and Non-Compliance Management

- Identify and correct non-compliances with corrective and preventive actions.

- Notify authorities in case of serious breaches a ecting the security or reliability of data.

- Consider terminating a researcher's or vendor's participation in cases of persistent noncompliance.

10. Safety Assessment and Reporting

- Continually evaluate the safety of the investigational product.

- Analyze and report serious and Suspected Unexpected Serious Adverse Reactions (SUSARs) to regulatory
authorities.

- Take immediate action in the event of unexpected risks to participants.

11. Insurance, Indemnity and Compensation

- Provide insurance or legal and nancial coverage in case of claims arising from the trial.

- Establish compensation policies for participants in the event of study-related injuries.

12. Management of the Product in Investigation

- Keep the Researcher's Brochure updated with relevant information.

- Ensure compliance with good manufacturing practices (GMP) and proper labeling.

- Ensure product availability and proper handling at research sites.

13. Data and Records Management

- Ensure the Con dentiality and quality of the data generated in the study.

- Apply quality control at all stages of data management.

- Specify data capture and storage in the protocol and related documents.

- Allow justi ed and documented corrections to data.

- Protect data from unauthorized access and alteration.

- Ensure data retention and access according to regulatory requirements.

- Ensure traceability and quality of statistical analysis.

14. Reports and Final Documentation

- Notify investigators and authorities in case of trial suspension.

- Prepare and submit trial reports as per regulatory requirements.

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 - Make public the results of the trial in accordance with applicable regulations.

Find the sponsor's responsibilities in detail in Annex 1, Section 3 of ICH E6(R3).

Important: In the context of Clinical Trials, the sponsor must ensure that the study is registered on publicly
accessible platforms, such as The WHO's International Clinical Trials Registry Platform (ICTRP) or the US
National Library of Medicine's clinical trails platform.

Example of the role of a Sponsor

A Sponsor is conducting a Phase III Clinical Trial to evaluate a new drug for hypertension. During Monitoring, it
has identi ed that one of the sites where the research is being conducted is presenting inconsistencies in the
clinical data such as: errors in the documentation of participants' blood pressure, lack of recorded data on
administration of the investigational drug, delay in reporting minor Adverse Events.

- To ensure that the study is conducted within Good Clinical Practice, the Sponsor performs the following
actions: Review Monitoring Reports and verify the magnitude of the problem. Determine whether the situation
represents a risk to participants.

- Implement corrective actions: retrain site sta on study Protocol and GCP. Increase Monitoring frequency as
site exclusion from the study would be considered if the problem persists.

- Reports the incidents to Regulatory Authorities and the IRB/IEC, including corrective actions implemented and
ensuring that a ected data are identi ed and corrected.

Analyze whether errors a ect the validity of the trial, consider an impact analysis on the results to take further
action if the data are not reliable.

Data Governance
Data Governance “provides guidance to the responsible parties (ie, investigators and sponsors) on appropriate
management of data integrity, traceability and security, thereby allowing the accurate reporting, veri cation and
interpretation of the Clinical Trial-related information.”

Attention: This topic should be read in conjunction with corresponding responsibilities for the Investigator and
the Sponsor.

Role of Data Governance

Ensure that the quality and quantity of the information generated in a Clinical Trial are su cient to address the
study objectives, provide con dence in the trial results, and support appropriate decision-making.

General Responsibilities of Data Governance

1. Management of Data Integrity, Traceability and Security

- Ensure accuracy in the collection, veri cation and interpretation of information.

- Implement systems and processes proportional to the risks and reliability of the results.

2. Management of Key Processes in the Data Life Cycle

- Protect and ensure the Con dentiality of participants' data.

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 - Manage computerized systems ensuring their suitability and correct use.

- Safeguard critical elements of the study (randomization, dose adjustments, Blinding).

- Assist in key decision making such as data nalization, unblinding, assignment of data for analysis, and
changes to study design.

3. Protecting Masking in Data Governance

- Design systems that protect the integrity of blinding.

- De ne and document roles and access to unmasked information.

- Implement mitigation strategies to prevent inadvertent disclosures.

- Assess the impact of any disclosure of unblinded data.

4. Elements of the Data Life Cycle

- De ne data veri cation processes according to their criticality.

- Incorporate relevant Metadata into data capture.

- Implement automated validations to improve data quality.

- Evaluate and document access logs, permission changes, and data modi cations.

- Maintain auditability of any changes in data and their reasons/justi cations.

- Ensure the integrity and accessibility of metadata during the study.

- Implement risk-based planned reviews.

- Correct errors by attributing changes to responsible people or systems.

- Record and justify any corrections.

- Ensure integrity and con dentiality in the transfer of data between systems.

- Document traceability and reconciliation of transferred data.

- De ne quality criteria for interim and nal analysis.

- Con rm and document data closure activities, such as medical coding and resolution of Protocol deviations.

- Archive data and metadata in an accessible and protected manner.

- Implement secure disposal procedures when no longer required by regulations.

5. Use and Security of Computerised Systems

- Document their proper use in data collection and management.

- Ensure that sta are trained in the use of the systems.

- Implement security controls to prevent unauthorized access.

- Include user authentication, rewalls, antivirus and anti-intrusion measures.

- Maintain backups and disaster recovery plans.

- Validate systems based on impact on participants and study outcomes.

- Document validation tests and controls, including changes and updates.

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 - Only activate study-speci c systems after receiving regulatory approvals.

- De ne contingency strategies for failures that may a ect the safety of participants or the results.

- Establish technical support mechanisms (help desk) to report and resolve problems.

- Manage user access based on speci c studio roles and needs

- Document and periodically review access permissions and assigned roles.

Examples of other roles in the application of good clinical

practice principles
Beyond the traditional key roles played by the IRB, Investigators and Sponsors, Patients and their communities
are fundamental pieces of the research process. The new GCP guideline stresses the importance of including
these groups at various stages of the study, from design to implementation and evaluation, as their participation
enriches the research approach and ensures that it responds to the real needs and speci c priorities from the
perspective of the research subject.

Trial Participant

“An individual who participates in a clinical trial, either as a recipient of the intervention or the investigational
product(s) or as a control.”

Study Participant

“Individuals involved in studies aimed at obtaining generalisable scienti c knowledge.”

Often, in human subjects' research, the terms participant, volunteer, or study subject are applied as synonyms
to refer to any individual who participates in a research study, whether experimental or observational.

There are also roles and responsibilities assigned to other individuals and teams whose work is critical to the
successful conduct of research, such as sub or co-investigator, scienti c committee, Service Providers, among
others. The way they are referred to may vary according to local regulations.

Collaboration and communication among all stakeholders are essential for the success of clinical research. Each
stakeholder plays a vital role in the process, contributing to the ethics, safety and scienti c validity of clinical
trials.

Essential Skills for Compliance with Good Clinical Practice

Each stakeholder involved in the clinical research process requires a unique set of skills to perform their role
e ectively. Continuing education and professional development in these areas is essential to maintain high
ethical and scienti c standards in research, thus ensuring the protection of participants and the validity of the
results.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) as a whole must possess a
thorough knowledge and understanding of ethical principles and regulations in clinical research, as well as the
needs of participants. It must have the ability to analyze research protocols and Informed Consent documents
with a critical and objective approach. The IRB/IEC must also have the ability to integrate diverse perspectives
in the ethical evaluation, including having members from di erent disciplines, and the skills to communicate
their decisions and recommendations clearly and concisely to investigators and other stakeholders.

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 The (Principal) Investigator must possess a sound understanding of research methodology, including study
design, statistics and data analysis. The Investigator must also possess knowledge of relevant ethical rules and
regulations. This role requires ability to lead and coordinate the research team, ability to communicate e ectively
with participants, with the research team and other stakeholders, and ability to identify and address problems
that may arise during the study, including ethical and safety issues.

The Sponsor must possess knowledge of relevant ethical rules and regulations, the ability to manage budgets
and secure adequate funding for the study, the ability to plan, implement and supervise research projects,
ensuring that timelines and quality standards are met. Finally, the Sponsor must possess a commitment to
ethical practices in research, including the protection of participants' rights.

For Data Governance, Sponsor and Investigator as the responsible parties, must be able to analyze and
manage clinical data, including the ability to validate data, identify inconsistencies and ensure data integrity
throughout the research process. They must be familiar /knowledgeable with data management tools and
technologies, including statistical analysis software and databases. They must also have the ability to
communicate clearly and e ectively with other members of the research team, the ability to make decisions
based on data analysis and applicable regulations, ensuring that ethics and scienti c validity are always
prioritized, and the ability to identify, assess and mitigate risks associated with data management, ensuring that
the necessary information protection measures are implemented.

Summary and key points to remember

The Institutional Review Board/Independent Ethics Committee (IRB/IEC), investigators, sponsors and Data
Governance are key stakeholders in research. However, it is essential to recognize that the active involvement of
participants and communities is equally necessary for the success of a Clinical Trial, or any other study with
human subjects. Their voice and experience not only enrich the research design but also ensure that it is
relevant and responsive to real needs. In addition, the operationalization and execution of a study requires the
collaboration of other critical roles, such as Sub-Investigators, scienti c advisory and Data Safety and
Monitoring Boards, Service Provider, and other professionals who bring their expertise in various areas. All these
actors should work together as pieces of a puzzle to ensure that the principles of ethics, integrity and
transparency are upheld, as set out in the GCP principles, which emphasize the importance of participant well-
being and the validity of the data. The inclusion of diverse perspectives at every stage of the research process
not only strengthens con dence in the results but also contributes to building a culture of shared responsibility
that is essential for clinical research.

Key points to remember:

- Key stakeholders in clinical research, such as the IRB/IEC, investigators, sponsors and data governance
o cers, play crucial and complementary roles that are vital to the success of the study

- Each stakeholder requires a unique set of skills including knowledge of ethical regulations, data analysis
skills, management skills and e ective communication, ensuring a collaborative approach

- Protecting the rights and welfare of participants is a central priority that must be respected and promoted by
everyone involved in the research process

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 Module 4: Principles applied in the Planning and
Design of the Study

Introduction

This module explores how the 11 principles of Good Clinical Practice, set out in the ICH GCP E6(R3) guideline,
re ect and apply in practice the fundamental ethical principles of the Belmont Report: Respect for Persons,
Bene cence and Justice, especially at the planning and design stage of a study.

The critical elements in clinical trial planning

In module 1, it has been mentioned that GCP guides the application of the principles of research ethics:

- Respect for Persons: autonomy and Informed Consent

- Bene cence: obligation to maximise bene ts and minimise risks

- Justice: fairness in the selection of participants

This module will examine how the principles of Good Clinical Practice (GCP) in uence decisions made during
the planning phase of a study. This includes the preparation of documents that must demonstrate adherence to
the fundamental ethical principles guiding research involving human participants.

When planning a new study, both the actors involved and the documents developed are critical elements. The
Investigator and the Sponsor not only organise the methodological design and the required resources, but they
also make concrete ethical decisions that impact on the conduct of the study and consequently on the future
participants. The principles of good clinical practices are relevant at this stage, although it is worth noting that,
particularly in the ICH GCP E6(R3), the importance of risk-based approach, a strong data governance and
involving patients and other stakeholders from the study design stage are emphasised. In addition, the
collaboration of a scienti c committee, as a Service Provider, may be necessary to ensure that planning includes
all elements and documents required for submission to and review by the IRB/IEC of the jurisdiction where the
study will be conducted.

