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5 Unethical Medical Experiments Brought Out of the Shadows of History

Prisoners and other vulnerable populations often bore the brunt of unethical medical experimentation..

Most people are aware of some of the heinous medical experiments of the past that violated human rights. Participation in these studies was either forced or coerced under false pretenses. Some of the most notorious examples include the experiments by the Nazis, the Tuskegee syphilis study, the Stanford Prison Experiment, and the CIA’s LSD studies.

But there are many other lesser-known experiments on vulnerable populations that have flown under the radar. Study subjects often didn’t — or couldn’t — give consent. Sometimes they were lured into participating with a promise of improved health or a small amount of compensation. Other times, details about the experiment were disclosed but the extent of risks involved weren’t.

This perhaps isn’t surprising, as doctors who conducted these experiments were representative of prevailing attitudes at the time of their work. But unfortunately, even after informed consent was introduced in the 1950s , disregard for the rights of certain populations continued. Some of these researchers’ work did result in scientific advances — but they came at the expense of harmful and painful procedures on unknowing subjects.

Here are five medical experiments of the past that you probably haven’t heard about. They illustrate just how far the ethical and legal guidepost, which emphasizes respect for human dignity above all else, has moved.

The Prison Doctor Who Did Testicular Transplants

From 1913 to 1951, eugenicist Leo Stanley was the chief surgeon at San Quentin State Prison, California’s oldest correctional institution. After performing vasectomies on prisoners, whom he recruited through promises of improved health and vigor, Stanley turned his attention to the emerging field of endocrinology, which involves the study of certain glands and the hormones they regulate. He believed the effects of aging and decreased hormones contributed to criminality, weak morality, and poor physical attributes. Transplanting the testicles of younger men into those who were older would restore masculinity, he thought.  

Stanley began by using the testicles of executed prisoners — but he ran into a supply shortage. He solved this by using the testicles of animals, including goats and deer. At first, he physically implanted the testicles directly into the inmates. But that had complications, so he switched to a new plan: He ground up the animal testicles into a paste, which he injected into prisoners’ abdomens. By the end of his time at San Quentin, Stanley did an estimated 10,000 testicular procedures .

The Oncologist Who Injected Cancer Cells Into Patients and Prisoners

During the 1950s and 1960s, Sloan-Kettering Institute oncologist Chester Southam conducted research to learn how people’s immune systems would react when exposed to cancer cells. In order to find out, he injected live HeLa cancer cells into patients, generally without their permission. When patient consent was given, details around the true nature of the experiment were often kept secret. Southam first experimented on terminally ill cancer patients, to whom he had easy access. The result of the injection was the growth of cancerous nodules , which led to metastasis in one person.

Next, Southam experimented on healthy subjects , which he felt would yield more accurate results. He recruited prisoners, and, perhaps not surprisingly, their healthier immune systems responded better than those of cancer patients. Eventually, Southam returned to infecting the sick and arranged to have patients at the Jewish Chronic Disease Hospital in Brooklyn, NY, injected with HeLa cells. But this time, there was resistance. Three doctors who were asked to participate in the experiment refused, resigned, and went public.

The scandalous newspaper headlines shocked the public, and legal proceedings were initiated against Southern. Some in the scientific and medical community condemned his experiments, while others supported him. Initially, Southam’s medical license was suspended for one year, but it was then reduced to a probation. His career continued to be illustrious, and he was subsequently elected president of the American Association for Cancer Research.

The Aptly Named ‘Monster Study’

Pioneering speech pathologist Wendell Johnson suffered from severe stuttering that began early in his childhood. His own experience motivated his focus on finding the cause, and hopefully a cure, for stuttering. He theorized that stuttering in children could be impacted by external factors, such as negative reinforcement. In 1939, under Johnson’s supervision, graduate student Mary Tudor conducted a stuttering experiment, using 22 children at an Iowa orphanage. Half received positive reinforcement. But the other half were ridiculed and criticized for their speech, whether or not they actually stuttered. This resulted in a worsening of speech issues for the children who were given negative feedback.

The study was never published due to the multitude of ethical violations. According to The Washington Post , Tudor was remorseful about the damage caused by the experiment and returned to the orphanage to help the children with their speech. Despite his ethical mistakes, the Wendell Johnson Speech and Hearing Clinic at the University of Iowa bears Johnson's name and is a nod to his contributions to the field.

The Dermatologist Who Used Prisoners As Guinea Pigs

One of the biggest breakthroughs in dermatology was the invention of Retin-A, a cream that can treat sun damage, wrinkles, and other skin conditions. Its success led to fortune and fame for co-inventor Albert Kligman, a dermatologist at the University of Pennsylvania . But Kligman is also known for his nefarious dermatology experiments on prisoners that began in 1951 and continued for around 20 years. He conducted his research on behalf of companies including DuPont and Johnson & Johnson.

Kligman’s work often left prisoners with pain and scars as he used them as study subjects in wound healing and exposed them to deodorants, foot powders, and more for chemical and cosmetic companies. Dow once enlisted Kligman to study the effects of dioxin, a chemical in Agent Orange, on 75 inmates at Pennsylvania's Holmesburg Prison. The prisoners were paid a small amount for their participation but were not told about the potential side effects.

In the University of Pennsylvania’s journal, Almanac , Kligman’s obituary focused on his medical advancements, awards, and philanthropy. There was no acknowledgement of his prison experiments. However, it did mention that as a “giant in the field,” he “also experienced his fair share of controversy.”

The Endocrinologist Who Irradiated Prisoners

When the Atomic Energy Commission wanted to know how radiation affected male reproductive function, they looked to endocrinologist Carl Heller . In a study involving Oregon State Penitentiary prisoners between 1963 and 1973, Heller designed a contraption that would radiate their testicles at varying amounts to see what effect it had, particularly on sperm production. The prisoners also were subjected to repeated biopsies and were required to undergo vasectomies once the experiments concluded.

Although study participants were paid, it raised ethical issues about the potential coercive nature of financial compensation to prison populations. The prisoners were informed about the risks of skin burns, but likely were not told about the possibility of significant pain, inflammation, and the small risk of testicular cancer.

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Unethical human research in the field of neuroscience: a historical review

Affiliations.

• 1 King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, P.O. Box: 12723, Jeddah, 21483, Saudi Arabia. [email protected].
• 2 King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
• 3 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
• PMID: 29460160
• DOI: 10.1007/s10072-018-3245-1

Understanding the historical foundations of ethics in human research are key to illuminating future human research and clinical trials. This paper gives an overview of the most remarkable unethical human research and how past misconducts helped develop ethical guidelines on human experimentation such as The Nuremberg Code 1947 following WWII. Unethical research in the field of neuroscience also proved to be incredibly distressing. Participants were often left with life-long cognitive disabilities. This emphasizes the importance of implicating strict rules and ethical guidelines in neuroscience research that protect participants and respects their dignity. The experiments conducted by German Nazi in the concentration camps during WWII are probably the most inhumane and brutal ever conducted. The Nuremberg Code of 1947, one of the few positive outcomes of the Nazi experiments, is often considered the first document to set out ethical regulations of human research. It consists of numerous necessary criteria, to highlight a few, the subject must give informed consent, there must be a concrete scientific basis for the experiment, and the experiment should yield positive results that cannot be obtained in any other way. In the end, we must remember, the interest of the patient must always prevail over the interest of science or society.

Keywords: Ethics; History; Neuroscience; Unethical research.

Publication types

• Historical Article
• History, 20th Century
• Human Experimentation / ethics
• Human Experimentation / history*
• Neurosciences / ethics
• Neurosciences / history*

A Brief History of Human Challenge Trials

For more than two centuries, scientists have been intentionally infecting patients with dangerous diseases in order to learn more

Theresa Machemer

Correspondent

Physicians promise in the Hippocratic oath to keep their patients from harm, so intentionally exposing people to a deadly disease would seem to run counter to that contract. But with human challenge studies, they do exactly that. In challenge studies, medical professionals purposefully expose patients to illnesses so that they can study the patient’s symptoms and immune system response. Such studies can also help physicians discover what vaccines will work to prevent the affliction. Historically in such experiments, the health of individual patients, usually voluntary but at times, horrifically, not, has been sacrificed for medical knowledge and future treatments.

Researchers are planning new human challenge trials as the race to develop vaccines against Covid-19 is in a full sprint, with Pfizer’s vaccine receiving authorization in several countries and Moderna’s not far behind. But the end of the pandemic won’t just come from these two pharmaceutical breakthroughs. In order to fully contain the spread of Covid-19, many treatments and vaccines may be necessary in order to vaccinate billions of people. And some experts say that the fastest way to test those second-generation vaccines is through human challenge trials.

Imperial College London intends to begin a human challenge study related to Covid-19 as soon as January. During the study, scientists would purposely infect up to 100 young, healthy volunteers with the coronavirus that causes Covid-19 in the hopes of accelerating the search for new vaccines.

Supporters of the controversial Covid-19 human challenge trial argue that if it can be done safely then it provides a uniquely controlled environment to study factors that are difficult to unravel in longer, large-scale Phase III trials of thousands of people. Critics say that challenge studies are either unnecessary because of vaccine successes so far, or should be put on pause until a later date when they can be run safely. Critics also point out that safety is a concern even for young volunteers because scientists do not know how to treat Covid-19 or what its long-term effects are, and evidence presented by the World Health Organization in September showed that at least a fifth of people between 18 and 34 who catch Covid-19 experience prolonged symptoms.

The debate over such a contentious experiment is nothing new. Human challenge trials are as old as inoculation itself. In 1796, English surgeon Edward Jenner tested the world’s first vaccine by exposing his gardener’s 8-year-old son to cowpox and then smallpox. Human challenge trials have since been used to study dozens of diseases from cholera to cancer, but early studies often put participants directly in harm’s way, not always with their knowledge.

Today, challenge studies undergo careful review by boards of experts before they can begin. A key requirement of an ethical study is that volunteers provide informed consent , proving that they understand the risks of joining a study. The first informed consent process was introduced more than a century after Jenner’s human challenge study.

In 1898, as the U.S. warred with Spain in Cuba, yellow fever —which can cause liver damage, nausea, high fever and bleeding—killed 13 times more soldiers than war wounds. So in 1900, the U.S. Army established a commission led by pathologist Walter Reed to figure out how yellow fever spread and how to stop it. Because only humans seemed to fall ill with the disease, Reed and three colleagues on the commission designed a human challenge study to test a leading theory of yellow fever transmission: mosquito bites.

Reed recognized that if he was correct, then the study itself would be incredibly risky. The need to expose volunteers to deadly disease would have to be weighed with the responsibility to keep the volunteers safe.

“The general that created the commission told Walter Reed… that he had to be absolutely sure that no harm would be caused to the volunteers,” says Enrique Chaves-Carballo , a historian of medicine at the University of Kansas. “He was pretty specific about that.”

To balance his superior’s order with the study’s inherent risk, the commission came up with a novel solution: the first informed consent contract. The commission created a document for volunteers to sign, stating that they understood the study’s risks. However, the form suggested that abstaining from the study was risky, too. The contract stated :

“The undersigned understands perfectly well that in the case of the development of yellow fever in him, that he endangers his life to a certain extent but it being entirely impossible for him to avoid the infection during his stay in the island, he prefers to take the chance of contracting it intentionally in the belief that he will receive from the said Commission the greatest care and the most skillful medical service.”

During the experiment, the scientists first allowed mosquitoes to bite yellow fever patients so the insects would pick up the disease. Then, they brought the mosquitoes to healthy volunteers, and allowed the mosquitoes to bite them. When volunteers fell ill, Reed scoured blood samples for the microbe causing their illness.

Those with yellow fever were prescribed complete bed rest and fasting except for “a few sips of champagne” and some pain medication, says Chaves-Carballo. Volunteers received a hefty payment of $100 in gold per mosquito bite, and another $100 if they fell ill.

In the first round of experiments, 11 volunteers got mosquito bites. Two fell ill, and survived. The third man to fall ill, Jesse W. Lazear, was one of the scientists running the study. He was bitten by accident and died of yellow fever 12 days later.

Though Reed considered ending the study after the death of his colleague, the commission instead named a sanitary station Camp Lazear in his honor. And by 1901 , Reed and the commission had shown through their mosquito bite experiments that the insects transmit yellow fever. Inoculation of more volunteers with yellow fever patients’ filtered blood samples showed that a virus causes the disease—making yellow fever the first human virus scientists discovered.

With the disease-causing culprit identified, Reed returned to George Washington University (then Columbian University) to teach, and other scientists picked up the search for a yellow fever vaccine. U.S. army physician William Gorgas and Cuban-born physician Juan Guiteras established an inoculation station for a new round of human challenge studies in Havana. They hoped to learn how to induce light cases of yellow fever with mosquito bites in order to give people immunity. More than 20 volunteers signed up for the first experimental inoculations in 1901, including the only woman to participate in the study, a military nurse named Clara Maass.

Maass was bitten five times without developing yellow fever, and received $100 to send home to her mother and nine siblings in New Jersey—a huge sum compared to her monthly pay of $30 .

Her sixth mosquito bite proved fatal. She and two other volunteers were infected with a particularly violent strain of the virus—the doctors didn’t know how to induce just light cases—and all three died in August of 1901.

“Some of the headlines of the newspapers are like, ‘Nurse Dies for a Hundred Dollars,’” says Chaves-Carballo. “People responded to the fact that she was a young nurse who was trying her best to help her family.”

Public outcry in the U.S. brought the Havana experiments to an end. Maass’ death brought the study’s exorbitant pay under fire, as such a large incentive may have interfered with the participants’ ability to accurately weigh the risk of joining the study. The fact that the study was run by the U.S. Army, and Reed’s participants were members of the military, also brought into question the participants’ ability to freely opt out of the study, says Monica McArthur , pediatrician and infectious disease specialist at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health.

“In a lot of the studies early on, the Walter Reed experiment and other studies, used what we would now consider vulnerable populations,” people who couldn’t freely agree to participate or make a fully informed decision, says McArthur. “Prisoners, for example, could be enrolled in studies.”

A classic example of a challenge study that relied on a vulnerable population is the Tuskegee Syphilis Study. Beginning in 1932 , the U.S. Public Health Service recruited about 600 poor African American men from around Tuskegee, Alabama, for a study of how syphilis worsens over time. About two-thirds of the men had syphilis, but the study doctors informed them they had “bad blood.”

After receiving this phony diagnosis, the men were persuaded to join the study in exchange for free meals, hospital access and treatment for “bad blood” and other unrelated conditions. The scientists also provided participants a burial stipend that would be paid to their survivors after their deaths.

Only about half of the men with syphilis received a treatment that was usually prescribed in the 1930s: doses of toxic arsenic and mercury. The doctors subjected the participants to blood draws and spinal taps, and after they died of syphilis, autopsies, all in pursuit of more information about the natural course of the disease. The study lasted for decades, and even after the medical community established that penicillin could cure the disease in the 1940s the men did not receive the medication.

In 1972, journalist Jean Heller of the Associated Press brought the Tuskegee Syphilis Study to light and shared how the doctors involved in the study had deceived the men participating. By then, only 74 of the men with syphilis still survived. Public outrage shut the study down three months after the report.

While the Tuskegee Syphilis Study relied on participants who were already ill, other studies exposed otherwise healthy people to deadly diseases. For example, from 1955 to 1970, a pediatrician exposed more than 50 children with mental disabilities to hepatitis in order to identify different strains of the disease and eventually develop vaccines. The trial took place at Willowbrook State School, a home for children and adults with developmental disabilities in Staten Island, New York.

The school was overcrowded and had a lengthy waitlist for new patients. But the study’s principal investigator, Saul Krugman, offered several parents the opportunity to cut the line if they agreed to enroll their children in the study. Krugman told them that their children were likely to catch the disease at the facility anyway, but by joining the study, they would have access to cleaner facilities and a chance at an eventual vaccine.

“I did feel coerced,” said Diana McCourt, who enrolled her daughter in the Willowbrook study, to Forbes ’ Leah Rosenbaum. “I felt like I was denied help unless I took this [opportunity].”

