Evaluation of the Research Protocol by Ethical Committee

*Paulo Santos, Pedro Teixeira, Helena Beça and Alberto Hespanhol*

#### **Abstract**

Nowadays, the submission of a research project to an ethical committee and its approval is mandatory. However, researchers often overlook this obligation, because they are too engaged in the design and the process of construction of the study, because of the common tight deadlines, and many times because some devaluation of the role of the committee. Based on our experience of 10 years working in an ethical committee, we propose a way to get close researchers and evaluators, respecting their own aims but bringing them together as partners in the investigation process, protecting patients' values, at the same time that makes it possible to implement strategies to answer to the research question and to create useful knowledge. Our aim is to smoothen the way researchers look to the ethical committee and, at the same time, to make them understand what really is at stake. Ethics should be a commitment for all and not an obligation.

**Keywords:** ethics, ethics committees, research, ethical analysis, beneficence, personal autonomy

#### **1. Introduction**

Medicine is born from the human need to survive to diseases. At first, someone within the tribe began to realize the constellation of symptoms and signs that defined the diagnosis, for which a proper treatment could make the difference in the course of the disease. The so-defined medical act gave him the mastery over life and death. The awareness of this power has given rise to a set of self-regulating norms, early transmitted to the disciples who applied to learn the noble art of healing. This ethical code became known as the Hippocratic oath of the School of Kos, in honor to Hippocrates, the father of scientific medicine, known for having received himself the knowledge from the hands of Asclepius the Greek god of medicine [1].

Based on a solid knowledge derived from the scientific method, medicine commits itself to the patient and society in simple but basic principles of beneficence, nonmaleficence, justice, truth, confidentiality, and respect for the human being. This commitment should be enough to ensure unblemished medical practice, both in the care and, no less important, in the research and experimentation.

But the twentieth century and the horrors exposed by the Holocaust of the Second Great War came to demonstrate that it was not enough.

On August 8, 1945, the countries that formed the Allied Forces in World War II signed the constitution agreement of the International Military Tribunal, to

prosecute the Nazi officers on charges of committing peace crimes, war crimes, and crimes against humanity (Control Council Law No. 10: Punishment of persons guilty of war crimes, crimes against peace and humanity). The initial trial in the city of Nuremberg, Germany, was followed by 12 other trials until 1949. The first of these trials became known as the medical case and resulted in the conviction of 16 of the 23 defendants for their involvement, among others, in research projects (high-altitude experiments; freezing experiments; malaria experiments; mustard gas experiments; sulfanilamide experiments; bone, muscle, and nerve regeneration experiments; bone transplantation experiments; seawater experiments; epidemic hepatitis experiments; sterilization experiments; vaccination experiments for yellow fever, smallpox, typhus and other rickettsiosis, paratyphoid A and B, cholera, and diphtheria; poison experiments; and incendiary bomb experiments) [2].

The question wasn't the possibility of conducting research in human beings but the way and circumstances under which it was done. This court had to define what were the permissible medical experiments, in accordance with ethics, morals, and law. The 10 principles emanating from this court formed the first code of ethical appreciation for research involving humans [2], later developed and extended in its application by the World Medical Association's Declaration of Helsinki (1964) [3]. Nevertheless, ethical evaluation was still a commitment of the investigators. The case of Tuskegee, USA, syphilis experience (1932–1972) has warned of the need for direct follow-up and the establishment of independent committees able to ensure the appraisal, evaluation, and guidance of research protocols, as proposed by the following Belmont Report [4]. The increasing complexity of ethical problems with the advance of knowledge has dictated the structuring of responses at the national level. In 1983, in France, President François Mitterrand established the "Consultatif National d'Ethique Committee," the first ethics committee for health and life sciences, with the mission to opine on ethical and social problems arising from progress in the fields of biology, medicine, and health. The increased specificity of experimental research in the new treatments has led to the establishment of research ethics committees with the highest technical capacity to fulfill their mission (US Institutional Review Boards, and the Ethics Committees for Clinical Research in Europe).

