Human subject research

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For experiments on non-human subjects, see Animal testing.

Human subject research (HSR), or human subject use (HSU) involves the use of human beings as research subjects. It is an important part of medical research, and many people volunteer for clinical trials of medical treatments. People also volunteer to be subjects for experiments in basic medical science and biology, as well as social and behavioral (psychological) research.

They are many examples throughout history of human research subjects being treated unethically, and there are therefore many requirements, guidelines, and procedures in place today to ensure similar events are not repeated. Requirements and guidelines exist at the national, academic, and scientific community levels.

Some experiments involve the testing of cosmetic products or ingredients on humans instead of animals. In some notable cases, doctors have performed experiments on themselves, when they have been unwilling to risk the lives of others. This is known as self-experimentation.

Contents

[edit] History

Human experimentation and research ethics evolved over time. This section depicts past atrocities that led to the strict policies that are in place today. On occasion, the subjects of human experimentation have been prisoners, slaves, or even family members. In some notable cases, doctors have performed experiments on themselves when they have been unwilling to risk the lives of others. This is known as self-experimentation.

[edit] Ancient History

Herophilos of Chalcedon was reputed by Celcus, amongst others, to have vivisected prisoners received from the Ptolemaic kings.

[edit] Middle Ages

Systematic experimentation and quantification were introduced into the study of physiology in 1025, by the influential Persian Muslim physician, Avicenna (Ibn Sina), in The Canon of Medicine (Al-qanun fi al-tibb).[1] He also introduced the use of biomedical research,[2] clinical trials,[3] randomized controlled trials,[4][5] drug tests[2] and efficacy tests[6][7] on human subjects.

Human dissections were carried out by Ibn Zuhr (Avenzoar),[8] who introduced the use of experimention in surgery during the 12th century,[9][10] as well as Ibn Tufail[11] and Saladin's physician Ibn Jumay in the 12th century, Abd-el-latif in 1200,[12] and Ibn al-Nafis in the 13th century.[13]

[edit] Early Modern Times

HSR experiments were recorded during vaccination trials in the 1700s. 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, in which he first tested smallpox vaccines on his son and neighbourhood children. In an instance of self-experimentation, Johann Jorg swallowed 17 drugs in various doses to record their properties. Conversely, the famous scientist Louis Pasteur "agonized over treating humans," though he was confident of previous results obtained through animal trials. He consented to treat a human only when he was convinced that the death of his first test subject, the child Joseph Meister, "appeared inevitable." (Rothman 1993)

[edit] Early 20th Century

In the 1900s, 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 well-known experiments to develop an inoculation for yellow fever led these advances. Reed's vaccine experiments were carefully scrutinized, however, unlike earlier trials. (Brady 1982)

HSR has also been performed on subjects without informed consent, both covertly and under coercion. The pretext of medical experimentation has been used as a justification for some atrocities. From 1932 until the 1970s, in the United States, citizens were experimented upon in the Tuskegee Study of Untreated Syphilis in the Negro Male.

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.[14][15][16][17]

[edit] Second Sino-Japanese War and World War II

In Japan, Unit 731, located near Harbin (Manchukuo), experimented with prisoner vivisection, dismemberment and induced epidemics on a very large scale from 1932 onward through the Second Sino-Japanese war. 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 all members of the units in exchange for a tiny part of the results, so that in post-war Japan, Shiro Ishii and others continued to hold honoured positions. The United States blocked Soviet access to this information. However, some unit members were judged by the Soviets during the Khabarovsk War Crime Trials. The effects were lasting and China is still working to counteract the effects of buried pathogen caches.[citation needed]

During the second World War, Nazi human experimentation occurred in Germany with particular bias towards euthanasia. At the war's conclusion, 23 Nazi doctors and scientists were tried for the murder of concentration camp inmates who were used as research subjects. Of the 23 professionals tried at Nuremberg, 15 were convicted. Seven of them were condemned to death by hanging and eight received prison sentences from 10 years to life. Eight professionals were acquitted. (Mitscherlich 1992)

The result of these proceedings was the Nuremberg Code. It includes the following guidelines, among others, for researchers:

Informed consent is essential.
Research should be based on prior animal work.
The risks should be justified by the anticipated benefits.
Research must be conducted by qualified scientists.
Physical and mental suffering must be avoided.
Research in which death or disabling injury is expected should not be conducted.

