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Human Experimentation: An Introduction to the Ethical Issues

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In January 1944, a 17-year-old Navy seaman named Nathan Schnurman volunteered to test protective clothing for the Navy. Following orders, he donned a gas mask and special clothes and was escorted into a 10-foot by 10-foot chamber, which was then locked from the outside. Sulfur mustard and Lewisite, poisonous gasses used in chemical weapons, were released into the chamber and, for one hour each day for five days, the seaman sat in this noxious vapor. On the final day, he became nauseous, his eyes and throat began to burn, and he asked twice to leave the chamber. Both times he was told he needed to remain until the experiment was complete. Ultimately Schnurman collapsed into unconsciousness and went into cardiac arrest. When he awoke, he had painful blisters on most of his body. He was not given any medical treatment and was ordered to never speak about what he experienced under the threat of being tried for treason. For 49 years these experiments were unknown to the public.

The Scandal Unfolds

In 1993, the National Academy of Sciences exposed a series of chemical weapons experiments stretching from 1944 to 1975 which involved 60,000 American GIs. At least 4,000 were used in gas-chamber experiments such as the one described above. In addition, more than 210,000 civilians and GIs were subjected to hundreds of radiation tests from 1945 through 1962.

Testimony delivered to Congress detailed the studies, explaining that “these tests and experiments often involved hazardous substances such as radiation, blister and nerve agents, biological agents, and lysergic acid diethylamide (LSD)....Although some participants suffered immediate acute injuries, and some died, in other cases adverse health problems were not discovered until many years later—often 20 to 30 years or longer.” 1

These examples and others like them—such as the infamous Tuskegee syphilis experiments (1932-72) and the continued testing of unnecessary (and frequently risky) pharmaceuticals on human volunteers—demonstrate the danger in assuming that adequate measures are in place to ensure ethical behavior in research.

Tuskegee Studies

In 1932, the U.S. Public Health Service in conjunction with the Tuskegee Institute began the now notorious “Tuskegee Study of Untreated Syphilis in the Negro Male.” The study purported to learn more about the treatment of syphilis and to justify treatment programs for African Americans. Six hundred African American men, 399 of whom had syphilis, became participants. They were given free medical exams, free meals, and burial insurance as recompense for their participation and were told they would be treated for “bad blood,” a term in use at the time referring to a number of ailments including syphilis, when, in fact, they did not receive proper treatment and were not informed that the study aimed to document the progression of syphilis without treatment. Penicillin was considered the standard treatment by 1947, but this treatment was never offered to the men. Indeed, the researchers took steps to ensure that participants would not receive proper treatment in order to advance the objectives of the study. Although, the study was originally projected to last only 6 months, it continued for 40 years.

Following a front-page New York Times article denouncing the studies in 1972, the Assistant Secretary for Health and Scientific Affairs appointed a committee to investigate the experiment. The committee found the study ethically unjustified and within a month it was ended. The following year, the National Association for the Advancement of Colored People won a $9 million class action suit on behalf of the Tuskegee participants. However, it was not until May 16, 1997, when President Clinton addressed the eight surviving Tuskegee participants and others active in keeping the memory of Tuskegee alive, that a formal apology was issued by the government.

While Tuskegee and the discussed U.S. military experiments stand out in their disregard for the well-being of human subjects, more recent questionable research is usually devoid of obvious malevolent intentions. However, when curiosity is not curbed with compassion, the results can be tragic.

Unnecessary Drugs Mean Unnecessary Experiments

A widespread ethical problem, although one that has not yet received much attention, is raised by the development of new pharmaceuticals. All new drugs are tested on human volunteers. There is, of course, no way subjects can be fully apprised of the risks in advance, as that is what the tests purport to determine. This situation is generally considered acceptable, provided volunteers give “informed” consent. Many of the drugs under development today, however, offer little clinical benefit beyond those available from existing treatments. Many are developed simply to create a patentable variation on an existing drug. It is easy to justify asking informed, consenting individuals to risk limited harm in order to develop new drug therapies for a condition from which they are suffering or for which existing treatments are inadequate. The same may not apply when the drug being tested offers no new benefits to the subjects because they are healthy volunteers, or when the drug offers no significant benefits to anyone because it is essentially a copy of an existing drug.