### **2. The ethical principle**

The ethics committees are now multidisciplinary boards, including medicine, nursing, social work, law, pastoral care, healthcare administration, and various specialty areas. Their role includes the ethics education, policy formation and review, ethics consultation, and research ethics [5]. In clinical investigation, every protocol must be submitted previously to the beginning of the study for consideration, comment, guidance, and approval. The ethics committees must be independent of the researcher, the promoter, and the sponsor and transparent in their function [6].

The ethics committees for health, especially in the context of clinical research, are thus born not from an internalization of the need for self-regulation but from an external, regulatory, and legal imposition. Since the beginning, they assume a problem-solving police nature that they rarely escape, as their mission includes the laws and regulations as well as applicable international norms and standards. It is common that the ethics committees focus much attention on legal and procedural aspects, answering to this feature, more than applying an individualistic appraisal of the factual project. Consequently, the researchers look at them more as obstacles to the execution of projects than as partners in their implementation.

**95**

*Evaluation of the Research Protocol by Ethical Committee*

daily care they need, or in participating in a research project.

Ethic must be above the law, respecting it, but discussing it and framing it towards the specific case [7], keeping in mind the protection of the human being. The primacy of ethics, which compromises us all, is certainly not the primacy of the ethics committees, as if they were the exclusive holders of the absolute truth, or its juridical version. The ethical appraisals must return to the Hippocratic matrix of the basic ethical principles to find their guiding path, combining the need for innovation and development in health, through research strategies, with respect for the human being in his or her dignity and vulnerability, in health or in illness, in the

The ethical principles were defined in 1971 by Thomas Beauchamp and James Childress [8]. Beneficence, non-maleficence, justice, and autonomy had become the basis of bioethical decision-making in the last 50 years. Despite the heated discussion about their interpretation, importance, and role of each one, they remain the most internationally accepted. Nevertheless, there's some controversy about their inability to answer to all the challenges posed by the complexity of current biomedical decisions. The same principles were adopted by clinical research as a key for ethical evaluation, ensuring the protection of the rights of participants. But there are several

Beneficence refers to the promotion of the best practices to improve the patient. However, many times, the beneficiary of the results in a research project is not the participant but the all other population that will receive the medicine under tests [9]. The principle of non-maleficence derives from the Hippocratic sentence of "primum non nocere," which means that doctor abstains from practice that put patients under danger. Although we may argue that the risk of harm is under control, we cannot guarantee for certain even in observational research. The principle of justice and equity reminds us to provide the best treatments to those who really need them. The randomization of the sample removes any selective allocation criteria. The autonomy respects the patient's freedom of choice, based on a sufficient given information. The informed consent freely expressed gives legitimacy to the inclusion of participants. Although the guaranties of the possibility of self-exclusion, no one really wants that to happen, which may compromise the very principle. The definition of autonomy has evolved over the last years, as the boundaries for information and self-determination, leading to structured forms almost widely accepted, but depersonalized and

Over time, other ethical principles have been defined and applied in scientific research. As ethical principles, by definition, require action, new procedures have been adopted to ensure respect for the participants in investigation protocols.

In 1978, the Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research [4] described the ethical principles for research in human beings: beneficence, justice, and the respect for the person. The respect for the participant implies that researcher must recognize the subjects' autonomy to their own will and assume the duty to protect the

In the 1998 Barcelona Declaration, a panel of experts defined the principles of autonomy, dignity, integrity, and vulnerability [10]. Autonomy comes up as an ideal to reach. Dignity is an intrinsic value of the individual, meeting himself with others. Integrity is the right to inviolability, implying the respect for privacy, personal ideas and expectations, and for patient's understanding of his own life and illness. Vulnerability expresses the susceptibility to be hurt. It is commonly understood as the condition of a patient before the threat of disease. In investigation, vulnerability refers to the fragility of participants before the methods. It implies the duty of not to harm the integrity of the participants and, at the same time, to protect their integrity. Classically, we consider children, pregnant women, and elders, but there

*DOI: http://dx.doi.org/10.5772/intechopen.92265*

differences in their application.

eventually far from the participant.

most vulnerable.

