Where the codes governing research on people came from
Many of the codes that govern research on people were written in response to particular tragedies and abuses. They run from the Ten Commandments and the Hippocratic Oath, through the Prussian directives on consent and the Weimar guidelines, to the Nuremberg Code, the Declaration of Helsinki, the US regulations around the Belmont Report and the Common Rule, EU Regulation 536/2014 and ICH good clinical practice. The concept of informed consent developed long before the Second World War. Abuses of vulnerable people continued after that war, and the system of research ethics that relies on committees of experts took shape at the NIH Clinical Center in the 1950s and 1960s.
What prompted the codes
Protection of clinical trial participants has often been prompted by significant national and global tragedies or by human abuses. By the early twentieth century, clinical trials had come under increasing government regulation as authorities recognised a need to better control emerging medical therapies. The realisation that medicinal products must be assessed thoroughly before they are marketed, and that the healthy individuals or patients in whom new products are first assessed must be safeguarded, was nurtured by a series of tragedies caused by a lack of ethical judgement, a lack of awareness, or both.
The oldest standards
The standards a society establishes apply not only to people enrolling in sponsored clinical trials but to healthcare as a whole.
The codified global standards include the Ten Commandments, the Hippocratic Oath and the Nuremberg Code. The Ten Commandments consist more of prohibitions than of permissions: "thou shalt not" is their predominant theme, setting out what should not be done to others in the community, and they address humans and no other context. The Hippocratic Oath can be summarised as the injunction to do no harm, which leaves open what constitutes harm, to whom it applies, and whether it reaches individuals, cohorts or society at large. So the oath is silent on which community a physician's actions can harm.
Consent before the Second World War
The first directive on informed consent came from Prussia. The advances in science of the late nineteenth century brought an increased demand for experimentation in human subjects, mainly carried out in hospitalised patients or prisoners and without their consent. In 1891, public controversy about the ethics of that practice caused the government of the Kingdom of Prussia to pass a directive decreeing that tuberculin for the treatment of tuberculosis must in no case be used against the patient's will. The first regulations on non-therapeutic research in Western medicine followed nine years later.
The first detailed directive on consent followed a public outcry over Albert Neisser's studies of syphilis. In 1898 Neisser, a German professor of dermatology and venereology, published the results of studies designed to find a cure for syphilis, in which he had inoculated serum from patients with syphilis into patients hospitalised for other reasons. When some of those inoculated, most of whom had been prostitutes, contracted syphilis, Neisser claimed that their infection was a result of their professional activity. In response, the Prussian parliament, assisted by a scientific commission of leading German experts including Rudolf Virchow, issued in 1900 the Richtlinien für Wissenschaftliche Experimente (Guidelines for Scientific Experiments). It was the first directive in history to require unambiguous consent of the subject after proper information given by a physician, and it may be the first reported regulatory document applicable to human experimentation and recognising the need to protect vulnerable populations.
In 1931, continued criticism of unethical human experimentation caused the government of the Weimar Republic to issue detailed Richtlinien für Neuartige Heilbehandlung und für die Vornahme Wissenschaftlicher Versuche am Menschen (Guidelines for New Therapy and Human Experimentation). These guidelines clearly distinguished therapeutic from non-therapeutic research, and on some counts they were stricter than the Nuremberg Code of 1947 or the Declaration of Helsinki of 1964: human experiments in dying patients, for example, were absolutely prohibited. So, contrary to common belief, the concept of informed consent developed long before the Second World War, and it was introduced not at the instigation of the research community but by government authorities.
The Nuremberg Code and the human rights instruments
The German pre-war regulations, however strict, did not prevent some of the worst atrocities ever performed under the cloak of medical research, which the Doctors' Trial brought to light. That trial, one of the subsequent Nuremberg Trials held in the US occupation zone from 1946, exposed experiments performed during the war on large numbers of Jewish prisoners, members of the Roma population, mentally or physically disabled Germans, and prisoners of war. One category aimed to advance the survival of German military personnel and included freezing, transplant, infection and mustard gas experiments in prisoners. Another sought to advance the racial goals of Nazi ideology through experiments on twins and through artificial insemination and sterilisation studies, all performed with a view to creating a master race. The experiments left thousands of victims physically and mentally mutilated, dead, or killed for the purpose of post-mortem measurements. It has been said that medical ethics would forever be changed after the Holocaust.
