Human subject research

Human subject research is systematic, scientific investigation that can be either interventional (a “trial”) or observational (no “test article”) and involves human beings as research subjects. Human subject research can be either medical (clinical) research or non-medical (e.g., social science) research.[1] Systematic investigation incorporates both the collection and analysis of data in order to answer a specific question. Medical human subject research often involves analysis of biological specimens, epidemiological and behavioral studies and medical chart review studies.[1] (A specific, and especially heavily regulated, type of medical human subject research is the "clinical trial", in which drugs, vaccines and medical devices are evaluated.) Human subject research in the social sciences often involves surveys, questionnaires, interviews, and focus groups.


Human subjects
The United States Department of Health and Human Services (DHHS) defines a human research subject as a living individual about whom a research investigator (whether a professional or a student) obtains data through 1) intervention or interaction with the individual, or 2) identifiable private information (32 CFR 219.102.f).(Lim,1990) [2] As defined by DHHS regulations: "Intervention"-physical procedures by which data is gathered and the manipulation of the subject and/or their environment for research purposes [45 CFR 46.102(f) [2] "Interaction"-communication or interpersonal contact between investigator and subject [45 CFR 46.102(f)]) [2] "Private Information"-information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public [45 CFR  46.102(f)] )] [2] "Identifiable information"-specific information that can be used to identify an individual [2]

Human subject rights
In 2010, the National Institute of Justice in the United States published recommended rights of human subjects: • Voluntary, informed consent • Respect for persons: treated as autonomous agents • The right to end participation in research at any time [3] • Right to safeguard integrity [3] • Benefits should outweigh cost • Protection from physical, mental and emotional harm • Access to information regarding research [3] • Protection of privacy and well-being [4] 2 Ethical guidelines Main article: Guidelines for human subject research Ethical guidelines that govern the use of human subjects in research are a fairly new construct.In 1906 some regulations were put in place in the United States to protect subjects from abuses.After the passage of the Pure Food and Drug Act in 1906, regulatory bodies were gradually institutionalized such as the Food and Drug Administration (FDA) and the Institutional Review Board (IRB).The policies that these institutions implemented served to minimize harm to the participant's mental and/or physical well being.

Nuremberg Code
Main article: Nuremberg Code In 1947, German physicians who conducted deadly or debilitating experiments on concentration camp prisoners were prosecuted as war criminals in the Nuremberg Trials.That same year, the Allies established the Nuremberg Code, the first international document to support the concept that "the voluntary consent of the human subject is absolutely essential".Individual consent was emphasized in the Nuremberg Code in order to prevent prisoners of war, patients, prisoners, and soldiers from being coerced into becoming human subjects.In addition, it was emphasized in order to inform participants of the risk-benefit outcomes of experiments.

Declaration of Helsinki
Main article: Declaration of Helsinki The Declaration of Helsinki was established in 1964 to regulate international research involving human subjects.
Established by the World Medical Association, the declaration recommended guidelines for medical doctors conducting biomedical research that involves human subjects.Some of these guidelines included the principles that "research protocols should be reviewed by an independent committee prior to initiation" and that "research with humans should be based on results from laboratory animals and experimentation".
3 History of medical abuse of human subjects

18th-19th century
Human subject research experiments were recorded during vaccination trials in the 18th century as doctors struggled to find a preventive of smallpox, which had very high mortality rates.In these early trials, physicians used themselves or their slaves as test subjects.Experiments on others were often conducted without informing the subjects of dangers associated with such experiments.A famous example of such research were the Edward Jen-ner experiments, where he tested smallpox vaccines on his son and neighbourhood children.

World War II
Jewish twins were kept alive to be used in Josef Mengele's medical experiments.These children from Auschwitz were liberated by the Red Army in January 1945.

Japanese Unit 731 Complex that used humans for experimentation for biological and chemical weapons, as well as live vivisections and other experiments
Several nations conducted experiments on human subjects before and during the war, justifying it on grounds of war exigency.