The IRB/IEC in its intent to safeguard the rights, safety, and well-being of all participants, and in the exercise of
its functions and responsibilities, should review the information regarding the proposed study through the
analysis of the following documents, based on ICH GCP E6(R3) in the context of Clinical Trials:

(a) Protocol and amendments;

(b) Informed consent material(s), Assent material(s), where applicable, and any updates, including the
description of the process for how informed consent and assent is to be obtained;

(c) Investigator's Brochure or current scienti c information, such as a basic product information brochure (e.g.,
Summary of Product Characteristics (SmPC), package lea et or labelling), as appropriate, including their
updates;

(d) Other trial-related information to be provided to the Trial Participant(s), including a description of the media
through which such information will be provided;

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 (e) Advertisement for participant recruitment (if used) and information on the recruitment process;

(f) Plans to compensate participants (if any);

(g) Ongoing updates to safety information;

(h) Investigator’s current curriculum vitae and/or other documentation evidencing quali cations;

(i) Any other documents that the IRB/IEC may need to ful l its responsibilities.

In addition to what is recommended by the GCP guidelines, the investigator and sponsor must strictly adhere to
the legal and regulatory framework in place in each jurisdiction where the study will be conducted. This means
complying with local laws on informed consent, data protection and privacy, and speci c regulations for
Monitoring and reporting Adverse Events.

In single-centre studies, ethics review is performed by the site-speci c IRB/IEC, which evaluates all ethical,
regulatory, and participant protection issues in accordance with local legislation for regulatory Compliance in a
single jurisdictional setting. In contrast, in multi-centre or multi-country studies, each research site must receive
local ethics approval or, in certain cases, endorse a centralised IRB/IEC, provided this is permitted by the
regulations of the participating countries. Ethics review in multi-centre or multi-country studies requires each
IRB/IEC to consider not only the international aspects of the study, but also the cultural, legal and ethical
particularities of their jurisdiction, including local regulations on informed consent, privacy and data security,
equitable selection of participants, and avoidance of any form of discrimination.

Complying with local regulations ensures not only the ethics of a study, but also its validity and legality in each
country where there is a participating site.

Both single-centre and multi-centre clinical studies can be designed as decentralised studies, i.e. using
methods and technologies that facilitate patients' participation from their homes or local communities, rather
than requiring their physical attendance at a research centre, such as a hospital or health centre. In a
decentralised single-centre study, all activities can be managed at a single site, using digital tools for data
collection, monitoring and consultation, which improves accessibility and participant retention. In a
decentralised multi-centre study, research sites in multiple locations are combined, allowing participants from
di erent regions to access research without having to travel to a central site, also using standard digital
technologies to ensure consistency and adherence to protocols across sites.

WHO GCT6 describes decentralised clinical trials as trials adopting simpli ed approaches in which some
aspects are conducted at or near participants' homes. It also mentions "point-of-care" designs, where a trial is
conducted in everyday clinical settings rather than specialised research environments. These trials can address
critical questions in real-world clinical care settings, facilitating participation and integrating the trial into routine
medical practice.

Although the ICH GCP E6(R3) guideline does not provide an explicit de nition of decentralised clinical trials
(DCT), it describes them as studies employing methods and technologies that enable patient participation from
various locations, including their homes, and utilise standard digital tools for data collection, monitoring, and
consultation, thus improving participant accessibility and retention.

Key documents developed in planning a study for IRB/IEC review

As outlined earlier, Principle 3 provides guidance on the review of study should be subject to an independent
review by an Institutional Review Board/Independent Ethics Committee (IRB/IEC).

Important: A study should NOT be initiated without prior approval from the ethics committee and regulatory
authorities of the jurisdiction in which the research will be conducted.

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 The documents to be submitted to the IRB/IEC may vary depending on the speci c requirements of the
jurisdiction and the study in question. However, the Protocol, Informed Consent form(s) (and Assent if
applicable) and the Investigators brochure are considered essential to meet the standards set by the ICH-GCP
E6(R3) guidelines and WHO GCT:

Protocol: is the main document describing the study design, methodology, objectives, procedures for statistical
collection and analysis, procedures for study management.

You can consult the EQUATOR guidelines, an international standard promoting quality and transparency in
health research, for recommendations on the minimum required elements for study protocols.

Prior to study initiation, the protocol must be reviewed and approved by the IRB/IEC. Any necessary
modi cations to the document during the conduct of the study must also undergo further ethical review in the
form of a Protocol Amendment, which is a documented description of a change or changes to a protocol.

Important: Always refer to the IRB/IEC Operational Manual for the jurisdiction(s) where the study will be
conducted to ensure that the protocol complies with local regulations.

Investigators' Brochure (IB)

Investigators' Brochure (IB) is the document that brings together all relevant clinical and pre-clinical information
about the Investigational Product. Its main purpose is to provide investigators with the information necessary to
understand the properties, e ects and risks of the investigational product to enable informed decision-making
for the safety of participants and for the ethical and scienti c conduct of a Clinical Trial. The content of the IB
should be tailored to the speci c characteristics of each study, although ICH GCP E6(R3) recommends
adjusting the content and depth of information to ensure that investigators understand the relevant details
without excessive or irrelevant information. In general terms, the IB should minimally contain:

- Investigational Product Description: composition, physical and chemical properties, formulation, and other
relevant aspects.

- Preclinical Results: information on animal studies and other preclinical data, including toxicity, pharmacology,
and pharmacokinetics.

- Previous Clinical Data: results of previous clinical studies, including information on dosage, adverse e ects
and observed e cacy.

- Pharmacology: information on absorption, distribution, metabolism and excretion of the investigational product
in humans.

- Safety and Risk Data: detailed description of side e ects, contraindications, and any information on risks and
management of adverse e ects.

- Product Handling Instructions: details on the preparation, administration and safe storage of the product.

- Dosage and Administration: recommendations on optimal dosage and administration, based on previous
studies.

ICH GCP E6(R3) stresses the importance of updating the IB in a continuous and timely manner to include any
relevant new information that may impact the safety or conduct of the study. Each update should be reviewed
by the IRB/IEC and shared with all investigators to ensure that they have the latest information on the product.
In addition to the documents described above, the preparation of the following is required as additional
documents (see example below) to ensure traceability of data and security of participants. Always consult the
IRB/IEC in your jurisdiction to ensure that all documents are prepared in accordance with local or regional
regulations, as appropriate.

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 Examples of other clinical trial-related documents that must be reviewed and approved by the IRB/IEC.

Standardised Operational Procedures (SOPs) are documents describing speci c procedures and standards for
the uniform and rigorous conduct of a clinical trial, as recommended by ICH GCP E6(R3) and WHO GCT. Their
main objective is to ensure all team members, regardless of their location or role, consistently apply these
procedures, thereby ensuring data quality and integrity, as well as ethical and regulatory Compliance. SOPs
should cover key trial activities such as participant selection and recruitment, Informed Consent, administration
of interventions, data collection, Adverse Event management, sta roles and responsibilities, and Monitoring
and Quality Control procedures. They should be regularly updated to ensure harmonisation and replicability of
the study across all involved sites.

Dissemination Material for Patients consists of informative resources designed to clearly communicate key
aspects of the clinical trial to patients and their families, following recommendations from ICH GCP E6(R3) and
WHO GCT. These materials aim to promote transparency and understanding of the study’s value and impact,
often presented in various formats such as lea ets, videos, or websites, tailored to di erent needs. They
facilitate access to essential information, strengthening trust and respect for the research, thus ful lling a crucial
ethical role by informing and empowering patients and communities.

Informed Consent Form

Informed Consent Form (and Informed Assent Form, where applicable): one of the key documents, as it ensures
that participants understand and freely agree to participate in the study. These forms should be prepared
according to the format required by the IRB/IEC, but in general terms, they should minimally include:

- Description of the study including its purpose, procedures and duration

- Explanation of the possible risks, burden and bene ts for the participant

- Information on nancial compensation (if any)

- Information on Con dentiality and ensuring the protection of the participant's privacy and data

- Statement that participation is voluntary, meaning that any person invited to participate may choose not to be
part of the study and that if accepts to participate, she or he may withdraw at any time without prejudice

- Contact details of the members of the research team to resolve doubts or clari cations throughout the study

Prior to implementation of the form(s) ensuring that participation in the study is voluntary and informed, these
must be reviewed and approved by the IRB/IEC. Some regions/IRB/IEC may require to review the primary
language version of ICF; if investigators have ICFs in other languages for speci c groups Any subsequent
modi cations to the document(s) throughout the study must also undergo further ethical review and approval,
ensuring that the information remains accurate and transparent to participants.

WHO GCT emphasises that essential Clinical Trial documents (Protocol, operating manuals, informed consent
forms, Monitoring and analysis plans) should be clear, concise, and proportionate to the risks involved.

Important: These documents should be easy to understand for investigators, participants, and Regulatory
Authorities, ensuring transparency and enabling the study to be easily replicated.

WHO GCT6 reinforces the need for all clinical trials to be reviewed and approved by an independent ethics
committee before they begin, with ongoing reviews throughout the study. The committee must ensure that the
trial respects participants' rights, dignity, safety, and well-being, evaluating the balance between potential
bene ts and risks, and ensuring that appropriate mechanisms are in place to monitor and manage emerging
ethical issues.

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 Important: Always refer to the IRB/IEC instruction jurisdiction(s) where the study will be conducted to ensure
that the consent (and assent, if applicable) form complies with local regulations.

The free and informed consent process, beyond a simple form

The ICH GCP E6(R3) emphasises informed consent as a central process to protect the rights, safety and well-
being of clinical trial participants. Beyond a form, the need for clarity, transparency and understanding in the
consent process is emphasized, integrating concepts of continuous improvement and technology in obtaining
consent. Additionally, it emphasizes the importance of the informed consent process adapted for vulnerable
populations and encourages the implementation of additional measures, such as consent by a legal
representative in situations where the participant does not have full capacity to understand or decide and the
presence of an independent witness. It is required that the information be provided in a clear and
understandable manner, ensuring that participants or their legal representatives adequately understand the risks
and bene ts for the purpose of an informed decision.

"Vulnerable Participants: Individuals whose willingness to volunteer in a clinical trial may be unduly in uenced by
the expectation, whether justi ed or not, of bene ts associated with participation or of a retaliatory response
from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a
hierarchical structure, such as medical, pharmacy, dental and nursing students; subordinate hospital and
laboratory personnel; employees of the pharmaceutical industry; members of the armed forces and persons
kept in detention. Other vulnerable participants may include persons in nursing homes, unemployed or
impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads,
refugees, minors and those incapable of giving consent.”

The Declaration of Helsinki recognizes that some people, groups and communities are more vulnerable in the
context of medical research, meaning that they may be at greater risk of harm or unfair treatment (e.g.
socioeconomic conditions, children, prisoners, or minority groups who are vulnerable to coercion in the consent
procedure). Excluding these populations from studies can exacerbate health disparities, so it is important to
evaluate the risks of including them in research versus the risks of leaving them out. To be included fairly and
responsibly, these people must receive speci c support and protection that consider their particular needs.
Furthermore, research should only be conducted with these populations if it truly meets their health needs and if
the bene ts of the ndings will accrue to them, or if the study cannot be conducted in less vulnerable groups.

