Selective Timeline of Medical Ethics and Clinical Research
The Internet Encyclopedia of Philosophy defines ethics as: “The field of ethics (or moral philosophy) involves systematizing, defending, and recommending concepts of right and wrong behavior. Philosophers today usually divide ethical theories into three general subject areas: metaethics, normative ethics, and applied ethics. Metaethics investigates where our ethical principles come from, and what they mean. Are they merely social inventions? Do they involve more than expressions of our individual emotions? Metaethical answers to these questions focus on the issues of universal truths, the will of God, the role of reason in ethical judgments, and the meaning of ethical terms themselves. Normative ethics takes on a more practical task, which is to arrive at moral standards that regulate right and wrong conduct. This may involve articulating the good habits that we should acquire, the duties that we should follow, or the consequences of our behavior on others. Finally, applied ethics involves examining specific controversial issues, such as abortion, infanticide, animal rights, environmental concerns, homosexuality, capital punishment, or nuclear war.”1
Ethical principles were not fully applied to medical/clinical research until the repugnant abuses of German and Japanese experiments on humans were revealed in the late 1930s and early 1940s. It is important to recognize that the extent of the ethical abuses and violation of basic morality were not anticipated in advance. Rather, ethical guidelines for clinical research were only codified after abuses occurred. Similarly, refinements in ethical guidelines for conducting clinical research were often precipitated by uncovering unethical clinical research that was “hidden” from the public view and scrutiny. Many of the abuses were funded by the US government and approved by ethical review boards. It is useful to review a timeline of the application of ethical principles over the last several decades as recent consideration is being given to altering or eliminating certain ethical guidelines to facilitate conducting clinical research fostered by dramatic increases in funding and discovery. In reviewing the timeline it will become apparent that, in spite of well documented abuses and subsequent rules to govern prevent their reoccurrence, ethical abuses continue, and disconcertingly, mimic previous abuses both in the manner in which they are approved and conducted and in defending their perceived scientific necessity in spite of dissenting opinions.
Ethical Principles Guiding Clinical Research
A common framework used in the analysis of medical ethics is the “four principles” Beauchamp Childress suggested a common framework for medical ethics which included:
- Respect for autonomy – the right to refuse or choose their treatment.
- Beneficence – a practitioner should act in the best interest of the patient.
- Non-maleficence – do no harm.
- Justice – fairness and equality in the distribution of scarce health resources including the decision of who gets what treatment.
(Principles of Biomedical Ethics by Tom L. Beauchamp and James F. Childress. 1985)
Additional values that are considered in medical ethics include:
- Respect for persons – the right to be treated with dignity.
- Truthfulness and honesty
- Informed consent
Ethical Abuses in Clinical Research
James Marion Sims. Between 1845 and 1849, Sims conducted experimental surgery on 12 female slaves with fistulas, brought to him by their masters. He operated on one of them 13 times before her fistula repair was declared a success. Sims did not use any anesthetic during his procedures; he argued that anesthesia was not yet fully accepted and he was unaware of the possibility of the use of ether. Sims also experimentally used a shoemaker’s awl to pry the skull bones of enslaved women’s babies into alignment which resulted in 100% mortality. He blamed the fatalities on “the sloth and ignorance of their mothers and the black midwives who attended them.”
Anti-vivisectionists took up cause against human experimentation during rapid growth of science claiming it would encourage physicians to expand experiments on humans for scientific knowledge rather than cures.
Walter Reed required consent of volunteers to test transmission of yellow fever by mosquitoes
Noguchi, a microbiologist at the Rockefeller Institute, injected orphans with inactive form of syphilis spirochete without permission.
Orange juice was withheld from orphan infants until scurvy developed. Following public outrage, the American Journal of Medicine, stated that the scurvy tests did not exploit the children. Rather it gave the orphans the opportunity to provide, “a large return to the community for their care devoted to them.” The harm to the infants was considered to be minimal.