The Willowbrook studies, which ended in 1970, revealed the existence of the A and B strains of hepatitis and sped up the development of a hepatitis B vaccine. But the studies progressed even as some in the medical community criticized Krugman’s methods. In 1966, anesthesiologist Henry K. Beecher published a landmark essay detailing 22 examples of ongoing unethical research on human subjects, including the Willowbrook hepatitis studies, in order to raise awareness and end unethical practices that continued despite the creation of international human experimentation guidelines—the Nuremberg Code in 1947 and the Declaration of Helsinki in 1964.

In addition to the Willowbrook study, Beecher highlighted one study in which melanoma, a serious form of skin cancer, was transferred from a woman to her mother “in the hope of gaining a little better understanding of cancer immunity.” The woman died on the same day that her mother was to receive the melanoma injection, so the doctors knew the cancer was deadly. Her mother died 451 days after receiving the injection.

Beecher concluded that an ethical approach to experimentation requires, first and foremost, the informed consent of study volunteers. “The difficulty of obtaining this is discussed in detail,” he writes, “But it is absolutely essential to strive for it for moral, sociologic and legal reasons. The statement that consent has been obtained has little meaning unless the subject or his guardian is capable of understanding what is to be undertaken and unless all hazards are made clear.”

Human challenge studies became less common after the 1970s with the conclusion of unethical studies that shocked the public. Since then, the Declaration of Helsinki has been amended seven times to clarify ethical standards for human experiments, most recently in October of 2013. The current declaration states that “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.”

When run well, challenge studies are still uniquely able to provide clear data about infectious diseases. “They are now coming back in favor with very rigorous ethical principles in place,” adds McArthur.

The University of Maryland used human challenge studies in 2012 and 2013 to develop a vaccine for cholera , which was approved by the FDA in 2016. Cholera was an ideal candidate for a safe human challenge study because it is well understood by scientists, is reliably treatable with fluids and antibiotics, and has no long-term effects after the infection is gone.

Informed consent procedures have come a long way since Reed’s contract. Volunteers can ask questions and seek outside guidance, and must pass an assessment designed by the researchers to prove that they understand the risks of a study. And the volunteers have the power to quit. “Every time there’s an encounter with the volunteer, it’s reaffirming that the volunteer is still willing and able to participate,” says McArthur.

According to a statement by Imperial College London, which still needs to have its experimental plan approved by government regulators before researchers can begin recruiting participants, volunteers’ safety is the number one priority. “It would be nice to see exactly how [Imperial College London] explains the risks and benefits to those participating in this study,” says Chaves-Carballo.

Covid-19 is different from other challenge study diseases: Scientists have been studying it for less than a year, physicians have no approved treatments to intervene if a volunteer’s illness becomes severe, and early evidence suggests Covid-19 can cause long-term effects even in young, previously healthy people. The Imperial College London study aims to first identify the minimum dose of coronavirus necessary to cause disease. The study would use that dose of virus to study how vaccines work in the body to prevent Covid-19, to look at potential treatments and study the immune response. The biomedical community remains split on whether such a study should be run, given all of the unknowns around Covid-19.

When scientists develop second- and third-generation vaccines, a challenge study allows researchers to work with just 100 people instead of tens of thousands. That means fewer people are asked to go without the vaccine for the sake of research. And by waiting to conduct a challenge study on Covid-19 until a later date, researchers might get access to new information about risk factors for severe disease, which could help make the study safer.

“I am not a fan of SARS-CoV-2 challenge studies,” says McArthur. “But if I’m playing devil’s advocate against myself, some of the very reasons [not to do a challenge study] that I listed might be reasons that someone else might say that a challenge study is beneficial. Because we don’t know that much about a disease, so we could learn more about it.”

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Theresa Machemer | READ MORE

Theresa Machemer is a freelance writer based in Washington DC. Her work has also appeared in National Geographic and SciShow. Website: tkmach.com

ALLIANCE FOR HUMAN RESEARCH PROTECTION

Advancing Voluntary, Informed Consent to Medical Intervention

• Board of Directors
• Distinguished Advisory Board
• Honor Roll–Exemplary Professionals
• First, do no Harm
• Human Rights
• Informed Consent
• Nuremberg Code
• Discrimination
• Medicalized Racism
• Gene Modification
• Depopulation
• Technocracy
• Propaganda – Censorship
• Clinical Trials
• Concealed Data
• Public-Private Partnerships
• Pharma Corrupt Influence
• Publication Bias
• Organ Harvesting
• Bioweapon Experiments
• Transhumanism
• Current Medical Atrocities
• Japanese Atrocities
• Nazi Atrocities
• Operation Paperclip
• CIA Mind-Control
• CIA Torture
• U.S. Radiation Experiments

Unethical Experiments

• Pandemic Control
• Great Reset
• Diabolical Lockstep
• Apartheid Policies
• Coronavirus Fear
• Covid Pandemic
• Government Overreach
• Vaccine Profit Engine
• Child Sacrifice
• Vaccine Mandates
• Vaccine Risks
• Vaccine Safety

Introduction: Unethical Medical Experiments 1980–2010

“The whole discipline of biomedical ethics rises from the ashes of the Holocaust…”   Arthur Caplan

The Nuremberg Code (1947) laid the foundation for biomedical ethics mandating that medical experiments conducted on human beings must conform to well-defined humane, ethical standards; foremost is immutable standard:

“The voluntary consent of the human subject is absolutely essential . The information sought is “unprocurable by other methods or means of study; the anticipated results will justify the performance of the experiment; the experiment is designed “to avoid all unnecessary physical and mental suffering or injury; risks to subjects be minimized to protect against “even remote possibilities of injury, disability or death.”

The Nuremberg Code makes clear that ethical standards protecting individual human rights supersede arguments invoking the “greater good of society.”

The Declaration of Helsinki (1964) expanded on a requirement of full disclosure:

“In medical research involving competent human subjects, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other relevant aspects of the study. “In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method.”        ( World Medical Association , 1964, 1996 2000)

Thirty years after the Nuremberg Code, the United States was confronted with the infamous Tuskegee Syphilis experiment which resulted in the government forging ethical research principles. The Belmont Report (1978, 1979) provided the template for the Code of Federal Regulations (45 CFR 46) followed by The Common Rule .

The overwhelming evidence that these ethical principles were much more frequently honored in their breach than in their observance. The record is clear: dubious medical experiments that failed to meet medical ethical standards have been — and are currently — approved not only by commercial corporate entities, but by academic and government review boards and institutions whose mandate is to ensure that the safety and rights of human subjects are protected.

Conflicts of interest, rather than ideologies have derailed medicine from its ethical tradition. The entire field of medical research is now permeated by conflicts of interest. All major academic institutions government agencies, including the National Institutes of Health, the Food and Drug Administration, the Center for Disease Control, the Environmental Protection Agency, are dependent upon major corporate money. Thus business ethics has usurped medical ethics. Read Doing Harm to the Most Vulnerable ; Read NIH Under Fire ; Read   Research Center Tied to Drug Company ;  Read CDC Covertly Tested Experimental Vaccine on Black/Latino Babies .

The only redress and reliable source of information comes from litigation when primary secret documents are uncovered during the discovery process. Read more here and here . Finally, unless they are stopped,  Medical Research Stakeholders Seek to Overturn Informed Consent .

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• Original article
• Open access
• Published: 01 April 2021

Unethical practices within medical research and publication – An exploratory study

• S. D. Sivasubramaniam 1 ,
• M. Cosentino 2 ,
• L. Ribeiro 3 &
• F. Marino 2  

International Journal for Educational Integrity volume  17 , Article number:  7 ( 2021 ) Cite this article

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The data produced by the scientific community impacts on academia, clinicians, and the general public; therefore, the scientific community and other regulatory bodies have been focussing on ethical codes of conduct. Despite the measures taken by several research councils, unethical research, publishing and/or reviewing behaviours still take place. This exploratory study considers some of the current unethical practices and the reasons behind them and explores the ways to discourage these within research and other professional disciplinary bodies. These interviews/discussions with PhD students, technicians, and academics/principal investigators (PIs) (N=110) were conducted mostly in European higher education institutions including UK, Italy, Ireland, Portugal, Czech Republic and Netherlands.

Through collegiate discussions, sharing experiences and by examining previously published/reported information, authors have identified several less reported behaviours. Some of these practices are mainly influenced either by the undue institutional expectations of research esteem or by changes in the journal review process. These malpractices can be divided in two categories relating to (a) methodological malpractices including data management, and (b) those that contravene publishing ethics. The former is mostly related to “committed bias”, by which the author selectively uses the data to suit their own hypothesis, methodological malpractice relates to selection of out-dated protocols that are not suited to the intended work. Although these are usually unintentional, incidences of intentional manipulations have been reported to authors of this study. For example, carrying out investigations without positive (or negative) controls; but including these from a previous study. Other methodological malpractices include unfair repetitions to gain statistical significance, or retrospective ethical approvals. In contrast, the publication related malpractices such as authorship malpractices, ethical clearance irregularities have also been reported. The findings also suggest a globalised approach with clear punitive measures for offenders is needed to tackle this problem.

Introduction

Scientific research depends on effectively planned, innovative investigation coupled with truthful, critically analysed reporting. The research findings impact on academia, clinicians, and the general public, but the scientific community is usually expected to “self-regulate”, focussing on ethical codes of conduct (or behaviour). The concept of self-regulation is built-in from the early stages of research grant application until the submission of the manuscripts for gaining impact. However, increasing demands on research esteem, coupled with the way this is captured/assessed, has created a relentless pressure to publish at all costs; this has resulted in several scientific misconduct (Rawat and Meena 2014 ). Since the beginning of this century, cases of blatant scientific misconduct have received significant attention. For example, questionable research practices (QRP) have been exposed by whistle blowers within the scientific community and publicised by the media (Altman 2006 ; John et al. 2012 ). Moreover, organisations such as the Centre for Scientific Integrity (CSI) concentrate on the transparency, integrity and reproducibility of published data, and promote best practices (www1 n.d. ). These measures focus on “scholarly conduct” and promote ethical behaviour in research and the way it is reported/disseminated, yet the number of misconduct and/or QRP’s are on the rise. In 2008, a survey amongst researchers funded by the National Institutes of Health (NIH) suggested there might be as many as 1,000 cases of potential scientific misconduct going unreported each year (Titus et al. 2008 ). Another report on bioRxiv (an open access pre-print repository) showed 6% of the papers (59 out of 960) published in one journal (Molecular and Cellular Biology - MCB), between 2009 and 2016, contained inappropriately duplicated images (Bik et al. 2018 ). Brainard ( 2018 ) recently reported that the number of articles retracted by scientific journals had increased 10-fold in the past 10 years. If the reported incidence of scientific misconduct is this high, then one can predict the prevalence of other, unreported forms of misconduct. The World Association of Medical Editors (WAME) has identified the following as the most reported misconduct: fabrication, falsification, plagiarism/ghost writing, image/data manipulation, improprieties of authorship, misappropriation of the ideas of others, violation of local and international regulations (including animal/human rights and ethics), inappropriate/false reporting (i.e. wrongful whistle-blowing) (www2 n.d. ).

However, WAME failed to identify other forms of scientific misconduct, such as; reviewer bias (including reviewers’ own scientific, religious or political beliefs) (Adler and Stayer 2017 ), conflicts of interests (Bero 2017 ), and peer-review fixing, which is widespread, especially after the introduction of author appointed peer reviewers (Ferguson et al., 2014 ; Thomas 2018 ). The most recent Retraction Watch report has shown that more than 500 published manuscripts have been retracted due to peer-review fixing; many of these are from a small group of authors (cited in Meadows 2017 ). Other reasons for retraction include intentional/unintentional misconduct, fraud and to a lesser extent honest errors. According to Fang et al. ( 2012 ), in a detailed study using 2,047 retracted articles within biomedical and life-sciences, 67.4% of retractions were due to some form of misconduct (including fraud/suspected fraud, duplicate publication, and plagiarism). Only 21.3% of retractions were due to genuine error. As can be seen, most of the information regarding academic misconduct is reported, detected or meta-analysed from databases. As for reporting (or whistle blowing), many scientists have shown been reticent to raise concerns, mainly because of the fear of aftermath or implications of doing so (Bouter and Hendrix 2017 ). An anonymous information-gathering activity amongst scientists, junior scientists, technicians and PhD students may highlight the misconduct issues that are being encountered in their day-to-day laboratory, and scholarly, activities. Therefore, this exploratory study of an interview-based study reports potentially un-divulged misconduct and tries to form a link with previously reported misconduct that are either being enforced, practiced or discussed within scientific communities.

Methodology

This qualitative exploratory study was based on informal mini-interviews conducted through collegiate discussions with technicians, PhD scholars, and fellow academics (N=110) within medical and biomedical sciences mainly in European higher education institutions including UK, Italy, Ireland, Portugal, Czech Republic and Netherlands (only 5 PhD students). PhD students (n=75), technicians (mostly in the UK; n=25) and academics/principal investigators (PIs; n=10), around Europe, have taken part in this qualitative narrative exploration study. These mini-interviews were carried out in accordance with local ethical guidance and processes. The discussions or conversations were not voice recorded; nor the details of interviewees taken to maintain anonymity. The data was captured (in long-hand) by summarising their views on following three questions (see below).

These answers/notes were then grouped according to their similarities and summarised (see Tables  1 and  2 ). The mini-interviews were semi-structured, based around three questions.

Have you encountered any individual or institutional malpractices in your research area/laboratory?

If so, could you give a short description of this misconduct?

What are the measures, in your opinion, needed to minimise or remove these misconduct?

we also examined recently published and/or reported (in media) unethical practice or misconduct to compare our findings (see Table  2 ). Fig.  1 summarises the methodology and its meta-cognitive reflection (similar to Eaton et al. 2019 ).

Interactive enquiry-based explorative methodology used in this study

Results and discussion

As stated above, this manuscript is an exploratory study of unethical practice amongst medical researchers that are not well known or previously reported. Hence, the methodology applied was more exploratory with minimal focus on standardisation, using details of qualitative approach and paradigm, or the impact of researcher characteristics and reflexivity (British Medical Journal (BMJ) – www3 n.d. ). Most importantly, our initial informal meetings prior to this study clearly indicated that the participants were reluctant to provide information that would assist for an analysis linked to researcher characteristics and/or reflexivity. Thus, the level of data presented herein would not be suitable for a full thematic analysis. We do accept this as a research limitation.

This study has identified some less reported (not well-known) unethical behaviours or misconduct. These findings from technician/PhD scholars and academics/PIs are summarised in Tables  1 and  2 . The study initially aimed to identify any previously unreported unethical research conducts, however, the data shows that many previously identified misconduct are still common amongst researchers. Since the interviews were not audio recorded (to reassure anonymity), the participants were openly reported the unethical practices within their laboratories (or elsewhere). This may cast doubts on the accuracy of data interpretation. To minimise this, we have captured the summary of the conversation in long-hand.

We were able to generalise two emerging themes linked to the periods of a typical research cycle (as described by Hevner 2007 ); (a) methodological malpractices (including data management), and (b) those that contravene publishing ethics. Researcher-linked behaviours happen during laboratory investigation stage, where researchers employ questionable research practices, these include self-imposed as well as acquired (or taught) habits. As can be seen from Tables  1 and  2 , these misconduct are mainly carried out by either PhD scholars, post-doctoral scientists or early career researchers. These reported “practices” may be common amongst laboratory staff, especially given the fact that some of these practices have been nicknamed (e.g. ghost repeats, data mining etc. – see Table  1 ). Individual or researcher-linked unethical behaviours mostly related to “committed bias”, by which the researcher selectively uses the data to suit their own hypothesis or what they perceive as ground-breaking. This often results in conducts where research (and in some cases data/results) is statistically manipulated to suit the perceived conclusion.

Although this is a small-scale pilot study, we feel this reflects the common trend in laboratory-based research. As mentioned earlier, although this study was set out to detect unreported research misconduct/malpractices, study participant reported some of the behaviours that were already reported in previous studies.

