**5. International ethical standards in medical research**

#### **5.1. History and legal basis of research ethics**

Research ethics is mostly developed as a concept in medical research, but the general principles apply for all fields of research. Informed consent and confidentiality are important for both sociological study and clinical research keeping both human and patient rights. As a reaction to malpractices that were revealed during the Nuremberg trials, the World Medical Association (established in Paris in 1947) adopted the DH in 1964, in Finland [100].

The DH stated that "for all research, the well-being of the individuals is the most important over all other interests and sets principles for medical research combined with medical care" [60].

#### **5.2. The Nuremberg Code**

The Nuremberg Code was the first international code of ethics for research on human subjects, introduced in 1947 after WWII, when the Nazi's outrageous experiments on human subjects were revealed to the world. The Nuremberg Code focused on medical research, consisting of only 10 rules which indicated the most basic and essential principles [101]. In fact, the Nuremberg Code has had a major influence on human rights law and medical ethics. In contrast, while the previous ethics codes focused on the obligations of the investigator toward the research subjects, the Nuremberg Code reverses that logic: The rights are directly awarded to the research subjects who is actually revolute to the view on research ethics [102].

#### **5.3. The Declaration of Helsinki (DH)**

**4.6. Genetic information and the privacy rule**

52 International Development

not direct identifier in Europe [95].

a person's genome strongly influence a person's health.

Research involving genetic information presents perhaps some of the most challenging areas for protecting the privacy of health information [92–94]. Recently, development makes it possible to learn a great deal about disease processes and individual variations in treatment effectiveness or susceptibility to disease from genetic analyses as the DNA sequences comprising

Human genome knowledge, combined with advances in computing capabilities, can help decipher the roles that genetics and the environment play in the origins of complex but common human diseases as cancer. Patient samples stored in bio-specimen banks can provide a wealth of information for addressing long-standing questions about health and disease, and efforts are underway to create large genomic databases for that purpose [74, 94]. These data are of paramount importance for any community that could affect the national security. Based on the strict privacy rules inside the European Union than the United States, DNA is

Genetic information does not itself identify an individual in the absence of other identifying information. Person's genetic code could be interpreted as a unique identifier and used to

The NIH starts requiring data from the Genome-Wide Association Study in January 2008. That database became publicly accessible until August 2008 then NIH removed the database from the public Website regarding patient privacy [95, 98]. Those concerns stemmed from a study showing that a new type of DNA analysis could confirm the identity of an individual in a pool of similarly masked data if that person's genetic profile was already known [99]. NIH intends to move the aggregate genotype data to a secure, controlled-access database with

Research ethics is mostly developed as a concept in medical research, but the general principles apply for all fields of research. Informed consent and confidentiality are important for both sociological study and clinical research keeping both human and patient rights. As a reaction to malpractices that were revealed during the Nuremberg trials, the World Medical

The DH stated that "for all research, the well-being of the individuals is the most important over all other interests and sets principles for medical research combined with medical care" [60].

The Nuremberg Code was the first international code of ethics for research on human subjects, introduced in 1947 after WWII, when the Nazi's outrageous experiments on human

match a sequence in another databank, which includes identifiers [96, 97].

policies for review and approval of data access requests in very strict manner [98].

Association (established in Paris in 1947) adopted the DH in 1964, in Finland [100].

**5. International ethical standards in medical research**

**5.1. History and legal basis of research ethics**

**5.2. The Nuremberg Code**

The World Medical Association (WMA) introduced the DH in 1964 to provide additional guidance for researchers beyond what was included in the Nuremberg Code [103]. Hence, the Declaration is longer and more detailed (37 articles) than the Nuremberg Code (10 articles). Since the publication of the DH, it has been amended nine times, most recently in October 2013 [104]. The DH is considered the best-known and most widely available guideline in medical research ethics [104].

The DH covers a broad assortment of topics such as privacy and confidentiality, research oversight, protocol development, protection of vulnerable subjects, publication, scientific design, the use of placebos, and access to treatments [104]. In many countries, the HD has been enacted as law (such as the Nuremberg Code in some U.S. courts), and adherence to its principles is a requirement of many national and international guidelines [105].