In 1940 in the United States, four hundred prisoners in Chicago were infected with malaria to study the effects of new and experimental drugs for the disease[citation needed]. Beginning in 1942, mustard gas experiments were conducted on 4,000 United States servicemen in order to study the effects on the human nervous system[citation needed]. These tests concluded in 1945[citation needed].

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.[18]

[edit] After World War II

[edit] In the United States

Numerous experiments were done on prisoners throughout the US. Many prisoners eventually filled lawsuits and these actions brought about many more investigations and suits against doctors, hospitals and pharmaceutical companies. [3] Experiments included high-risk cancer treatments, the application of strong skin creams, new cosmetics, dioxin and high doses of LSD. Many incidents were documented in government reports, ACLU findings and various books including Acres of Skin by Allen M. Hornblum. The Stateville Penitentiary Malaria Study is one of many examples.

The CIA ran an extensive toxicology and chemical/biological warfare program in cooperation with the US military. The Edgewood Arsenal and US Army Medical Research Institute for Infectious Diseases at Fort Detrick in Maryland were the main headquarters for such studies. At such centres, the agency developed many toxins, incapacitants, mind-altering substances and carcinogens. The CIA allegedly attempted to use toxins to assassinate Fidel Castro and other world leaders such as General Abdul Karim Quassim of Iraq and Patrick Lumumba of the Congo who nationalized Congo's mineral mines[citation needed]. Mind-control substances were studied to facilitate interrogation and toxins were used as weapons in assassination. One of the toxins that the CIA studied extensively was derived from red algae called dinoflagellate which produces the red tide[citation needed].

The MK-ULTRA project was a CIA run human experiment program where prisoners and unwitting subjects were administered hallucinogenic drugs in attempt to develop incapacitating substances and chemical mind control agents, in an operation run by Sidney Gottlieb. CIA researchers at the Bien Hua prison conducted human experiments on Vietnamese Communist subjects as a form of torture[citation needed]. The CIA was accused of murdering one of the unwitting subjects of the CIA LSD tests named Frank Olson [4]. The CIA claimed that the man committed suicide as an after-effect of the LSD but the family exhumed the body and a forensic pathologist found evidence of blunt trauma to the head suggesting that he was knocked out before being thrown out of the window of a hotel. This supported the Olsen family's claims that the CIA had killed him because he wanted to expose the MK-Ultra program [5]. The Church Investigation revealed some information on this project.

A Manhattan District Attorney opened up an investigation but did not have enough evidence to prosecute. It is interesting to note that soon after this happened, the former CIA director William Colby drowned and he would have been a key witness. Dr. Sidney Gottlieb requested that William Colby destroy most of the documents on the MK-Ultra program. Some suspect that the trial would produce information that would devastate the reputation of the William Colby and other officials involved in MK Ultra[6].

The CIA also recruited the University of Pennsylvania dermatology professor named Dr. Albert Kligman to run the studies at Holmsburg Prison. Kligman also conducted human studies on the effects of blistering agents on human skin [7].

[edit] In Pinochet's Chile

Human experimentation was carried on in Colonia Dignidad, headed by ex-Nazi Paul Schäfer and used as a concentration camp by the DINA, Augusto Pinochet's secret police, according to March 2005 declarations by former CIA and DINA agent Michael Townley. These experimentations would have been carried out on detainees, with the cooperation of the DINA, the Bacteriological War Army Laboratory located in Colonia Dignidad, and German occupants of the Colonia Dignidad.[19] (requires additional sources, English language)

[edit] Human vivisection

Vivisection has long been practiced on human beings. Herophilos, the "father of anatomy" and founder of the first medical school in Alexandria, was described by the church leader Tertullian as having vivisected at least 600 live prisoners. In recent times, the wartime programs of Nazi Dr. Josef Mengele, Shiro Ishii, founder of the Japanese military Unit 731, and Dr. Fukujiro Ishiyama at Kyushu Imperial University Hospital, conducted human vivisections on concentration camp prisoners in their respective countries during World War II [20].[citation needed]

In November 2006, Doctor Akira Makino confessed to Kyodo news having performed surgery and amputations on condemned prisoners, including women and children in 1944 and 1945 while he was stationed on Mindanao.[21] 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, were involved in vivisections over mainland China.[22]

Human volunteers can consent to be subjects for invasive experiments which may involve, for example, the taking of tissue samples (biopsies), or other procedures which require surgery on the volunteer. These procedures must be approved by ethical review, and carried out in an approved manner that minimizes pain and long term health risks to the subject [8]. Despite this, the term is generally recognized as pejorative: one would never refer to life-saving surgery, for example, as "vivisection." The use of the term vivisection when referring to procedures performed on humans almost always implies a lack of consent.[citation needed]