In contrast, established academics, professors and PIs tend to commit publication-related misconduct. These can be divided into author-related or reviewer-related misconduct. The former includes QRPs during manuscript preparation (such as selective usage of data, omitting outliers, improper ethical clearance, authorship demands etc). The latter is carried out by the academics when they review others manuscripts and includes delaying review decisions, reciprocal reviewing etc.

From tables above, it seems that most of the reported misconduct can be easily prevented if specific and accurate guidelines or code of conduct are present in each research laboratory (see below). This aspect, for example is of minor impact in the clinical research, where the study protocol is rigorously detailed in advance, the specific analysis that will be included in the final report specified in advance with clear primary or secondary endpoints, and all the analysis/reports need to be stored for the final study revision/conclusion. All these different steps are regulated by Good Clinical Practice guidelines (GCP; National Institute for Health Research Clinical Research Network (NIHR CRN- www4 n.d. ).

This by no means indicates that in clinical research fraud does not exist, but that it is easier to discover it than in laboratory based-investigations. The paper of Verhagen et al. ( 2003 ) clearly refers to a specific situation that commonly happens in a research laboratory. The majority of experiments within biomedical research are conducted on tissues or cells. Therefore, the experimental set-ups, including negative and positive controls can easily (and frequently) be manipulated. This can only be prevented by using Standard Operating Procedures (SOP) and well written and clear regulation such as Good Laboratory Practice (GLP; Directive 2004 /9/EC), and written protocols. However, at present, no such regulations exist apart from in industry-based research, where GLP is mandatory. In a survey-based systematic review, Fanelli ( 2009 ) reported that approximately 2% of scientists claimed they had fabricated their data, at some point in their research career. It is worth noting, Fanelli’s study (as well as ours) only reported data from those who were willing admit engaging in these activities. This cast questions on actual number of occurrences, as many of them would not have reported misconduct. Other authors have highlighted the same issue and cast doubt on the reproducibility of scientific data (Resnik and Shamoo, 2017 ; Brall et al, 2017 ; Shamoo 2016 ; Collins and Tabak 2014 ; Kornfeld and Titus 2016 ).

The interview responses

We also wanted to understand the causes of these QRPs to obtain a clear picture of these misconduct. Based on interview responses, we have tried to give a narrative but critical description of individual perceptions, and their rationalisation in relation to previously published information.

Methodological malpractices

The data reported herein show that PhD scholars/post-doctoral fellows are mostly involved in laboratory-linked methodological misconduct. Many of them (especially the post-doctoral scientists) blamed supervisory/institutional pressures on not only enhancing publishing record, but also maintaining high impact. One post-doctoral scientist claimed “ there is always a constant pressure on publication; my supervisor said the reason you are not producing any meaningful data is because you are a perfectionist ”. He further recalled his supervisor once saying “ if the data is 80% correct, you should accept it as valid and stop repeating until you are satisfied ”.

Likewise, another researcher who recently returned from the US said “ I was an excellent researcher here (home country), but when I went to America, they demanded at least one paper every six months ”. “ When I was unable to deliver this (and missed a year without publishing any papers), my supervisor stopped meeting me, I was not invited for any laboratory meetings, presentations, and proposal discussions; in fact, they made me quit the job ”. A PhD student recalled his supervisor jokingly hinting “ if you want a perfect negative control, use water it will not produce any results ”. Comments and demands like these must have played a big role in encouraging laboratory based misconduct. In particular, the pressure to publish more papers in a limited period led to misconduct such as data manipulation (removing outliers, duplicate replications, etc.) or changing the aim of the study, and as a consequence including data set that were not previously considered, because the results are not in line with the original aim of the study. All these aspects force the young researchers to adopt an attitude that leads them to obtain publishable results by any means (ethical or not) – A “ Machiavellian personality trait ” as put by Tijdink et al. ( 2016 ). Indeed, an immoral message is being delivered to these young researchers (future scientists), enhancing cheating behaviours. In fact, Buljan et al. ( 2018 ) have recently highlighted the research environment, in which a scientist is working, as one of the potential causes of misconduct.

Behaviours that contravene publishing ethics

Academics (and PIs) have mostly identified misconduct linked to contravening publishing ethics. This finding itself shows that most of the academics who took part in this study has less “presence” within their laboratories. When confronted with the data obtained from PhD scholars and technicians, some of them vehemently denied these claims. Others came up with a variety of excuses. One lecturer/researcher said, “ I have got far too much teaching to be in my laboratory ”. Another professor said, “ I have post-docs within my laboratory, they will look after the rest; to be honest, my research skills are too old to refresh!” One PI replied, “ why should I check them? No one checked me when I was doing research ”. All these replies show a lack of care for research malpractices. It is true that academics are under pressure to deliver high impact research, carry out consultancy work, get involved with internationalisation within academia and teach (Edwards and Roy 2017 ). However, these pressures should not undermine research ethics.

One researcher claimed to have noticed at least two different versions of “ convenient ethical clearance ”. According to him, some researchers, especially those using human tissues, avoid specifying their research aims; and instead write an application in such a way that they can use these samples for a variety of different projects (bearing in mind of possible future developments). For example, if they aim to use the tissue to study a particular protein, the ethical application would mention all the related proteins and linked pathways. They justify this by claiming the tissues are precious, therefore they are “ maximising the effective use of available material ”. Whilst understanding the rationale within their argument, the academic who witnessed this practice asked a question “ how ethical it is to supply misleading information in an ethical application ?” He also highlighted issues with backdating ethical approval in one institution. That is, the ethical approval was obtained (or in his words “ staged ”) after the study has been completed. Although this is one incident reported by one whistle-blower, it highlights the institutional malpractices.

Selective use of data is another category reported here and elsewhere (Priya Satalkar & David Shaw, 2019 ; Blatt 2013 ; Bornmann 2013 ). One academic reported incidences of researchers purposely avoiding data to maximise the statistical significance. If this is the case, then the validity of reported work, its statistical significance, and in some cases its clinical usage are in question. What is interesting is that, as elegantly reported by Fanelli ( 2010 ), in the highest percentage of published papers, the findings always report the data that are in line with the original hypothesis. In fact, the number of papers published reporting negative results are very limited.

Misconduct relating to authorships have been highlighted in many previous studies (Ploug 2018 ; Vera-Badillo et al. 2016 ; Ng Chirk Jenn 2006 ). The British Medical Journal (BMJ – www5 n.d. ) has classified two main types of misconduct relating to authorships; (a) omission of a collaborator who has contributed significantly to the project and (b) inclusion of an author who has not (or minimally) contributed. Interestingly in this study, one academic claimed that he was under pressure to include the research co-ordinator of his department as an author in every publication.

He recalled the first instance when he was pressurised to include the co-ordinator, “ It was my first paper as a PI but due to my institutional policy, all potential publications needed to be scrutinised by the co-ordinator for their worthiness of publication ”, “ so when I submitted for internal scrutiny, I was called by the co-ordinator who simply said there is nothing wrong with this study, but one important name is missing in authors’ list ” (indirectly requesting her name to be included). Likewise, another PI said, “ it is an unwritten institutional policy to include at least one professor on every publication ”. Yet another PI claimed, “ this is common in my laboratory – all post-doctoral scientists would have a chance to be an author ” “ by this way we would build their research esteem ”. His justification for this was “ many post-doctoral scientists spend a substantial amount of time mentoring other scientists and PhD students, therefore they deserve honorary authorships ”. Similar malpractices have also been highlighted by other authors (Vera-Badillo et al. 2016 ; Gøtzsche et al. 2007 ) but the worrying finding is that in many cases, the practice is institutionalised. With regards to authorships, according to the International Committee of Medical Journal Editors (ICMJE – www6 n.d. ), authorships can only be given to those with (a) a substantial contribution (at least to a significant part of the investigation), (b) involvement in manuscript preparation including contribution to critical review. However, our discussions have revealed complementary authorships, authorship denial, etc.

Malpractices in peer-review process

The final QRP highlighted by our interviewees relates to the vreviewing process. One academic openly admitted, “ I and Dr X usually use each other as reviewers because we both understand our research”, he further added, “the blind reviewing is the thing of the past, every author has his own writing style, and if you are in one particular research field, with time, you would be able to predict the origin of the manuscript you are reviewing (whether it is your friend or a person with a conflicting research interest!”. Another academic said that “ the era of blind reviewing is long gone, authors are intentionally or unintentionally identifying themselves within the manuscripts with sentences such as ‘previously we have shown’. “This allows the reviewer to identify the authors from the reference list ”. He further claimed he also experienced reviewers intentionally delaying acceptance or asking for further experiments to be carried out, simply because they wanted their manuscript (on a related topic) to be published first! Incidences like this, though minimal, cast questions on the reviewing process itself.

Recent reports by Thomas ( 2018 ) and Preston ( 2017 ) (see also Adler and Stayer 2017 ) have highlighted issues (or scams) such as an author reviewing his own manuscripts! Of course, many journals do not use the suggested reviewers; instead, they build a database of reviewers and randomly select appropriate reviewers. Still, it is not clear how robust this approach is in curtailing reviewer-based misconduct. Organisations such as Retraction Watch constantly pick up and report these malpractices, yet there are no definite sanctions or punishment for the culprits (Zimmerman 2017 )

One of the academic interviewees recalled an incidence in which an author has been dismissed due to a serious image manipulation scam, yet obtained a research tenure in another institution within 3 months of dismissal. Galbraith ( 2017 ) reviewed summaries of 284 integrity-related cases published by the Office of Research Integrity (ORI), and found that in around 47% of cases the researchers received moderate punishment and were often permitted to continue their research. This highlights the need for a globalised approach with clear sanction measures to tackle research misconduct. Although this is a small-scale study, it has highlighted that despite measures taken by research regulatory bodies, the problem of misconduct is still there. The main problem behind this is “the lack of care” underpinned by pressures for esteem.

Limitations

This is an exploratory study with minimal focus on standardisation, using details of qualitative approach and paradigm, or the impact of researcher characteristics and reflexivity. Therefore, the level of data presented herein is not suited for a full thematic analysis. Also, this is a small-scale study with a sample size of of 110 participants who are further divided into sub-groups (such as PhD students, technicians and PIs). This limits the scope of analysing variability in the responses of individual sub-groups, and therefore might have resulted in voluntary response bias (i.e. responses are influenced by individual perceptions against research misconduct). Yet, the study has highlighted the issue of research misconduct is worth pursuing using a large sample. It also highlighted the common QRPs (both laboratory and publication related) that need to be focussed further, enabling us to establish a right research design for future studies.

The way forward

This exploratory study (and previously reported large scale studies) showed QRP is still a problem in science and medical research. So what are the way forward to stop these types of misconduct? Whilst it is important to set up confirmed criteria for individual research conduct, it is also important to set up institutional policies. These policies should aim at promoting academic/research integrity, with paramount attention on the training of young researchers about research integrity. The focus should be on young researchers attaining rigorous learning/application of the best methodological and professional standards in their research. In fact, the Singapore statement on research integrity (www7 n.d. ), not only highlights the importance of individual researchers maintaining integrity in their research, but also insists the roles of institutions creating/sustaining research integrity via educational programmes with continuous monitoring (Cosentino and Picozzi 2013 ). Considering the findings from this study, it would also be appropriate to suggest an international regulatory body to regularly monitor these practices involving all stakeholders including governments.

In fact, this (and other studies) have highlighted the importance of re-validating the “voluntary commitment” to follow the research integrity. With respect to individual researchers, we propose using a unified approach for early career researchers (ECRs). They should be educated about the importance of ethics/ethical behaviours (see Table  3 ) for our suggestion for ECRs). We feel it is vital to provide compulsory ethical training throughout their career (not just at the beginning). It is also advisable to regularly carry out “peer review” visits/processes between laboratories for ethical and health/safety aspects. Most importantly, it is time for the research community to move away from the expectation of “self-governance” establish and international research governance guidelines that can monitored by individual countries.

We, do agree this is a small-scale pilot study and due to the way it was conducted, we are unable to carry out a full thematic analysis. This was mainly because the participants were extremely reluctant to offer information to formulate researcher characteristics. Also, the study data in many cases conforms to the previously reported fact, that QRP and research misconduct is still a problem within science and medicine. Yet, this study has attempted to narrate the previously unreported justifications given by the interviewees. In addition, we were able to highlight that these activities are becoming regular occurrence (those nick-named behaviours). We also provided some directives on how academic pressures are inflicted upon early career researchers. We also provided some recommendations in regard to the training ECRs.

Significance

The study has highlighted the negative influence on supervisory/peer pressures and/or inappropriate training may be main causes for these misconducts, highlighting the importance on devising and implementing a universal research code of conduct. Although this was an exploratory investigation, the data presented herein have pointed out that unethical practices can still be widespread within biomedical field. It highlighted the fact that despite the proactive/reflective measures taken by the research governance organisations, these practices are still going on in different countries within Europe. As the study being explorative, we had the flexibility to adapt and evolve our questions in reflection to the responses. This would help us to carry out a detailed systematic research in this topic involving international audience/researchers.

Concluding remarks

To summarise, this small-scale interview-based narrative study has highlighted that QRP and research misconduct is still a problem within science and medicine. Although they may be influenced by institutional and career-related pressures, these practices seriously undermine ethical standards, and question the validity of data that are being reported. The findings also suggest that both methodological and publication-related malpractices continue, despite being widely reported. The measures taken by journal editors and other regulatory bodies such as WAME and ICMJE may not be efficient to curtail these practices. Therefore, it would be important to take steps in providing a universal research code of conduct. Without a globalised approach with clear punitive measures for offenders, research misconduct and QRP not only affect reliability, reproducibility, and integrity of research, but also hinder the public trustworthiness for medical research. This study has also highlighted the importance of carrying out large-scale studies to obtain a clear picture about misconduct undermining research ethics culture.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article

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Acknowledgements

Authors wish to thank the organising committee of the 5th international conference named plagiarism across Europe and beyond, in Vilnius, Lithuania for accepting this paper to be presented in the conference. We also sincerely thank Dr Carol Stalker, school of Psychology, University of Derby, for her critical advice on the statistical analysis.

Not applicable – the study was carried out as a collaborative effort amongst the authors.

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Dr Sivasubramaniam has produced the questionnaire with interview format with the contribution of all other authors. He also has read the manuscript with the help of Prof Consentino. The latter also contributed for the initial literature survey and discussion. Drs Marino and Ribario have helped in the data collection and analysis. The author(s) read and approved the final manuscript.

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Sivasubramaniam, S.D., Cosentino, M., Ribeiro, L. et al. Unethical practices within medical research and publication – An exploratory study. Int J Educ Integr 17 , 7 (2021). https://doi.org/10.1007/s40979-021-00072-y

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“The Doctor as a Humanist”: The Viewpoint of the Students

Conference Report and Reflection by Poposki Ognen (University Pompeu Fabra); Castillo Gualda Paula (University of Balearic Islands); Barbero Pablos Enrique (University Autonoma de Madrid); Pogosyan Mariam (Sechenov University); Yusupova Diana (Sechenov University); and Ahire Akash (Sechenov University)

The practice of Medicine as a profession has become very technical; doctors rely on fancy investigations, treatment algorithms and standardized guidelines in treating patients. In a lot of universities, medical students and residents are trained without appreciating the importance of art and the humanities in delivering good care to patients and their families. Factual knowledge is imposed on us, as students, from scientific evidence delivered by highly specialized professionals: those who know more and more about niche subjects.

As a result, when someone decides to become a doctor , it seems that scientific training is the sole priority, with most attention being given to the disease-treatment model. As medical students, we are taught very specific subjects, leaving little or no space or time for any cultural enrichment programs. And yet, Personal growth as a doctor and a human being cannot be achieved unless one is exposed to the whole range of human experience. Learning from art and artists can be one such means of gaining these enriching experiences. We can learn from historians, and from eminent painters, sculptors, and writers, as well as from great scientists. How do we achieve these ends? The following essay summarizes and reviews one attempt at providing answers. The 2nd “Doctor as a Humanist” Symposium took place at Sechenov University in Moscow from the 1 st to the 3 rd of April, 2019, to explore the holistic perspective of interpersonal treatment.