“Some individuals, groups, and communities are in a situation of more vulnerability as research participants due
to factors that may be xed or contextual and dynamic and thus are at greater risk of being wronged or incurring
harm. When such individuals, groups, and communities have distinctive health needs, their exclusion from
medical research can potentially perpetuate or exacerbate their disparities. Therefore, the harms of exclusion
must be considered and weighed against the harms of inclusion. In order to be fairly and responsibly included in
research, they should receive speci cally considered support and protections. Medical research with individuals,
groups, or communities in situations of particular vulnerability is only justi ed if it is responsive to their health
needs and priorities and the individual, group, or community stands to bene t from the resulting knowledge,
practices, or interventions. Researchers should only include those in situations of particular vulnerability when
the research cannot be carried out in a less vulnerable group or community, or when excluding them would
perpetuate or exacerbate their disparities3.”

The ICH GCP E6(R3) emphasizes that investigators and sponsors, beyond conducting a careful evaluation of
potential risks versus anticipated bene ts, must ensure that the informed consent process adequately
communicates whether the expected bene ts of the study justify the risks associated with their participation in
it. It must be ensured that the rights, safety and well-being of all participants, especially those who are
vulnerable, are protected. This includes the need to implement additional protection measures for groups in
vulnerable situations and ensure that their inclusion in research is adequately justi ed.

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 The nancial compensation o ered to participants, if applicable, must be fair and reasonable and clearly
described in the informed consent process. Participants should be informed about the nature of the
compensation, how it will be calculated and when they will be paid. This means that it should re ect not only the
costs associated with participation (such as transportation, time, and potential inconveniences), but also
prevent compensation from becoming an excessive incentive that could in uence the participant's decision to
join the study. Compensation should not be so high that it results in coercion or exploitation, especially in
vulnerable populations.

The ICH GCP E6(R3) states that when considering compensation, the context and needs of the population
involved must be assessed. For example, in vulnerable populations, special care must be taken to ensure that
compensation is not interpreted as coercive. Compensation should be viewed as recognition of the individual's
time and participation in the study, and not as a means to in uence their decision to participate. Investigators
should ensure that compensation does not place undue pressure on participants, especially those in di cult
nancial situations who might feel compelled to participate for nancial reasons.

The informed consent is not a single event, but an ongoing process of communication between the research
team and the participant that is recorded through the signing of the consent form (and assent, where
applicable), and must be obtained in a language and level of complexity that participants can understand.
Documentation of informed consent should be done in such a way that there is a clear record of the
participant's decision to participate. In addition, consent process forms and their revisions must be stored
properly and securely to protect the con dentiality of the data. GCP stresses the importance of reviewing and
updating the information provided to the participant throughout the study, especially if there are changes that
a ect their decision to continue participating. It is essential that the information provided to participants or legal
representative, where appropriate, at recruitment, as well as throughout the study, is clear, accurate and
understandable according to the cognitive pro le, avoiding the use of technical or ambiguous terminology that
may hinder comprehension. Likewise, the information must explain the concept of uncertainty surrounding any
clinical study. ICH GCP E6(R3) recognises the role of technology in obtaining consent, such as the use of
electronic and multimedia platforms to facilitate and enhance the participant's understanding. It also recognises
the possibility of electronic consent (e-Consent), as long as it complies with the ethical standards and
regulations of the jurisdiction where the study will be conducted and is approved by the relevant IRB/IEC.

ICH GCP E6(R3) introduces recommendations on the use of technology for the informed consent process,
recognising that digital tools can improve the accessibility, comprehensibility and e ciency of consent, provided
they are used ethically and with respect for the rights of participants.

The WHO GCT recommends that informed consent should be a continuous, clear, and culturally sensitive
process, ensuring participants adequately understand the purpose, procedures, risks, and bene ts of the
clinical trial, as well as their right to withdraw at any time. The consent process should be adapted to the needs
and characteristics of the participant, including innovative methods such as electronic consent (duly approved
by an IRB/IEC), and ensure ongoing communication about any new relevant information that arises during the
study.

The investigator(s) and/or sta involved in the consent process must be adequately trained. This includes
training in communication skills and the ability to answer questions and clarify doubts in an ethical and
transparent manner.

IRB/IEC approval is not just a regulatory requirement

Both the ICH GCP E6(R3) and the Declaration of Helsinki stress that no study should be initiated without ethical
review of its design, procedures and key documents, including the protocol, informed consent, and
investigator's brochure. Review by an IRB/IEC ensures that the rights, safety, well-being, and risk-bene t
balance is favourable and ethical for each participant, especially for those in vulnerable conditions.

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 Important: Ethics Committee approval is not only a regulatory requirement, but also a critical component for the
scienti c and ethical validity of the study.

As presented in Module 3, the IRB/IEC has the responsibility to review the submitted documents to con rm the
suitability and quali cations of the research team members, to assess the scienti c validity of the proposed
study, that risks are minimised and bene ts are maximised, and that informed consent is clear, understandable,
and tailored to the characteristics of the participant population. Ethical review also includes ensuring fairness
and equity in the selection of participants, respecting their dignity and protecting those who may be in
vulnerable situations. In addition, it has the responsibility to monitor the research on an ongoing basis,
evaluating amendments and reports to ensure that ethics and safety are maintained throughout the study.

Independent ethics review fosters public con dence and trust in research, generating results that can be
accepted by the scienti c community and contribute to the advancement of health sciences.

Summary and key points to remember

This module addressed the planning stage of a research study, highlighting the importance of ethics and safety,
guided by several key principles of ICH GCP E6(R3) that ensure a participant-centred approach at each stage of
the study. Throughout the content, the main focus was on integrating the following principles:

– Principle 1: Ethics and Participant Rights

Ethics should guide all study decisions. Ethics Committee (IRB/IEC) review and Informed Consent are
fundamental to protecting the rights, dignity and autonomy of participants, ensuring their understanding and
voluntary consent.

– Principle 2: Informed Consent and Protection of Vulnerable Groups

Informed consent, rather than a simple form, must be a clear and accessible process that ensures the
participant's understanding of the study. In vulnerable populations, additional safeguards are required, including
the availability of legal representatives and the use of accessible technologies.

– Principle 3: Independent Review by the Ethics Committee

Independent IRB/IEC review protects the rights and safety of participants by ensuring that the study meets
ethical and scienti c standards. The review is an ongoing process that includes the evaluation of amendments
and safety reports.

– Principle 4: Scienti c and Ethical Study Design and Conduct (Risk-Bene t Balance)

The planning of a clinical trial requires continuous assessment of the risk-bene t balance, which is crucial for
the protection of participants. This principle is especially relevant in protocol design and ethical review, where it
is ensured that the risks are reasonable in relation to the expected bene ts.

– Principle 7: Data Quality and Con dentiality

Data protection and con dentiality are essential to respect the privacy of the participants. Data should be
collected, stored and handled securely, in line with privacy regulations and GCP standards. This should be set
out in the protocol and additional documents, where appropriate.

– Principle 11: Compensation and Avoidance of Coercion

Compensation to participants should be fair and non-coercive. This is especially important to avoid vulnerable
populations feeling coerced to participate for economic reasons.

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 Key points to remember

- Studies involving human beings, should be based on ethical principles of respect for persons, bene cence and
justice, ensuring that bene ts are maximised and risks to participants are minimised

- No study should be initiated without the ethical evaluation of documents re ecting the study design and
procedures. These documents should be well structured and comply with ethical, regulatory and scienti c
requirements

- The protocol should clearly describe the methods of data collection, storage and access, and researchers
should protect sensitive information of all participants

- Informed consent is an ongoing process, not a single event, to ensure that participants understand the risks,
bene ts and purposes of the study. It should be clear, accessible and in understandable language

- Technology can facilitate the consent process, improving accessibility and comprehension, as long as local
ethical and regulatory standards are met and respected

- For vulnerable populations, additional protections should be implemented and consent obtained through legal
representatives, with the presence of an impartial witness, where appropriate

- Every study should carefully assess the risk-bene t balance, ensuring that it is favourable and ethical. For
vulnerable populations, the risk-bene t balance should be reviewed with special care and a thorough
justi cation for inclusion in the study should be provided

- Compensation to participants should be fair and reasonable, and should not represent a coercive incentive. In
vulnerable populations, compensation should be carefully assessed to avoid unduly in uencing the decision to
participate

- The initial ethics review should be followed by ongoing monitoring by the IRB/IEC, including review of
amendments and adverse event to protect participants throughout the duration of the study

- In multi-centre or international studies, each site must comply with local regulations and have IRB/IEC
approval, taking into account the cultural and legal particularities of each jurisdiction.

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 Module 5: Principles applied in the initiation of the
study

Introduction
This module will explore how the 11 principles of Good Clinical Practice set out in the ICH GCP E6(R3) guideline
re ect and apply in practice the fundamental ethical principles of the Belmont Report; Respect for Persons,
Bene cence and Justice - especially at the initiation phase of a study.

The study is already approved by the IRB/IEC and regulatory

bodies. What next?
The initiation of a study is the point at which all necessary preparations are completed and the trial is ready to
recruit the rst participant, following approval from the IRB/IEC and Regulatory Authorities. This includes
activities such as:

-Training the research team (see Principle 5)

- Making sure all study agreements are in place, including a signed Clinical Trial Agreement (CTA), budget or
payment schedule agreement, and insurance/indemnity certi cates led in the Trial Master File (TMF)
(ICH E6(R3) 3.6);

- Organizing and distributing Investigational Products;

- Making sure Investigator's Brochure (IB) is reviewed/signed by site sta ;

- File supplier‑quali cation documents for IMP per ICH E6(R3) 3.4;

- Setting up document management systems, and securing necessary resources including TMF & regulatory
binder setup;

- Create folder structure and le essential documents (delegation log, SOPs, training records; IRB
correspondence) with version control (ICH E6(R3) 3.6 & Sec 10).

These preparatory steps ensure that the trial is conducted in Compliance with the approved Protocol and
applicable regulations, thereby upholding quality and ethical standards (Principles 1, 8, 10). The initiation of the
study, therefore, only involves preparation without the involvement of any participants.

Important: the de nition of "study initiation" can vary depending on the guidelines or regulatory bodies involved.

Before the research team begins to carry out the study protocol, it is essential to set up the operational structure
of the trial. This includes training the team on standardised procedures for data collection and management, as
well as managing research products, Monitoring and Data‑Management plans which include nalising
risk‑based monitoring schedule, complete data‑management plan, and validate EDC/IRT systems with user
guides in the TMF (ICH GCP E6(R3) 3.1.4) (see Principle 5). This preparation phase is crucial to ensure strict
adherence to ethical and methodological standards, guaranteeing participant safety and data validity.

Importantly, for IRB/IEC review, each member of the research team has submitted documentation verifying
minimum training and experience for study participation. These requirements vary according to the category of
risk of the study, but typically include academic training, curriculum and publications on previous experience in
clinical research and, if possible, in studies similar to the one to be conducted, demonstrated knowledge of
Good Clinical Practice (GCP), as well as applicable local and international regulations.