[edit] Guidelines

[edit] Declaration of Helsinki

Main article: Declaration of Helsinki

In 1964, the World Medical Association developed a code of research ethics that came to be known as the Declaration of Helsinki. It was a reinterpretation of the Nuremberg Code, with an eye to medical research with therapeutic intent. Subsequently, journal editors required that research be performed in accordance with the Declaration. This document set the stage for the implementation of the Institutional Review Board (IRB) process. (Shamoo & Irving 1993)

[edit] Beecher Article

In 1966, anaesthesiologist Dr. Henry K. Beecher wrote an article, "Ethics and Clinical Research," describing 22 examples of research studies with controversial ethics that had been conducted by reputable researchers and published in major journals. Beecher wrote, "Medicine is sound, and most progress is soundly attained..." He believed, however, that if unethical research were not prohibited it would "do great harm to medicine." Beecher provided estimates of the number of unethical studies and concluded "unethical or questionably ethical procedures are not uncommon." (Beecher 1996)

[edit] Belmont Report

The Public Health Service Syphilis Study was among the most influential in shaping public perceptions of research involving human subjects. When the press exposed the study, the US Congress appointed a panel that determined that the PHS Syphilis Study should be stopped immediately and that overseeing of human research was inadequate. The panel recommended that federal regulations be designed and implemented to protect human research subjects in the future. Subsequently, federal regulations were enacted, including the National Research Act, 45 Code of Federal Regulations 46, and 21 Code of Federal Regulations 50.

In 1974, the United States Congress authorised the formation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, known to most people in research ethics as the National Commission. Congress charged the National Commission with the task of identifying the basic ethical principles that affect the decision to use, or to not use, human research subjects. To accomplish this task, the National Commission looked at writings and discussions that had taken place to date and asked, "What are the basic ethical principles that are used to judge the ethics of human subject research?" Congress also asked the National Commission to develop guidelines to assure that human research is conducted in accordance with those principles.

In 1979, the National Commission met and published the Belmont Report. The Belmont Report is required reading for everyone involved in human experimentation. The Belmont Report identifies three basic ethical principles that underlie human experimentation. These principles are commonly called the Belmont Principles. The Belmont Principles include:

  • Respect for persons
  • Beneficence
  • Justice

[edit] CIOMS

The Council for International Organizations of Medical Sciences (CIOMS) has written an International Ethical Guidelines for Biomedical Research Involving Human Subjects.

[edit] APA Ethics Code

The American Psychological Association (APA) has a documented ethics code pertaining to the practice of Psychology and associated research. This document contains great guidelines for the use of deception in research. For members of the APA, these are hard requirements levied against their membership. They are also requirements for any research project conducted, funded, or managed by the APA.

[edit] Requirements

[edit] US Federal Research

The following policies codify requirements that must be followed for any research conducted or supported by the US Federal Government.

[edit] Common Rule

This is the US codifitation of regulated policy based on the guidelines of the Belmont Report. It combines and supersedes previous disparate regulatory codes.

45 CFR 46
Title 45 Code of Federal Regulations, Part 46 (45 CFR 46) is the primary set of Federal regulations regarding the protection of human subjects in research and is often reffered to as the Common Rule. It defines the laws, criteria for exemption, as well as definition and formulation of Institutional Review Boards (IRBs). Some Government agencies (e.g., DoD, FDA, etc.) have established their own implementation of this code that supersedes portions or all of 45 CFR 46.
32 CFR 219
This is the Department of Defense (DoD) implementation of 45 CFR 46, Subpart A. Subparts B, C, and D of 45 CFR 46 still apply to DoD supported research. It differs from 45 CFR 46 in the criteria for exemptions.
21 CFR 50
This is the implementation of the Common Rule by the Food & Drug Administration (FDA). It applies to research associated with the development of any food, drug, or medical device.

[edit] US DoD Research

The following policies are required for any research conducted or supported by the US Department of Defense (DoD).

[edit] DoD Directives

DoD Directive 3216.02
This document defines additional requirements for HSR supported by the Department of Defense.
10 USC 980
Title 10, United States Code, Subtitle A, Part II, Chapter 49, Section 980 (10 USC 980) addresses the limitations on use of humans as experimental subjects. It basically states that funds canot be deployed prior to obtaining informed consent.

