# Professionalism/Human subjects in clinical research

The use of human subjects in research is a controversial topic. It faces many of the same issues that are present in using animals in research although the issues are even more complicated when humans are brought into the picture.
Does the cost of one human life justify the benefit to society as a whole? What rights do clinical patients have if they voluntarily submit themselves to research? To answer these questions and explore the ethical issues surrounding human subjects in clinical research it is most helpful to examine cases were there was an ethical failure and the guidelines that have come about because of these failures.

## Cases
### Pharmacological Experiments
#### Tuskegee Experiment

An infamous clinical study conducted between 1932 and 1972 in Tuskegee, Alabama by the U.S. Public Health Service to study the natural progression of untreated syphilis in poor, rural black men who thought they were receiving free health care from the U.S. government. Out of the 600 men involved in the experiment, 399 had previously contracted syphilis before the study, 201 were without the disease. The men were never told they had syphilis. The men were told they were being treated for "bad blood," a local term used to describe several illnesses, including syphilis, anemia and fatigue. They truly believed that they were receiving excellent free medical care. The largely immoral part of the experiment is that by 1947, penicillin was widely recognized as the standard treatment for syphilis. However, the African Americans involved in the experiment were not given the treatment that could cure them, and were continued to be tested on 25 year after a cure had been found.
By the end of the study in 1972, only 74 of the test subjects were alive. By 1947 penicillin had become standard therapy for syphilis. The US government sponsored several public health programs to form "rapid treatment centers" to eradicate the disease. When campaigns to eradicate venereal disease came to Macon County, study researchers prevented their patients from participating. The Tuskegee scientists continued the study without treating any participants and withholding penicillin and information about it from the patients. In addition, scientists prevented participants from accessing syphilis treatment programs available to others in the area.

#### Northfield Lab Clinical Trials

In 2003, Northfield Laboratories reached an agreement with the FDA to begin a three year clinical trial of its blood substitute; PolyHeme. The blood substitute does not require blood type matching, and has a 12 month shelf life, which makes it ideal for emergency situations. Part of the trial agreement was that it may only be changed by mutual agreement of the parties, or if FDA identifies a substantial scientific issue relevant to safety or efficacy after the trial has begun. Northfield was approved to test PolyHeme on non-consenting patients, because of the emergency research exemption, which allows a waiver of consent when patients are unable to give informed consent due to the emergency situation. In 2004, the Office for Human Research Protections(OHRP) raised concern that the emergency research exemption did not apply in this case, because other available treatments were not unproven or unsatisfactory, a requirement for the consent waiver. The OHRP requested that the FDA conduct an internal review, but the FDA did not start the review until late 2005. The FDA could also not stop the trial due to the terms of the agreement with Northfield. The three year study went through to completion in 2006. Later that year the Wall Street Journal published an article claiming that the company tried to hide findings from an earlier study showing that use of PolyHeme increased risk of heart attack. Northfield denied these allegations, but then in 2008 The Journal of the American Medical Association published results finding that use of blood substitutes caused a 30% increased risk of death, and three-fold increase in heart attack rate. This lead to Northfield Lab's bankruptcy in 2009. Northfield Labs rushed to get its product approved, because of the potential profitability, but in the end went bankrupt. If Northfield labs was patient, and went through extensive testing, they may not have had the same faith.

#### Pfizer in Africa

In 1996, an outbreak of measles, cholera, and bacterial meningitis occurred in Nigeria. Pfizer representatives traveled to Kano, Nigeria to administer an experimental antibiotic, trovafloxacin, to approximately 200 children. Local Kano officials report that more than 50 children died in the experiment, while many others developed mental and physical deformities.
Pfizer contends that meningitis, not its drugs, was responsible for the deaths and injuries. Pfizer spokesman say that Epidemics sweep Africa’s arid “meningitis belt” on dust-filled winds during the dry season every year, and more than 12,000 Africans died of meningitis in 1996; in addition, the drugs in the trial were given only to children who were already very sick. Thus justifying their actions and attempting to claim the moral high ground by "helping" these children.
Families of children who died or were injured while on the second antibiotic contended that Pfizer had prescribed low doses of the drug to make the results for Trovan look better. Parents of the children claim that Pfizer did not tell them that their children were getting the experimental drug.
In 2010, a secret 2009 State Department cable exposed by WikiLeaks said that a Pfizer official in Nigeria told American diplomats that the company had hired private investigators to “uncover corruption links” to Nigeria’s former attorney general in order to pressure him to drop the Trovan lawsuits.
In 2011 the first payments were made to Nigerian families who lost children under a settlement reached two years prior. Four families received $175,000 each from a $35 million fund created under the settlement between Pfizer and Nigeria’s northern Kano State, where the brief trial of the experimental drug, Trovan, took place.

#### San Antonio Contraceptive Study

In the early 1970's a San Antonio contraception clinic in San Antonio ran a study to test different types of oral contraception. Some woman were given placebos, and a high number of unplanned pregnancies resulted.

### Psychological Experiments
#### Milgram's Obedience Study

The Milgram experiment on obedience to authority figures was a series of notable social psychology experiments conducted by Yale University psychologist Stanley Milgram, which measured the willingness of study participants to obey an authority figure who instructed them to perform acts that conflicted with their personal conscience. It involved 3 members the teacher, the learner, and the experimenter. The teacher and learner were both in on the experiment and the teacher was told that they were to administer a shock to the learner to teach them a sequence. If the learner failed the shock increased. The goal of the subject was to see how far people would go if encouraged by the experimenter, the "authority figure". The results were shocking, 60% of the participants went to the maximum level, 300V.