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 Important That in addition to complying with the formal requirements, it is necessary for the researcher and the
team to be able to interpret the protocol, demonstrate technical knowledge and communication skills, especially
for those members responsible for the Informed Consent process, or procedures that require contact with the
participants.

During the training of the research team, the following core areas of knowledge must be covered at a minimum:

- Study protocol

- Good clinical practice with a focus on protection of participants' rights, safety, and Con dentiality of data.

- The process of obtaining informed consent and the right of participants to withdraw from the study at any
time.

- Risk management, identi cation and reporting of Adverse Events, and emergency plans to ensure that the
team acts quickly and appropriately to protect participants.

In addition to training the team in recording and managing study documentation, ensuring that all data and
procedures are clearly and accurately documented.

To keep the research team up to date in their competencies, ongoing training is recommended, especially if the
study extends over a long period of time or if changes in the protocol or regulations arise. This training should
include updates on the study, regulatory changes, and review of any ethical or practical challenges that have
arisen.

The Council for International Organizations of Medical Sciences (CIOMS) guidelines focusing on ethics in health
research and the protection of research participants, in line with the GCP, stress the importance of both research
teams and sponsors receiving adequate and ongoing training. CIOMS also recommends that both Investigators
and Sponsors keep documented records of training as a measure of transparency and ethical compliance (see
Principle 10). This documentation allows for veri cation that all sta have received the necessary training and
are quali ed for their speci c roles.

The WHO GCT recommends that, before initiating a clinical trial, the research team must be adequately trained
in standardised operational procedures to ensure quality and consistency in data collection and management. It
also highlights that the principal investigator and other researchers must have su cient quali cations and
experience to guarantee that the study is conducted ethically and scienti cally. Finally, it emphasises that the
sponsor bears the fundamental responsibility for ensuring that all aspects of the trial comply with ethical,
regulatory, and methodological standards, actively overseeing all activities from the beginning to the end of the
study. This training includes not only technical and regulatory aspects, but also ethical and safety management,
in accordance with standards such as ICH-GCP E6 (R3) and international ethical guidelines such as the
Declaration of Helsinki and CIOMS.

Participant Selection: Recruitment and Enrolment

When the team has duly completed the training, has the essential documents in their nal and approved version,
and the research site has all the necessary resources and materials for the study, the selection of participants
will begin.

Pre‑recruitment setup

- Inclusion/Exclusion criteria nalisation: de ne and document criteria per Protocol (ICH E6(R3) B.5.1–B.5.2)

- Recruitment plan & materials: develop site‑speci c strategies and IRB‑approved adverts/scripts
(ICH E6 (R3) B.5, guidance on advertising)

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 - Screening & Pre‑screening Logs: set up logs to record all approached, screened, and screen‑fail subjects
(ICH E6 (R3) B.5.3)

- Consent document veri cation: ensure all ICF versions (and translations) are IRB‑approved and available on
site (ICH E6 (R3) 2.8.5), also for some other settings, country speci c requirements must be met, for example,
other settings require that documents are stamped by the ethics committees

- In the context of a Clinical Trial, the guidelines make a distinction between the terms recruitment and
enrolment, although both are key steps in the participant selection process.

Recruitment activities

- Material Approval: verify all yers, adverts, and scripts have IRB/IEC approval and comply with local
advertising rules

- Community Engagement: implement any community‑outreach plans or site‑speci c engagement (e.g., local
liaison, focus groups)

Recruitment is the stage that begins after all initial preparations have been completed and when the research
team is ready to contact and select potential study participants. The start of recruitment marks the rst direct
interaction of the study with research subjects and is performed following IRB/IEC and regulatory approvals,
where applicable. The Informed Consent process is a key element of recruitment, as the ethical guidelines for
protecting and respecting the rights of participants uphold. At this point, approved materials should be used to
adequately inform potential participants, ensuring their informed and uncoerced decision before formally
including them in the study. As seen in module 4, the informed consent form (and Assent, where appropriate) is
the document through which a person's free and voluntary decision to participate in the study is recorded.

Applying ICH GCP Principles to subject selection and

recruitment
ICH GCP E6(R3) provides clear guidelines for the selection of trial subjects with respect to:

Respect/Autonomy. Prior to an individual's participation in a Clinical Trial, Informed Consent, must be obtained
on a voluntary basis (Principle 2). This means that participants must fully understand the objectives of the trial,
the procedures to be followed, the potential risks and bene ts, and their right to withdraw from the trial at any
time without a ecting their health care. Participants' data must be protected in accordance with data protection
regulations and must not be used for any purpose other than the study in question (Principle 3).

Population Representativeness: ensure selection re ects intended future‐use population, avoiding bias in age,
sex or ethnicity

Bene cence/Non-male cence: Researchers should provide detailed information about the study, including
potential bene ts and risks. In addition, appropriate methods must be used to ensure that participants fully
understand the information provided (Principle 1).

Justice: Recruitment should be fair and non-discriminatory, ensuring that participants are included in
accordance with the inclusion and exclusion criteria de ned in the study Protocol, without marginalising
vulnerable groups without ethical justi cation (Principle 1 and Principle 2).

In addition, the participant selection process, i.e. recruitment and enrolment, must be transparent and follow
ethical procedures to ensure that participants are not inappropriately induced or misled to participate in the
study. is an internationally recognized ethical, quality and scienti c standard2, 3 for the design, conduct, and
reporting of clinical studies involving human participants. Its primary objective is to ensure the protection of
participants' rights, safety, and well-being, while also guaranteeing the reliability and credibility of study data
and results.

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 Important: Study initiation refers to the preparatory and organisational activities necessary before a clinical trial
begins, without involving participants yet. In contrast, the start of recruitment involves direct interaction with
potential participants, obtaining their consent, and selecting them according to established ethical and
regulatory requirements for enrolment in the study.

The standards for the handling and documentation of research

products
At the beginning of this module, it was highlighted that training of research teams in the proper handling of
investigation products (e.g. drugs, medical devices, biological samples) is important not only to ensure their
quality and integrity, but also to care for the environment. In addition, all shipments and receipts of
investigational products must be thoroughly documented, including the date, courier details, condition upon
arrival, and chain-of-custody signatures. These logs should be led in the Trial Master File (TMF), and any
discrepancies must be escalated in accordance with ICH E6(R3) section 3.15.3.

In this regard, the ICH GCP E6(R3) establishes a set of minimum standard procedures related to research
products (Principle 11), ensuring that they are treated in a rigorous manner and in accordance with best ethical
and scienti c practice.

Handling of Investigational Products (IPs): Products should be handled by trained personnel, ensuring that the
necessary transport, storage, destruction, and disposal conditions are followed to preserve their quality and
integrity. IPs should be stored under speci ed conditions (e.g., 2–8 °C). Calibrated temperature monitors should
be used to record twice‑daily readings, and excursions must be documented with root‑cause and corrective
actions.

Quality Control and traceability: The use of each product or material should be documented in detail, including
accountability and reconciliation. This includes tracking batch/lot numbers, as well as quantities received,
dispensed, returned, and destroyed. Inventory should be reconciled monthly, and reconciliation reports led in
the TMF per ICH E6(R3) 3.15.3. There should be a system to track the origin, receipt, distribution, and use of
each product or material at each phase of the trial. Any changes or incidents related to the product should be
recorded and managed according to the procedures established in the study Protocol.

Documentation: Product-related records, such as chain of custody, quality reports, and distribution records,
should be complete, accurate, and easily accessible for auditing. Documentation should ensure transparency
and allow veri cation of all investigational product-related activities at any time during and after the trial. These
records should also comply with local and global regulations, such as Good Manufacturing Practices (GMP) and
regulations as appropriate, maintain destruction certi cates and waste‑manifest logs for Audit traceability (e.g.
FDA, EMA, etc.)

Destruction and discarding: When investigational products are no longer needed (e.g. at the end of a study or
when a quality problem is detected), they should be destroyed according to the procedures established in the
protocol and with the corresponding regulations, ensuring that they are not used inappropriately.

Good Manufacturing Practice (GMP) standards refer to a set of guidelines and regulatory requirements designed
to ensure the consistent quality, safety and e cacy of products, particularly pharmaceuticals, medical devices
and foods8-10. GMP standards cover various aspects of production, including facility design, equipment,
personnel training, raw material handling and quality control processes. By following these principles,
manufacturers can reduce the risks associated with contamination, mix-ups and other errors that could
compromise the quality of their products. product integrity. The World Health Organisation (WHO)8 sets the
internationally recognised benchmark for GMP standards, providing comprehensive guidelines applicable
worldwide. The WHO GMP guidelines serve as the basis for Regulatory Authorities around the world, including
the European Union (EU)9 and the United States.

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 These standards cover the ethical requirements and key principles of ICH GCP E6(R3) as applied to the
handling of investigation products:

- Respect/Autonomy: Information about products should be clear so that participants understand their role in
the study and the products being used.

- Bene cence/Non-male cence: Products should be handled and used to maximise the bene ts to participants,
minimising any potential harm.

- Justice: Ensures that all products are distributed and used equitably, without creating unnecessary risks.;

It is essential in a Clinical Trial to protect both the integrity of the product and the safety and rights of
participants by ensuring that products are managed by quali ed personnel, stored in appropriate conditions,
and accurately documented. Compliance with regulations and recommendations allows for full product
traceability, facilitates audits and reviews, and ensures that each product meets the quality standards necessary
to maintain the scienti c validity of the study.

Summary and key points to remember

Ethics in research involving human beings depends largely on stakeholders being aware of, and respecting,
both the study protocols and the rights of the participants. In this way, a prepared team strengthens the integrity
of the study and ensures that all phases of the study are conducted in line with GCP and international
regulations. This approach encourages both investigators and sponsors to develop a thorough understanding of
the ethical and technical aspects of the study. Proper research product management is essential to the reliability
of clinical trials and helps to avoid con icts of interest, minimise risks and maximise respect for participants'
rights throughout the research.

Before initiating the study, a stakeholder meeting should be held with investigators, sponsors, and site sta to
review the ethical requirements, nal study details (including the principles of the Belmont Report), and
timelines. Attendance and action items from this meeting must be documented in the Trial Master File (TMF) in
accordance with ICH E6(R3) section 2.5.

Throughout the content, the main focus was on the integration of the following principles:

– Principle 1: Ethics and Participant Rights

Ethics should guide all study decisions to protect the rights, dignity and autonomy of participants, ensuring their
understanding and voluntary consent. Con rm all consent materials are IRB‑approved, include teach‑back
scripts, and that sta demonstrate competency in voluntary‑consent techniques (ICH E6(R3) 2.8.1)

– Principle 2: Informed Consent

This principle is essential when selecting participants, as the consent process ensures that they are fully
informed of the objectives, procedures, risks, and bene ts of the study. This principle guides the development
and implementation of screening and training protocols to obtain informed consent in an appropriate and ethical
manner. Use a consent log to track consent dates, versions, and participant queries. File signed ICFs in the TMF
within 24 hours of signing (ICH E6(R3) 2.8.5)

– Principle 3: Compliance with Ethical and Regulatory Approvals

To begin research, it is essential to have the approval of a Research Ethics Board (IRB/IEC/IEC) and the relevant
regulatory authorities. This initial step ensures that the study complies with current ethical and regulatory
principles before interacting with participants. Preparatory activities, such as training of the team and
organisation of the research products, are required to comply with regulations and to ensure an ethical basis,
quality and scienti c rigour. Verify IRB/IEC and regulatory approvals are in the TMF before any recruitment.
Include approval letters, Protocol amendments, and correspondence in your Regulatory Binder (ICH E6(R3) 4.1)

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– Principle 5: Competence and Quali cation of Study Personnel

Training of the team is crucial to ensure that all team members have the necessary experience and knowledge to
carry out their duties. At this stage, the team should be trained not only in the technical and operational aspects
of the study, but also in ethical principles and the protection of participants' rights, in compliance with Good
Clinical Practice.