#### *Evaluation of the Research Protocol by Ethical Committee DOI: http://dx.doi.org/10.5772/intechopen.92265*

*Bioethics in Medicine and Society*

bomb experiments) [2].

Research in Europe).

**2. The ethical principle**

prosecute the Nazi officers on charges of committing peace crimes, war crimes, and crimes against humanity (Control Council Law No. 10: Punishment of

persons guilty of war crimes, crimes against peace and humanity). The initial trial in the city of Nuremberg, Germany, was followed by 12 other trials until 1949. The first of these trials became known as the medical case and resulted in the conviction of 16 of the 23 defendants for their involvement, among others, in research projects (high-altitude experiments; freezing experiments; malaria experiments; mustard gas experiments; sulfanilamide experiments; bone, muscle, and nerve regeneration experiments; bone transplantation experiments; seawater experiments; epidemic hepatitis experiments; sterilization experiments; vaccination experiments for yellow fever, smallpox, typhus and other rickettsiosis, paratyphoid A and B, cholera, and diphtheria; poison experiments; and incendiary

The question wasn't the possibility of conducting research in human beings but the way and circumstances under which it was done. This court had to define what were the permissible medical experiments, in accordance with ethics, morals, and law. The 10 principles emanating from this court formed the first code of ethical appreciation for research involving humans [2], later developed and extended in its application by the World Medical Association's Declaration of Helsinki (1964) [3]. Nevertheless, ethical evaluation was still a commitment of the investigators. The case of Tuskegee, USA, syphilis experience (1932–1972) has warned of the need for direct follow-up and the establishment of independent committees able to ensure the appraisal, evaluation, and guidance of research protocols, as proposed by the following Belmont Report [4]. The increasing complexity of ethical problems with the advance of knowledge has dictated the structuring of responses at the national level. In 1983, in France, President François Mitterrand established the "Consultatif National d'Ethique Committee," the first ethics committee for health and life sciences, with the mission to opine on ethical and social problems arising from progress in the fields of biology, medicine, and health. The increased specificity of experimental research in the new treatments has led to the establishment of research ethics committees with the highest technical capacity to fulfill their mission (US Institutional Review Boards, and the Ethics Committees for Clinical

The ethics committees are now multidisciplinary boards, including medicine, nursing, social work, law, pastoral care, healthcare administration, and various specialty areas. Their role includes the ethics education, policy formation and review, ethics consultation, and research ethics [5]. In clinical investigation, every protocol must be submitted previously to the beginning of the study for consideration, comment, guidance, and approval. The ethics committees must be independent of the researcher, the promoter, and the sponsor and transparent in their function [6]. The ethics committees for health, especially in the context of clinical research, are thus born not from an internalization of the need for self-regulation but from an external, regulatory, and legal imposition. Since the beginning, they assume a problem-solving police nature that they rarely escape, as their mission includes the laws and regulations as well as applicable international norms and standards. It is common that the ethics committees focus much attention on legal and procedural aspects, answering to this feature, more than applying an individualistic appraisal of the factual project. Consequently, the researchers look at them more as obstacles

to the execution of projects than as partners in their implementation.

**94**

Ethic must be above the law, respecting it, but discussing it and framing it towards the specific case [7], keeping in mind the protection of the human being. The primacy of ethics, which compromises us all, is certainly not the primacy of the ethics committees, as if they were the exclusive holders of the absolute truth, or its juridical version. The ethical appraisals must return to the Hippocratic matrix of the basic ethical principles to find their guiding path, combining the need for innovation and development in health, through research strategies, with respect for the human being in his or her dignity and vulnerability, in health or in illness, in the daily care they need, or in participating in a research project.