United Kingdom
De-classified documents of the National Archives revealed that during the 1930s and 1940s, the British Army used hundreds of Irish and native British Indian Army soldiers as "guinea pigs" in their experiments to determine if mustard gas inflicted greater damage on Indian skin compared to British skin.It is unclear whether the trial subjects, some of whom were hospitalised by their injuries, were all volunteers. [5]

United States
Main article: Unethical human experimentation in the United States Fort Detrick in Maryland was the headquarters of US biological warfare experiments.Operation Whitecoat involved the injection of infectious agents into military forces to observe their effects in human subjects. [6]

Japan
Human subject research in Japan began in World War II.It continued for some years after.During the American occupation of Japan, General Douglas MacArthur gave immunity from prosecution to those Japanese who conducted human research, in exchange, the Japanese gave all of the results of their experiments to the United States. [7]it 731, a department of the Imperial Japanese Army located near Harbin (then in the puppet state of Manchukuo, in northeast China), experimented on prisoners by conducting vivisections, dismemberments, and bacterial inoculations.It induced epidemics on a very large scale from 1932 onward through the Second Sino-Japanese war. [7]It also conducted biological and chemical weapons tests on prisoners and captured POWs.With the expansion of the empire during World War II, similar units were set up in conquered cities such as Nanking (Unit 1644), Beijing (Unit 1855), Guangzhou (Unit 8604) and Singapore (Unit 9420).After the war, Supreme Commander of the Occupation Douglas MacArthur gave immunity in the name of the United States to Shiro Ishii and all members of the units in exchange for all of the results of their experiments. [7]e United States blocked Soviet access to this information.The Soviets prosecuted some of the Unit 731 members during its Khabarovsk War Crime Trials.
In November 2006, Doctor Akira Makino confessed to Kyodo news that he had performed surgery and amputations on condemned prisoners, including women and children, in 1944 and 1945 while he was stationed on Mindanao. [8]] In 2007, Doctor Ken Yuasa testified to The Japan Times and said that he believes that at least 1,000 persons working for the Shōwa regime, including surgeons, conducted surgical research on mainland China. [14] incidents throughout the 1950s, former Unit 731 members infected prisoners and mental health patients with deadly diseases. [15]In 1958, a large number of infants were brought to Kobe Medical School and forcibly administered sugar by having needles inserted through their noses and into their stomachs.A tube was inserted into their anuses to determine how the sugar was processed by their digestive systems.Many of the infants experienced diarrhea and anal bleeding.The parents were never informed that their children were being used as test subjects. [16]

Germany
Namibian sterilization Dr. Eugen Fischer began sterilization experimentation in German-occupied South West Africa during World War I.A supporter of forced sterilization as a means to prevent the growth of inferior populations and a member of the Nazi Party, Eugen focused his experimentation on mixed-race children in order to justify the Nazi Party's ban on interracial marriage.As a result of Fischer's research in Namibia, Germany prohibited marriages between people of different races in its colonies. [17]

Main articles: Nazi human experimentation and Doctors' Trial
Testimony at the Nuremberg Trials after World War II revealed that Dr. Josef Mengele had conducted medical experiments on numerous prisoners and especially Jewish, Gypsy and other children in Nazi concentration camps.The Allies developed the Nuremberg Code to try to prevent such abuses in the future . [18]During the Nuremberg Trials, 23 Nazi doctors and scientists were prosecuted for the unethical treatment of concentration camp inmates, who were often used as research subjects with fatal consequences.Of those 23, 15 were convicted, 7 were condemned to death, 9 received prison sentences from 10 years to life, and 7 were acquitted. [19]3 Post World War II