To begin our essay, we would like to clarify some key concepts, such as culture, humanism and humanities, as they were employed at the conference. Culture is a complex phenomenon that includes knowledge, beliefs, artistic production, morals, customs and skills acquired by being part of a society, which can be transmitted consciously or unconsciously, by individuals to others and through different generations.

The humanities are academic disciplines that study the cultural aspects and frailties of being human, and use methods that are primarily analytical, critical, or speculative, which distinguish them from the approaches of the natural sciences. Humanism is the practice of making the human story central. Consequently, the studies of humanities, so invested in human stories, is one aspect of practicing humanism.

Technological and practical progress in medicine has been impressive in the past fifty years. Nevertheless, patients still suffer from chronic conditions such as heart failure, chronic lung disease, depression, and many others. These are conditions where technology cannot significantly change the outcomes or reverse the underlying condition. One of the ways to alleviate suffering is through compassion and empathy where the doctor is a professional who listens to, understands and comforts the patient, as well as engaging the patient as a fellow human being. We need arts and humanities as doctors’ tools to comfort and, perhaps, even to heal. We also need them to remind us that we are ‘merely human’ ourselves, and that we share our humanity with our patients, as equals.

Unquestionably, there are fundamental requirements that every physician must internalize; the conference goal was to explain that one such requirement is the humanistic view. Opera, poetry, philosophy, history, the study of dialectics, biographical readings, and even volunteering abroad can be means of engaging the world for positive change. Sometimes called  “soft” skills, these are in fact necessary and valuable qualities to empower ourselves as persons, as well as doctors. The 2nd The Doctor as a Humanist Symposium placed the corner stone in a global project that aims to understand medicine as a multidisciplinary subject, and to establish the concept of humanistic medicine both as a science and an art where the patient and the doctor are human beings working together.

STUDENT PARTICIPATION

The event united experts in Medicine and the Humanities from all over the world. The speakers (doctors, nurses and students) were from Russia, the USA, the UK, Spain, Italy, Germany, Mexico and more. Each day’s program was both intense and diverse, and included plenary lectures and panel sessions. Medical students were highly involved in all parts of the conference, offering us a great chance to introduce our projects, share our opinions on various topics, and discuss our questions connected with the role of the humanities in medicine.We participated in roundtable discussions, which were chaired by experts from different countries. Even though this made us nervous, at the same time it was very important for us, as students, to be a part of it. We discussed the future of medical humanities from various perspectives, and above all our thoughts and ideas were listened to and commented on, on an equal basis with the world’s experts. For once, we could see that our views were being taken into consideration, and we hope that in the future this will be the norm and NOT the exception. We are the future of medicine, and our voices should be heard, too.

At the end of the first day there was a students’ session, where we gave our opinions on the relative importance of the medical humanities from a multicultural viewpoint, and on this particular roundtable there were students from Russia, Spain, Iran, Mexico, Italy, as well as a Nursing resident. One of the students during the session shared her view that “I would like to see medicine through the lens of humanism and empathy, and also implement all its principles in my professional life on a daily basis”. All participants agreed, and although we were representing different countries and cultures there was no disagreement about this. Even though we have not yet faced many of the obstacles of the world of medicine, we can see the role of compassion in clinical practice better perhaps than our seniors. We shared our points of view about this question and its relevance in the different countries. It was an incredible moment, as experts and professors demonstrated a great interest in our ideas.

The program was extremely diverse; however, the main idea that most speakers expressed was how to find, sustain and not lose humanist goals. Brandy Schillace gave an impressive presentation entitled “Medical Humanities today: a publisher’s perspective”, which studied the importance of writing and publishing not only clinical trials, but also papers from historians, literary scholars, sociologists, and patients with personal experiences. The nurses Pilar d’Agosto and Maria Arias made a presentation on the topic of the Nursing Perspective that is one of the main pillars of medical practice. Professor Jacek Mostwin (Johns Hopkins University) shared his thoughts on patients’ memoirs. An Italian student, Benedetta Ronchi presented the results of an interview on medical humanities posed to the participants and speakers during the symposium. The plurality of perspectives made this conference an enriching event and showed us how diverse ideas can help us become better doctors. More importantly, it reminded us of our common humanity.

A significant part of the symposium was dedicated to Medicine and Art. Prof Josep Baños and Irene Canbra Badii spoke about the portrayal of physicians in TV medical dramas during the last fifty years. The book “The role of the humanities in the teaching of medical students” was presented by these authors and then given to participants as gifts. Dr Ourania Varsou showed how Poetry can influence human senses through her own experience in communicating with patients. She believed that many of the opinions and knowledge that we have internalized should be unlearned in order to have a better understanding of the human mind. The stimulus of poetry makes this possible. Poetry allows us to find new ways to express ourselves, and thus increase our emotional intelligence and understanding of other people’s feelings.

One of the most impressive lectures was by Dr Joan.B Soriano, who spoke about “Doctors and Patients in Opera” and showed how the leading roles of physicians in opera have changed over the centuries. People used to consider the doctor as the antihero, but with time this view has transformed into a positive one that plays a huge role in history.

It is important to be professional in your medical career, but also to be passionate about the life surrounding you; for instance, Dr Soriano is also a professional baritone singer. For students, this Symposium was full of obvious and hidden messages, which gave us much lot of food for thought. As Edmund Pellegrino, the founding editor of the Journal of Medicine and Philosophy , said: “Medicine is the most humane of sciences, the most empiric of arts, and the most scientific of humanities.”

CHOOSING ONE WORD

To conclude our summary of the students’ viewpoint each of us chose One word to encapsulate our thoughts about the symposium.

The Doctor as a Humanist is a multicultural event where everyone can learn and contribute to this global necessity to put the heart and soul back into medicine. Of course, we are aware and delighted that other organizations are championing the cause of the Humanities in Medicine, and in some cases, such as https://www.dur.ac.uk/imh/ , they have been doing so for many years.

As medical students, we appreciate how we have been placed at the centre of the symposium, which we believe has made this new initiative rather special. We hope that students of Medicine and from other disciplines come and participate in future symposia.

If you want to learn more, and see how you can participate, please contact the International student representatives, Mariam ( [email protected] ) and David ( [email protected] ).

Acknowledgements

Assistance provided by Jonathan McFarland (c) and Joan B. Soriano (University Autonoma de Madrid) was greatly appreciated during the planning and the development of the article.

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Red Medicine: Socialized Health in Soviet Russia

Russian Medical History and the Training of Doctors

PRIOR to the Revolution, Russia was extremely backward in its medical provision for the mass of the people. Since that time a vast advance has been made. The sanitation and public health of Russia, which were also imperfect, remain so, though to a much smaller degree, to the present day.

Our review of present conditions in preventive and clinical medicine in Russia is based on inquiries and inspections during a relatively short visit; and although it has been associated with much study of authoritative writings, we do not pose as competent to judge the merits of Russian medicine as a whole, but only of this medicine as we have been able to observe it. We are confident, however, that even when all its present incompleteness and imperfections are emphasized, the wide sweep of the newly organized medicine of Russia presents features from which other countries may derive important lessons.

In judging the present position of medical practice in Russia, her past in medicine must be borne in mind.

An excellent account of Russian medicine in the past is given in Colonel F. H. Garrison's "Russian Medicine Under the Old Regime" in the Bulletin of the New York Academy of Medicine , September, 1931. The following statements are derived largely from this source.

In the reign of Ivan IV, "the Terrible" (1533-84), a contemporary of Queen Elizabeth of England, four physicians, two surgeons, eight surgical dressers, eight barbersurgeons, and four apothecaries were brought from Germany, but how many of these escaped the enemies by whom their ship was attacked is not clear. In 1557 two English physicians were brought to Moscow by the Russian ambassador. At the end of the sixteenth century, Garrison states, the first Russian medical publication was printed.

With the reign of Peter the Great (1682-1725) a new. order of things began. He may be regarded as the creator of Russian medicine, as he was the first person in power who attempted seriously to Europeanize Russia. It is to him that the first hospital (1706) and medical school (1707) in Russia owe their foundation; and in some other respects, he acted in accord with his motto : "I am of those who seek knowledge and are willing to learn." He gave his army an organized medical service. During his European travels he "picked up all the training he could get on medicine and surgery" and is said to have tapped dropsies and even couched cataracts on his own subjects, "sometimes with untoward results." (Garrison)

The reign of Catherine II (1762-96) was a period of cultural awakening, rather than, in Garrison's words, a time of "true progression towards economic and social betterment." Queen Catherine was inoculated against smallpox by an Englishman. In this reign a medical college and hospitals for the insane and for venereal diseases were opened, as well as foundling asylums. By 1804, according to Garrison, there were medical faculties in five Russian institutions, namely, the Universities of Moscow, Dorpat, Kharkov, and Kazan, and the Medico-Chirurgical Academy in St. Petersburg. But, except at the academy, which became the Military. Medical Academy in 1835, the teaching was "poor and feeble in quality." The Napoleonic wars had left Russia exhausted and unready for any scientific advance.

Pirogov (1810-81) became professor of surgery at the Military Medical Academy in 1840, and he lifted it to a very high level of efficiency. He introduced dissections and pathological anatomy into the teaching of medical students; and he deserves to be regarded as the greatest figure in the history of Russian medical practice.

A succession of distinguished medical scientists have followed him; among whom the names of Metchnikov (1845-1916), whose work was done chiefly in Paris, and of Pavlov, born in 1849 and still living, are of worldwide repute.

But although there were distinguished Russian scientists, physicians, and surgeons, the number of practitioners was entirely inadequate and the vast majority of the people of prerevolutionary Russia outside the large cities were almost destitute of medical aid.

The emancipation of the serfs in 1861 was both an effect and a cause of greater attention to the wellbeing of the individual. Shortly afterwards territorial selfgovernment in the form of district (zemstvo) assemblies was established, and along with this came local administrative control of medical aid. But for most of Russia medical care remained in the hands of unskilled persons and sometimes of the country clergy; and in view of its vast extent of territory and the widely scattered distribution of its villages the problems of supplying medical aid for these inevitably remained unsolved. The Russian peasant could not, and, if he were called upon to do so, could not now, afford to pay a doctor.

Gradually, however, medical provision became less exiguous, and here and there some hygienic propaganda and actual preventive work began.

Medical provision and hygienic work increased each decade, and in the years immediately preceding the Revolution there were some hospitals in most large centres of population, and a limited amount of medical aid was accessible to the poor. For the welltodo, medical aid of a high standard was generally available, and many sanatoria and hospitals were provided. This provision for the poor remained miserably inadequate.

The medical departments of universities were well equipped, and medical students were well trained, better than now; but their number was very inadequate for Russia's needs.

Then came the two revolutions of 1917; and during the four years which followed, external war and civil war, revolution, famine, and disease decimated the population and left the survivors impoverished and enfeebled.

The protracted struggle against famine and disease had serious effects on medical education and practice. Medical schools and hospitals received scarcely any funds. No repairs were possible, and food and means of heating for these institutions and their staff failed. (1) Students and professors suffered alike. Only bare subsistence was possible, and professors stood in line for their daily rations. Gantt says, "distinguished professors spent part of their time in squads shoveling snow."

On the inceion of the New Economic Policy in 1921, with its partial supersession of "war communism," the position of hospitals somewhat improved. Medical schools also improved slowly, and during later years there has been a marvelous advance in the volume of medical education and in the amount and quality of medical aid provided for the masses of the people. The new medical education, hitherto, in view of the very great increase in the numbers educated, is, as might be expected, inferior to the old in quantity and quality; but for the first time this education is bringing medical aid of a fair quality to the masses of the people.

Post-Revolution General Education

General, cannot be separated entirely from medical, education, and a few words are needed as to this, additional to what is stated in Chapter X. Prior to the Revolution the few were well educated, while the people generally were almost entirely illiterate. The new regime meant the abolition of the existing schools for the children of the upper classes and the substitution of a system in which millions receive at least elementary instruction. Civic instructionnaturally communism as taught by Marx and developed by Leninoccupies a prominent place throughout school life. In 'every school elementary education, to quote official language, is "combined with a course of political and cultural education," including "the basic principles of the social order under the Soviets."

The amount of illiteracy has been enormously reduced, and, as we have said in Chapter X, 90 per cent of adults, aged, from eight to fifty, have received a primary education. This, however, still leaves a considerable part of the adult Russian population unable to read or write. It is the steady policy of the Soviet administration to reduce this illiteracy of adults, and we saw elementary school teaching undertaken as a side activity in factories, in sanatoria, and also in institutions for the treatment and reform of former prostitutes. The voluntary work undertaken by the Pioneers often takes the form of teaching the illiterate. The creches and kindergartens, to which most children in the first eight years of life are taken, are also centres of elementary instruction; and all those seen by us were well equipped and models of cleanliness. In them the children are instructed in selfcontrol and cleanly personal habits. They are taught at a very tender age to wash and dress themselves and in all respects to conform to hygienic habits. In the elementary schools, in the vast numbers of open air schools and day camps, and in the juvenile clubs which belong to the Youth Movement, education, including Communist civic instruction, is proceeding continuously.

Post-Revolution Medical Education

That is the background for the recent extension of medical education. As members of the proletariat receive preferential nomination, many students now starting their medical training have had inadequate education. Many candidates are adults and sometimes married. They are selected by committees of their. fellowworkers, as are also nonmedical university students. The choice depends greatly on the social occupation of the student, manual workers having a preference. There is probably some favoritism in choosing candidates for training, as well as in medical appointments. But "graft" is treason in Russia, and it is doubtful if it exists in this connection. This does not mean that there is an absence of "political pull" in the sense of influence of the Communist Party on behalf of any candidate. We met doctors who had been selected for medical training by these committees, and in the instances thus encountered the selection was justified. Evidently, however, deficiency of preliminary general and scientific education must lower the standard of subsequent medical service. This is recognized by hygienic and medical leaders in the official world of Russia, and doubtless the quality of students selected, as well as the details of present medical instruction, will improve as they need to do. Even now it is indubitable that, although the average individual standard of training of the multitude of medical students of today is lower than that of the fewer students in pre-Revolution days, the aggregate quantity as well as the quality of medical aid available for the mass of the people is being enormously increased and improved.

We were informed by Dr. Vladimirsky, Commissar of Health of the R.S.F.S.R., that in 1932 there were 36,000 medical students, and it was hoped that by 1937 the present deficiency of doctors would be overtaken. He estimated that Russia was still short of 20,000 physicians, as compared with the quota of the Five Year Plan, and that this meant retardation of public health and of medicine. It was officially considered that eventually as an ideal there should be one doctor to 1,000 population.

He stated that they were quite aware that Russian methods of medical education needed overhauling, as, he believed, was the case in other countries.

The extension of medical education is indicated in figures supplied by the Commissar of Health of Moscow. In 1912 there were six institutions for medical training in the Soviet Union; in 1930 there were thirtyfour. In 1912 there were no medical research institutions; now there are one hundred and six such institutions, thirtyfive of which are supervised by the Governments of constituent republics, while seventyone are regional and autonomous, i.e., under separate cities and autonomous republics.

Medical Education in Rostov

At Rostov we obtained interesting information as to the training of medical students in its university. Until last year there was a fouryear course of medical training; now it has been increased to five years, as before the war. It was stated that most of the large cities now had a medical faculty for training students. "Each student is carefully chosen as a medical student, and he has a monetary allowance to cover expenses. For definite work in the hospital done 'by him, he is paid according to current rates. The choice of candidates for medical students is decided by a commission, applications for vacancies being sent from schools and works. On these applications a Workmen's Committee first sits, and their recommendations come before a commission consisting of a representative of: (1) the administrative medical faculty, (2) the professorial staff, (3) the trade " unions, and (4) the student workers.

The final decision as to candidates rests with this commission. Any exhibition of favoritism means a "row" and much discussion in workers' journals.

From the beginning of his course each student must engage in practical work bearing on his future career.