#### **5.4. International Ethical Guidance from the Council for International Organizations of Medical Sciences (CIOMS)**

The CIOMS was formally constituted by the WHO and the United Nations Educational, Scientific, and Cultural Organization (UNESCO) in 1949, and it still remains under the aegis of these two specialized UN agencies. In 1982, CIOMS proposed the International Ethical Guidelines for Biomedical Research Involving Human Subjects. The purpose of these guidelines was to indicate how the ethical principles that were set forth in the 1975 version of the DH could be effectively applied. Emphasis was on application in developing countries, given their socioeconomic circumstances, laws, regulations, and executive and administrative arrangements. The guidelines were revised in 1993 and in 2002 [106]. The CIOMS guidelines are more detailed than the DH. They consist of 21 articles with many commentaries for each article which explain in detail many different situations. The CIOMS guidelines have had covered the topics of ethical justification and scientific validity of research, ethical review committees, informed consent registration, susceptibility of individuals, risk/benefits relationship, choice of control in clinical trials, privacy, compensation for injury in research, and national capacity to provide healthcare services [107].

In the meanwhile, the agreement on Human Rights and Biomedicine or the Oviedo Convention, adopted by the Ministers of the Council of Europe in 1996, stated that there is a strong connection between research ethics and human rights [108–110]. Including the primacy of the interest and human well-being, informed consent, and privacy are the corners of the research. The agreement sets standards for the use of the human genome and human embryos research [111].

UNESCO's Universal Declaration on Bioethics and Human Rights and CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects are all other important international declarations and agreement [112, 113].

Within the European regulatory framework, research ethics is based on the evident European commitment to human rights. Firmly enshrined in the treaties, compliance with human rights is fundamental for all European policy domains [114].

#### **5.5. Informed consent and conflict of obligations**

Informed consent constitutes the cornerstone of research ethics in human subjects. It is the most important to recognize that there are differences between informed consent for participation in research and informed consent for patient care. Its importance is to unravel the gray zone especially in vulnerable groups [115, 116].

A great problem occurred when the doctor is both the investigator and the provider of patient care [115, 116], especially in developing countries where it may be impossible to separate the roles of investigator and care giver. In this case, the conflict of interest in many occasions could be obvious concerning that in developing countries grossly inadequate health care resources and the pressures to enroll research subjects may concentrate more on patients' best interests [117].

Informed consent is basic requirement in research involving human being, research, genetic material or biological samples, and data collection. The rights and interests of the research subjects are fully respected especially during children research [117, 118], vulnerable adults (elderly, prisoners, mentally deficient persons, comatose, severely injured patients, and psychiatric patients), and people with certain cultural, religious, or traditional backgrounds [118].

There are various requirements for a valid informed consent that must be fulfilled, such as the four requirements that Jennifer S. Hawking explains per her quotation: "*First*, only those potential subjects who pass the requirements for decision-making competence should be asked to give consent (when it is necessary to enroll incompetent subjects an appropriate surrogate must give consent). *Second*, there must be full disclosure of all the relevant information, *Third*, the subject or surrogate must understand the information, and *Fourth*, he or she must then consent freely or voluntarily" [119].

Shamoo and Resnik specify three challenges of acquiring informed consent in developing countries. *First*, there is the possible presence of linguistic barriers that might make it difficult to acquire effective consent. It can be necessary to use interpreters in order to converse with subjects in their native language and translations of consent documents, and other material such as brochures, questionnaires, and visual aid must be produced. Some words may not translate easily into different languages which may affect interpretation of the text presented to the subjects. Furthermore, some populations may have no written language, so use of a consent form or other such document can be problematic [77]. The *second* challenge is that there can be conceptual or cultural obstacles to effective consent. People from developing and unindustrialized countries may have little comprehension of Western concepts such as disease, cause and effect, genetics/DNA, virus, bacteria, and so on.

In order to assure that the requirement of full understanding is met, it is necessary to adapt the form and content of procedures for obtaining informed consent to the educational level of the potential subjects of research [78]. *Third* and last, many African nations consist of tribal governance. The leaders of the tribe may need to give permission before any member of the tribe can be recruited into a study and the members may not believe they have any right to decide by themselves whether to participate or not. They may not even comprehend the notion of individual decision [77].