American soldiers were infected with typhoid and forced to undergo surgery for gallbladder removal.
A study of the effects of untreated syphilis was conducted in 400 African American men. Researchers withheld treatment even when penicillin became available. Research subjects were not informed that they were experimental subjects. Those who attended the Tuskegee clinic thought they were getting treatment for “bad blood.” The Tuskegee Syphilis Study was sponsored by the U.S. Department of Health.5
Morally repugnant research was conducted by German scientists on concentration camps prisoners including men, women, and children. Japanese scientists conducted experiments on Chinese prisoners of war. Ellie Wiesel later argued that the Nazi killers knew how to differentiate between good and evil. But their sense of reality was impaired.
Secret research on radiation effects on human beings was conducted on individuals who were not informed that they were participating in research studies. The experiments were conducted on cancer patients, pregnant women, and military personnel and sponsored by the US Government.
Prisoners at Statesville penitentiary in Illinois were infected with malaria through mosquito bites and subsequently used for a variety of unproven treatments for malaria.
829 pregnant women at a health clinic run by Vanderbilt University were administered drugs that they were told were good for them and their babies. The drugs actually contain radioactive iron.
17 individuals (composed of working-class individuals including five African-Americans and one six-year-old boy who spoke only Chinese) were injected with plutonium to determine its effect.
Massachusetts Institute of Technology researchers fed oatmeal that included radioactive iron and calcium to 74 mentally deficient and disabled boys at the Walter E. Fernald State School in Massachusetts.
The Nuremberg Code for research on human subjects was formulated and adopted. The Nuremberg Code was used in the Nuremberg Trials to convict Nazi scientists of war crimes.
1950s to mid-1960s
Doctors working for the National Aeronautics and Space Administration, the Army, Navy, and Air Force administered total body radiation to individuals with cancer who thought they were getting approved safe and effective cancer treatment.
Cancer cells (HeLa cells) were injected into the skin of patients and prisoner without informed consent to determine if the cancer cells were rejected or grew.
Mind control experiments using LSD were conducted by the CIA. Research subjects were not informed of the experimental nature of the studies.
Researchers conducted hepatitis experiments on mentally disabled children at The Willowbrook State School. Children were deliberately infected with hepatitis and natural progression was observed. The experiments were approved by the New York Department of Health.
The Helsinki Declaration, a set of ethical principles for research on human subjects, was developed by World Medical Association, Helsinki Declaration. Revised several times, most recently in 2013.
Beecher published a New. England Journal of Medicine article exposing 22 unethical studies including the Tuskegee syphilis study and the Willowbrook hepatitis study.
The national media and Congress focused on unethical research practices with human subjects, including the Tuskegee study.
The National Research Act was approved by Congress. Federal agencies developed human research regulations, e.g. 45 CFR 46, 21 CFR 50,54,56.
The Belmont Report was released by the National Commission. It addressed principles of ethical research on human subjects and became a key document in human research ethics regulations in the U.S.
Major revisions of federal human research regulations are published.
Betrayers of Truth was published by Broad and Wade addressing misconduct in science.
All U.S. government agencies, except the EPA, are required to accept one regulatory framework, known as “the common rule” (45 CFR 46).
46 years after the secret experiments using plutonium injections were completed a reporter for the Albuquerque Tribune, Eileen Welsome, discovered their names and story. Not until 1995 did the US government acknowledged the wrongs committed and the fact that informed consent was not obtained for the experiments.
The Clinton Administration apologized for secret human radiation experiments conducted from 1940s-1980s.
Human gene therapy experiments at the University of Pennsylvania resulted in the death of Jessie Gelsinger. Increased scrutiny of conflicts of interest including institutions required. The University settled the case for an undisclosed amount of money.
Marcia Angell, in an editorial in the New England Journal of Medicine, wrote that placebo studies in infants in resource poor countries are unethical. Drs Ho and Wilfert resigned from editorial board in protest. In spite of numerous statements to the contrary, NIH continued to support HIV studies in infants using placebo comparisons.
