Human subject research

Human subject research is a systematic investigation that can be either research or clinically oriented and involves the use of human subjects in any capacity. Systematic investigation incorporates both the collection and analysis of data in order to answer a specific question. Examples of research oriented investigation include surveys, questionnaires, interviews, and focus groups. Examples of clinically oriented investigation include analysis of biological specimens, epidemiological and behavioral studies and medical chart review studies. Human subject research is used in various fields including research on basic biology, clinical medicine, nursing, psychology, sociology, political science, and anthropology. As research has become formalized the academic community has developed formal definitions of "human subject research", largely in response to abuses of human subjects.

Ethical guidelines
Ethical guidelines that govern the use of human subjects in research are a fairly new construct. It wasn’t until 1906 that specific regulations were put in place 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 wellbeing.

Kefauver-Harris Drug Amendment
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 then 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 1950 thalidomide incident in Western Europe where pregnant mothers were prescribed the sedative thalidomide which was inaccurately marketed as sleeping pills. This incident lead to the deformity of over 12,000 newborns.

National Research Act/Belmont Report
As a consequence of the political outcomes of the Tuskegee Syphilis Experiment, the National Research Act was passed in 1974. This act lead to the creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission was given the responsibility of drafting the Belmont Report and was tasked with determining the boundary between research and routine practice, the role of risk-benefit analysis, guidelines for participation and the definition of informed consent.The Office of Human Research Protection. (1979) Institutional Review Board Guidebook. "Introduction, Section B: “The Belmont Report.”The Belmont Report laid the foundation for ethical standards in the United States. The three tenets that it established were respect for persons, beneficence, and justice.

Nuremberg Code
In 1948, German physicians who conducted deadly or debilitating experiments on concentration camp prisoners underwent criminal proceedings in the Nuremberg Trials. That same year, following the Nuremberg Trials, the Nuremberg Code was established. The Nuremberg Code was the first international document that supported the concept that "the voluntary consent of the human subject is absolutely essential". The emphasis that was placed on individual consent in the Nuremberg Code was aimed at keeping participants informed of the risk-benefit outcomes of experiments.

Declaration of Helsinki
The Declaration of Helsinki was established in 1964 as a means of governing international research. 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”.

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)

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)

"Interaction"- communication or interpersonal contact between investigator and subject [45 CFR 46.102(f)])

"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)] )]

"Identifiable information"- specific information that can be used to identify an individual

Human subject rights

 * Voluntary, informed consent


 * Respect for persons: treated as autonomous agents


 * The right to end participation in research at any time


 * Right to safeguard integrity


 * Benefits should outweigh cost


 * Protection from physical, mental and emotional harm


 * Access to information regarding research


 * Protection of privacy and well-being

18th- 19th century
Human subject research experiments were recorded during vaccination trials in the 18th century. 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 Jenner experiments, where he tested smallpox vaccines on his son and neighbourhood children.

20th century
In the 20th century, as the progress of medicine began to accelerate, the concept of the various codes of ethics of scientific disciplines changed dramatically, and the treatment of research subjects along with it.

Walter Reed's experiments to develop an inoculation for yellow fever led these advances. Reed's vaccine experiments were carefully scrutinized, however, unlike earlier trials.

World War II




Infamous cases of human subject abuse in the 20th century were conducted during World War II by the Imperial Japanese Army (Unit 731 in China) and the Nazis, the latter an example of research involving prisoners which came to light in the Nuremberg Doctors' Trial and led to the Nuremberg Code of ethical conduct for human subject research. Research in the second half of the 20th century has been characterized by increasing attempts to protect human subjects through national agencies, institutional ethical review boards, and informed consent.

Britain
De-classified documents of the National Archives revealed that during the 1930s and 1940s, the British Army used hundreds of British 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.

United States
Fort Detrick in Maryland was the headquarters of US biological warfare experiments. Operation Whitecoat involved the injection of infectious agents to observe their effects in human subjects.

Japan
Human subject research in Japan began in World War II but continued for some years after, since the American occupation of Japan secretly pardoned all those who did human research.

Unit 731, a department of the Imperial Japanese Army located near Harbin (then puppet state of Manchukuo, in northeast China), experimented with prisoner vivisection, dismemberment, bacteria inoculation and induced epidemics on a very large scale from 1932 onward through the Second Sino-Japanese war. They also used prisoners and captured POWs for testing with biological and chemical weapons. With the expansion of the empire during World War II, many other units were implemented in conquered cities such as Nanking (Unit 1644), Beijing (Unit 1855), Guangzhou (Unit 8604) and Singapore (Unit 9420). After the war, Supreme commander of 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. The United States blocked Soviet access to this information; some unit members were judged by the Soviets during the 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. In 2007, Doctor Ken Yuasa testified to The Japan Times that he believes at least 1,000 persons working for the Shōwa regime, including surgeons, did surgical research in mainland China.