The final judgement of the trial in 1947 enumerated ten principles of what the trial's medical expert witnesses, Leo Alexander and Andrew Ivy, and its judges and prosecutors considered legitimate medical research, derived from the natural law of all people. Those ten principles on the ethical conduct of medical research involving human subjects became the Nuremberg Code, the first international guidance, codified after the war so that the experiments on people captured and held in prison camps would not happen again. The Nuremberg Code protects people placed in situations over which they have no control, and its main underlying principle is that people must be given the opportunity to consent to or refuse participation in an experimental situation.
The Universal Declaration of Human Rights, adopted by the General Assembly of the United Nations in the same period, 1947 to 1948, substantiated global concern about the involuntary maltreatment of human subjects. The International Covenant on Civil and Political Rights of 1966, a United Nations human rights treaty protecting individuals' civil and political rights, states in particular that no one shall be subjected without his consent to medical or scientific treatment.
The Declaration of Helsinki
Spurred by the Doctors' Trial and by details of the human experiments performed by the Japanese Army's biological and chemical warfare research Unit 731 in China, the idea of an international medical organisation setting ethical guidelines for physicians across the world was born in 1945 in the House of the British Medical Association, a meeting place for doctors from the allied nations during the war. The World Medical Association was founded in 1947, and among its first activities was drafting a modernised version of the ancient Oath of Hippocrates, which its general assembly adopted in 1948 as the Declaration of Geneva. Also inspired by the horrors of the Second World War, the idea of a position paper recommending how physicians should conduct biomedical research involving human subjects was born in 1953, and another disaster intervened before it was adopted. That disaster was thalidomide. In its wake, many countries introduced stricter assessment, approval and monitoring procedures for new medicinal products.
The World Medical Association finally adopted the Declaration of Helsinki in 1964 as a consensus of standards for the treatment of humans. It was the medical community's first significant effort to regulate research in human subjects, an aim on the association's agenda since after the war. It expanded on the principles of the 1947 Nuremberg Code and linked them to the 1948 Declaration of Geneva, and it may also have had much to do with the devastating effects of thalidomide on thousands of infants. Among its general principles are that medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights, and that the goal of generating new knowledge can never take precedence over the rights and interests of individual research subjects. Consistent with the World Medical Association's mandate, the Declaration addresses the medical profession only.
The Declaration was revised in 2013. One view expected an update and held that the Declaration should address the considerations that come with advances in technology and communication, including how information can be misrepresented. The 2024 revision process of the Declaration held two separate public comment periods to maximise input by all stakeholders and the public: the first earlier in 2024, and the second from 4 to 24 June 2024.
Vulnerable people in postwar vaccine research
Postwar vaccine research exploited prisoners, African Americans, the poor and the mentally ill. Orphanages, prisons, charity hospitals and institutions for the mentally ill were natural choices for proof-of-concept studies, safety trials and efficacy trials. In 1959 the Archbishop of Philadelphia commented: "Our research teams want these infants because they are always available in quantity and under conditions which permit a wide variety of controls." Research that harms participants in any way has come to be more commonly taught as unacceptable, no matter how highly advantageous the results.
United States regulation
In the United States, federal regulations for the protection of human subjects in research have evolved in response to increasing awareness of ethical issues. Throughout history, failure to have meaningful regulatory oversight has led to complacency and tragedies. The Triangle Shirtwaist Factory fire led to laws requiring, among other things, fire extinguishers, alarm systems and automatic sprinklers, and regulating the hours women and children could work, and similar disasters in human research led to laws designed to protect its subjects.
The Elixir Sulfanilamide incident of September 1937 hastened the 1938 Federal Food, Drug, and Cosmetic Act, first introduced in the Senate on 6 January 1937, which was the first law to require that a drug's safety be proven. Its new-drug section, requiring a drug's safety to be demonstrated, protected the United States from a potential thalidomide disaster like those seen in England and Germany in the 1960s. The thalidomide tragedy nonetheless led to the enactment of the Kefauver-Harris Drug Amendments of 1962, a bill pending at the time, which introduced a proof-of-efficacy requirement for drugs for the first time.