Main article: Syphilis experiments in Guatemala
From 1946 to 1948 U.S. scientific researchers in Guatemala infected hundreds of mental patients with sexually transmitted diseases (STD).Researchers from the U.S. Public Health Service (PHS) conducted experiments on approximately 1,500 male and female patients housed at Guatemala's National Mental Health Hospital. [20]The scientists injected the patients with gonorrhea and syphilis-and encouraged many of them to pass the disease on to others.The experiments were done in cooperation with the Guatemalan government.
The PHS carried out the experiments under the guise of syphilis inoculations.In 2010 these experiments were re-vealed by Susan Reverby of Wellesley College, who was researching a book on the Tuskegee syphilis experiments.
The US Secretary of State Hillary Clinton issued an official apology to Guatemala. [21]President Barack Obama apologized to President Álvaro Colom, who had called these experiments 'a crime against humanity'. [22]

Sweden
In Sweden, the Vipeholm experiments were conducted.Mentally handicapped test subjects were exposed to large amounts of sugar to induce dental caries.

United Kingdom
In the United Kingdom (voluntary) human experimentation at Porton Down in the 1950s, led to the death of Ronald Maddison.

Beecher Paper
In a 1966 paper noted British anesthesiologist Henry K. Beecher described 22 published medical studies in which patients had been subjects with no expected benefit to the patient of the experiment. [23]This has been characterized as unethical.For example, patients infused with live cancer cells had been told in one study that they were receiving "some cells," without being told this was cancer.Though identities of the authors and institutions had been stripped, the 22 studies were later identified as having been conducted by mainstream researchers and published in prestigious journals within approximately the previous decade.The 22 cases had been selected from a set of 50 that Beecher had collected.He presented evidence that such unethical studies were widespread and represented a systemic problem in medical research rather than exceptions. [23][24]echer had been writing about human experimentation and publicizing cases that he considered to be bad practice for nearly a decade.His 1965 briefing to science writers and his 1966 paper gained widespread news coverage and stimulated public reaction. [24][25]The paper has been described as "the most influential single paper ever written about experimentation involving human subjects." [26]The United States Office for Human Research Protections credits Beecher through this paper as "ultimately contributing to the impetus for the first NIH and FDA regulations." [27]echer was instrumental in developing solutions to such abuses.He noted that a common element in these studies was that some experimental subjects, such as military personnel or mentally handicapped children in institutions, were not in a position to freely decline consent. [24]eecher believed that rules requiring informed consent were not alone sufficient, as truly informed consent was an unattainable ideal.He worked both to define the rules and conditions for informed consent, and to establish institutional review boards as an additional layer of oversight regarding research protocols. [24][25]

United States
Main article: Unethical human experimentation in the United States Since the late 19th century, numerous human experiments were performed in the United States, which were later characterized as unethical.They were often performed illegally, without the knowledge, consent, or informed consent of the test subjects.
Examples have included the deliberate infection of people with deadly or debilitating diseases, exposing people to biological and chemical weapons, human radiation experiments, injecting people with toxic and radioactive chemicals, surgical experiments, interrogation/torture experiments, tests involving mind-altering substances, and a wide variety of others.Many of these tests were performed on children and mentally disabled individuals.In many of the studies, a large number of the subjects were poor, racial minorities, and/or prisoners.
Often, subjects were sick or disabled people, whose doctors told them that they were receiving "medical treatment."They were used as the subjects of harmful and deadly experiments, without their knowledge or consent.
In reaction to this, interest groups and institutions have worked to design policies and oversight to ensure that future human subject research in the United States would be ethical and legal.
Public outcry over the discovery of government experiments on human subjects led to numerous congressional investigations and hearings, including the Church Committee, Rockefeller Commission, and Advisory Committee on Human Radiation Experiments, amongst others.These inquiries have not resulted in prosecutions.Not all subjects involved in the trials have been compensated or notified that they were subjects of such trials.
In 1962, the Kefauver-Harris Drug Amendment was passed by the United States Congress.This amendment made changes to the Federal Food Drug & Consumer Act by requiring drug companies to prove both safety and effectiveness of their products.Consequently, drugs were required to have Food and Drug Administration (FDA) approval before being marketed to consumers.Additionally, informed consent became a participation requirement and rules were put into place.This regulation was influenced by the results of 1950 use of thalidomide in Western Europe for pregnant women.They were prescribed the sedative thalidomide, which was inaccurately marketed as sleeping pills.Women gave birth to more than 12,000 infants born with deformities due to effects from the drug in utero.

