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.,2,3
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
A study of the effects of untreated syphilis 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 and Japanese scientists on Chinese prisoners of war.
Secret research on radiation effects on human beings. Individuals 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.
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.6
1950s to mid-1960s
Injection of cancer cells (HeLa cells) into the skin of patients and prisoner without informed consent to determine if the cancer cells were rejected or grew.
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.
Mind control experiments using LSD conducted by CIA. Research subjects were not informed of experimental nature of the studies.
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 2013.7
Beecher published a New. England Journal of Medicine article exposing 22 unethical studies including the Tuskegee syphilis study and the Willowbrook hepatitis study.8 1972
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 becames a key document in human research ethics regulations in the U.S.9
Major revisions of federal human research regulations are published.10
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).
The Clinton Administration apologized for secret human radiation experiments conducted from 1940s-1980s.11
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.12
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.13
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.15
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 study.16
The NIH and NSF revise their conflict of interest rules for funded research.17
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 was not been changed significantly since 1981.
The federal Office for Human Research Protections (OHRP) determined that the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) tried to evaluating oxygen administration for premature infants violated federal regulations by failing to inform parents of “reasonably foreseeable risks” of death or blindness. SUPPORT study. NIH is subsequently accused of attempting to influence OHRP’s decision.18
- 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. http://www.wma.net/en/30publications/10policies/b3/
- 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. http://articles.latimes.com/1995-10-04/news/mn-5321 Gene Experiments. http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html3_1_radiation-experiments
- Gene experiments. http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html
- Angell M. The ethics of clinical research in the Third World. N Engl J Med 1997; 337(12): 847-9.
- CHEERS Study. http://www.nytimes.com/2005/04/09/politics/epa-halts-florida-test-on-pesticides.html?_r=0
- 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
- SUPPORT study. http://www.sciencemag.org/news/2014/05/nih-officials-accused-improperly-influencing-investigation-premature-infant-study