– Principle 8: Clarity of protocol

Although applicable throughout all stages, at the initial stage it is essential for study design and planning. The
protocol should contain clear guidelines on team training, participant selection criteria, and handling of
investigational products, ensuring consistent and transparent execution of procedures.

– Principle 10: Clear roles and responsibilities

In the preparation phase, it is important that each team member has a clear understanding of their
responsibilities and roles. This includes speci c roles in recruiting participants, obtaining informed consent, and
handling research products so that they receive training appropriate to each assigned role or function.

– Principle 11: Compliance with Good Manufacturing Practices

For studies involving investigational products (e.g., drugs or devices), it is crucial from the outset that these
products comply with quality, handling, and storage regulations. This ensures the safety of participants and
avoids risks related to poor quality products or avoidance of inappropriate, altered or improper use.

Key points to remember:

- Ensure that the study is approved by the Research Ethics Board (IRB/IEC/IEC) and, if necessary, by regulatory
authorities.

- Before involving participants, it is essential to complete all preparatory activities, including team training,
organisation of research products, and document management systems.

- All team members should be trained in the study protocol, Good Clinical Practice (GCP) and ethical issues,
including obtaining informed consent and Adverse Event reporting. Ongoing training is essential, especially for
prolonged studies or studies with changes in regulations/protocols.

- Both investigators and sponsors should keep records of completed training. This not only ensures
transparency but also ensures that all sta are adequately prepared for their roles.

- Recruitment involves initial contact with potential participants and must follow IRB/IEC-approved procedures
in compliance with ethical guidelines respecting the rights of participants, ensuring informed decisions free of
coercion.

- Obtaining informed consent is crucial to respecting participants' autonomy. This process ensures that they
understand the objectives, procedures, risks, and bene ts, and guarantees their right to withdraw at any time
without consequences.

- Research products must be handled according to ethical and scienti c standards. This includes detailed
documentation of each use, Quality Control, safe storage, and safe destruction and disposal procedures to
protect their integrity and that of participants.

- Traceability of products is key. Complete and accurate records of receipt, distribution, and use of products
facilitate audits and ensure that quality standards are maintained at all stages of the study.

- In studies involving drugs or devices, it is essential that they meet established quality standards, minimising
risks and ensuring the safety of participants.

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 Module 6: The principles applied in the Conduct of
the Study focused on Risk Management

Introduction
This module studies how the principles of Good Clinical Practice (GCP) around quality, ethics, risk management
and monitoring are applied in the conduct of the study.

The critical elements in the conduct (or execution) of an

investigation
The conduct of a study, mainly a Clinical Trial, involves putting into practice the prede ned and approved (by
IRB and regulatory bodies) methodology and operating procedures, for which the research team was duly
trained during the study initiation and preparation period. At study start, it is important to complete and le an
initial site risk assessment in the Trial Master File (TMF) identifying critical‑to‑quality factors (e.g. handling of the
investigational medical product (IMP), Informed Consent) and their likelihood/impact as per ICH E6(R3), 3.10.1.3.
It is vital to update the assessment quarterly or upon major Protocol Amendments.

Therefore, we now turn to how the principles of good clinical practice impact the execution of a study.

This phase involves di erent stakeholders working together to ensure Compliance with ethical and quality
principles, where each plays a key role in ensuring that the study is conducted safely, ethically and in
accordance with international standards of Good Clinical Practice(GCP)1, 2.

Important: Research Ethics Committee (IRB/IEC): Responsible for making periodic reviews during the execution
of the study to ensure that ethical standards are maintained. This includes reviewing amendments to update
documents, Monitoring participant recruitment and the informed consent process, and overseeing participant
safety throughout the study.

Sponsor: An individual, company, Institution or organization that takes responsibility for the initiation,
management and arrangement of the nancing of a clinical trial, as well as ensuring its implementation in
accordance with regulations and ethical principles. During implementation, the sponsor establishes monitoring,
auditing and risk management processes, ensuring that the study is conducted according to Protocol and that
the safety of participants is protected.

Investigator (and Research Team): Responsible for leading the study at the study site and overseeing all
participant-related activities. Together with his or her team, the investigator must ensure compliance with the
protocol and local regulations, ensure that procedures are carried out correctly and that information about
participants is kept con dential and secure. The team is also responsible for the informed consent process and
clinical data management.

Data Governance: Responsible for ensuring the integrity, security and quality of data as it is generated and
managed. According to ICH GCP E6(R3), data governance during study execution is essential to ensure that the
data collected are valid, auditable, and useful for analysis, while maintaining respect for participant privacy and
complying with ethical and regulatory standards.

In clinical trials, various stakeholders play critical roles beyond sponsors and investigators3-5.

Regulatory Authorities, such as the FDA, EMA, or local equivalents, are responsible for overseeing compliance
with national and international regulations. They have the authority to suspend or terminate a study if signi cant
risks to participants are identi ed.

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 Contract Research Organisations (CROs) are often contracted by sponsors to manage speci c tasks related to
the administration, monitoring, and overall management of the study. CROs represent the sponsor and must
adhere to the same ethical and regulatory standards, ensuring that trial activities align with the protocol and
participant safety is maintained.

Additionally, certain studies, especially those posing higher risks, require a Data Safety Monitoring Committee
(DSMC or DMC). This independent committee is responsible for regularly reviewing safety and e cacy data in
real time, making recommendations on study adjustments or even discontinuation if risks to participants
surpass the potential bene ts.

The interaction between stakeholders in the conduct phase of a clinical trial is deeply linked to the principles of
Good Clinical Practice, which establish guidance for each role and responsibility to ensure that the rights, safety
and well-being of participants are prioritised, that data are accurate and veri able, and that study activities are
conducted in accordance with ethical and legal standards. By establishing a clear structure of collaboration and
accountability, stakeholders contribute to quality execution based on risk management and the competence
and training of all sta involved. Alignment of each stakeholder's objectives with these principles reinforces the
integrity of the clinical trial and ensures that it is conducted in an ethical and scienti c manner.

Important: Each stakeholder has a critical role to play in the implementation of GCP principles during conduct of
the study (See roles and responsibilities in Module 3).

As you can see, the conduct phase of a study requires rigorous attention to several critical elements to ensure
participant protection, protocol compliance, data quality, and ongoing monitoring (Principles 1 to 11). Proper
execution also depends on continuous sta training and e ective communication among all stakeholders. In this
context, risk management is a fundamental aspect of maintaining the safety of participants and the integrity of
the study.

Risk based approach: risk management, data safety and

monitoring
ICH GCP E6(R3) de nes the risk-based approach as a proportionate and systematic methodology for identifying
and managing risks that could signi cantly impact critical factors a ecting trial quality. This includes identifying
risks before the trial starts and throughout its duration, assessing them based on their likelihood of occurrence,
detectability, and potential impact on participant safety and the reliability of trial results. Control of these risks
should be proportionate to their importance and integrated into the protocol design, monitoring plans,
agreements between parties, and team training. Develop and le a risk management plan (RMP) that lists each
identi ed risk, its root cause, mitigation measures, responsible parties, and review schedule. Reference this plan
in the protocol and revisit at each major study milestone. This approach allows for a more focused allocation of
resources, directing attention to areas of higher risk while minimising the burden on lower-risk aspects of the
trial. By implementing risk-based strategies, sponsors can enhance the overall quality of trials while reducing
costs and timelines, particularly relevant when there is a growing recognition of the need for more adaptive and
e cient trial designs.

Risk management
Risk management is de ned as a systematic process applied to identify, assess, control, communicate, review,
and document the risks associated with the quality of a clinical trial (Principle 3). This process focuses on
identifying areas of increased risk (e.g. adverse events, problems with protocol compliance, or deviations that
may compromise the validity of the study) and taking measures to minimise or control those risks. In ICH GCP
E6(R3), risk management is closely linked to participant safety and study data quality, considering the
identi cation and mitigation of risks in both clinical procedures and data collection (Principles 1, 3, 6, 7).

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 Principles and actions of risk management:

- Identi cation of potential risks, especially in areas a ecting participant safety and data integrity. Use issue‑log
templates to record new risks as they arise

- Assessing the likelihood and impact of each risk. Rate each risk for likelihood, detectability, and impact.

- Controlling risks through appropriate mitigation measures. Implement mitigation actions (e.g., retraining, SOP
updates).

- Communication of risks and their controls to all parties involved. Circulate risk‑status reports at periodic team
meetings

- Continuous review and monitoring of risks, adjusting control measures as necessary. Schedule formal RMP
reviews quarterly or upon major deviations

- Documentation of each step of the process to ensure transparency and traceability. File all risk‑logs, meeting
minutes, and Corrective and Preventive Actions (CAPA) records in the TMF. CAPA are a systematic approach
part of the Quality System used to document deviations, investigate root causes, and implement actions to
prevent recurrence.

Risk management focuses on identifying and mitigating risks that may a ect both the safety of participants and
the overall integrity of the study, with the aim of protecting participants and ensuring that the study is conducted
safely and in accordance with ethical standards.

Participants safety and the overall integrity of the study, with the aim of protecting participants and ensuring that
the study is conducted safely and in accordance with ethical standards (See Module 3).

Data safety
Data safety and quality refers to ensuring that the data collected during the study are accurate, complete,
veri able, and reliable. It therefore focuses on the accuracy and consistency of the information recorded,
ensuring that the results of the study are valid and can be correctly interpreted and veri ed, and is fundamental
to ensuring the scienti c validity of the study results. The data quality involves de ning key indicators (e.g.,
query rate <5%, CRF‑completion time <48 hrs), generate weekly QC dashboards, and escalate metric breaches
per QMP (ICH E6(R3) 3.2)

- Accuracy and consistency of the data collected

- Veri cation of data integrity through audits and Monitoring

- Quality Control in data collection, recording and storage

According to ICH E6(R3), Reference Safety Information (RSI) can be found in various documents—primarily in
the Investigator's Brochure (IB), but also in alternatives such as Standard Operating Procedures (SOP) or risk
management plans, depending on Applicable Regulatory Requirements. An RSI log should be maintained within
the IB and updated with any new safety data within 30 days of receipt. Additionally, the IB revision history must
be led in the Trial Master File (TMF), in accordance with ICH E6(R3) section 2.8.2. The IB, should contain a list
of adverse reactions and their frequency or severity, derived from prior knowledge of an investigational
medicinal product. These procedures serve as a reference for assessing whether an adverse reaction is
expected or unexpected in the course of a Clinical Trials.