In his first year he must assist in minor medical and surgical work, including cleaning up after the work is finished.

In his second year the medical student has to help in actual nursing; and in his next three years the student likewise engages in practical medical work at various hospitals, polyclinics, and ambulatoria, while continuing his scientific training.

When qualified, the doctor is offered a post at once. He may have specialized from the end of his third year, though this is a debatable policy. He is required to be fairly competent in all branches of medicine, as he may have to practise alone in a country district.

The risks of inadequate training of new doctors are appreciated, and still more the need for additional trained nurses. Lay workers in hospitals are being utilized, and it is intended to give selected candidates from these full medical training. A recent regulation has made the conditions for becoming medical students more stringent.

Postgraduate courses are given to doctors every three years, so far as is practicable.

Some home visits are made by nurses, in relation to child welfare, tuberculosis, and venereal disease, but these are not fully organized.

Medical Education in Tiflis

In Tiflis the population has been augmented, apart from growth of trade, by the growth of the city as a university centre for Georgia and the neighboring republics. A separate section of the town has become a university centre in which some 15,000 students live. There are special institutes in various branches of science and medicine at the university; and students have special residential quarters. The largest of these institutes is devoted to agriculture, as this is the chief industry of Georgia. Before the Revolution the university had only some 2,000 students.

In Tiflis there are 945 doctors, and in all Georgia 2,080. Dr. Kuchaidze, Commissar of Health for Georgia, declined to draw a distinction between physicians and public medical officers; for "all doctors are health officers," and only the chiefs of public medical departments do not engage in some form of clinical work.

Dr. Kuchaidze stressed the fact as had been done in every centre visited by usthat the general plan of medical and of public health work is identical throughout Russia, local circumstances necessarily implying some variations in detail.

There is a medical institute attached to the University of Georgia, in Tiflis, where since 1919 medical students are trained. Practical medical work is begun in the second year of training. All students are paid by the Government and are also trained gratuitously. The full medical course is five years.

There is a special "technicum" for training of midwives and a subsidiary variety of doctors. Instruction to midwives is given not only in the Russian and Georgian languages, but also in several other languages of the Trans-Caucasian confederation of republics. Midwives are required by law to call in a doctor on the occurrence of an obstetric complication. Their course of training covers three years; and the practice of unqualified women is prohibited, though not strictly so. In towns at least 95 per cent of the midwives are trained. In most villages are voluntary social workers who assist in maintaining the standard of maternity and child welfare work.

There was evidence of the provision of postgraduate courses of instruction in each chief city visited by us. These are said to be a new development, not seen in pre-Revolution Russia. The extent to which this postgraduate instruction is utilized varies much in different parts of Russia. In one city we were told that while normally it is obligatory for every doctor each second or third year to have four months of postgraduate medical teaching, this has not so far been generally practicable, owing to dearth of doctors. In one or two cities we were informed that it was generally enforced; in others, that the scarcity of doctors had prevented this. Rural doctors are specially encouraged to take these courses; their expenses are paid during the course, as are those of other doctors.

There is no complete provision, as yet, for the special training of sanitary officers, or for insisting on their possessing a satisfactory diploma before they undertake public health supervision and control. Some special training is given to medical men for public health work at the Institute of Health, Moscow, which we discussed with Professor Landis, its head. This institute is concerned both with the teaching of hygiene and research in that field. Hitherto graduation at the institute is not made a condition of official appointments; but such graduates have preference for important posts. Doctors appointed to administrative posts are sent to the institute for instruction and training.

(1) A review of this period is given in an article on "Medical Education in Soviet Russia," by Dr. W. Horsley Gantt, in the British Medical Journal, June 14, 1924.

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• Guillain-Barre syndrome (acute polyradiculitis) in the anamnesis.
• The axillary temperature at the time of vaccination is more than 37.0 ° C.
• Acute infectious diseases (recovery earlier than 4 weeks before vaccination) according to anamnesis.
• Donation of blood or plasma (in the amount of 450 ml or more) less than 2 months before inclusion in the study.
• Severe and/or uncontrolled diseases of the cardiovascular, bronchopulmonary, neuroendocrine systems, gastrointestinal tract, liver, kidneys, hematopoietic, immune systems.
• Is registered at the dispensary for tuberculosis, leukemia, oncological diseases, autoimmune diseases.
• Any confirmed or suspected immunosuppressive or immunodeficiency condition in the anamnesis.
• Splenectomy in the anamnesis.
• Neutropenia (decrease in the absolute number of neutrophils less than 1000/mm3), agranulocytosis, significant blood loss, severe anemia (hemoglobin less than 80 g/l) according to anamnesis.
• Anorexia according to anamnesis.

Prior or concomitant therapy

• Vaccination with any vaccine carried out within 30 days before vaccination / the first dose of the studied vaccine or planned administration within 30 days after vaccination / the last dose of the studied vaccine.
• Prior vaccination with an experimental or registered vaccine that may affect the interpretation of the study data (any coronavirus or SARS vaccines).
• Long-term use (more than 14 days) of immunosuppressants or other immunomodulatory drugs (immunoregulatory peptides, cytokines, interferons, immune system effector proteins (immunoglobulins), interferon inducers (cycloferon) during the six months preceding the study, according to anamnesis.
• Treatment with systemic glucocorticosteroids (≥ 20 mg of prednisone, or an analog, for more than 15 days during the last month).
• Volunteers who received immunoglobulin preparations or blood transfusion during the last 3 months prior to the start of the study according to anamnesis.

Other non-inclusion criteria

• Participation in any other clinical trial within the last 3 months.

Exclusion criteria:

• Withdrawal of Informed consent by a volunteer;
• The volunteer was included in violation of the inclusion/non-inclusion criteria of the Protocol;
• Any condition of a volunteer that requires, in the reasoned opinion of a medical researcher, the withdrawal of a volunteer from the study;
• Taking unauthorized medications (see section 6.2);
• The volunteer refuses to cooperate or is undisciplined (for example, failure to attend a scheduled visit without warning the researcher and/or loss of communication with the volunteer), or dropped out of observation;
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I.M. Sechenov First Moscow State Medical University is the first and the oldest medical school in Russia tracing its history from the medical faculty of Moscow Imperial University founded in 1758.

Having passed the path of glory I.M. Sechenov First MSMU enriched national and world science with many distinguished scientists and significant discoveries, and brought up thousands of physicians devoted to their work.

Many of the University alumni have been recognized internationally for their outstanding contribution to global medicine and other spheres. Botkin S.P., Korsakoff S.S., Pirogov N.N., Sechenov I.M., Sklifosovsky N.V., and Chekhov A.P. are the most renowned.

The history of First MSMU is tightly connected with the history of medical education and healthcare in Russia. The University is a cradle of most national medical schools and scientific medical societies, first medical journals, guidebooks and manuals.

Inauguration of the Imperial Moscow University (Moscow State University since 1917)

First lectures at the IMU medical faculty

Beginning of continuous lecturing at the medical faculty

S.G. Zybelin and P.D. Veniaminov, first Russian professors at the medical faculty

Imperial Moscow University was granted a right of conferring a Doctor of Medicine degree

F.I. Barsuk-Moiseev was the first to be conferred with a Doctor of Medicine degree after defending the thesis entitled About Breathing

Opening of the first teaching hospitals at Nikitskaya street

Publication of the first issue of the Medical and Physical Journal

Professors, lecturers, and students of the IMU medical faculty took part in the Patriotic War of 1812. The buildings, books and manuals of the faculty were burnt away

Completion of restoration of the faculty buildings burnt in fire of 1812. Opening of the Clinic Institute

Beginning of practical studies for students at the Old Ekaterinian Hospital

V.A. Basov was the first to perform an operation for artificial fistula in animals

Construction of the University Campus on Devichye Pole comprising 15 teaching hospitals and institutes

Ivan M. Sechenov was elected professor of the Chair of Physiology

The 12 th International Congress of Physicians was held at the IMU medical faculty

Scientists of the medical faculty took part in the First Congress on the Higher Medical Education Reform

Establishment of a postgraduate course at the medical faculty

Beginning of practice for fourth-year students

Reorganization of the medical faculty of Moscow State University into First Moscow Medical Institute (First MMI), an independent higher medical institution with two faculties, the therapeutic prophylactic faculty and the sanitary and prophylactic (sanitary and hygienic since 1935) faculty

Foundation of the Central Research Laboratory

Decree of the USSR Supreme Soviet Presidium on awarding First MMI with an Order of Lenin. Changing the First MMI abbreviation into First MOLMI

Professors, lecturers, and students of First MOLMI took part in the Great Patriotic War

First MOLMI was named after I.M. Sechenov

Moscow Pharmaceutical Institute was transformed into the Faculty of Pharmacy of I.M. Sechenov First MOLMI

Organization of the evening faculty of medicine (2nd faculty of medicine since 1969)

Dr. B. Egorov, I.M. Sechenov First MOLMI graduate, became a member of the Voskhod spacecraft crew

Organization of the Faculty of Advanced Training for Physicians (nowadays Postgraduate Professional Training of Physicians)

Establishment of the Faculty of Training of Research and Teaching Staff.

On the Resolution of the USSR Council of Ministers I.M. Sechenov First Moscow Medical Institute was raised to I.M. Sechenov Moscow Medical Academy of the USSR Ministry of Public Health

Establishment of the Faculty of Higher Nursing Training

Establishment of the Faculty of Preventive Medicine for Postgraduate Professional Training

Establishment of the Faculty of Health Care Management

The 1st and the 2nd faculties of medicine were united into a single Faculty of Medicine

Establishment of the Faculty of Dentistry

Celebration of the 250-year history. The University is awarded a Platinum Uncia 2008

I.M. Sechenov Moscow Medical Academy was granted a status of the University and has changed its name into I.M. Sechenov First Moscow State Medical University

Nobel Prize winner Barry J. Marshall has been entitled the Professor Emeritus of I.M. Sechenov First MSMU

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Twenty two students (twelve medical students, six students in Dental Medicine and four students in Pharmacy) have undergone their summer internship at the training and clinical facilities of Medical University-Varna. For two weeks interns trained at the academic and clinical facilities, under the direct supervision and guidance of leading professors in their respective fields. Summer…

Sechenovsky scientists shared experiences with Chinese counterparts

Our delegation of the Department of Preventive and Emergency Cardiology under the Institute of Vocational Education has participated in three major international events: Second Sino-Russian Conference of Young Scientists on Heart Diseases, Eighth Sino-Russian Conference on Medicine and Pharmacology, Sixth Sino-Russian Conference on Heart Disease in the Cold Climatic Zone. Sechenov First MSMU researchers were…

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Why Human Subjects Research Protection Is Important

Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study. The road leading to the current regulations and ethical considerations has been long and checkered.

Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations.

Results: Key documents—from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011—that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research.

Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research. The examples also reinforce the importance of individual responsibility. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities.

INTRODUCTION

Participation of human subjects in research presents a challenging ethical dilemma. A research subject may be asked to participate in a study of no benefit and no substantial risk or in a study with the potential for significant benefit but also significant risk. In placebo-controlled studies, subjects may be exposed to significant risk for no benefit to the individual. These variants are confounded by treatment protocols—most commonly encountered in oncology trials—that compare the effect of an investigational arm to the standard of care, further blurring the distinction between research and medical treatment.

Institutional review boards (IRBs) have the federally mandated responsibility to review research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in the study. The road leading to the current regulations and ethical considerations has been long and checkered. The system that has evolved minimizes the risks for unethical behavior and serious adverse events but is not infallible. Understanding how we have arrived at the current approach and analyzing some of the ethical lapses that directed this course support efforts to continually reevaluate the regulations in order to improve the safety of subjects who are willing to participate in research activities.

EVOLUTION OF HUMAN SUBJECTS PROTECTION

Our current approach to human subjects protection has evolved with efforts to understand questionable ethical behavior in research over the course of several hundred years. One might suggest that the jester conscripted to sample the king's food to ensure that it was safe to eat presaged the use of vulnerable populations as subjects for research, but the evolution of the management of smallpox is perhaps a more applicable early perspective on research in humans. Three centuries ago, reports of good outcomes following variolation—inhalation of the scabs from persons infected with smallpox—were circulating in Asia. In 1717, Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey, became an advocate of variolation after learning about it in Constantinople. In 1721, after she returned to England, Lady Montagu and the Princess of Wales urged variolation of “several prisoners and abandoned children” by having smallpox scabs inserted under their skin. Several months later, the children and prisoners were deliberately exposed to smallpox. When none contracted the disease, the procedure was deemed safe, and members of the royal family were treated according to this new protocol. 1

Later that same century, Edward Jenner developed inoculation with a vaccine. Many of his contemporaries had noted that milkmaids who had contracted cowpox seemed immune to the much more lethal smallpox. In May 1796, Jenner isolated material from the cowpox lesions on the milkmaid Sarah Nelms and inoculated 8-year-old James Phipps who developed fever and malaise about 9 days after the inoculation. Some accounts report that Phipps was the son of Jenner's gardener. A few months later, Jenner deliberately inoculated Phipps with material from fresh smallpox lesions, and the child remained healthy. The adoption of this process was not immediate but slowly spread and is widely cited as the first scientific approach proving vaccination. 2

This early use of children and prisoners portends a long history of selecting what are now considered vulnerable populations to be the subjects of research. Participation was commonly without consent, with no knowledge of their participation, and with no explanation of the research. Information was withheld from those selected to participate in research activities perceived as dangerous to more acceptable members of society, and the therapies developed were generalized only if they were proven relatively safe and effective in what are now recognized as vulnerable populations.

Numerous instances of research experiments in subsequent years exposed vulnerable subjects to risk, including a pivotal research disaster in Germany just before World War II that led to regulations for human subjects participation in research projects.

The Reich Circular of 1931

As reported by Sir Graham Wilson in the book The Hazards of Immunization , “Between 10 December 1929 and 30 April 1930, 251 of 412 infants born in the old Hanseatic town of Lubeck received three doses of BCG [bacillus Calmette-Guerin] vaccine by the mouth during the first ten days of life. Of these 251, 72 died of tuberculosis, most of them in two to five months and all but one before the end of the first year. In addition, 135 suffered from clinical tuberculosis but eventually recovered; and 44 became tuberculin-positive but remained well.” 3

Bonah and Menut describe how Albert Calmette was able to establish the BCG vaccine as a nonexperimental “prophylactic treatment” against tuberculosis. 4 By definition, a medical experiment, as opposed to any other medical action, has definite ethical implications and consequences. Even though the BCG vaccine was in experimental stages, Calmette convinced a court that the vaccine was a “post-experimental, routine medical treatment.” By avoiding the definition of an experiment, Calmette did not have to inform the children's parents about the risks of the vaccine. As a result of this tragedy, Dr Julius Moses, a critic of unethical human experimentation who referred to “experimental mania,” drafted guidelines for human experimentation. After debate in parliament and the press, the guidelines were published and became official in 1931. The guidelines applied to everyone in Germany. 5 , 6

These rules for research in human subjects were issued as the Reich Circular of 1931 ( Figure 1 ). The document is quite informative for its contrast with later events in Germany and worth reviewing for correlation with ethical concepts now well accepted in ethical thinking. It is worth noting that these guidelines emphasize special responsibilities for utilization of “innovative therapy,” suggesting a similar level of responsibility for these procedures as for research.

The Reich Circular, 1931 6

World War II and the Nuremberg Code

Despite the ethical ideals espoused in the Reich Circular, the travesty of the Holocaust followed shortly afterward, leading to war criminal trials after the surrender of Germany ended World War II in Europe.