Manufacturers, of course, hope that animal tests will give an indication of how a given drug will affect humans. However, a full 70 to 75 percent of drugs approved by the Food and Drug Administration for clinical trials based on promising results in animal tests, ultimately prove unsafe or ineffective for humans. 2 Even limited clinical trials cannot reveal the full range of drug risks. A U.S. General Accounting Office (GAO) study reports that of the 198 new drugs which entered the market between 1976 and 1985, 102 (52 percent) caused adverse reactions that premarket tests failed to predict. 3 Even in the brief period between January and August 1997, at least 53 drugs currently on the market were relabeled due to unexpected adverse effects. 4

In the GAO study, no fewer than eight of the drugs in question were benzodiazepines, similar to Valium, Librium, and numerous other sedatives of this class. Two were heterocyclic antidepressants, adding little or nothing to the numerous existing drugs of this type. Several others were variations of cephalosporin antibiotics, antihypertensives, and fertility drugs. These are not needed drugs. The risks taken to develop these drugs by trial participants, and to a certain extent by consumers, were not in the name of science, but in the name of market share.

As physicians, we necessarily have a relationship with the pharmaceutical companies that produce, develop, and market drugs involved in medical treatment. A reflective, perhaps critical posture towards some of the standard practices of these companies—such as the routine development of unnecessary drugs—may help to ensure higher ethical standards in research.

Unnecessary Experimentation on Children

Unnecessary and questionable human experimentation is not limited to pharmaceutical development. In experiments at the National Institutes of Health (NIH), a genetically engineered human growth hormone (hGH) is injected into healthy short children. Consent is obtained from parents and affirmed by the children themselves. The children receive 156 injections each year in the hope of becoming taller.

Growth hormone is clearly indicated for hormone-deficient children who would otherwise remain extremely short. Until the early 1980s, they were the only ones eligible to receive it; because it was harvested from human cadavers, supplies were limited. But genetic engineering changed that, and the hormone can now be manufactured in mass quantities. This has led pharmaceutical houses to eye a huge potential market: healthy children who are simply shorter than average.

Short stature, of course, is not a disease. The problems short children face relate only to how others react to their height and their own feelings about it. The hGH injection, on the other hand, poses significant risks, both physical and psychological.

These injections are linked in some studies to a potential for increased cancer risk, 5-8 are painful, and may aggravate, rather than reduce, the stigma of short stature. 9,10 Moreover, while growth rate is increased in the short term, it is unclear that the final net height of the child is significantly increased by the treatment.

The Physicians Committee for Responsible Medicine worked to halt these experiments and recommended that the biological and psychological effects of hGH treatment be studied in hormone-deficient children who already receive hGH, and that non-pharmacologic interventions to counteract the stigma of short stature also be investigated. Unfortunately, the hGH studies have continued without modification, putting healthy short children at risk.

Use of Placebo in Clinical Research

Whooping cough, also known as pertussis, is a serious threat to infants, with dangerous and sometimes fatal complications. Vaccination has nearly wiped out pertussis in the U.S. Uncertainties remain, however, over the relative merits and safety of traditional whole-cell vaccines versus newer, acellular versions, prompting the NIH to propose an experiment testing various vaccines on children.

The controversial part of the 1993 experiment was the inclusion of a placebo group of more than 500 infants who get no protection at all, an estimated 5 percent of whom were expected to develop whooping cough, compared to the 1.4 percent estimated risk for the study group as a whole. Because of these risks, this study would not be permissible in the U.S. The NIH, however, insisted on the inclusion of a placebo control and therefore initiated the study in Italy where there are fewer restrictions on human research trials. Originally, Italian health officials recoiled from these studies on ethical as well as practical grounds, but persistent pressure from the NIH ensured that the study was conducted with the placebo group.