The safety reporting should be integrated into routine activities and every participant contact throughout the
study. It should not be viewed as an isolated or exceptional event. Documenting unfavourable medical events in
a study participant is required and applies to all Adverse Events1, 7. These may include unexpected or serious

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 side e ects and should be recorded in accordance with local and international regulations. Both the sponsor
and the investigator should notify the IRB/IEC and regulatory bodies about Serious Adverse Event (SAEs).

Reference Safety Information (RSI), in clinical trial “contains a cumulative list of Adverse Drug Reaction that are
expected for the investigational product being administered to participants in a clinical trial. The RSI is included
in the Investigator’s Brochure or alternative documents according to applicable regulatory requirements6, 7".

The Investigator's Brochure (IB), should contain a list of adverse reactions and their frequency or severity,
derived from prior knowledge of an investigational medicinal product. These procedures serve as a reference for
assessing whether an adverse reaction is expected or unexpected in the course of a clinical trial.

The safety reporting should be integrated into routine activities and every participant contact throughout the
study. It should not be viewed as an isolated or exceptional event. Documenting unfavourable medical events in
a study participant is required and applies to all adverse events1, 7.These may include unexpected or serious
side e ects and should be recorded in accordance with local and international regulations. Both the Sponsor
and the Investigator should notify the IRB/IEC and regulatory bodies about Serious Adverse Events.

– Example decision tree for adverse event reporting examples, developed by NIHR

Other formal documents, separate from the Investigator Brochure, detail how risks identi ed during the study
will be managed.

Standard Operating Procedures (SOP) are a set of operational documents that standardize procedures for
conducting a study. They are essential for risk management as they provide detailed procedures for preventing,
detecting, and mitigating risks throughout the study. These procedures include data management, safety

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 monitoring, reporting adverse events, and implementing necessary changes to the study. They should be
designed to ensure that all study activities are conducted consistently, appropriately, and in accordance with
ethical and scienti c standards. The Risk Management Plan includes an initial assessment of the risks, the
controls in place to mitigate them and the corrective actions to be taken if the risks materialise. It is an
operational document for carrying out all actions de ned in risk assessment1. Its purpose is to guide the
proactive and adaptive management of risks in the clinical trial, allowing the implementation of speci c controls
to minimise potential problems (preventive measures), corrective actions, and optimise study monitoring.

ICH GCP E6(R3) establishes the RSI as a basis for assessing whether adverse events observed in study
participants are expected or unexpected. Also, it suggests that the RSI be updated as new relevant data on the
safety of the study product are collected. This allows investigators and Regulatory Authorities to maintain
adequate judgment in interpreting safety events during the trial.

Important: Reference safety information (RSI) can be contained or maintained within di erent documents,
primarily the Investigator's Brochure or alternative documents as standard operating procedures, risk
management plan, per applicable regulatory requirements.

Monitoring
Monitoring and data safety reports should generate evidence that the study is following established Protocols,
quality standards, and ethical principles. Monitoring Reports are conducted by clinical monitors and may be
internal or from a third party. Ongoing monitoring is key to risk management, as it allows for the detection of
protocol deviations and other problems before they become signi cant threats. Monitoring reports ensure that
the study complies with Good Clinical Practice (GCP) and that the data are reliable and complete, le each
on‑site or centralised monitoring report with ndings, Corrective and Preventive Action (CAPA) plans, and
follow‑up logs in the TMF per ICH E6(R3) 3.11.4.6(b). It is important to schedule remote source‑data review
between visits for high‑risk sites.

Risk based approach

A risk-based approach includes participant safety, data quality, and continuous Monitoring in the conduct of a
Clinical Trial. It relies on a number of key documents to identify, assess, control and mitigate risks throughout
the trial. Importantly, some may be integrated or closely related to the Investigator's Brochure (IB).

The risk-based approach in clinical trials is fundamental to both ICH GCP E6(R3)1 and WHO GCT2. Both
guidelines agree that this approach should be applied proactively and continuously throughout the study,
focusing on the early identi cation of critical factors for quality and actively managing associated risks.
Additionally, risk management should be proportionate and speci cally adapted to the context of the trial,
avoiding burdensome or excessive strategies.

Important: Both guidelines emphasise directing e orts and resources towards aspects essential for participant
safety and scienti c validity, adjusting monitoring and Quality Control to the particular risks of the study, thus
enhancing overall trial e ciency.

Summary and Key points to remember

The conduct of a clinical study involves various stakeholders such as the Sponsor, the principal Investigator, the
research team, ethics committees, Regulatory Authorities, and the participants.

These actors interact and collaborate to ensure that the study is carried out protecting the safety of the
participants and the integrity of the data based on all the GCP principles. The essential processes include risk
assessment and management, continuous Monitoring applied through a risk-based approach, formalized

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 through di erent documents, such as the Investigator's Brochure (IB), Adverse Events reports, risk management
plan, and monitoring reports, which allow structuring, guiding, and documenting the development of the clinical
study in a transparent manner and in accordance with established regulations. These elements together
guarantee Compliance with the GCP guidelines.

Although all GCP principles are directly applied during the conduct of a study, throughout the content of this
module, the focus was mainly on the integration of the following principles:

– Principle 3: Independent Review by the Ethics Committee

The IRB/IEC reviews and approves the Protocol, Informed Consent, and other documents. This applies on an
ongoing basis throughout the study including evaluation of participant recruitment procedures, safety, and
scienti c validity of the study. Throughout the study, the committee must continue to monitor the progress of the
study and verify that ethical standards and regulations are being followed. It also evaluates reports of adverse
events and other ethical problems that may arise during the study. If new risks or problems are identi ed, the
committee may require corrective action, such as adjustments to the protocol or informed consent. Periodic,
independent IRB oversight is conducted in accordance with applicable ethical standards and regulations. This
may include reviews of study documentation, monitoring visits, and hearings.

– Principle 5: Focus on Risk Management

Risk identi cation and mitigation is a central component of the execution phase. It highlights the need to
implement a risk-based quality management approach. This allows for prioritizing critical aspects of the study,
such as participant safety and data quality, ensuring that resources are optimally allocated to address the most
signi cant risks and to make informed decisions in real time.

– Principle 6: Participant Safety

States that the risks of a study must be continuously assessed and managed to protect the safety of
participants. Identifying, monitoring, and mitigating risks are essential to ensure that participants do not su er
unnecessary harm. In addition, this principle underlines the need for the potential bene ts of the study to justify
the risks, which must be constantly assessed as the trial progresses, with a focus on the safety and well-being
of participants at all times.

– Principle 7: Proportionality of Study Processes

Balance the intensity of interventions and the stringency of study controls with the risks associated with the trial
and the relevance of the data collected, ensuring that the measures implemented are appropriate and
proportionate.

– Principle 8: Quality in Data Collection and Management

The accuracy, completeness and consistency of data are essential for the reliability of results. This requires that
all clinical and nonclinical data be recorded, managed and stored in a manner that allows for accurate
interpretation and veri cation. Each member of the research team must follow standardized procedures to
capture and store data in a way that faithfully re ects clinical observations. This not only ensures their integrity
but also facilitates traceability and scienti c validity in subsequent analyses.

– Principle 9: Quality and Quantity of Information

This establishes that clinical studies must be executed with a rigorous focus on data quality and the integrity of
results. The processes related to data collection, management and analysis must be carried out in an e cient,
accurate, transparent manner, and aligned with the objectives of the study, in order to generate reliable results
that support scienti c and regulatory decisions.

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 Key points to remember

- Participant safety should always be prioritised. This involves continually assessing and reducing risks to
protect their well-being

- Adverse events should be monitored and reported according to local and international regulations to ensure
that the bene ts of the study outweigh the risks

- It is essential to identify and manage study risks, especially those a ecting participant safety and data quality

- Measures to prevent or correct problems should be taken and documented on an ongoing basis, ensuring
transparency throughout the process

- Constant monitoring helps to identify problems before they become serious. Monitoring Reports should
con rm that ethical standards and protocol are followed, ensuring that data are reliable

- The Ethics Committee oversees the safety and ethics of the study. It periodically reviews key documents and
may request adjustments to the protocol if new risks arise

- Data collection procedures should be tailored to the risk level of the study, without creating unnecessary
burdens for either participants or the team

- It is essential that data be accurate, complete and consistent, ensuring their scienti c validity. Clear
procedures must be followed to maintain traceability and ensure their reliability in analyses

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 Module 7: Principles applied in the Conclusion,
Closing and post-trial

Introduction
This module explores how the 11 principles of Good Clinical Practice (GCP) that are set out in the ICH E6(R3)
guidelines, re ect and apply in practice the fundamental ethical principles of the Belmont Report: Respect for
People, Bene cence and Justice, in the phase of nalization and dissemination of the results of a clinical trial.
This includes not only meeting reporting and veri cation requirements, but also ensuring that data is properly
communicated to the various stakeholders (sponsors, regulatory authorities and participants), as well as ful lling
post-trial responsibilities.

Critical Elements in Clinical Trial Completion

Completing a Clinical Trial involves much more than completing nal evaluations and collecting data. This
process includes the nal review of the information collected, the consolidation of the data, and the
corresponding noti cation to all interested parties. In accordance with the ICH GCP E6(R3) standard, we use
di erent terms to refer to this stage, such as end of study, closure of the study, and closure of a study site or
study centre, each with a speci c meaning within the clinical trial life cycle.
Study completion refers to the time when all study activities related to data collection, participant intervention,
and implementation of Protocol procedures are completed. It is achieved when all scheduled visits or
interventions with participants are completed and all relevant data has been collected for analysis. It marks the
end of the active phase of the study, i.e. the implementation described in module 6, but does not necessarily
imply its full closure from an administrative or regulatory perspective.
Study centre closure refers to the process of completing all activities at a speci c research centre. It occurs
when a speci c site or centre has completed all study-related activities, including follow-up of participants,
completion of visits, and administrative closure of site operations. This closure is part of the overall study
closure process and ensures that the site is ready to archive all study documents and close any outstanding
activities.
Study closure is the formal process by which the entire clinical trial is completed. It includes collecting all data,
resolving any outstanding issues, closing all research sites, notifying Regulatory Authorities, and submitting the
nal report. The study is closed once all the procedures have been completed, the results have been analysed
and the nal report has been presented. It also involves Compliance with all ethical, regulatory, and contractual
obligations to formalize the conclusion of the research.

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 End of the study (data collection) Study Site Closure Closing of the study

Completion of activities related to

data collection, participant
The process of ending all activities Formal process to completely
interventions, and protocol
at a speci c site. close the study.
procedures.

All scheduled visits or interventions Completion of follow-up of It includes the closure of all sites,
are completed. participants and all scheduled the nal collection of data and its
visits. analysis.

All the relevant data for analysis Administrative closure and Resolution of outstanding issues
has been collected. preparation for archiving of site and noti cation to regulatory
documents. authorities.

Compliance with all ethical,

regulatory and contractual
obligations.

Delivery of the nal report.