Tuskegee syphilis experiment Main article: Tuskegee syphilis experiment
From 1932 to 1972, the Public Health Service contracted with the Tuskegee Institute for a long-term study of syphilis.During the study, more than 600 African-American men were studied who were not told they had syphilis.In an effort to better understand the disease, researchers denied the men access to the known treatment of the antibiotic penicillin.They recorded observations of the effects of the disease over time.Under the impression they were being treated for "bad blood", the participants were given free healthcare by the government. [28]s ineffective treatment was given to the subjects, twothirds of the group had died by the end of the 40-year experiment.A leak in 1972 led to cessation of the study and severe legal ramifications.It has been widely regarded as the "most infamous biomedical research study in U.S. history". [29]cause of the public outrage over this, in 1974 Congress passed the National Research Act, to provide for protection of human subjects in experiments.The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established.It was tasked with establishing the boundary between research and routine practice, the role of riskbenefit analysis, guidelines for participation, and the definition of informed consent.Its Belmont Report established three tenets of ethical research: respect for persons, beneficence, and justice. [30]oject MKUltra Main article: Project MKUltra

International clinical drug trials 4.1 Argentina
"In 2008, in the Argentine province of Santiago del Estero, seven babies died while taking part in trials for an experimental vaccine made by GlaxoSmithKline to prevent pneumonia and related diseases." [31]

India
In 2005, the legislature repealed a 2004 law that required international companies to ensure that drugs received safety approval in their home countries before being tested in India.The number of pharmaceutical drug trials has increased in India. [32]

Africa
Since the late 20th century, African nations have often been the sites of clinical testing by large international pharmaceutical companies.In some cases, rural communities have developed iatrophobia (fear of doctors) after undergoing or learning of highly controversial medical experimentation.The fundamental distrust lies in the potential confrontation of Hobson's choice: "Experimental medicine or no medicine at all".Multiple cases of ethically questionable experiments have been documented. [33]

Depo-Provera in Zimbabwe
In the late 20th century, Depo-Provera was clinically tested on Zimbabwean women.Once approved, the drug was used as a population control measure in the 1970s.Commercial farm owners put pressure on native women workers to accept the use of Depo-Provera. [34]opulation control interests motivated many of the family planning programs.This led to its eventual ban in Zimbabwe. [34]ningitis testing in Kano, Nigeria A clinical trial in Nigeria involving the Pfizer drug Trovan to treat meningitis resulted in 200 children being disabled and the deaths of 11.Because of these casualties, the Nigerian government sued Pfizer over whether it had appropriately obtained informed consent in Kano, where the study had taken place. [35][36]Pfizer argued in court that it had met all regulations for drug testing.Many Nigerians mistrust the use of medical vaccines and also refuse to participate in medical trials. [35]V/AIDS short-course AZT testing in Zimbabwe In 1994 United States drug companies began conducting trials of the drug AZT on HIV-positive African subjects with the goal of developing treatments to reduce the transmission of HIV/AIDs during childbirth.[37] With funding from the National Institutes of Health (NIH) and Centers for Disease Control (CDC), the program tested over 17,000 Zimbabwean women for the efficacy of AZT in preventing transmission of HIV/AIDS during childbirth.Half of the women were given a placebo rather than the drug, and the subjects were not informed of the potential dangers of the treatment.According to Peter Lamptey, the head of the AIDS Control and Prevention Program, "if you interviewed the people in the study, most wouldn't understand to what they had actually consented."[37] An estimated 1000 newborns of women in the study contracted HIV/AIDS, although this could have been avoided by treating the women with known drugs.The testing was ceased in 1998 when the CDC claimed to have obtained sufficient data from experiments in Thailand.[37] 5 Other experiments