The ethical principles were defined in 1971 by Thomas Beauchamp and James Childress [8]. Beneficence, non-maleficence, justice, and autonomy had become the basis of bioethical decision-making in the last 50 years. Despite the heated discussion about their interpretation, importance, and role of each one, they remain the most internationally accepted. Nevertheless, there's some controversy about their inability to answer to all the challenges posed by the complexity of current biomedical decisions.

The same principles were adopted by clinical research as a key for ethical evaluation, ensuring the protection of the rights of participants. But there are several differences in their application.

Beneficence refers to the promotion of the best practices to improve the patient. However, many times, the beneficiary of the results in a research project is not the participant but the all other population that will receive the medicine under tests [9]. The principle of non-maleficence derives from the Hippocratic sentence of "primum non nocere," which means that doctor abstains from practice that put patients under danger. Although we may argue that the risk of harm is under control, we cannot guarantee for certain even in observational research. The principle of justice and equity reminds us to provide the best treatments to those who really need them. The randomization of the sample removes any selective allocation criteria. The autonomy respects the patient's freedom of choice, based on a sufficient given information. The informed consent freely expressed gives legitimacy to the inclusion of participants. Although the guaranties of the possibility of self-exclusion, no one really wants that to happen, which may compromise the very principle. The definition of autonomy has evolved over the last years, as the boundaries for information and self-determination, leading to structured forms almost widely accepted, but depersonalized and eventually far from the participant.

Over time, other ethical principles have been defined and applied in scientific research. As ethical principles, by definition, require action, new procedures have been adopted to ensure respect for the participants in investigation protocols.

In 1978, the Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research [4] described the ethical principles for research in human beings: beneficence, justice, and the respect for the person. The respect for the participant implies that researcher must recognize the subjects' autonomy to their own will and assume the duty to protect the most vulnerable.

In the 1998 Barcelona Declaration, a panel of experts defined the principles of autonomy, dignity, integrity, and vulnerability [10]. Autonomy comes up as an ideal to reach. Dignity is an intrinsic value of the individual, meeting himself with others. Integrity is the right to inviolability, implying the respect for privacy, personal ideas and expectations, and for patient's understanding of his own life and illness. Vulnerability expresses the susceptibility to be hurt. It is commonly understood as the condition of a patient before the threat of disease. In investigation, vulnerability refers to the fragility of participants before the methods. It implies the duty of not to harm the integrity of the participants and, at the same time, to protect their integrity. Classically, we consider children, pregnant women, and elders, but there

are many other ways of turning vulnerable, such as the invitation to participate in a research of the doctor to his patient.

More than the statement in the ethical issues of a paper, assuring that the authors were committed with Declaration of Helsinki and Oviedo Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine, researchers should incorporate the ethical principles since the formulation of the research question and in the entire definition of study design and results analysis, in the assumptions they make, and in the decisions they take.

### **3. Checklist of the ethical appraisal**

The ethical appraisal of a research protocol often starts with a descriptive characterization of the study. Checking the presence or absence of certain elements in the protocol may assist this task. **Table 1** presents the checklist of ethical appraisal. It does not pretend to be a definitive tool of decision, since the ethical appraisal of a research protocol is not an assignment that may be reduced to a checklist. This table should be perceived as a summary tool to help structure and guide critical thinking regarding ethical research assessment.