The use of double-blind placebo-controlled studies is the “gold standard” in the research community, usually for good reason. However, when a well-accepted treatment is available, the use of a placebo control group is not always acceptable and is sometimes unethical. 11 In such cases, it is often appropriate to conduct research using the standard treatment as an active control. The pertussis experiments on Italian children were an example of dogmatic adherence to a research protocol which trumped ethical concerns.

Placebos, Ethics, and Poorer Nations

The ethical problems that placebo-controlled trials raise are especially complicated in research conducted in economically disadvantaged countries. Recently, attention has been brought to studies conducted in Africa on preventing the transmission of HIV from mothers to newborns. Standard treatment for HIV-infected pregnant women in the U.S. is a costly regimen of AZT. This treatment can save the life of one in seven infants born to women with AIDS. 12 Sadly, the cost of AZT treatment is well beyond the means of most of the world’s population. This troubling situation has motivated studies to find a cost-effective treatment that can confer at least some benefit in poorer countries where the current standard of care is no treatment at all. A variety of these studies is now underway in which a control group of HIV-positive pregnant women receives no antiretroviral treatment.

Such studies would clearly be unethical in the U.S. where AZT treatment is the standard of care for all HIV-positive mothers. Peter Lurie, M.D., M.P.H., and Sidney Wolfe, M.D., in an editorial in the New England Journal of Medicine , hold that such use of placebo controls in research trials in poor nations is unethical as well. They contend that, by using placebo control groups, researchers adopt a double standard leading to “an incentive to use as research subjects those with the least access to health care.” 13 Lurie and Wolfe argue that an active control receiving the standard regimen of AZT can and should be compared with promising alternative therapies (such as a reduced dosage of AZT) to develop an effective, affordable treatment for poor countries.

Control Groups and Nutrition

Similar ethical problems are also emerging in nutrition research. In the past, it was ethical for prevention trials in heart disease or other serious conditions to include a control group which received weak nutritional guidelines or no dietary intervention at all. However, that was before diet and lifestyle changes—particularly those using very low fat, vegetarian diets—were shown to reverse existing heart disease, push adult-onset diabetes into remission, significantly lower blood pressure, and reduce the risk of some forms of cancer. Perhaps in the not-too-distant future, such comparison groups will no longer be permissible.

The Ethical Landscape

Ethical issues in human research generally arise in relation to population groups that are vulnerable to abuse. For example, much of the ethically dubious research conducted in poor countries would not occur were the level of medical care not so limited. Similarly, the cruelty of the Tuskegee experiments clearly reflected racial prejudice. The NIH experiments on short children were motivated to counter a fundamentally social problem, the stigma of short stature, with a profitable pharmacologic solution. The unethical military experiments during the Cold War would have been impossible if GIs had had the right to abort assignments or raise complaints. As we address the ethical issues of human experimentation, we often find ourselves traversing complex ethical terrain. Vigilance is most essential when vulnerable populations are involved.

• Frank C. Conahan of the National Security and International Affairs Division of the General Accounting Office, reporting to the Subcommittee of the House Committee on Government Operations.
• Flieger K. Testing drugs in people. U.S. Food and Drug Administration. September 10, 1997.
• U.S. General Accounting Office. FDA Drug Review: Postapproval Risks 1976-85. U.S. General Accounting Office, Washington, D.C., 1990.
• MedWatch, U.S. Food and Drug Administration. Labeling changes related to drug safety. U.S. Food and Drug Administration Home Page; http://www.fda.gov/medwatch/safety.htm . September 10, 1997.
• Arteaga CL, Osborne CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res . 1989;49:6237-6241.
• Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen on serum insulin-like growth factor I levels in stage I breast cancer patients. J Natl Cancer Inst . 1990;82:1693-1697.
• Stoll BA. Growth hormone and breast cancer. Clin Oncol . 1992;4:4-5.
• Stoll BA. Does extra height justify a higher risk of breast cancer? Ann Oncol . 1992;3:29-30.
• Kusalic M, Fortin C. Growth hormone treatment in hypopituitary dwarfs: longitudinal psychological effects. Canad Psychiatric Asso J . 1975;20:325-331.
• Grew RS, Stabler B, Williams RW, Underwood LE. Facilitating patient understanding in the treatment of growth delay. Clin Pediatr . 1983;22:685-90.
• For a more extensive discussion of the ethical status of placebo-controlled trials see especially: Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research II: ethical, legal and regulatory myths. J Law Med Ethics . 1996;24:252-259.
• Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunnodeficiency virus in developing countries. N Engl J Med . 1997:337:12:853.