Key stakeholders in the completion phase of study

In the completion phase of a study, the ICH GCP E6(R3) guideline identi es several key stakeholders, each with
speci c roles and responsibilities essential to ensure the adequate, ethical, and safe closure of the study, such
as:

– Independent Ethics Committee (IEC)

Responsible for safeguarding the rights, safety, and well-being of study participants. During completion, their
role includes evaluating the nal results of the study, ensuring the protection of the interests and well-being of
the participants during the process. Ensure that participants are informed of relevant outcomes, as well as any
information that may a ect their long-term health. While the IEC ensures the protection of the interests of the
participants, and this is one of its main purposes, they are also to protect the PI, the Centre (in terms of the
disparity in the relationship with the Sponsor), and that the studies have scienti c and social validity. For studies
involving treatment, the IRB/IEC should evaluate plans for treatment after the completion of the study, if it has
been shown to be bene cial and appropriate for the patient's long-term health. This topic is discussed in more
detail in further on in Post-study responsibilities.

– Sponsor

Responsible for ensuring and con rming that all completion and closing procedures are performed in
accordance with applicable Protocol Amendments and regulations. Ensure that the data collected is accurate,
complete, and has been validated prior to the closure of data management. Submit nal reports to regulatory
agencies, including e cacy and safety data. Facilitate access to results and publish ndings in Compliancewith
regulatory and ethical transparency requirements. Maintain a complete archive of documents, records, and data
essential to meeting traceability and future access requirements. Inform participants and research centers about
the results and closure of the study. In the case of studies involving treatment, the sponsor is encouraged to
provide access to post-study treatment where appropriate, working in coordination with Regulatory Authorities
and the IRB/IEC, ensuring that any ongoing access plans are approved and comply with local and international
regulations. This is discussed in more detail in Module 3

– Researcher (and Research Team based on delegated role)

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 Responsible for ensuring that all required information is recorded and completed on data collection and other
relevant records. Ensure that any previously unreported Adverse Events are documented and reported prior to
study closure. Inform the ethics committee about the closure of the study and present the nal reports of
results. Retain key records and study documentation as needed for future inspections and audits. Provide
necessary care to participants, especially if post-trial follow-up is required

+ Data Governance

Responsible for reviewing and validating data collected during study execution to ensure accuracy,
completeness, and consistency. Prevent unauthorized manipulation or modi cation of data. Store them securely
and protect them from loss, damage or unauthorised access. Ensure that the storage structure allows
traceability. Archive documents and data for a speci c period of time that complies with local regulations and
sponsor policies, allowing for traceability and future access. Protect the identity and privacy of participants.
Comply with data privacy regulations, according to international and local standards. This includes ensuring
that, in the post-study phase, data that may be used in future research does not compromise the privacy of
participants.

Other stakeholders involved in the completion of the Clinical Trial include:

– Regulatory authorities

(e.g. the FDA, EMA, or their local equivalents) are responsible for evaluating the safety and e cacy data
submitted by the sponsor to approve or deny the continuation of the development or commercialization stages.
They verify that the study has complied with all applicable regulations and has been completed in accordance
with ethical procedures. They ensure that any residual risks are documented and mitigated for patient safety in
the future.

– Contract Research Organization (CRO)

in which the sponsor has delegated tasks to a CRO. This organization acts on your behalf in various operational
functions. During the closing phase, their responsibilities include overseeing and executing the logistical and
technical closure of the study, including data collection and preparation of the nal report. Ensure that all
documents are on le and complete for delivery to the sponsor and, if applicable, regulatory authorities. Assist
in the review of data and documents, conducting internal audits to ensure compliance with quality standards.

The termination or closure phase not only brings study activities to an end, but also solidi es the commitment of
all stakeholders to scienti c integrity and ethical responsibility in clinical research. The interaction between them
focuses on the protection of the rights and well-being of the participants, as well as on scienti c transparency.
In order for the study to be closed ethically, the GCP principles require that all data be veri able and that each
study activity has been carried out in accordance with established quality standards and regulations. By
complying with these standards at the close of the study, the data and ndings become a reliable source of
information that can guide future decisions in the clinical setting, thus contributing to science for the
development and/or updating of health policies.

Transparency in technical-scienti c data and reports

The transparency of data in technical-scienti c reports plays a fundamental role in the completion and closure
phase of a research project, to validate the integrity and reliability of the results. All data and analysis must be
documented in a clear and accessible way, allowing stakeholders, including sponsors, Regulatory Authorities,
and the scienti c community, to evaluate results accurately and con dently.
The results of the study should be communicated through technical and scienti c reports, not only to
disseminate the ndings, but also to ensure that the methodological information and data collected are
traceable and veri able, complying with ethical and regulatory principles.
The GCPs establish a variety of documents, reports and presentations that are presented during the conduct of
the study and in the completion phase of the study.

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 Document Description

Final report of the study This is a comprehensive document that

summarises and analyses the data obtained
in the Clinical Trial and is usually presented
to the Research Ethics Committee (REC). It
includes information on methodology,
results, interpretation of the data, and
overall conclusions.
Protocol deviation report This document includes all signi cant
deviations from the protocol approved or
not approved during the trial.
Safety reports and Adverse Events These documents should include detailed
information about Serious Adverse Events
(SAEs) as well as other safety concerns that
arose during the study. These documents
should be properly reviewed and led, as
they are essential to ensure post-study
security.
Noti cation of Study Closure It is a formal noti cation informing ICN of
the closure of the study, detailing the
reasons for closure (termination,
suspension, or early termination), and
con rming that all participants have been
adequately treated, either with treatment
closure or necessary follow-up.
Study Closure Checklist This document ensures that all necessary
steps for study closure have been
completed, including nal data collection,
review of essential documents, and
noti cation to the IRB/IEC and regulatory
authorities of study closure.
Follow-up report This document should include observations
on protocol Compliance, data quality, and
any signi cant deviations or ndings.

In accordance with the ICH GCP E6(R3) guidelines, upon completion or closure of a clinical study,
the Investigator or Sponsor must submit the essential documents mentioned above to ensure ethical and
regulatory compliance, as well as the correct completion of the study. Additionally, it is important to note that
depending on local law, ethics committees and regulatory bodies may require additional documentation.
Therefore, both the researcher and the sponsor should consult the laws and regulations of the relevant
jurisdiction to ensure full compliance with local requirements.

Transparency in this documentation ensures that clinical studies reliably contribute to scienti c knowledge and
enable informed decisions in both the clinical and public health elds.

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 Post-Study Responsibilities
Completion of the study does not imply the end of all responsibilities to participants and other stakeholders. The
post-study phase includes assessing additional risks and bene ts, ongoing follow-up of participants (if
necessary), and updating the research to institutional ethics committees and regulatory agencies.

One of the highlights of the ICH GCP E6(R3) update is the focus on the post-trial responsibilities of
the Investigator and Sponsorafter the clinical study is completed, to ensure the protection of the rights, safety
and well-being of the participants, as well as the integrity of the data obtained. They must continue to ensure
the well-being of the people who participated in the study; this includes providing access to appropriate
treatment, if needed, and following local rules and regulations that protect participants, especially if alternative
treatments are not available to them after study completion.

The sponsor must ensure that information about the results of the study is provided appropriately and that
participants are informed of results that may a ect their health or treatment. This must be done in a clear and
timely manner. The ICH GCP E6(R3) standard emphasizes the importance of sharing results responsibly, not
only with participants, but also with relevant stakeholders such as researchers and health authorities,

The Declaration of Helsinki3 and the Council of International Organizations of Medical Sciences (CIOMS)5
Guidelines also meaningfully address post-trial responsibilities, as both documents underscore the importance
of ensuring the continued protection of Clinical Trial participants even after the completion of the study.

Important: Every stakeholder, from the sponsor to ethics committees to Regulatory Authorities, plays a critical
role in implementing GCP principles for completion, closure, and post-study.

Summary and Key points to remember

The completion phase of a clinical study is a key moment in which the results are consolidated and validated,
ensuring Compliance with the principles of Good Clinical Practice (GCP) and ethical and legal standards. At this
stage, rigorous data and documentation management is essential to ensure the accuracy, veri ability, and
integrity of the results. Transparency in nal reports becomes a fundamental pillar, facilitating review
by Regulatory Authorities and the ethical dissemination of ndings. This module addressed the completion of
research, highlighting the importance of ethics and safety, guided by several key principles of the ICH GCP
E6(R3) that ensure a participant-centered approach at each stage of the study. Throughout the content, the
focus was mainly on the integration of the following principles:

– Principle 1: Protection of participants

During the completion phase, it should be ensured that the rights and well-being of participants remain
protected, even after the conclusion of the study. This includes o ering medical follow-up or access to
treatments that have been shown to be bene cial for participants during the trial, especially if the study
treatment turns out to be the only one available. Respect for the rights of participants implies that they must be
informed of the results of the trial, especially if these may have implications for their health or treatment.
Transparency in the communication of results ensures that participants understand the implications of their
participation and, if necessary, receive appropriate care after study completion. As well as respect for
Con dentiality and privacy. This includes careful management of study data and protection of sensitive
information in accordance with ethical and legal regulations.

– Principle 3: independent review and follow up by the IRB/IEC

While the Research Ethics Committee (ERB) initially reviews the Protocol and Informed Consent, it must also
review the nal trial report, including the results, conclusions, Adverse Events, and ethical implications. If
Serious Adverse Events (SAEs) or long-term complications are identi ed, the committee should assess whether

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 additional follow-up is necessary to protect the health of participants. The IRB must also ensure that study
results are disclosed ethically and responsibly, and that all applicable ethical and regulatory standards are met,
including protection of participants' privacy, data handling, post-study follow-up, access to treatment, and
compensation for damages (if applicable).

– Principle 8: Clarity of protocol

During the completion phase, the protocol serves as a guide to evaluate the correct execution of the study and
the validity of the results obtained. The protocol must have been rigorously followed in all its phases, and during
its completion, a review must be carried out to ensure that there have been no signi cant deviations that could
a ect the validity of the results. In the event of modi cations or deviations, they must be duly documented and
justi ed.

– Principle 9: Quality and quantity of information

During the nalization phase, an exhaustive analysis is carried out to guarantee the reliability and validity of the
results obtained. This includes data integrity veri cation, process Quality Control, rigorous analysis of results,
and proper management of adverse events. Transparency and external review are also essential to ensure that
results are presented objectively and responsibly

– Principle 11: Adherence to Good Manufacturing Practices

In the nalization phase, all research products used in the study are reviewed to ensure that they have been
manufactured and managed in accordance with Good Manufacturing Practices (GMP) standards and protocol
speci cations. This includes verifying compliance in the manufacture, storage, handling, disposal, and
distribution of products, as well as reviewing documentation and conducting audits to ensure that products
have been used correctly, without a ecting the integrity of Clinical Trial results.

Key points to remember

• The completion of a clinical study involves not only data collection and nal evaluation, but
also reporting and consolidating results to all stakeholders. Closure includes completion of the study, closure of
the site and administrative closure

• The results of the study should be documented in a clear and accessible way, allowing for
accurate assessment by stakeholders (Sponsor, regulatory authorities and the scienti c community). Reports
must be traceable and veri able

• Upon completion, the Investigator and sponsor must ensure the well-being of participants,
including access to treatment if needed. In addition, they must communicate the results to participants and
other stakeholders in an ethical and understandable way

• The protection of participants' rights and well-being should be ensured even after the
completion of the study, with medical follow-up and access to treatment if necessary. This also includes
protecting the con dentiality and privacy of data

• The Ethics Committee and regulatory bodies, where appropriate, should review the nal
results of the study, including adverse e ects and ethical implications, and ensure that all regulations related to
the protection of participants and disclosure of results are complied with

• During its execution, it is veri ed that the research products have been manufactured, stored,
handled and disposed of in accordance with GMP standards, ensuring that the integrity of the results is not
compromised.