Ethical relativists have used cultural differences, like lack of understanding of the concept "individual consent," as a defense for departing from widely accepted ethical standards for informed consent. Furthermore, in developing countries, women are sometimes thought of as less than men and their husbands sometimes make all the decisions, even those that only affect their wife's health and her enrolment in medical studies [78].

#### **5.6. Animal research ethics**

UNESCO's Universal Declaration on Bioethics and Human Rights and CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects are all other important

Within the European regulatory framework, research ethics is based on the evident European commitment to human rights. Firmly enshrined in the treaties, compliance with human rights

Informed consent constitutes the cornerstone of research ethics in human subjects. It is the most important to recognize that there are differences between informed consent for participation in research and informed consent for patient care. Its importance is to unravel the gray

A great problem occurred when the doctor is both the investigator and the provider of patient care [115, 116], especially in developing countries where it may be impossible to separate the roles of investigator and care giver. In this case, the conflict of interest in many occasions could be obvious concerning that in developing countries grossly inadequate health care resources and the pressures to enroll research subjects may concentrate more on patients'

Informed consent is basic requirement in research involving human being, research, genetic material or biological samples, and data collection. The rights and interests of the research subjects are fully respected especially during children research [117, 118], vulnerable adults (elderly, prisoners, mentally deficient persons, comatose, severely injured patients, and psychiatric patients), and people with certain cultural, religious, or traditional backgrounds [118]. There are various requirements for a valid informed consent that must be fulfilled, such as the four requirements that Jennifer S. Hawking explains per her quotation: "*First*, only those potential subjects who pass the requirements for decision-making competence should be asked to give consent (when it is necessary to enroll incompetent subjects an appropriate surrogate must give consent). *Second*, there must be full disclosure of all the relevant information, *Third*, the subject or surrogate must understand the information, and *Fourth*, he or she must

Shamoo and Resnik specify three challenges of acquiring informed consent in developing countries. *First*, there is the possible presence of linguistic barriers that might make it difficult to acquire effective consent. It can be necessary to use interpreters in order to converse with subjects in their native language and translations of consent documents, and other material such as brochures, questionnaires, and visual aid must be produced. Some words may not translate easily into different languages which may affect interpretation of the text presented to the subjects. Furthermore, some populations may have no written language, so use of a consent form or other such document can be problematic [77]. The *second* challenge is that there can be conceptual or cultural obstacles to effective consent. People from developing and unindustrialized countries may have little comprehension of Western concepts such as

disease, cause and effect, genetics/DNA, virus, bacteria, and so on.

international declarations and agreement [112, 113].

is fundamental for all European policy domains [114].

**5.5. Informed consent and conflict of obligations**

zone especially in vulnerable groups [115, 116].

then consent freely or voluntarily" [119].

best interests [117].

54 International Development

In Europe, the Commission report estimates that over 12 million animals are used for experimental or other scientific purposes each year. The most common used animals for these purposes are rodents, rabbits, mice, and rats [120].

The European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, adopted in 1986, is the first important document protecting the animals used in experiments [114]. This directive since its application in 1986 is meant to ensure the protection of animals used in experiments or for other scientific purposes and sets standards for control on the use of laboratory animals, housing and care of the animals, and for the training of the personnel involved in the animal testing [114]. Apart from setting standards, the directive aims at reducing the numbers of animals used for experiments, following the concept of the "Three R's (replacement, reduction, and refinement)."

For the Ethics Review organized by the European Commission, the researcher should provide all the details of the species (and strains) used, justify why they are used, explain why the anticipated benefits of the research justify the use of animals, and why methods avoiding the use of animals cannot be used [114, 115]. National authorities are responsible for the implementation of the Directive on the Protection of Animals [114].

#### **5.7. Twelve golden rules to ethical research conduct**

According to the 12 golden rules, each researcher must ensure that his/her research will fulfill the following criteria [114, 121]:

Respects the persons before, during, and after the research, follow the "Do no harm" principle, realize the rights of individuals to privacy, personal data protection and freedom of movement, informed consent for human being research, treat animals with respect following the three Rs: Replacement, Reduction, and Refinement when designing animal research, never misuse terrorists or military organizations, respect integrity of an individual and that any modification (genetic or technological) does not interfere with this principle, always respect environment biodiversity, and finally build on the understanding that any benefits are for the good of the society [122–124].