The NIH and the Office of Human research Protection (OHRP) required ethics training of individuals engaged in clinical research.
CHEERS study halted by EPA. Advocacy groups and members of Congress claimed that the study was intentionally exposing children to pesticides.14
The US Food and Drug Administration (FDA) published its controversial decision to abandon the Declaration of Helsinki as a guide for clinical research ethics.
Susan Reverby, Professor of Women’s Studies at Wellesley College, discovered unethical clinical research conducted in Guatemala by the US government from 1946 to 1948. Over 1300 subjects were deliberately infected with sexually transmitted infections to determine the effectiveness of penicillin. Only 700 subjects were given penicillin and 83 died as a result of the study. Research subjects were not informed of the experiment.
President Obama apologized for the Guatemala research studies..
The NIH and NSF revise their conflict of interest rules for funded research.
The Office of Human Research Protections announces proposed changes to the Common Rule to enhance human subject protections and reduce investigator burden. The Common Rule had not changed significantly since 1981.
The federal Office for Human Research Protections (OHRP) determined that the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) trial to evaluating oxygen administration for premature infants violated federal regulations by failing to inform parents of “reasonably foreseeable risks” of death or blindness. NIH was subsequently accused of attempting to influence OHRP’s decision.
National Institutes of Health launched an international study of HIV broadly neutralizing monoclonal antibody (VRC01) in 4,000 research subjects. The study mimicked two infamous studies―Tuskegee and Guatemala, universally declared unethical for withholding effective treatment in disadvantaged populations. The experimental monoclonal antibody had no proven efficacy in humans and would not become therapeutic product. Research subjects in income poor countries were told that even though there was no benefit to them for their participation, “mankind” would benefit. Men, but not women, in the study were provide with free treatment known to prevent HIV transmission. A subgroup of infants, born to poor and disadvantage South African pregnant women at high risk for HIV infection were also studied. Known effective preventive treatment was withheld until after the experimental agent was administered. Following complaints that the study was unethical and exploited vulnerable populations, the FDA and the US Office for Human Research Protections reviewed the study and still deemed it was ethical.
Lethal Dedcisons. The Unnecessary Deaths of Woman and Children from HIV/AIDS is published exposing the exploitation and unethical experiments in women and children in poor countries. http://lethaldecisions.com/
Ethics definntion. http://www.iep.utm.edu/ethics/
21st Century Cures Act http://khn.org/news/grab-bag-of-goodies-in-21st-century-cures-act/
Summary 21st Century Cures Act. https://www.congress.gov/bill/114th-congress/house-bill/6
Ethics timeline. http://www.niehs.nih.gov/research/resources/bioethics/timeline/
Tuskegee experiments https://www.cdc.gov/tuskegee/timeline.htm
Nuremberg Code. https://history.nih.gov/research/downloads/nuremberg.pdf
Declaration of Helsinki. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
Beecher HK. Ethics and clinical research. N Engl J Med. 1966 Jun 16;274(24):1354-60.
Belmont Report. In: Summary of Important Documents in the Field of Research Ethics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632196/
Federal Human Research Regulations. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/
Clinton apologizes for Guatemala studies. http://www.nytimes.com/1999/03/11/world/clinton-offers-his-apologies-to-guatemala.html
Gene therapy experiments https://www.nytimes.com/topic/person/jesse-gelsinger
Angell M. The ethics of clinical research in the Third World. N Engl J Med 1997; 337(12): 847-9.
FDA abandons Helsinki Declaration. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1500825/
Obama apology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828982/
HHS tightens conflict of interest rules. https://www.nih.gov/news-events/news-releases/hhs-tightens-financial-conflict-interest-rules-researchers
NIH Launches Large Clinical Trials of Antibody-Based HIV Prevention https://www.niaid.nih.gov/news-events/nih-launches-large-clinical-trials-antibody-based-hiv-prevention