The Nuremberg trials that began in 1945 and concluded in 1947 were held in response to the atrocities Germany committed during the war. The so-called Doctors’ Trial represents a major turning point in human research protection. Twenty-three physicians were indicted, accused of crimes against humanity by conducting criminal scientific and medical experiments on concentration camp prisoners. Sixteen defendants were found guilty. 7

Several German doctors had argued that no international law or informal statement differentiated between legal and illegal human experimentation, despite the aforementioned Reich Circular. Two US doctors who worked with the prosecution during the trial, Andrew Ivy and Leo Alexander, objected to this argument. On April 17, 1947, Dr Alexander submitted a memorandum to the United States Counsel for War Crimes outlining 6 points defining legitimate medical research. The trial verdict reiterated almost all of these points in a section entitled Permissible Medical Experiments and expanded the original 6 points into 10. These 10 points became known as the Nuremberg Code ( Figure 2 ). 8

The Nuremberg Code, 1947 10

Similar atrocities were carried out on Chinese citizens in Japanese camps; of particular note are the biological warfare experiments at Unit 731 in the Pacific theater that were obscured by agreements made during the surrender of Japan and with the complicity of the United States. 9 The details of these atrocities remained classified until they were acknowledged by Congress in the Japanese Imperial Government Disclosure Act of 2000 (Pub L No. 106-567, Title VIII of the Intelligence Authorization Act of 2000) that called for declassification and release of records related to Japanese war crimes during World War II. 10

Declaration of Helsinki

The tenets of the Nuremberg Code, while guiding the future for human research protection, represent a military code of conduct with no standing in civil international or US law. By absolutely requiring the voluntary consent of the individual, the Nuremberg Code notably does not address the needs of children or other special populations unable to provide consent. The Nuremberg Code inspired the World Medical Association (WMA)—an international association currently comprised of 114 national medical associations, including the American Medical Association—to propose a similar code of conduct for participating members by publishing the Declaration of Helsinki in 1964. This document reiterates the provisions of the Nuremberg Code and expands the provisions to allow for the participation of children and other potentially compromised subjects in research. The Declaration of Helsinki serves as a guideline for ethical research and has been amended 7 times, most recently at the WMA General Assembly in October 2013, to reflect contemporary ethical issues as they have evolved since the initial statement in 1964. 11

Ethics Violations in the United States

Meanwhile, research continued in the United States with particular concerns attached to research involving vulnerable populations, exemplified by numerous studies involving institutionalized children and studies that breached ethically sound research practices. Henry Beecher, a well-recognized physician at Massachusetts General Hospital, surveyed the contemporary literature to identify ethical concerns and organized lectures around his observations. These lectures eventually culminated in a special article published in the New England Journal of Medicine in 1966. 12

In “Ethics and Clinical Research,” Beecher reported that he had reviewed 100 consecutive articles published in 1964 “in an excellent journal,” and after culling his list to address the editor's request, selected 12 articles that demonstrated serious ethical concerns. The purpose of Beecher's article was to demonstrate the widespread lapse in ethical issues in medical research and to encourage reform in the ethical approach to human subjects research that inspired Congress to reconsider legislative reforms for human subjects protection.

An article by Jean Heller that appeared in the Washington Star on July 25, 1972 placed an exclamation point in the history of human research ethics. 13 Heller reported on a long-term study sponsored by the US Public Health Service on the effect of syphilis if left untreated in poor rural African American subjects. Officially known as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” the study enrolled 399 subjects with syphilis and 201 uninfected controls from the African American community surrounding Tuskegee, AL for “treatment of bad blood.” In exchange for taking part in the study, the men received free medical examinations, free meals, and burial insurance but were not given the benefit of providing informed consent. No treatment was provided; the research plan was to follow the subjects to establish a natural history for the disease if left untreated. Although originally projected to last 6 months, the study continued for 40 years. 14

Treatments available at the onset of the trial in 1932, even if provided, were not very effective and would have been heavy metals, involving at least 30 months of treatment, a 30% cure rate, and significant toxicity. By 1945, penicillin had been proven to be an effective therapy for syphilis with few side effects. Once penicillin was established as effective, the US Public Health Service set up centers for treatment but determined that the data from the Tuskegee experiments were too important to abandon and decided that the study should be continued with no treatment provided to the participants. Similar determinations were made in subsequent years, with the last review occurring as recently as 1969. 14

While medical research such as the Tuskegee study garnered most of the attention for ethical lapses, other areas of research involving human subjects also raised concerns. The Milgram experiments carried out in the early 1960s at Yale University are a lightning rod for discussion of ethical issues in human subjects research in social sciences. 15 Intrigued by the Nuremberg trials defendants’ argument that they were simply following orders, Stanley Milgram set out to determine if the German defendants were particularly obedient to authority figures compared to other members of society. Milgram recruited subjects for an experiment in learning via newspaper ads. The male research subjects were assigned to act as a teacher asking questions of a learner (a confederate of Milgram) who was attached to electrodes. The teachers were instructed to increase the severity of electrical shocks if the learner answered the questions incorrectly. Shocks were labeled from 15v to 450v, with 15v indicated as mild, 300v as severe, and 450v as XXX. Many of the teacher subjects eventually shocked the learner at 450v and exhibited increasing signs of distress as the shocks they delivered increased in perceived severity. 15 These experiments evoked significant concern among those in social sciences in regard to the questionable ethics of the deception used, as well as the potential for long-term psychological harm that might be incurred by unwitting participants.

Federal Policy for Protection of Human Subjects and the National Research Act

The public outcry over the Tuskegee study, other reports of ethical lapses in both medical and social research, and the alarm in the medical community raised by Dr Beecher's article in the New England Journal of Medicine led Congress to action. On May 30, 1974, the US Department of Health, Education, and Welfare (DHEW), responsible for oversight of the National Institutes of Health, replaced previous policies with comprehensive regulations governing the protection of human subjects (45 CFR §46). 16 One month later in July 1974, Congress passed the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 Title II of the act, Protection of Human Subjects of Biomedical and Behavioral Research, created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. Along with being assigned several other tasks, the National Commission was directed to make recommendations to the DHEW secretary about the ethical principles that should underlie human subjects research. 18

The Belmont Report

The National Commission issued several reports in response to the directives. The most notable among a collection of important documents is the Belmont Report, named after the Smithsonian conference center where the group convened, that was issued in 1978. 19 This document, widely regarded as the landmark analysis of ethics in human subjects research, serves as the foundation for discussion of ethical concerns in research ethics involving human subjects, as well as the source of federal regulations for research established by the Office for Human Research Protections (OHRP).

The Belmont Report is divided into three sections. The first section briefly states the National Commission's recognition that even as the report was being written, the distinction between medical practice and research was blurred. The report defines medical practice as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation for success. Research, on the other hand, is defined as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).” This section further expounds on the conflation between the use of the terms experimental and research. When used in reference to a procedure or treatment that significantly deviates from typical (ie, a treatment that is “new, different or untested”), the report notes that an “experimental” treatment is not necessarily research. Although they excluded “experimental” treatment from research and the applicable anticipated regulations, the National Commission strongly recommended that such treatments should eventually be incorporated into formal research protocols “to determine if they are safe and effective.” The first section of the Belmont Report concludes with the recognition that practice and research may go hand in hand: “the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.” 19 This language is reminiscent of the Reich Circular recommendation regarding “innovative therapy.”

The second section is the heart of the report and defines three principles that should guide the discourse surrounding any ethical concerns related to research in human subjects: respect for persons, beneficence, and justice. The principle of nonmaleficence, now commonly accepted as one of the four principles of biomedical ethics, was notably absent.

• Respect for persons : The principle of respect for persons requires that “individuals should be treated as autonomous agents,” and those with “diminished autonomy are entitled to protection.” These concepts inform “two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.” The National Commission defines the elements that would be necessary to qualify as an autonomous individual and explores circumstances that would define those who should be considered to be of diminished autonomy and thus deserving of protection.
• Beneficence : The principle of beneficence as defined by the National Commission encompasses the concept of do no harm included in the Hippocratic Oath and notes that the term is commonly thought “to cover acts of kindness or charity that go beyond strict obligation.” The National Commission proposes two general rules that inform beneficence as an obligation: “(1) do not harm and (2) maximize possible benefits and minimize possible harms.” The implications of these duties within the context of both individual investigators and society at large are examined.
• Justice : The principle of justice is posed as the following question: “Who ought to receive the benefits of research and bear its burdens?” This principle is broad in potential implications and can be summarized as evaluating the appropriate distribution of the risks and burdens of research among individuals, groups, or even situations in which inherent inequalities may need to be considered to reach an ethically informed decision. The National Commission proposes the following framework for beginning these discussions: “(1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.” The discussion of justice continues with the historic context for including the principle of justice and how lapses in justice (ie, the Tuskegee study) were the primary impetus for the formation of the National Commission.

The final section of the Belmont Report addresses the application of these principles and the implications of their requirements when considering three important elements of research involving human subjects: informed consent, assessment of risks and benefits, and selection of subjects for research.

Informed consent. The consent process has three components: information, comprehension, and voluntariness. Reaching agreement on an appropriate standard for evaluating the quality of information that should be provided to potential participants about a proposed research project is difficult and eventually ends with the suggestion that the standard of “the reasonable volunteer” might best fulfill the requirements of respect for persons, beneficence, and justice. A caveat is provided, citing the problem posed by research where “informing subjects of some pertinent aspect of the research is likely to impair the validity of the research,” a key area of ethical concern (lack of disclosure) raised by the Milgram study discussed previously. The National Commission proposes that such studies may only be appropriate if “(1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them,” further noting that “Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.” 19

Regarding the component of comprehension, the Belmont Report states, “The manner and context in which information is conveyed is as important as the information itself.” The level of comprehension is also important within the context of the individual's ability to understand the information, with emphasis that the obligation for ensuring subject understanding increases in importance relative to the level of risk posed by participation in the study. The National Commission suggests that some level of questioning the subject to ensure comprehension is appropriate and even suggests that written responses to questions may be appropriate if risks are exceptionally high. 19 If participation of subjects with compromised abilities is anticipated, researchers must be particularly diligent in evaluating the level of comprehension by the subject's proxy and ensure that the proxy is indeed capable of representing the best interests of the subject. The report even suggests that the proxy might need to be present or available during the research interventions to withdraw the subject from the study if the proxy perceives that withdrawal may be in the subject's best interest.

Voluntariness is a concept consistently emphasized in the Reich Circular, the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. Although voluntariness may appear to be self-evident, it may be the most difficult concept to address. The Belmont Report emphasizes that the subject must be “free of coercion and undue influence.” Coercion is specifically defined as “an overt threat of harm” and in most circumstances is relatively easy to evaluate. However, arguments can be made about what defines “undue influence.” Discussions about appropriate levels of compensation for participation are common, particularly when studies involve financial or other considerations made to possibly financially compromised subjects. The Belmont Report specifically notes, “inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.” Other concerns related to undue influence involve social standing, employment, or other circumstances that may be difficult to assess but are worthy of consideration for individual subjects.

Assessment of risks and benefits. The National Commission notes that a favorable risk/benefit assessment is associated with the principle of beneficence. This definition is particularly appropriate in that the National Commission's interpretation of beneficence includes the duty of nonmaleficence. The Belmont Report examines the meaning of risk and benefit in the setting of potential types of harm that may be experienced by individual subjects, the families of the individual subjects, society at large, or special groups of subjects in society. Benefits are also discussed in relation to the individual and society at large. In summarizing the risks and benefits of research, the Belmont Report states

…assessment of the justifiability of research should reflect at least the following considerations:

Brutal or inhumane treatment of human subjects is never morally justified.

Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures.

When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject—or, in some rare cases, to the manifest voluntariness of the participation).

When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits.

Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. 19

Selection of subjects for research. The third element, selection of subjects for research, finds its primary guidance in the principle of justice where the moral requirements demand that the procedures and outcomes for the selection of subjects are fair to the individual and within the social context. Participation in potentially beneficial research should be fairly distributed to all who wish to participate, and risky research should not be offered only to less desirable subjects. In the context of society, risks should be distributed after careful consideration of the burdens and the ability of individuals in identifiable groups to bear those burdens. As a generalization, adults should be considered before children, and participation by institutionalized individuals should invoke very careful consideration. Even with these safeguards, the National Commission believed that the selection of subjects may continue to reflect injustice arising from social, racial, sexual, and cultural biases institutionalized in society. Harking back to the ethical concerns that prompted the National Commission, the Belmont Report concludes with the following: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.” 19

Although not included in the body of the report, a footnote specifically addresses the difficulty in extrapolating these tenets to human subjects research in the social sciences: “Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.” 19 An appropriate ethical approach for some areas of social and psychological studies remains elusive. Matthew Salganik, professor of sociology at Princeton University, discusses the issues surrounding the difficulty in applying the Belmont Report recommendations at his blog. 20

The Belmont Report was submitted to Congress on April 18, 1979.

Other Reports by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research

Although the Belmont Report is the centerpiece for the analysis of research in human subjects, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research provided significant additional guidance for Congress to consider as the legislators moved forward to formulate regulations for the governance of human subjects in research. During the 4 years of the National Commission's appointment, other publications provided analysis of concerns related to specific questions (Table), and many of the recommendations were incorporated into the subsequent regulations for human subjects protection. 21

Table .

Human Subjects Protection in Research Reports From the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1974-1978 21

FOIA, Freedom of Information Act.

Principles of Biomedical Ethics

Another landmark publication from 1979 deserves attention for its sustained influence on the field of biomedical ethics and its deviation from the three ethical principles put forth by the Belmont Report. In Principles of Biomedical Ethics , Tom Beauchamp and James Childress argue for inclusion of nonmaleficence as an independent principle to formulate the now-familiar four principles that inform contemporary bioethical discourse. 22 As previously noted, nonmaleficence is considered a duty under the umbrella of the principle of beneficence in the Belmont Report. Beauchamp and Childress maintained that the tradition to do no harm central to the tenets of the Hippocratic Oath incorporates the concept of nonmaleficence at its core and is essential to any discussion of the ethics of medical practice. As such, they argued, this concept should be considered as separate from and not subsidiary to beneficence: “First, to confuse them is to obscure distinctions that we make in ordinary moral discourse. Second, ordinary moral discourse expresses the defensible conviction that we have certain duties not to injure others that are not only distinct from but also more stringent than our duties to benefit others.” 22 The authors make the distinction that the negative duty to cause no harm should be encompassed by nonmaleficence, and the positive but not so strongly established moral duty to benefit others should constitute the core of beneficence. The authors acknowledged that other eminent scholars disagreed with the separation of nonmaleficence and beneficence, but they constructed an argument that has been upheld by the historic inclusion of nonmaleficence in most bioethics discussions following their book's original publication (the book is now its seventh edition). The book has had a significant influence on the still-evolving field of bioethics contemporary to its publication and the Belmont Report. Both authors regularly served as staff members for the Kennedy Institute Intensive Bioethics Course, and Beauchamp served as staff philosopher for the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research that produced the Belmont Report. The authors acknowledged the influence of several other members of the commission and other colleagues who contributed significantly to their deliberations as their work progressed.

US Legislative Updates, 1981

DHEW officially became the Department of Health and Human Services (HHS) in 1980, and in response to the Belmont Report, the HHS and the US Food and Drug Administration (FDA) significantly revised their protection of human subjects regulations in 1981 (45 CFR §46 and 21 CFR §50). 16 , 18 , 23

These regulations specifically address concerns related to vulnerable populations in Subparts B, C, and D, incorporating the recommendations from the National Commission. The Research on the Fetus report 24 informed Subpart B (additional protections for pregnant women, human fetuses, and neonates), Subpart C (additional protections for prisoners) reflected the recommendations in Research Involving Prisoners , 25 and Subpart D (additional protections for children) was informed by the Research Involving Children report. 26

HUMAN SUBJECTS PROTECTION OVERSIGHT

Oversight in the united states.

