Ethics and Ethical Review: Lessons from History | Quorum Review IRB
The Hippocratic Oath was the earliest guidance on medical ethics in the Western world. Written between the third and fifth centuries BC, the Greek medical text advises the physician to enter homes only for the benefit of the sick, abstain from all intentional harm or injustice to patients, and maintain confidentiality.
Until the 20th century, the physician administering treatment or conducting research generally operated under a professional code of ethics and his/her personal conscience rather than a systematic code of law. Without centralized oversight, many physicians made tremendous advances in medicine through experimental treatments, with discoveries ranging from various types of anesthesia to the smallpox vaccine.
However, the experiments were often less than ethical and involved vulnerable populations, such as slaves, prisoners, and children. The smallpox vaccine was first tested in 1796, when Edward Jenner exposed a healthy 8-year-old boy to cowpox, and a few weeks later, to the smallpox virus, which killed a full third of those who contracted it. In the early 19th century, Dr. William Beaumont spent about a decade exploiting his handyman’s stomach wound to observe digestive processes with no benefit to the patient.
Crimes Against Humanity
The atrocious experiments of the Nazi concentration camps threw into sharp focus the need for researchers to solidify their code of ethics. In the 1930s and ’40s, Nazi physicians and their administrators forced prisoners into experiments with results ranging from psychological trauma to disfigurement to death. Twenty-three physicians received sentences for their crimes at the Nuremberg Trials, which began in 1946.
The judgment at Nuremberg led to the Nuremberg Code, a set of research ethics principles for human experimentation. Among the Code’s requirements are the following:
- The voluntary consent of the participant is absolutely essential, and the participant should have legal capacity to give consent.
- The experiment should aim at positive results for society that cannot be procured in some other way.
- The experiment should be designed in a way that avoids unnecessary physical and mental suffering and injuries.
While the Nuremberg Code served as a major influence on research ethics, many researchers—particularly American researchers—assumed it didn’t apply to them. After all, Americans had a better sense of ethics than Nazi doctors, didn’t they?
Numerous cases of unethical research in the 20th century showed that Americans were capable of abuses, too, and that additional codes and regulations were in order. Just a couple of the research wrongs included:
- The Tuskegee Syphilis Study: Enrolling a population of low-income African-American males in rural Alabama, this Public Health Service study did not provide adequate informed consent or treatment for what became a treatable condition. The research lasted from 1932-1972 and led to unnecessary deaths and syphilis in women and children outside the study.
- The Willowbrook Study: Starting in the late 1950s and continuing for over a decade at the Willowbrook State School in New York, this experiment involved a researcher and his staff injecting mentally disabled children with hepatitis to study the disease. Issues included, among others, exploitation of a vulnerable population, lack of informed consent, and coercion of participants’ parents.
Although the United States had its share of unethical research, a global tragedy was what triggered the first American law requiring the consent of research subjects.
Developed by the West German pharmaceutical company Chemie Grünenthal GmbH, thalidomide was a wildly popular sleeping pill in Europe (It was never approved in the United States). Doctors stated that even pregnant women could use it, and this population especially appreciated thalidomide because it reduced morning sickness. However, animal testing on the drug never assessed the substance’s teratogenic effects, and thalidomide eventually caused more than 10,000 birth defects worldwide.
The Drafting of Laws & Guidance
Inspired by the thalidomide tragedy, the U.S. Congress enacted the Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act of 1962. In addition to ensuring informed consent in clinical trials, the law required drug manufacturers to prove drug safety and efficacy prior to approval, the accurate disclosure of drug side effects, and the cessation of generic drugs from being marketed as new breakthrough medications.
Soon after the Kefauver-Harris Amendment, the World Medical Association (WMA) released the Declaration of Helsinki, another monumental document for medical research ethics. The 1964 version addressed concerns beyond those in the Nuremberg Code and recommended that study protocols receive review by an “independent committee.”
Just as the thalidomide tragedy prompted the Kefauver-Harris Amendment, the Tuskegee and Willowbrook studies helped inspire the drafting of the Belmont Report. Issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research—a committee created by the National Research Act of 1974—the Belmont Report identifies ethical principles and guidelines for human subject research. The three core principles of respect for persons, beneficence, and justice greatly influenced researchers of the time and continue to steer research today.
A Regulatory Framework
In the United States, a system of human subject protection slowly formed over the final few decades of the 20th century.
In addition to bringing about the Belmont Report, the National Research Act of 1974 established the institutional review board (IRB) system of reviewing human subject research. A type of ethics review committee, the IRB aims to protect the rights and welfare of research participants. Countries around the globe have similar committees with varying names. For example, Canada’s version of the IRB is the research ethics board (REB).
The Department of Health and Human Services (DHHS) and Food and Drug Administration (FDA) first issued regulations based on the Belmont Report in 1981. Currently, FDA regulations generally address the approval of medical products (e.g., drugs, devices, biologics) while the DHHS regulations (sometimes referred to as the Common Rule) specifically apply to federally funded research and also to research for which institutions have elected to apply DHHS regulations.
In 1990, the United States, various European countries, and Japan established the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) at a meeting in Brussels. ICH eventually issued its Good Clinical Practice (GCP) Guidelines, an international quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials.
While reviewing a new research protocol or changes to previously approved research, an IRB or other ethics review committee will need to adjust its review to the type of research under consideration. Some of the IRB/ethics review committee’s questions may include:
- For FDA-regulated research, does the trial meet the 21 CFR 56.111 Criteria for IRB approval of research?
- Does the research involve “equipoise” (a state of uncertainty about the therapeutic merits of each arm in the trial)?
- Is the use of placebo justified?
- What are the less obvious risks of the trial? (For example, the research may involve questionnaires asking sensitive questions about the participant’s suicidal thoughts or sex life.)
- Is the informed consent form understandable? Does it reflect the protocol and include all the elements of informed consent required by applicable regulation?
- Will the trial enroll populations—including vulnerable populations—affected by the condition under study?
- Is deception justified? (Although deception is generally unacceptable, it is sometimes necessary.)
- Does the investigator or trial staff have a conflict of interest?
- What are the researchers’ plans for the participant’s biological specimens?
The Importance of Adaptability
Although a strong regulatory framework is in place for those conducting research in the 21st century, that framework must be malleable as research evolves. And the industry—including sponsors, investigators, and ethics review committees—must learn from mistakes.
During a Phase I study of the drug TGN1412 in the United Kingdom in 2006, all six participants experienced multi -organ failure after their first infusion. Following this disaster, researchers determined that individuals in a cohort should not be dosed at the same time. The safety of a dose should be determined in the smallest number of individuals as possible before additional participants receive that dose.
Approaches to research must not only be reactive. The industry should be proactive to keep pace with such research trends as genome mapping, big-data research, data collection and sharing via smartphones, using social media platforms as recruitment and retention avenues, eConsenting, and the ever-expanding natural products and supplements industry.
As ethics review committees encounter the research of the future, they can always look to past landmark documents—such as the Belmont Report, the Declaration of Helsinki, and the Nuremberg Code—to guide their reviews and their understanding of research rights and wrongs.