Overall the research protocol proposal is assessed for its merit and integrity alongside with the description of appropriate and rigorous methods and procedures committed to non-maleficence. The use of sound scientific methods is warranted. Although this is not the main focus of the consideration it is important to assure that the use of resources and enrolment of participants is based on solid scientific grounds. Additionally, appropriate academic conduct in terms of references


**97**

subsequent follow-up.

and authorship authorizations in the use of tools and instruments for research is required. The main focus of attention is usually placed in all the interactions with participants. From first contact where the study is presented to enrollment in the study followed by all the activities required to the end of the study and eventual

**Data analysis** Yes No **Merit and integrity**

Exploratory • Detailed explanation of statisti-

*Evaluation of the Research Protocol by Ethical Committee*

**Data collection** Yes No

**Data storage** Yes No

**Participant safety** Yes No

**Reporting** Yes No

**Funding** Yes No

**Participants enrolment** Yes No **Non-maleficence**

• Consideration of benefits and costs (risks) weighting for individual and for community interests is expected • Commitment to respect the integrity, dignity and autonomy of participants is expected • Appropriate informed consent presentation is expected • Appropriate procedure of data protection is expected • Appropriate procedure for adverse event reporting is

cal analytical plan is expected (viz., identifying all variables and statistical tests use) • Commitment to report and make results public is expected • Declaration of any conflict of interest is expected

expected

*DOI: http://dx.doi.org/10.5772/intechopen.92265*

Clear description of the procedure to

**Ethical appraisal**

enroll participants

*Questionnaire Individual interview*

*other bodily fluids)*

*participants*

management

participants

events

anxiety)

applicable)

Prespecified

protocol

research

**Table 1.**

Gathering data from people

*Group interview (e.g., focus group) Biological sampling (blood, urine, saliva, sputum, feces, semen, tissue or* 

Gathering data from clinical records *Anonymized or pseudonymized data Written informed consent from* 

Safety measures for database

Written informed consent from

Procedure for reporting of adverse

Identification of possible risks or harm to participants (e.g., stress or

Insurance (intervention studies, if

Publication or registry of the

Intention to publish the study

Funding protocol (if applicable)

*Checklist of the ethical appraisal.*

Compromise to send a report of the

*Bioethics in Medicine and Society*

decisions they take.

**Ethical appraisal**

vitae

literature

questions

*Pre-post intervention Control group* Observational *Cohort Case–control Cross-sectional Qualitative*

*Mixed methodology*

Other

Individual researchers curriculum

Coherent rationale supported by

Clear and answerable research

*Validation (e.g., scale development)*

**Problem** Yes No

**Questions** Yes No

research of the doctor to his patient.

**3. Checklist of the ethical appraisal**

regarding ethical research assessment.

are many other ways of turning vulnerable, such as the invitation to participate in a

The ethical appraisal of a research protocol often starts with a descriptive characterization of the study. Checking the presence or absence of certain elements in the protocol may assist this task. **Table 1** presents the checklist of ethical appraisal. It does not pretend to be a definitive tool of decision, since the ethical appraisal of a research protocol is not an assignment that may be reduced to a checklist. This table should be perceived as a summary tool to help structure and guide critical thinking

Overall the research protocol proposal is assessed for its merit and integrity alongside with the description of appropriate and rigorous methods and procedures committed to non-maleficence. The use of sound scientific methods is warranted. Although this is not the main focus of the consideration it is important to assure that the use of resources and enrolment of participants is based on solid scientific grounds. Additionally, appropriate academic conduct in terms of references

**Research team** Yes No **Merit and integrity**

**Design** Yes No **Appropriate and rigorous** Experimental • Coherence between research

• Research team CVs are expected to demonstrate capacity to develop the study

• Relevance and feasibility of the

questions and research design is

• Efficient resource allocation is

• Appropriate bias identification and mitigation strategies are

study is expected

expected

expected

expected

More than the statement in the ethical issues of a paper, assuring that the authors were committed with Declaration of Helsinki and Oviedo Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine, researchers should incorporate the ethical principles since the formulation of the research question and in the entire definition of study design and results analysis, in the assumptions they make, and in the

**96**


#### **Table 1.**

*Checklist of the ethical appraisal.*

and authorship authorizations in the use of tools and instruments for research is required. The main focus of attention is usually placed in all the interactions with participants. From first contact where the study is presented to enrollment in the study followed by all the activities required to the end of the study and eventual subsequent follow-up.