To this point, this review has focused on some of the historic events and documents precipitating evaluation of the ethical requirements for human subjects research in the United States and a review of the regulations that evolved from that history. The question not yet addressed is how these regulations should be enforced. As with the discussion of research ethics, the approach to enforcement of regulations also lies within the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 In addition to establishing the National Commission responsible for the Belmont Report, the National Research Act elected to perpetuate the regulatory mechanism for research extant within many departments of DHEW that evolved from the US Public Health Service requirements initiated by the Surgeon General in 1966. The background of this development is described in William Curran's article, “Government Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies.” 27

This system for review of human subjects research within DHEW as described in The Institutional Guide to DHEW Policy on Protection of Human Subjects 28 became the model for institutional review boards (IRBs) that the National Research Act would require of grantees and contractees for review of research involving human subjects. The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was specifically charged with reviewing the function of IRBs and making recommendations for integrating the role of the IRB into the regulatory process to provide oversight of the application of ethical principles and of the regulations. 18

On September 1, 1978, the National Commission completed the less spectacular but equally important report, Institutional Review Boards , 29 before submitting the Belmont Report on September 30 that same year. Institutional Review Boards outlines the National Commission's concept of the ideal environment for the application of the federal regulations.

In the introduction to the report, the National Commission provides this understated assessment of the role of the IRB: “This review of proposed research by IRBs is the primary mechanism for assuring that the rights of human subjects are protected.” 29 The document outlines the ideal responsibilities of the IRB in the oversight of research to ensure that human subjects receive appropriate protections and ethical treatment for their willingness to participate in research, sometimes at no benefit to themselves. The National Commission summarized their objective as follows:

In the recommendations that follow, the Commission expresses its judgment about the ways in which those elements [that must be considered in balancing society's interests in protecting the rights of the subjects and in developing knowledge that can benefit the subjects or society as a whole] ought to be brought to bear on research practices, so that a reasonable and ethical balance of society's interests may be attained.

The Commission's deliberations begin with the premise that investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others, who are independent of the research, must share this responsibility, because investigators are always in positions of potential conflict by virtue of their concern with the pursuit of knowledge as well as the welfare of the human subjects of their research.

The Commission believes that the rights of subjects should be protected by local review committees operating pursuant to federal regulations and located in institutions where research involving human subjects is conducted. 29

The document continues this proposal and is seemingly all-inclusive in its conception of the IRB. Highlights include a list of the requirements that must be met to approve research and details for reviewing and approving the consent process, including the essential elements to be included and the safeguards that should be in place to ensure that the process is respected. Specific recommendations also address the constitution of the IRB; how it should be funded; and legal protections for the board, the process, and its members.

Most of the recommendations from the Institutional Review Boards report were incorporated into the HHS regulations—HHS being the responsible federal agency—as part of the rules revision in 1981 in response to the Belmont Report and several other publications of the National Commission. Acting independently from HHS, the FDA also adopted IRBs as a regulatory mechanism, with regulations first issued in 1981 as part of the agency's response to provisions of the National Research Act. 18 , 30

One particularly relevant recommendation of the National Commission from Institutional Review Boards remained outstanding after the changes in 1981: “Recommendation (1) (A) Federal law should be enacted or amended to authorize the Secretary of Health, Education, and Welfare to promulgate regulations governing ethical review of all research involving human subjects that is subject to federal regulation.” 29

The report notes significant “variations arising out of differences in wording, imposition of additional requirements, introduction of minor changes, etc.” among the different agencies apart from DHEW involved in research involving human subjects and expresses concern that this variability places an unnecessary burden on the individual IRBs for interpreting and properly enforcing the regulations. The National Commission's recommendation was to establish “DHEW as the sole authority” for regulations, expressing the belief that such a rule “would reduce the burden on IRBs to interpret and apply the regulations to which they are subject. Moreover, uniformity would assure a minimum level of protection to human subjects of research, no matter which federal agency is supporting the research or which entity is conducting it.” 29 Having inherited the mantle of responsibility from the now-extinct DHEW and recognizing the reality of this assessment, the newly designated HHS explored implementation of this recommendation, particularly as it related to the function of IRBs. As with most changes affecting multiple branches of government, the process became complex. In December 1981, the President's Commission for the Study of Ethical Problems in Medicine and in Biomedical and Behavioral Research, a new commission appointed by Congress in 1978, entered the fray and recommended that all federal departments and agencies adopt the HHS regulations (45 CFR §46). In addition, an ad hoc Committee for the Protection of Human Subjects—composed of representatives and ex officio members from departments and agencies that conducted, supported, or regulated research involving human subjects—was appointed in May 1982 by the president's science advisor to respond to the recommendations of this new commission. After much consideration and negotiation, these efforts were finally addressed by adoption of the Federal Policy for the Protection of Human Subjects, known as the Common Rule, in 1991 and codified in the individual regulations by 15 federal departments and agencies. Each of these agencies includes in its chapter of the Code of Federal Regulations (CFR) section numbers and language that are identical to those of the HHS codification at 45 CFR §46, Subpart A for the regulation of human subjects participation in research. The HHS regulations also include Subparts B, C, and D as additional regulations pertaining to vulnerable subjects. 16 , 31

In addition to harmonizing the regulations across agencies of the federal government, the Common Rule requires institutions that receive funds for research involving human subjects from federal agencies that are signatories to the Common Rule to certify that the research has been reviewed and approved by an IRB that meets the specific requirements for composition, for functioning, and for the criteria followed to approve research. By mandate of the Common Rule, IRBs are empowered to approve, require modifications of, or disapprove research activities and are required to conduct continuing review of ongoing research at least annually.

The FDA concurs with the Common Rule but claims special privilege in not signing on to it. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR §50 and §56 so that they conformed to the Federal Policy for the Protection of Human Subjects to the extent permitted but noted that the FDA is a regulatory agency that rarely supports or conducts research under its regulations. 32

International Oversight

With the adoption of the Common Rule, regulations for human subjects research conducted within the United States became well established, but research has never been confined by the borders of the United States. Even though a project funded by federal monetary support may have some leverage to require adherence to US regulations, significant numbers of human research subjects participate in studies well beyond the influence of the US regulations. The international norms for participation of human subjects in research evolved along a course that frequently cross-pollinated with the concepts culminating in the Common Rule. The Declaration of Helsinki was an early statement of basic tenets that should apply to all research involving human subjects, and it has continued to evolve, with updates reflecting new issues as they become relevant. While addressing the ethical concepts, the Declaration of Helsinki does not provide an organizational or regulatory framework for human subjects protection. Providing this framework on an international basis presented a challenge well beyond the challenge of harmonizing regulations across different federal agencies as was accomplished by the Common Rule. The difficulties encountered in implementing the Common Rule represent only a microcosm of the enormous task of harmonizing regulatory and organizational concepts across the borders of different cultures and political systems. However, this task was particularly relevant because of the evolution of research into an international enterprise with multicenter drug trials and the expansion of vaccine trials in children. Many of these studies are conducted by multinational contract research organizations that have access to populations of subjects with exposure to diseases that may not be widely encountered in the United States.

An argument can be made that the process for oversight of human subjects in research at the international level started in 1948 before the Declaration of Helsinki when the United Nations Educational, Scientific and Cultural Organization (UNESCO) joined with the World Health Organization (WHO) to establish a permanent Council for Coordination of International Medical Congresses, formally constituted in Brussels in 1949 as a nongovernmental organization with the purpose of facilitating “the exchange of views and scientific information in the medical sciences by securing continuity and coordination between international organizations of medical sciences, by making their work known, and by providing them with material aid where necessary.” 33 The scope of activities gradually expanded to include collaborative efforts among international medical activities in addition to the coordination of participating congresses. In 1992, the name of the council was changed to the Council for International Organizations of Medical Sciences (CIOMS), and its statutes were revised to reflect the expanded role. 33

The original council ventured into medical research by organizing a 1959 meeting in Vienna under the auspices of UNESCO and the WHO “to discuss the principles, organization and scope of ‘controlled clinical trials,’ which must be carried out if new methods or preparations used for the treatment of disease are to be accurately assessed clinically.” The executive secretary summarized the meeting: “The conference was in itself an experiment.” 34

Following this meeting, the council became much more involved in considerations regarding research and particularly the participation of human subjects in research trials, eventually publishing Proposed International Guidelines for Biomedical Research Involving Human Subjects in 1982. The purpose of the guidelines was “to indicate how the ethical principles that should guide the conduct of biomedical research involving human subjects, as set forth in the Declaration of Helsinki, could be applied, particularly in developing countries, given their socioeconomic circumstances, laws and regulations, and executive and administrative arrangements.” 35 This quote is from the background notes for International Ethical Guidelines for Biomedical Research Involving Human Subjects published in 1993 after discussion and reconsideration of the comments received in response to the proposed guidelines. 35

The publication of the guidelines in 1993, soon after the name change to CIOMS, represented a landmark for international research ethics. The steering committee included an international staff of 24 members and an even larger list of advisors and consultants. The committee was co-chaired by Robert Levine from Yale University, who was listed as a “Special Consultant” on the Belmont Report and authored the first four articles for discussion in the appendix to the Belmont Report, and John H. Bryant, an American physician with a distinguished career in international medical practice. In addition to the Declaration of Helsinki, the International Ethical Guidelines for Biomedical Research Involving Human Subjects was strongly influenced by the Belmont Report as demonstrated by the inclusion of the following text under the heading General Ethical Principles:

All research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for persons, beneficence and justice. It is generally agreed that these principles, which in the abstract have equal moral force, guide the conscientious preparation of proposals for scientific studies. 35

The guidelines acknowledge the evolution of the principles following the publication of the Belmont Report with the statement, “Beneficence further proscribes the deliberate infliction of harm on persons; this aspect of beneficence is sometimes expressed as a separate principle, non-maleficence (do no harm).” 35

The table of contents of the 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects , provided in Figure 3 , outlines the subjects the steering committee felt to be the most pertinent issues for research conducted in an international setting. In addition to the obvious influence of the Declaration of Helsinki, this document reinterprets many of the issues presented in the Belmont Report, in reports from the presidential commissions, and in 45 CFR §46, Subparts A, B, C, and D to provide an adaptable set of guidelines suitable for application across a broad spectrum of cultural and political environments. The notable exception to the similarities with the US regulations is the inclusion of a guideline titled “Compensation of Research Subjects for Accidental Injury” that provides for the following: “Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependents are entitled to material compensation. The right to compensation may not be waived.” 35 To date, no uniform program for compensation of human subjects injured in research is addressed in the US regulations.

Table of Contents, International Ethical Guidelines for Biomedical Research Involving Human Subjects, 1993 35

The International Ethical Guidelines for Biomedical Research Involving Human Subjects was updated in 2002, and CIOMS continues its efforts to revise the guidelines as dictated by changes in research requiring human subjects.

THE GUATEMALA SEXUALLY TRANSMITTED DISEASES STUDY

All the efforts described to this point promoted regulations and procedures based on an ethically sound approach to protecting human subjects who, by consent or proxy, will be participating in research. The ethics of the research environment seems to have improved as a result of these efforts both in the United States and internationally. Notable instances of particularly egregious studies have come to light since the publication of the Belmont Report, but most of these studies originated before that document was issued. One study in particular raised eyebrows for its similarity to the transgressions committed in the Tuskegee study and, after investigation, was found to have ties to the Tuskegee study.

In October 2010, the United States disclosed that the US Public Health Service sponsored studies of sexually transmitted diseases in Guatemala beginning in 1946. This exposé began with the discovery of documents among papers donated by Dr John Cutler to the library at the University of Pittsburgh. Before retiring, Cutler was on the faculty at the university's School of Public Health following a long career in the US Public Health Service where he had been one of the staff members involved with the Tuskegee study. Hoping to gain insight into the Tuskegee study, Dr Susan Reverby from Wellesley was reviewing Cutler's papers when she came across previously unknown information about experiments investigating sexually transmitted diseases in Guatemala that Cutler and his associates conducted. 36 An account in the American Journal of Public Health reports that “… more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases” and many were never treated. 37

When the details of these experiments came to light, they precipitated an apology from President Barack Obama and specific directives to the Presidential Commission for the Study of Bioethical Issues, a commission appointed by Obama, to “convene a panel to conduct, beginning in January 2011, a thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government. I also request that the Commission oversee a thorough fact-finding investigation into the specifics of the U.S. Public Health Service Sexually Transmitted Diseases Inoculation Study” ( Figure 4 ). 38

Directive from President Barack Obama to investigate the Guatemalan studies, 2010 38

The Presidential Commission's first report, “ Ethically Impossible” STD Research in Guatemala from 1946 to 1948 , provides a detailed account of the history surrounding the Guatemala studies and all of the supporting evidence. In the preface, the Presidential Commission reports, “With dual responsibilities to give a full and fair accounting of events largely hidden from history for nearly 65 years and also provide an assessment of the current system, the Commission decided to publish two reports. This is the first report, a historical account and ethical assessment of the Guatemala experiments.” 38

The specific political circumstances in which the experiments were conceived and carried out is critical to gaining some understanding of how ethically questionable research, however ill-conceived, was carried out by people who most probably had good intentions. The significance of the deleterious effects of sexually transmitted diseases among troops in World War II and how those effects precipitated the experiments are difficult to understand in today's world of effective antibiotics. In the 1940s wartime environment, however, understanding all aspects of sexually transmitted diseases was perceived as a crucial aspect of the military's ability to field an effective fighting force for the war in Europe. The experiments must be viewed in this historic context to understand the powerful motivation behind the studies.

The “ Ethically Impossible ” report includes an excerpt from a 1943 letter from Dr Joseph Earle Moore, Chair of the Subcommittee on Venereal Diseases under the National Research Council, to A. N. Richards, Chair of the Medical Research Committee of the Office of Scientific Research and Development, in which Moore wrote that he expected “approximately 350,000 fresh infections with gonorrhea [in the Armed Forces], [which] will account for 7,000,000 lost man days per year, the equivalent of putting out of action for a full year the entire strength of two full armored divisions or of ten aircraft carriers.” 38 Moore estimated that the cost of treating the anticipated infections would be $34 million, equivalent to approximately $440 million today, adjusted for inflation.

Within this context, serious planning to meet the challenge of understanding and treating sexually transmitted diseases appears to have coalesced at the national level in 1942. Planning for these studies continued through the following year, with one of the principals suggesting “the possibility of using federal prisoners, Army prisoners, or conscientious objectors as an alternative” for research subjects. 38 In 1943, experiments began at the US Penitentiary in Terre Haute, IN, that continued for 2 years. The focus of the experiments was on efforts to infect prisoners with Neisseria gonorrhoeae to test various methods for prophylaxis and treatment. Isolates of bacteria were applied directly to the penises of subjects in an effort to reliably infect the “volunteers.” However, the failure to reliably infect subjects in this fashion clearly indicated that studies of prophylactic techniques would not be possible with this approach, leading to consideration of other options.

The studies were performed under the direction of Dr John F. Mahoney, then head of the US Public Health Service/Venereal Disease Research Laboratory (VDRL) set up within the US Marine Hospital in Staten Island, NY. Mahoney directed the Terra Haute prison studies from his Staten Island laboratory, while 28-year-old Dr Cutler ran the studies at the prison. Following the end of World War II in 1945, the military support for the studies was less enthusiastic, but the Public Health Service remained committed to supporting the research with plans to move the research to Guatemala. A 1947 article Mahoney published in the Journal of Venereal Disease Information provides some insight into why the studies were moved: “It has been considered impractical to work out, under postwar conditions in the United States, the solution of certain phases concerned with the prevention and treatment of syphilis. These problems are largely concerned with the development of an effective prophylactic agent for both gonorrhea and syphilis and the prolonged observation of patients treated with penicillin for early syphilis. Because of the relatively fixed character of the population and because of the highly cooperative attitude of the officials, both civil and military, an experimental laboratory in Guatemala City has been established….” 39

As fate would have it, a Guatemalan physician named Funes, who had served a fellowship at the VDRL and returned to Guatemala, was essential to the transition of the studies to his country. In August 1946, Cutler transitioned from Terra Haute to Guatemala at Funes's urging. Cutler staffed a clinic that provided the regular health inspections required for registered sex workers and suggested that the facility provide an environment of “normal exposure” through which sexually transmitted diseases could be more predictably transmitted. The studies in Guatemala evaluated possible prophylactic intervention “in cooperation with the Guatemalan Venereal Disease Control Department” that Funes directed and the local penitentiary “where exposure of volunteers to infected prostitutes would provide the testing opportunities.” 38 Enrolling prisoners, a contained and restricted population, after they had had sexual intercourse with commercial sex workers known to be infected with sexually transmitted diseases, promised to establish, according to Cutler, a “rapid and unequivocal answer as to the value of various prophylactic techniques” through the preferred technique of “normal exposure.” 38

After beginning with studies of “normal exposure” in prisoners, Cutler expanded the population of research subjects to include patients in a psychiatric hospital and again tried artificial means of infection, including scarification—mechanically damaging the skin and mucous membranes of the penis—to enhance the likelihood of infecting the subject. An even more aggressive study included at least 7 women in a psychiatric institution who were infected by the injection of syphilis specimens directly into the subarachnoid space surrounding the brain. Only 5 of them later received medical therapy. 38 In addition, studies to follow the serology of children in a large orphanage were undertaken to better understand the specificity of tests for sexually transmitted diseases, an additional goal of the Guatemalan studies.