The system of medical research ethics was developed at the National Institutes of Health (NIH) Clinical Center in the 1950s and 1960s, including the move away from trusting the judgement of the individual researcher, in matters relating to patients and research subjects, to reliance on committees of experts. It has been argued that the obvious alternative, a code of ethics, was not adopted because it would have curbed researchers' freedom to a greater extent, and that the Clinical Center's policy in the early 1950s was that research came first and patients second.
In its formative years the Clinical Center sought more healthy research subjects by recruiting prisoners and conscientious objectors, to whom becoming a test subject was sold as a heroic service. Some of its research practices have been held to defy belief. One healthy volunteer, after a year on other wards for studies of the thyroid and of new steroids, became the only person in the control arm of studies of whether LSD helped people with schizophrenia in psychotherapy. Signed informed consent forms at first met resistance. Lawyers who wanted signed consent and liability release forms to protect the NIH from litigation fought researchers who wanted to do as they pleased. It was argued that there must be something inherently wrong with young people who volunteer for medical testing, so that they could not give meaningful consent.
Ethics committees later spread from the NIH to other sites, and it has been argued that this was a way of transferring liability from the NIH to the institutes where it funded research and of placating Congress, which approves NIH funding, and a concerned public. On that account, ethical review was a form of insurance, a way of preventing lawsuits, and a system instituted to protect the interests of researchers, the NIH and its Clinical Center rather than those of patients and research subjects.
The Tuskegee Syphilis Experiment, conducted by the US Public Health Service from 1932 to 1972, led to the 1979 Belmont Report, to the establishment of the federal Office for Human Research Protections, and to federal laws and regulations requiring institutional review boards. The Tuskegee investigators defended not giving information to participants by stating that they never withheld it. Participants were told that all study findings would be publicly available. A sharecropper with a limited education and no access to a desegregated library or to medical journals, however, had no realistic way to obtain that information.
The US National Research Act of 1974 authorised federal agencies to develop regulations for human research. The Belmont Report of 1979, released by the US National Commission, documented key principles of ethical research and influenced research ethics regulations in the US. The Common Rule of 1991, 45 CFR 46, established a regulatory framework applicable to all US federal agencies. Later responses include the Advisory Committee on Human Radiation Experiments, dated 1994, formed after the total radiation tests at the Oak Ridge Institute for Nuclear Studies to follow up people used as test subjects in experiments with ionising radiation. They also include the first major revisions to the Common Rule since 1991, dated 2018, which answered ongoing changes in the research landscape such as tissue banks.
The Belmont Report is very similar in its principles to the Declaration of Helsinki and the Nuremberg Code. Together with several federal offices set up to protect humans involved in research, Title 21 of the Code of Federal Regulations and the Common Rule, it addresses human subject protection under the US government's authority.
International good clinical practice
The International Council for Harmonisation (ICH), dating from 1990, is a consensus among countries and governments to apply established guidelines to how people are treated. In 1996 the ICH published Good Clinical Practice, which remains the industry standard for the ethical conduct of clinical trials. Industry trade associations, such as the pharmaceutical industry trade group PhRMA and the Association of the British Pharmaceutical Industry, have each established their own standards of protection, most of them based on ICH good clinical practice (E6) and on the standard set out in the Declaration of Helsinki.
A rule change dropped the US Food and Drug Administration's requirement that clinical trials reported in new drug applications adhere to the Declaration of Helsinki, and the new rule requires only that trials conducted abroad follow good clinical practice and include review and approval by an independent ethics committee. A major difference between the Declaration and good clinical practice is the Declaration's insistence on using the best available treatment rather than placebo where possible. An estimated 35% of all trials reported in such applications already took place abroad, and the change was expected to raise that share.
Privacy in EU regulation
A principal consideration of EU Regulation 536/2014 is the protection of privacy, which earlier declarations, standards and codes had not addressed.