#### Stanford Prison Experiment

The Stanford prison experiment was a study of the psychological effects of becoming a prisoner or prison guard. Twenty-four male students out of 75 were selected to take on randomly assigned roles of prisoners and guards in a mock prison situated in the basement of the Stanford psychology building. The participants adapted to their roles well beyond expectations, as the guards enforced authoritarian measures and ultimately subjected some of the prisoners to psychological torture. Many of the prisoners passively accepted psychological abuse and, at the request of the guards, readily harassed other prisoners who attempted to prevent it. The experiment even affected the head researcher himself, who, in his role as the superintendent, permitted the abuse to continue. Two of the prisoners quit the experiment early and the entire experiment was abruptly stopped after only six days. Certain portions of the experiment were filmed and excerpts of footage are publicly available.

### Radiation Experiments
#### Atomic Energy Commission Experiments

In 1995 the Energy Department admitted to over 430 radiation experiments conducted by the Atomic Energy Commission between the years 1944 and 1974. Over 16,000 people were radiated, some of whom did not know the health risks or did not give consent.
These experiments were designed to help atomic scientists understand the human hazards of nuclear war and radiation fallout. Because the entire nuclear arms buildup was classified secret, these experiments were all stamped secret and allowed to take place under the banner of protecting “national security.”
Amazingly, these clandestine studies were conducted at the most prestigious medical institutions and colleges, including the University of Chicago, the University of Washington, the Massachusetts Institute of Technology, Vanderbilt University in Nashville, and the previously mentioned universities.

#### Manhattan Project Experiments

The Manhattan Project was the world’s first time experimenting with atomic energy and radiation. Nothing was known at the time of the effects of radiation on the human body and the only way to find out was to experiment.
In 1945, as part of the Manhattan Project, three patients at Billings Hospital at the University of Chicago were injected with plutonium.
In 1946, six employees of a Chicago metallurgical lab were given water that was contaminated with plutonium-239, so that researchers could study how plutonium is absorbed into the digestive tract.

## Ethical Guidelines
### Organizations

As a result of the Tuskegee Experiment as well as other unethical episodes in US History several organizations were put in place to help monitor clinical research involving humans. Among these organizations was the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, formed in 1974 to shape bioethics policy in the United States. This organization published the Belmont Report. A second such organization is the Office for Human Research Protections, which is an office within the United States Department of Health and Human Services that deals with ethical oversight of clinical research. Institutional review boards also known as ethical ethics committee's also became more common after the Tuskegee Experiment. These boards are formally chosen to approve, review, and monitor bio-medical and behavioral research involving humans.

### Codes of Ethics

* Nuremberg Code: The first international code of ethics. Created in 1949 after the Nazi war criminal trials. Says that voluntary consent is absolutely essential.
* Kefauver-Harris Drug Amendment : Created after Thalidomide was approved in Europe, but then was found to cause birth defects. Required that all drugs were to be shown safe and effective on animals, before humans testing. Also required informed consent of patients, and that all clinical results were reported to FDA.
* Declaration of Helsinki : Created by the World Medical Association to add to the Nuremberg code. Gave a code of ethics for biomedical research involving humans. The origin for Institutional Review Boards.
* National Research Act/Belmont Report : Created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in response to the Tuskegee experiment.

## Conclusion

It is undeniable that human research is necessary and valuable. If fact we are lucky to live in a day and age where guidelines have been created for human subjects in clinical research so that those who do wish to experiment may do so safety and ethically. This connection and desire to help their subject is part of what makes a researcher professional. If their goal is to prove a result, to make money, or any other goal not related to the well being of their subjects they are prone to an ethical breach. These other goals all provide logical reasons that may incline someone to momentarily disregard the responsibility they carry by dealing with other humans. Confusion may arise as Human research is a difficult subject. The potential benefits can cause us to forget that these rewards come at a cost that at best is difficult to quantify. In layman's terms the problems surrounding human research often fall under the category "the ends justified the means". So even if a researcher deems themselves to have ethical interests at heart they may find themselves in a bad situation. As seen through the above case studies breaches of ethics often appear when the test subjects are of a lower class. It is likely that these researchers are justifying their choices by saying that these individuals added little to society and that their losses, which should be minimal, are compensated monetarly. The means involved harming/experimenting on those who were of "little value" and the ends where beneficial to all future humans. With this mindset how could we not see the great value in human research? The problem with this logic lies in the idea that we have a right to judge others and determine their lives for them. Even withholding critical information can be overstepping ones bounds when dealing with Human Subjects.
It is vital that future researchers keep their fellow man and the ethical guidelines set by those before them in their mind. By actively trying to avoid situations where an ethical breach may occur old mistakes will not be repeated and humanity may move forward.

## References

* ↑ Northfield Reaches Agreement With FDA on Special Protocol Assessment For Pivotal Phase III Trial, PR Newswire Association, 2003
* ↑ PolyHeme - Artificial Blood & Emergency Medicine Research
* ↑ Ethicists blast study testing fake blood, 2006
* ↑ The Future of Clinical Trials Evaluating Blood Substitutes, 2008
* ↑ Northfield Laboratories to liquidate under Chapter 11, 2009
* ↑ Research Compliance
* ↑ http://www.hss.doe.gov/healthsafety/ohre/roadmap/achre/chap1_2.html
* ↑ Eileen Welsome (1999). The Plutonium Files: America's Secret Medical Experiments in the Cold War. New York: Dial Press. pp. 146–148. ISBN 0-385-31402-7.
* ↑ Goliszek, 2003: pp. 136-137
* ↑ Research Compliance
* ↑ Nuremberg Code, Regulations and Ethical Guidelines, OHRP
* ↑ Belmont Report, Regulations and Ethical Guidelines, OHRP