[edit] Process

[edit] US Federal Research

Before an institution can conduct or be engaged in any HSR project, it must obtain a Human Subject Use Assurance. This is approval from the Department of Health and Human Services (HHS) to conduct HSR based on review of the institutions HRPP and their commitment to comply with all applicable requirements and guidelines. This Assurance is then linked to specific Institutional Review Boards (IRBs) that will review each individual research project.

Before a Federally supported HSR project can even begin, it must be approved by an Institutional Review Board (IRB), and then possibly by the conducting institution, and also possibly by the supporting agency (if it is different than the IRB organization and institution).

[edit] Scope

This section attempts to explain when HSU policies apply based on the criteria and definitions in the policy documents.

[edit] US Federal Research

[edit] Is It HSR

Just because a project involves the use of human participants does not mean it constitutes human subject research. The activities must meet the definition of research, and the use of the human participants must meet the definition of human subjects. The definitions are written as such to include situations where the human is the subject of the experiment, their environment is manipulated by the researchers, and data regarding their responses are collected. If the project does not meet the definition of Human Subject Research, then the requirements do not apply, and the project does not require an IRB review or informed consent. However, it is best to have an IRB make this determination and document the decision.

[edit] Is It Exempt From Policies

If a project is defined as Human Subject Research, it may still be considered Exempt. This generally means that the project is minimal risk, and the requirements do not apply. The protocol for the project must meet one of the exempt categories defined in the Common Rule. By definition then, an IRB does not need to perform a full review on the project, and informed consent is not required. However, again, an IRB needs to make this determination and document the decision. In these situations, the guidelines in the Belmont Report should still be followed since it is still Human Subject Research.

[edit] Ongoing Issues

[edit] 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.

[edit] Terminology

Engaged
An institution is engaged in human subjects research when its employees or agents either:
  1. intervene or interact with living individuals for research purposes; or
  2. obtain individually identifiable private information for research purposes (32 CFR 219.102.d-f).
Exempt
Not subject to HSU policies because it meets one or more of the exemption criteria defined in 32 CFR 219.101.b.
Human Subject
A living individual about whom an investigator conducting research obtains:
  1. Data through intervention or interaction with the individual, or
  2. Identifiable private information (32 CFR 219.102.f).
Interaction
Communication or interpersonal contact between investigator and subject (32 CFR 219.102.f).
Intervention
Physical procedures by which data are gathered as well as manipulations of the subject or the subject’s environment that are performed for research purposes (32 CFR 219.102.f).
Minimal Risk
The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (32 CFR 219.102.i).
Private Information
Individually identifiable 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 (32 CFR 219.102.f).
Research
A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge (32 CFR 219.102.d).

[edit] Endnotes

  1. ^ Katharine Park (March 1990). "Avicenna in Renaissance Italy: The Canon and Medical Teaching in Italian Universities after 1500 by Nancy G. Siraisi", The Journal of Modern History 62 (1), p. 169-170.

    "Students of the history of medicine know him for his attempts to introduce systematic experimentation and quantification into the study of physiology".