Studies in which subjects were intentionally infected were completed in the later months of 1948, and Cutler left Guatemala in December 1948 to join a WHO Disease Demonstration Team in India. From April 1949 to July 1950, this team worked to establish a venereal disease control demonstration in various parts of India and teach advanced methods of control for sexually transmitted diseases. Meanwhile, the US Public Health Service hired Funes and another Guatemalan physician, Dr Salvado, to continue “the observation of certain of the patient groups” after Cutler left Guatemala. Funes's staff collected data on residents of the orphanage, inmates of the penitentiary, individuals from the psychiatric hospital, schoolchildren, and the members of “various Indian tribes in the vicinity of Guatemala” who had participated in the experiments. Funes was hired to “advise concerning the clinical examinations of treated patients, their re-treatment as may be required, the collection of blood specimens for serologic examinations at periodic intervals, the preparation and shipment of all blood specimens collected for serologic examination” to the United States, and “the submission of such reports as may be necessary for the completion of the study of this patient group.” 38 Based on the one report available in the Cutler Documents, Funes and his staff followed approximately 248 people from the mental institution, completing 243 blood draws and 170 lumbar punctures. Several of those subjects tested positive for syphilis during the follow-up experiments. The subjects from the psychiatric hospital were followed until at least 1953. The published work resulting from the Guatemala experiments also indicates that Funes continued to do serological testing on the children at the orphanage until at least 1949.

The experiments in Terra Haute were conducted and supported by many of the same people involved in the Guatemala experiments with the same goal of finding suitable prophylaxes for sexually transmitted diseases. However, throughout their discussion of the background leading to the experiments in the United States and the subsequent Guatemalan experiments, the Presidential Commission provides details of concerns voiced among those planning the studies. These details construct a compelling argument that all along the way there was an undercurrent of concern that the studies proposed were at the least controversial, most probably unethical, and in some instances arguably illegal. The Presidential Commission reached the conclusion that “Conducting the experiments in Guatemala provided an opportunity to work with reduced concern for some of the key obstacles associated with the Terre Haute experiments: fear of adverse legal consequences and bad publicity.” In a footnote to the report, the authors point out that “These concerns followed the researchers to Guatemala, however, as evidenced by some of their efforts to limit and restrict access to information about the work.” 38

The Presidential Commission summarized their findings as follows: “In the Commission's view, the Guatemala experiments involved unconscionable violations of ethics, even as judged against the researchers’ own understanding of the practices and requirements of medical ethics of the day.” The report concludes

Although some individuals are more blameworthy than others, the blame for this episode cannot be said to fall solely on the shoulders of one or two individuals. The unconscionable events that unfolded in Guatemala in the years 1946 to 1948 also represented an institutional failure of the sort that modern requirements of transparency and accountability are designed to prevent. In the final analysis, institutions are comprised of individuals who, however flawed, are expected to exercise sound judgment in the pursuit of their institutional mission. This is all the more true and important when those individuals hold privileged and powerful roles as professionals and public officials. One lesson of the Guatemala experiments, never to take ethics for granted, let alone confuse ethical principles with burdensome obstacles to be overcome or evaded, is a sobering one for our own and all subsequent generations. We should be ever vigilant to ensure that such reprehensible exploitation of our fellow human beings is never repeated. 38

The second charge from President Obama to the Presidential Commission was to provide a “thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.” The Presidential Commission addressed this directive in their report Moral Science: Protecting Participants in Human Subjects Research that was completed in December 2011. 40

Regarding whether the regulations would prevent abuses similar to the studies in Guatemala, the Commission noted, “Existing evidence suggests both that the rules governing federal research today adequately guard against abuses analogous to those perpetrated in Guatemala in the 1940s and that current regulations generally appear to protect people from avoidable harm or unethical treatment, insofar as is feasible given limited resources, no matter where U.S.-supported research occurs.” 40 The report summary continued as follows:

The current U.S. system provides substantial protections for the health, rights, and welfare of research subjects and, in general, serves to “protect people from harm or unethical treatment” when they volunteer to participate as subjects in scientific studies supported by the federal government. However, because of the currently limited ability of some governmental agencies to identify basic information about all of their human subjects research, the Commission cannot say that all federally funded research provides optimal protections against avoidable harms and unethical treatment. The Commission finds significant room for improvement in several areas where, for example, immediate changes can be made to increase accountability and thereby reduce the likelihood of harm or unethical treatment. 40

The report outlines the Presidential Commission's observations and recommendations based on a thorough review of federally funded research, including studies that may involve human subjects in other countries. One issue the Commission raised was the general lack of accessibility to data: “there is no ready source that comprehensively describes its [the federally funded human research enterprise] basic characteristics, such as level of funding, or number of studies, subjects, or geographic locations. Instead, what exists are isolated pockets of information and some descriptive summaries.” 40 This difficulty in acquiring information prompted the Presidential Commission's first recommendation to improve accountability through public access: “accountability can and should be refined through improving access to basic information about the scope and volume of human subjects research funded by the government.” The commission cites precedent for this recommendation from the Institute of Medicine–issued Responsible Research: A Systems Approach to Protecting Research Participants , with its recommendation to extend the oversight system to all research, regardless of funding source or research setting. 41

Treatment and compensation for research-related injuries were also identified as an issue of concern, a subject that has been scrutinized regularly in past discussions as human research protection has evolved. Obama's Commission noted that this issue still required attention at the time of their review, pointing out that most other developed countries require sponsors, investigators, or others engaged in research to provide treatment or reimbursement free of charge to the subject for research-related injury or illness. As discussed earlier, one of the deviations from the general agreement between CIOMS and US regulations is the recommendation for subject compensation in the CIOMS guidelines. The Presidential Commission “draws a bright line affirming the view of most bioethicists and others, including the majority of nations supporting human subjects research around the globe, that human subjects should not individually bear the costs of care required to treat harms resulting directly from that research.” 40 Recognizing that previous bioethics commissions and other advisory bodies had opined in favor of compensation or treatment for research-related injuries with relative silence by the government, the Commission advocated a response as to reasons for changing or maintaining the status quo. This issue remains open with no progress as this article is being written.

The Commission also asked that the OHRP examine, recognize, and define when protections delineated in foreign laws and regulations are accepted as equivalent to US regulations and exercise its longstanding authority to recognize these protections when available. Protections offered by international partners have been a source of confusion, as the federal regulations state that equivalent protections from international studies should be accommodated but do not provide guidance for how they should be defined. This directive has been reevaluated several times since its inception, including a specific request from the United Kingdom in 2007 to provide a determination of equivalence for human research protections afforded by UK regulations. As of the Commission's report in 2011, the OHRP had not formally recognized any country's protections as equivalent.

The Commission also noted that the FDA, while not signatory to the Common Rule, does adhere to the regulations at 45 CFR §46, Subpart A whenever possible and accepts data from foreign studies that comply with certain international standards for human subjects protection, such as studies that abide by good clinical practice, the Declaration of Helsinki, or certain host country regulations. This practice should provide a model to develop a system for recognizing equivalent protections as currently regulated by provisions in the Common Rule.

In its final recommendation, Promoting Current Federal Reform Efforts, the Presidential Commission called for broad reform of federal research rules and procedures beyond simply addressing equivalent protections.

The Commission supports the federal government's proposed reforms to:

a) Restructure research oversight to appropriately calibrate the level and intensity of the review activities with the level of risk to human subjects;

b) Eliminate continuing review for certain lower-risk studies and regularly update the list of research categories that may undergo expedited review;

c) Reduce unnecessary, duplicative, or redundant institutional review board review in multi-site studies. Regardless of the process used to review and approve studies, institutions should retain responsibility for ensuring that human subjects are protected at their location as protection of human subjects includes much more than institutional review board review. The use of a single institutional review board of record should be made the regulatory default unless institutions or investigators have sufficient justification to act otherwise;

d) Make available standardized consent form templates with clear language understandable to subjects;

e) Harmonize the Common Rule and existing regulations of the Food and Drug Administration, and require that all federal agencies conducting human subjects research adopt human subjects regulations that are consistent with the ethical requirements of the Common Rule; and

f) Work toward developing an interoperable or compatible data collection system for adverse event reporting across the federal government. 40

Most of these provisions were included in the revisions to the Common Rule that updated the original provisions from 1991 and were effective January 21, 2019, with the exception of staged implementation of single IRB review for multisite studies. Twenty federal agencies follow the Common Rule, with the notable exception of the FDA. So far, no official indication of the FDA's intent has been provided, although the expectation is that some effort will be made to harmonize the regulations—at least in a similar fashion as previous agreements.

OTHER HUMAN SUBJECTS PROTECTION FAILURES

This exposition of how we have arrived at the current rules and regulations for protecting human subjects who participate in research is lengthy but is at best an outline. Even this abbreviated history should elicit an appreciation of the complexity of the ethics surrounding protection of human subjects in research. A fair question is whether these provisions have significantly altered the landscape since Dr Beecher published his concerns in the New England Journal of Medicine in 1966. A cursory review turns up a few exceptions to the relative safety afforded by the current protections, with three that are particularly instructive.

Jesse Gelsinger

Jesse Gelsinger had just turned 18, the legal age for consent, when he volunteered in 1999 for a phase 1 gene therapy study designed for treatment of ornithine transcarbamylase (OTC) deficiency. Phase 1 studies are designed primarily to determine the appropriate dose of a drug. Gelsinger was born with a mild form of OTC that was well controlled by diet and drug therapy; he had minimal risk of serious complications from the disease as long as he followed his treatment protocol. He did not stand to benefit significantly from his participation in the phase 1 study but felt that he should volunteer because of the knowledge that might benefit others.

Gelsinger died 4 days after receiving an experimental therapy consisting of a gene attached to an adenovirus that would theoretically serve as a delivery system to insert the new gene into the DNA of his liver cells. The death was unexpected in a relatively healthy 18-year-old, and the outcome precipitated a long and contentious investigation into how the protections that should have prevented Gelsinger from participating in the study were circumvented or ignored. The investigation uncovered questions regarding (1) information that should have been included in the consent form, (2) the actual risk posed by the study based on complications from similar studies that were not disclosed in reports to regulatory bodies, (3) why Gelsinger was enrolled in the study in violation of the protocol's inclusion/exclusion criteria, (4) the potential risk/benefit analysis based on the mild nature of his disease that would argue against his participation, and (5) an undisclosed conflict of interest for the director of the gene studies program that may have clouded decisions at critical points during conduct of the study. 42 - 45

Examination of this study demonstrates that the protections afforded to subjects are well established but still depend on the assumption that the individuals responsible for every step of the evaluation and approval of studies and those who actually conduct the research all perform reliably in their roles.

Johns Hopkins Lead Abatement Study

Another notable case revolves around the issues of appropriate consent, appropriate risks for children (or any vulnerable population), and disclosure of results obtained in research studies. The Kennedy Krieger Institute (KKI), an affiliate of Johns Hopkins Children's Center, conducted a study evaluating the effectiveness of lead abatement programs in low-income housing in Baltimore, MD during the 1990s. The study recruited families to live in houses either untouched or treated with different abatement techniques to determine which processes were most effective in protecting children from the significant neurologic effects of elevated lead levels that were endemic among children living in low-income housing in Baltimore. The goal was “to find a relatively inexpensive and effective method for reducing—though not eliminating—the amount of lead in children's homes and thereby reducing the devastating effect of lead exposure on children's brains.” 46 A total of 108 families with young children were recruited to live in houses with lead levels ranging from none to levels just below the existing legal limit, and the children's serum lead levels were monitored. In two homes, the lead levels in the children crossed into toxic levels, but the families were not informed or advised to move out of the toxic environment. Eventually, a lawsuit was filed on behalf of the two children, and it raised significant ethical questions surrounding informed consent, appropriate risks, and disclosure of results that are reviewed at length in the article “With the Best Intentions: Lead Research and the Challenge to Public Health.” 46 The Maryland Court of Appeals opinion equated the multiyear lead study with the Tuskegee study in its egregious disregard for research ethics in a vulnerable population.

Ellen Roche

Ellen Roche was a healthy 24-year-old laboratory technician at the Johns Hopkins Asthma and Allergy Center. She volunteered to take part in a 2001 lung function physiology experiment in which normal pulmonary function in healthy volunteers would be manipulated by inhalation of hexamethonium, a compound that interferes with normal nervous system interaction with the lungs to mimic a mild asthma attack. Although it had been used in the 1950s to treat hypertension, hexamethonium fell into disuse as more effective drugs became available, and the FDA withdrew approval in 1972. Of note, hexamethonium was never approved as an inhaled medication. Roche was the fourth patient to receive hexamethonium in the trial. At least one previous subject had had mild persistent respiratory symptoms that the investigator dismissed as a cold. Roche became very ill, with significant pulmonary abnormalities presenting within 24 hours. The symptoms progressed to multisystem organ failure, and she died within a month. 47 , 48

The ensuing investigation turned up several concerns:

• The literature search relied on PubMed and one contemporary textbook of pulmonary medicine to explore the potential use of hexamethonium for the purpose proposed in the research plan. Neither source revealed any indication of concerns, although other databases and older textbooks warned of significant pulmonary complications associated with hexamethonium.
• No request was made to determine if the FDA required an investigational new drug application, even though the medication was no longer approved and had never been approved as an inhalational drug.
• The consent form referred to hexamethonium as a medication but failed to mention that FDA approval had been withdrawn.
• A few subjects included in previous studies used inhaled hexamethonium with no mention of problems in the subsequent publications, but two subjects did have significant difficulties that were not reported as the investigator did not consider them related to the drug.
• The hexamethonium used in the study was of chemical grade and was not prepared as a pharmaceutical agent. 47 , 48

This list is not complete and raises many concerns, but the focus of the investigation became the lack of adequate research to confirm that the compound used to induce asthma symptoms was safe. The responsibility for this failure primarily attached to the investigator, with additional concern focusing on a review process that failed to follow proper procedures for approval of the protocol. During the follow-up, several articles from the 1950s reporting that hexamethonium could cause fatal lung inflammation similar to the pulmonary complications leading to the demise of Ellen Roche were identified. PubMed's coverage of the literature starts in the mid-1960s. In addition, review of the FDA records related to the withdrawal of hexamethonium in 1972 cited the drug's “substantial potential toxicity” as one element leading to the decision. 48

The examples of ethical issues from history and the scarcity of contemporary examples demonstrate that regulations for the protection of humans participating in research have evolved in a way that minimizes the probability of harm to subjects choosing to participate in research. These examples also reinforce the importance of individual responsibility to faithfully execute the requirements of their assigned roles. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Furthermore, these examples support the argument that no amount of regulation or oversight can completely remove the variable of individual failures to adhere to the rules or accept the responsibility associated with their role in research that may precipitate serious unexpected consequences. The rules and expectations for those charged with the review, administration, and performance of research requiring human subjects can only minimize the probability that these instances will occur. The point at which the primary responsibility of protecting human subjects from preventable harm deviates to focus on some other aspect of the research that leads to harm is rarely predictable. Simplified to the world of Monty Python, “Nobody expects the Spanish Inquisition!”

ACKNOWLEDGMENTS

The author has no financial or proprietary interest in the subject matter of this article.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Systems-Based Practice.