Main article: Stanford prison experiment
A study conducted by Philip Zimbardo in 1971 examined the effect of social roles on college students at Stanford University.Twenty-four male students were assigned to a random role of a prisoner or guard to simulate a mock prison in one of Stanford's basements.After only six days, the abusive behavior of the guards and the psychological suffering of prisoners proved significant enough to halt the two-week-long experiment. [38]

Main article: Milgram Experiment
In 1961, Yale University psychologist Stanley Milgram led a series of experiments to determine to what extent an individual would obey instructions given by an experimenter.Placed in a room with the experimenter, subjects played the role of a "teacher" to a "learner" situated in a separate room.The subjects were instructed to administer an electric shock to the learner when the learner answered incorrectly to a set of questions.The intensity of this electric shock was to be increased for every incorrect answer.The learner was a confederate (i.e.actor), and the shocks were faked, but the subjects were led to believe otherwise.Both prerecorded sounds of electric shocks and the confederate's pleas for the punishment to stop were audible to the "teacher" throughout the experiment.When the subject raised questions or paused, the experimenter insisted that the experiment should continue.Despite widespread speculation that most participants would not continue to "shock" the learner, 65 percent of participants in Milgram's initial trial complied until the end of the experiment, continuing to administer shocks to the confederate with purported intensities of up to "450 volts". [39][40]Although many participants questioned the experimenter and displayed various signs of discomfort, when the experiment was repeated, more than 60 percent of subjects were willing to obey instructions to administer the shocks through the final one. [41]

Main article: Asch conformity experiments
Psychologist Solomon Asch's classic conformity experiment in 1951 involved one subject participant and multi-ple confederates; they were asked to provide answers to a variety of different low-difficulty questions. [42]In every scenario, the multiple confederates gave their answers in turn, and the subject participant subject was allowed to answer last.In a control group of participants, the percentage of error was less than one percent.However, when the confederates unanimously chose an incorrect answer, 75 percent of the subject participants agreed with the majority at least once.The study has been regarded as significant evidence for the power of social influence and conformity. [43]

Robber's Cave Study
A classic advocate of Realistic conflict theory, Muzafer Sherif's Robber's Cave experiment shed light on how group competition can foster hostility and prejudice. [44]n the 1961 study, two groups of ten boys each who were not "naturally" hostile were grouped together without knowledge of one another in Robber's Cave State Park, Oklahoma. [45]The twelve-year-old boys bonded with their own groups for a week before the groups were set in competition with each other in games such as tugof-war and football.In light of this competition, the groups resorted to name-calling and other displays of resentment, such as burning the other group's team flag.
The hostility continued and worsened until the end of the three-week study, when the groups were forced to work together to solve problems. [45]

Main article: Bystander effect
The Bystander Effect is demonstrated in a series of famous experiments by Bibb Latane and John Darley [45] In each of these experiments, participants were confronted with a type of emergency, such as the witnessing of a seizure or smoke entering through air vents.A common phenomenon was observed that as the number of witnesses or "bystanders" increases, so does the time it takes for individuals to respond to the emergency situation.This effect has been shown to promote the diffusion of responsibility by concluding that, when surrounded by others, the individual expects someone else to take action. [45]

Main article: Cognitive Dissonance
Human subjects have been commonly used in experiments testing the theory of Cognitive dissonance after the landmark study by Leon Festinger and Merrill Carlsmith. [46]In 1959, Festinger and Carlsmith devised a situation in which participants would undergo excessively tedious and monotonous tasks.After the completion of these tasks, the subjects were instructed to help the experiment continue in exchange for a variable amount of money.All the subjects had to do was simply inform the next "student" waiting outside the testing area (who was secretly a confederate) that the tasks involved in the experiment were interesting and enjoyable.It was expected that the participants wouldn't fully agree with the information they were imparting to the student, and after complying, half of the participants were awarded $1, and the others were awarded $20.A subsequent survey showed that, by a large margin, those who received less money for essentially "lying" to the student came to believe that the tasks were far more enjoyable than their highly paid counterparts. [46]See also

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