In incidents throughout the 1950s, former Unit 731 members infected prisoners and mental health patients with deadly diseases. In 1958, a large number of infants were brought to Kobe Medical School and forcibly administered sugar by inserting a needle through their nose and into their stomach. A tube was inserted into the anus to determine how the sugar was processed by the system. Many of the infants experienced diarrhea and anal bleeding. The parents were never informed that their children were being used as test subjects.

Germany
In the 1904 Herero and Namaqua Genocide in present day Namibia, in Southern Africa, people were used as test subjects in medical experiments.

At the end of the war, 23 Nazi doctors and scientists were put on trial for the unethical treatment of concentration camp inmates, often used as research subjects with fatal consequences (see Nazi human experimentation). Out of those 23, 15 were convicted, 7 were condemned to death, 9 received prison sentences from 10 years to life, and 7 were acquitted (see the Doctors' Trial).

Guatemalans used for STD experiments
U.S. scientific researchers infected hundreds of Guatemalan mental patients with sexually transmitted diseases from 1946 to 1948. Researchers from the U.S. Public Health Service conducted experiments on 696 male and female patients housed at Guatemala's National Mental Health Hospital. The scientists injected the patients with gonorrhea and syphilis—and even encouraged many of them to pass the disease on to others. The experiments were done in conjunction with the Guatemalan government. The US Public Health Service carried out the experiments under the guise of syphilis inoculations. When some of the inmates did not contract the disease, the researchers created abrasions on the inmate's body and poured the bacteria into the abrasion. When that failed, they injected the disease straight into the inmates' spines. In 2010 these experiments were revealed by Susan Reverby of Wellesley College who was researching a book on Tuskegee experiments. This led to Secretary of State Hillary Clinton issuing an official apology. President Barack Obama apologized to President Álvaro Colom who had called these experiments 'a crime against humanity'.

Sweden
In Sweden, the Vipeholm experiments were conducted, where 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 anesthesiologist Henry K. Beecher described 22 published medical studies where patients had been experimented on with no expected benefit to the patient. In one study, for example, patients infused with live cancer cells had been told they were receiving "some cells" without specifying that they were 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, and he presented evidence that studies he considered unethical were even more widespread and represented a systemic problem in medical research rather than exceptions. Though Beecher had been writing about human experimentation and publicizing cases that he considered to be bad practice for nearly a decade, it was a 1965 briefing to science writers and the 1966 paper that finally earned widespread news coverage and stimulated public reaction. The paper has been described as "the most influential single paper ever written about experimentation involving human subjects." The Office for Human Research Protections credits this paper as "ultimately contributing to the impetus for the first NIH and FDA regulations."

In addition to documenting the extent of problems in human subject research, Beecher was instrumental in formulating the solutions. One common aspect to many of Beecher's cases was that some experimental subjects, such as military personnel and mentally handicapped children in institutions, were not in a position to freely decline consent. Beecher believed that rules requiring informed consent were not by themselves sufficient, as truly informed consent was an unattainable ideal. He worked both in defining the rules and conditions for informed consent and in establishing institutional review boards as an additional layer of oversight regarding research protocols.

United States
There have been numerous human experiments performed in the United States, which have been considered unethical, and were often performed illegally, without the knowledge, consent, or informed consent of the test subjects.

Many types of experiments were performed including the deliberately infecting 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 or prisoners. Often, subjects were sick or disabled people, whose doctors told them that they were receiving "medical treatment," but instead were used as the subjects of harmful and deadly experiments, without their knowledge or consent. The ethical, professional, and legal implications of this in the United States medical and scientific community were quite significant, and led to many institutions and policies which attempted 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 and not all subjects involved in the trials have been compensated or notified of their participation.

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."

Israel
In Israel, a former worker of Negev Nuclear Research Center filed lawsuit, claiming that employees of the Center were given drinks with uranium without medical supervision and without obtaining written consent.

India
The prevalence of pharmaceutical drug trials are drastically increasing in India. AstraZeneca has opened a drug-testing facility in Bangalore and Pfizer has done the same in Bombay. In 2005, the law that was put in place a year prior that required for drugs to receive safety approval in their home countries before being tested in India was repealed.

Nigeria
Pharmaceutical giant Pfizer came under fire in 2001 for allegedly testing meningitis drugs on Nigerian children.

Questionable psychological experiments
Several experiments have been conducted on consenting volunteers whose ethical nature is now considered questionable. Following exposure of these experiments, rules regarding informed consent have been tightened.
 * The Milgram experiment, in which many subjects were shown they were capable of inflicting discomfort (by electric shock) on other humans if under orders to do so
 * The Stanford prison experiment, in which many participants became violent and abusive of each other.
 * The Monster Study that was conducted on orphans in 1939 in an attempt to induce stuttering.