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 Module 8: Summary of good clinical practice
principles and nal re ections

Introduction
This module provides a summary of the core principles of Good Clinical Practice (according to the new R3
update), and their scope beyond clinical trials evaluating interventions.

ICH GCP E6(R3) core principles

The International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline is periodically updated
to re ect advances in ethics and research methodologies, as well as new regulatory needs. Below is a summary
of the 11 principles outlined in ICH GCP E6(R3), including the main stakeholders responsible for ensuring
compliance with each principle, as well as key documents essential for their implementation.

– Principle 1: Ethics and Participant Wellbeing

Description:

The safety and wellbeing of participants is the priority. The study must follow the ethical principles of the
Declaration of Helsinki.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers, Data Governance, Patient group representative

Documents:

Study Protocol Amendments, Informed Consent, Safety Reporting and Monitoring

– Principle 2: Informed Consent

Description:

Participants must give their free and informed consent, receiving clear information. Includes acceptability of
remote consent for decentralised trials.

Stakeholders:

IRB/Ethics Committee, Sponsor, Investigators, Participant/legal representative

Documents:

Informed Consent Forms, Patient Information Material

– Principle 3: Independent Review by an Ethics Committee

Description:

Reviewed and approved by an independent ethics committee to ensure participant protection and scienti c
rigour.

Stakeholders:

IRB/Ethics Committee, Sponsor, Investigators

Documents:

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Approved Protocol, Informed Consent Forms, Investigator's Brochure (IB), Ethics Approval

– Principle 4: Scienti c Quality

Description:

Trials must be based on sound scienti c knowledge and meet the proposed research objectives.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers, Scienti c Committee

Documents:

Research Protocol, Data Management Plan

– Principle 5: Quali cation of Researchers

Description:

Trials must be conducted by quali ed personnel with the necessary training and experience.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers

Documents:

CVs, Training Records, GCP Certi cates

– Principle 6: Quality by Design

Description:

Quality should be integrated from the design phase. Identify critical risks and de ne quality objectives and
Monitoring Plans.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers

Documents:

Protocol, Investigator Brochure, Risk and Monitoring Plans

– Principle 7: Proportionality in Processes and Risks

Description:

Study measures must be proportionate to risks and continuously re-evaluated to protect participants and data
quality.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers

Documents:

Protocol, Risk Plans, Investigator Brochure, Monitoring Plan

– Principle 8: Clear and Feasible Protocols

Description:

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 Protocols must be clear, feasible, and consistently applied to ensure reliable study delivery.

Stakeholders:

IRB/Ethics Committee, Sponsor, Researchers

Documents:

Protocol, SOPs, Risk Plan, Investigator Brochure, Monitoring Plan

– Principle 9: Generating Reliable Results

Description:

High-quality data collection ensures results are accurate, traceable, and reliable.

Stakeholders:

Sponsor, Researchers, Auditors

Documents:

Protocol, Databases, Monitoring Reports, Data Management Plan

– Principle 10: Clarity in Roles and Responsibilities

Description:

The roles and responsibilities of all parties involved must be clearly de ned and documented to ensure the
proper and ethical conduct of the trial. The Guideline includes suggestions for minimizing unnecessary
complexity in trial processes and documentation.

Stakeholders:

Sponsor, Researchers, Regulators

Documents:

Contracts, Delegation of duties agreements, Supervision plan and activity records

– Principle 11: Compliance with Good Manufacturing Practices

Description:

Products under investigation must comply with Good Manufacturing Practices (GMP) standards, ensuring
quality, proper handling, and regulatory compliance.

Stakeholders:

Sponsor, Researchers, IRB/Ethics Committee

Documents:

GMP Certi cate, Standard Operating Procedures and Product Handling Record

Key new updates

It is worth noting that the latest revision, ICH GCP E6(R3), includes the following signi cant updates compared
to the previous version:

– Strengthening Ethical Oversight and Patient Involvement

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 ICH E6(R3) expands the requirements for ethical oversight, promoting greater patient involvement in the design
and conduct of studies, as well as in decision-making. This expansion responds to the growing awareness of
the importance of patient values and preferences in clinical research. The Ethical Responsibilities section in the
R3 version includes more detailed guidelines for ethics committees to ensure that patients are treated with
respect, and that their rights and welfare are given priority. It also suggests that committees and Sponsors
consider prior consultation with patient representatives when designing trials.

– Focus on Quality by Design and Risk Management

An emphasis is placed on proactive risk management and the implementation of a Quality by Design approach,
which involves aiming the design of the Protocol Amendments and all trial components to maximize the
likelihood of trial success (i.e., that the trial will answer the research question). The Quality Management in Trials
section is updated to encourage a systematic approach to identifying, assessing, mitigating and Monitoring
risks. The guidance states that risks should be assessed in terms of their impact on participant protection and
data reliability. The responsibilities of sponsors and monitors are also clari ed, highlighting the need for speci c
Monitoring Plans based on the nature of the study and its risks.

– Adaptation to Emerging Technologies

ICH E6(R3) introduces guidelines for the use of digital technologies and remote monitoring methods in Clinical
Trial. In the section on monitoring, the guidance addresses how digital technologies (such as remote data
collection platforms) can improve the accuracy and e ciency of monitoring, as long as security and privacy
standards for participants are maintained and approved by IECs and local regulatory bodies.

– Clari cation of Responsibilities for Sponsors and Research Personnel

The new revision de nes the responsibilities and roles of research personnel and sponsors, including data
governance. The Roles and Responsibilities section expands guidelines for the sponsor and Investigator,
seeking to avoid duplication of e orts or lack of clarity. The sponsor should ensure that the investigator has
adequate resources, experience and training, and that a robust system for reporting adverse events is in place.

– Emphasis on Data Protection and Privacy

ICH E6(R3) explicitly calls for the protection of participant privacy, with recommendations to ensure data
Con dentiality in Compliancewith global data protection regulations. This update is found in the Protection of
Participant Information section, where sponsors are encouraged to adopt secure data management practices.
R3 recommends anonymization techniques and strict control of access to sensitive data, aligning with
regulations such as the GDPR in Europe, or its corresponding local regulations.

Ethical and rigorous practice in clinical research beyond clinical

trials
Although the original purpose of ICH GCP E6(R3) is to regulate Clinical Trials evaluating interventions, these
principles should be applicable to other types of trials, especially those involving data from human participants.
The inclusion of a focus on ethics, quality, and participant safety is also relevant in other types of non-
interventional clinical trials. Although not the primary focus of ICH GCP, certain principles (ethical review,
Informed Consent, and Con dentiality) must be applicable to observational studies or studies based on real
world data (RWD), where participants’ data are collected without direct intervention in their exposures or
treatments. In Qualitative and Mixed-Methods Studies, some principles of the GCP guideline (e.g., those related
to ethics, independent review, informed consent, and con dentiality) should also be considered, especially in
qualitative studies exploring patient knowledge, attitudes, perceptions, diagnoses, or disease management.
These types of studies, although they di er in their objectives and methodologies, also require Compliance with
strict ethical standards to respect and protect participants and ensure the validity of the data. Therefore, the
adoption of GCP principles in non-interventional studies promotes an ethical and quality approach to research.

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 Summary and Key points to remember
This course reviewed how the 11 principles of GCP that guide and apply ethical and regulatory Compliance,
strengthen the reliability and value of research. Although ICH GCP E6(R3) is primarily intended for Clinical Trials
in humans, especially those for regulatory registration purposes with health authorities, its principles should be
applied in other study designs, as they promote respect and transparency in the research process, which is
essential to obtain high-quality results that improve the health and well-being of people and communities,
regardless of the type of research.

Key points to remember:

• The International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines
have undergone signi cant revisions, culminating in the release of ICH GCP E6(R3). This update aims to
enhance the quality and e ciency of clinical trials while ensuring the protection of participants. The
recommendations of ICH GCP E6(R3) re ect a comprehensive approach to clinical trial management,
emphasizing exibility, stakeholder engagement, and the integration of modern technologies.

• The importance of Con dentiality and protection of personal data of participants is

emphasized, in line with international data protection regulations.

• One of the primary recommendations of the ICH GCP E6(R3) guidelines is the need for
exibility in the application of GCP principles to accommodate the diverse nature of clinical trials, which can
vary signi cantly in terms of risk, complexity, settings and therapeutic areas.

• The ICH GCP E6(R3) principles, although intended for interventional studies, can and should
be extended to non-interventional studies, as they ensure the protection of participants and promote
responsible practices and quality standards of all types of research.

• The R3 version reinforces the role of ethics committees and encourages public involvement
and the active involvement of participants in the design of studies to ensure that the guidelines are both
inclusive and operationally feasible. This approach promotes trial diversity and a more inclusive and patient-
centred research, with detailed guidelines for sponsors to describe the rationale for inclusion/exclusion of
participants to improve trial generalisability and ensure that their rights and preferences are respected.

• A quality management approach is introduced that integrates the identi cation and
assessment of risks from the study design. This method allows for more controlled research adapted to the
speci c risks of each study, ensuring that the data obtained are reliable and safe.

• The guidelines promote exible trial designs, including decentralized elements and real-world
data integration, to accommodate diverse trial types and settings. The guidelines introduce greater exibility to
accommodate di erent trial types, including hybrid and decentralized clinical trials (DCTs). Remote site visits,
electronic Informed Consent, and telemedicine-based assessments are now explicitly supported. This exibility
helps trials remain adaptive while ensuring compliance with ethical and regulatory requirements.

• Emphasis on proportionality and risk-based Monitoring. This includes the adoption of a ‘ t-

for-purpose’ approach to trial conduct and allows for a more focused allocation of resources, directing attention
to areas of higher risk while minimizing the burden on lower-risk aspects of the trial. By implementing risk-based
strategies, sponsors can enhance the overall quality of trials while reducing costs and timelines when there is a
growing recognition of the need for more adaptive and e cient trial designs.

• The incorporation of digital technologies and remote monitoring methods and Data
Acquisition Tools (DAT), the acceptability of remote consent and reference to home nurses expand the scope of
traditional designs and increase community participation in trials. The incorporation of digital tools and
platforms can enhance data collection, monitoring, and reporting, ultimately improving the e ciency of trials.
After COVID-19 pandemic, remote monitoring and virtual trial designs have become increasingly important.

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These require the approval of ethics committees and local Regulatory Authorities and must be implemented with
high standards of security and privacy.

In conclusion, the ICH GCP E6(R3) guidelines represent a signi cant advancement in the eld of clinical
research. By emphasizing exibility, stakeholder engagement, innovative technologies, risk-based monitoring,
and research teams' training, the guidelines aim to enhance the quality and e ciency of clinical trials while
ensuring the protection of participants. As the landscape of clinical research continues to evolve, adherence to
these updated guidelines will be crucial for fostering trust, transparency, and collaboration among all
stakeholders involved in the clinical trial process.

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