The first century physician Celsus justified experiments on condemned criminals in Egypt using wording that became a classic defense for hazardous experimentation: "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries." [Brady and Jonsen].

Both the ethics regarding human subjects research and regulations for such research have changed considerably since Celsius’ time. This module discusses the evolution of ethical review principles, and how they have influenced research involving human subjects.

By the end of this module you will be able to:

• Discuss why ethics are necessary when conducting research involving human subjects.
  
• Describe the major historical events that have influenced how research involving human subjects is conducted.
  
• Identify problems with past studies that have violated ethical standards.
• Describe the Belmont Principles.
  
• Discuss the ethical standards for research that guide us today.

Risks to the subject or society must be weighed against potential benefits. The probability of harm relative to the probability of benefit should be determined, as well as the relative magnitude of risks and possible benefits. As an aside, payment for study participation should never be considered a benefit. One of the most difficult things that researchers and IRBs have to do is to determine that the potential benefits of the outcomes of the research outweigh the risks of conducting the research. This is difficult because:

• Neither the potential benefits or risks can be known ahead of time
• The risks are assumed by individuals, while the benefits may accrue to society at large rather than to individuals.

Research ethics has evolved. Among the first human subject research experiments to be documented were vaccination trials in the 1700's. In these early trials physicians used themselves or their family members as test subjects. For example:

• Edward Jenner (1749-1823) first tested smallpox vaccines on his son and on neighborhood children.
  
• Johann Jorg (1779-1856) swallowed 17 drugs in various doses to record their properties.
  
• Louis Pasteur (1822-1895) "agonized over treating humans," even though he was confident of the results obtained through animal trials. He finally did so only when he was convinced the death of the child, the first test subject, "appeared inevitable." [Rothman]

Society's high regard for the medical profession, however, was not to last. At the end of World War II, 23 Nazi doctors and scientists were put on trial for the murder of concentration camp inmates who were used as research subjects. Of the 23 professionals tried at Nuremberg, 15 were convicted, 7 were condemned to death by hanging, 8 received prison sentences from 10 years to life, and 8 were acquitted. [Mitscherlich & Mielke] Included in the legal judgment and sentences handed down at the culmination of the trial were ten points describing required elements for conducting research with humans. These points became known as the Nuremberg Code.

In summary, the Nuremberg Code includes the following guidance for researchers:

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

The Code had little impact on researchers in the United States, who thought that the principles in the Code were already implicit in their work and that it was simply a document to condemn the Nazi atrocities and to convict the Nazi doctors. There were a number of problems with the Code itself. For example it did not have the strength of law, it was created post hoc, and it applied to only non-therapeutic human subjects research.

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. In principle, this document set the stage for the implementation of the Institutional Review Board (IRB) process. [Shamoo & Irving]

In 1966 Dr. Henry K. Beecher, an anesthesiologist, wrote an article (Beecher HK. "Ethics and Clinical Research" NEJM June 16, 1966) 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;" however, if unethical research is not prohibited it will "do great harm to medicine." Beecher provides estimates of the number of unethical studies and concludes, "unethical or questionably ethical procedures are not uncommon." [Beecher]

Beecher’s article played an important role in heightening the awareness of researchers, the public, and the press to the problem of unethical human subjects research. "Until this article we assumed that unethical research could only occur in a depraved regime like the Nazis."- Robert J. Levine, MD (personal communication).

Initiated by the Public Health Service, this study was designed to document the natural history of syphilis in African-American men.

At the time the study began there was no known treatment for syphilis. Hundreds of men with syphilis and hundreds of men without syphilis (serving as controls) were enrolled into the study. The men were recruited without truly informed consent. They were deliberately misinformed about the need for some of the procedures. For example, spinal taps were described as necessary and special "free treatment."

Even after penicillin was found to be a safe and effective treatment for syphilis in the 1940's, the men were denied antibiotics. The study continued to track these men until 1972 when the first public accounts of the study appeared in the national press. The study resulted in 28 deaths, 100 cases of disability, and 19 cases of congenital syphilis. [Levine]

Ethical problems: lack of informed consent, deception, withholding information, withholding available treatment, putting men and their families at risk, exploitation of a vulnerable group of subjects who would not benefit from participation.

The Public Health Service (PHS)Syphilis Study is among the most influential in shaping public perceptions of research involving human subjects. After, media sources reported on the PHS Syphilis Study, Congress formed an Ad Hoc Panel. The Panel determined that the PHS Syphilis Study should be stopped immediately and that oversight 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 Congress authorized 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 to identify the basic ethical principles that underlie the conduct of human research--to look at the writings and discussion that had taken place up to this time and to ask, "What are the basic ethical principles that people are using 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 the last several years reports of unethical studies including gene transfer, cancer, and psychiatric research have heightened the public awareness of these issues even further. Two recent examples follow:

Death of a Normal Volunteer

On March 31, 1996, a 19-year-old Asian American student at the University of Rochester responded to an advertisement for study subjects to undergo bronchoscopy for the harvest of alveolar macrophages. The bronchoscopy was difficult and required numerous doses of topical lidocaine. The investigators repeatedly asked the subject if she wanted to continue and the subject nodded her head "yes". The study was completed, but the subject returned to the hospital in cardiac arrest from an overdose of lidocaine and died April 2, 1996. An investigation into this death revealed that the protocol did not limit lidocaine doses, that the doses were not documented, that the subject was not observed after the bronchoscopy, and that the concentrations of lidocaine were increased without IRB approval.

The need for protecting human subjects through research ethics and regulations is as prevalent now as ever. Applying the Belmont principles to our studies is an important start:

• From the principle of respect for persons we need to conduct initial and continuing informed consent. We need to evaluate whether the research allows subjects to withdraw from the research and maintains the welfare of each subject.
  
• From the principle of beneficence we need to evaluate the social and scientific value of the research, the scientific validity of the research, and determine whether the research has a favorable risk benefit ratio.
  
• From the principle of justice we need to evaluate whether there is fair subject selection. We also need to evaluate the inclusion and exclusion criteria and the methods of recruitment.

Additional considerations in research ethics include the following:

A responsible PI will:

• Obtain team management skills
  
• Encourage questions from colleagues and staff
  
• Listen to the concerns of the research staff, as they may be the first to point out problems with the protocol and with compliance
  
• Build consensus with the research team
  
• Eliminate intimidation by those in supervisory positions

Authority relationships are not limited to the PI and the staff, but can also include the authority of the sponsor over the PI, the authority of the PI over the subject, and the authority of the protocol over the PI.