  2. ^ a b Huff, Toby (2003), The Rise of Early Modern Science: Islam, China, and the West, Cambridge University Press, p. 218, ISBN 0521529948 
  3. ^ David W. Tschanz, MSPH, PhD (August 2003). "Arab Roots of European Medicine", Heart Views 4 (2).
  4. ^ Jonathan D. Eldredge (2003), "The Randomised Controlled Trial design: unrecognized opportunities for health sciences librarianship", Health Information and Libraries Journal 20, p. 34–44 [36].
  5. ^ Bernard S. Bloom, Aurelia Retbi, Sandrine Dahan, Egon Jonsson (2000), "Evaluation Of Randomized Controlled Trials On Complementary And Alternative Medicine", International Journal of Technology Assessment in Health Care 16 (1), p. 13–21 [19].
  6. ^ D. Craig Brater and Walter J. Daly (2000), "Clinical pharmacology in the Middle Ages: Principles that presage the 21st century", Clinical Pharmacology & Therapeutics 67 (5), p. 447-450 [449].
  7. ^ Walter J. Daly and D. Craig Brater (2000), "Medieval contributions to the search for truth in clinical medicine", Perspectives in Biology and Medicine 43 (4), p. 530–540 [536], Johns Hopkins University Press.
  8. ^ Islamic medicine, Hutchinson Encyclopedia.
  9. ^ Rabie E. Abdel-Halim (2005), "Contributions of Ibn Zuhr (Avenzoar) to the progress of surgery: A study and translations from his book Al-Taisir", Saudi Medical Journal 2005; Vol. 26 (9): 1333-1339.
  10. ^ Rabie E. Abdel-Halim (2006), "Contributions of Muhadhdhab Al-Deen Al-Baghdadi to the progress of medicine and urology", Saudi Medical Journal 27 (11): 1631-1641.
  11. ^ Jon Mcginnis, Classical Arabic Philosophy: An Anthology of Sources, p. 284, Hackett Publishing Company, ISBN 0872208710.
  12. ^ Emilie Savage-Smith (1996), "Medicine", pp. 951-2, in (Morelon & Rashed 1996, pp. 903-962)
  13. ^ Dr. Sulaiman Oataya (1982), "Ibn ul Nafis has dissected the human body", Symposium on Ibn al-Nafis, Second International Conference on Islamic Medicine: Islamic Medical Organization, Kuwait (cf. Ibn ul-Nafis has Dissected the Human Body, Encyclopedia of Islamic World).
  14. ^ Report: Britain Tested Chemical Weapons on Indian Colonial Troops Voice of America 2 September 2007
  15. ^ Indian soldiers used as guinea pigs during British Raj September 2, 2007 The News, Internationl, Pakistan
  16. ^ When Indians were guinea pigs The Hindu Times September 2, 2007
  17. ^ Indian Troops Were Part of WWII Gas Tests UPI September 1, 2007
  18. ^ [1]
  19. ^ Michael Townley fue interrogado por muerte de Frei Montalva, Radio Cooperativa, March 30, 2005 (Spanish)
  20. ^ Barenblatt, Daniel (2003). A Plague Upon Humanity. London: HarperCollins. ISBN 0060933879. 
  21. ^ Japanese doctor admits POW abuse, http://news.bbc.co.uk/2/hi/americas/6185442.stm
  22. ^ "I was afraid during my first vivisection, but the second time around, it was much easier. By the third time, I was willing to do it." Vivisectionnist recalls his day of reckoning, http://search.japantimes.co.jp/cgi-bin/nn20071024w1.html

[edit] References

  • Beecher, Henry K. "Ethics And Clinical Research." The New England Journal of Medicine. Vol 274 No. 24, June 16, 1966, 1354 - 1360
  • Brady, Joseph V. and Jonsen, Albert R. "The Evolution of Regulatory Influences on Research with Human Subjects." Human Subjects Research - A Handbook for Institutional Review Boards. Ed. Greenwald, Robert A. et al. New York: Plenum Press, 1982. 3 - 18
  • Fisher, Jill A. (2007). "Governing Human Subjects Research in the USA: Individualized Ethics and Structural Inequalities". Science & Public Policy 34 (2): 117-126. doi:10.3152/030234207X190973. 
  • Mitscherlich, Alexander and Mielke, Fred. "Epilogue: Seven Were Hanged." Ed. Annas, George J and Grodin, Michael A. The Nazi Doctors And The Nuremberg Code - Human Rights in Human Experimentation. New York: Oxford University Press, 1992. 105 - 107
  • Morelon, Régis & Roshdi Rashed (1996), Encyclopedia of the History of Arabic Science, vol. 3, Routledge, ISBN 0415124107
  • Rothman, David J. "Ethics and Human Experimentation: Henry Beecher Revisited." The New England Journal of Medicine. Vol. 317, No. 19, Nov.5, 1987 - Public Responsibility in Medicine and Research, Boston, April 1 - 2, 1993
  • Shamoo, Adil E. and Irving, Dianne N. "Accountability in Research." 1993 in press - Public Responsibility in M

[edit] Further reading

  • Goliszek, Andrew. In the Name of Science: A History of Secret Programs, Medical Research, and Human Experimentation, St. Martin's Press 2003, ISBN 0-312-30356-4
  • Hornblum, Allen. Acres of Skin: Human Experiments at Holmesburg Prison: A True Story of Abuse and Exploitation in the Name of Medical Science. Routledge, 1998.
  • Kevorkian, Jack: A brief history of experimentation on condemned and executed humans. JAMA 77 (1985) pp.215-226
  • Lederer, Susan: Subjected to science. Human experimentation in America before the Second World War Baltimore, Maryland: Johns Hopkins University Press 1995
  • Moreno, Jonathan D. Undue Risk: Secret State Experiments on Humans. W H Freeman 1999, Routledge 2001.
  • Welsome, Eileen. The Plutonium Files: America's Secret Medical Experiments in the Cold War. Dell Publishing (Random House), 1999.

[edit] See also

[edit] External links