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The ethics of experimenting with human brain tissue

Nita a. farahany.

Professor of law and philosophy at Duke University, director of the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA

Henry T. Greely

Professor of law, director of the Center for Law and the Biosciences, and director of the Stanford Program in Neuroscience and Society at Stanford University, California, USA

Difficult questions will be raised as models of the human brain get closer to replicating its functions, explain Nita A. Farahany , Henry T. Greely and 15 colleagues.

If researchers could create brain tissue in the laboratory that might appear to have conscious experiences or subjective phenomenal states, would that tissue deserve any of the protections routinely given to human or animal research subjects?

This question might seem outlandish. Certainly, today’s experimental models are far from having such capabilities. But various models are now being developed to better understand the human brain, including miniaturized, simplified versions of brain tissue grown in a dish from stem cells — brain organoids 1 , 2 . And advances keep being made.

These models could provide a much more accurate representation of normal and abnormal human brain function and development than animal models can (although animal models will remain useful for many goals). In fact, the promise of brain surrogates is such that abandoning them seems itself unethical, given the vast amount of human suffering caused by neurological and psychiatric disorders, and given that most therapies for these diseases developed in animal models fail to work in people. Yet the closer the proxy gets to a functioning human brain, the more ethically problematic it becomes.

There is now a need for clear guidelines for research, albeit ones that can be adapted to new discoveries. This is the conclusion of many neuroscientists, stem-cell biologists, ethicists and philosophers — ourselves included — who gathered in the past year to explore the ethical dilemmas raised by brain organoids and related neuroscience tools. A workshop was held in May 2017 at the Duke Initiative for Science & Society at Duke University in Durham, North Carolina, with limited support from the US National Institutes of Health (NIH) BRAIN Initiative. A similar US meeting was held last month on related topics.

Here we lay out some of the issues that we think researchers, funders, review boards and the public should discuss as a first step to guiding research on brain surrogates.

SAFE SURROGATES

Three classes of brain surrogate offer researchers a way to investigate how the living human brain works, without the need for potentially risky — if not ethically impossible — procedures in people.

Brain organoids can be produced much as other 3D multicellular structures resembling eye, gut, liver, kidney and other human tissues have been built 2 – 4 . By adding appropriate signalling factors, aggregates of pluripotent stem cells (which have the ability to develop into any cell type) can differentiate and self-organize into structures that resemble certain regions of the human brain 5 – 7 .

Investigators use different approaches. They might coax pluripotent stem cells to turn into specific populations of neural cells, such as those specific to a particular brain region. Or they can allow the pluripotent cells to differentiate on their own, in which case both neural cells and other cell types might be generated 2 . Brain organoids resembling particular brain regions can even be combined into ‘brain assembloids’ to enable researchers to study the formation of neural circuits and cellular interactions between different regions 8 .

Compared with 2D sheets of neural cells in a dish, the 3D structures last longer (for around two years 9 ) and can consist of more types of cell. They also mimic key features of developing brains. For instance, in later stages of fetal development, the cerebral cortex switches from generating neurons to creating glial cells (the various other cell types in the brain that nourish, surround and protect neurons). This process can be captured in brain organoids, allowing investigators to gain insights that would be experimentally and ethically extremely challenging, if not ethically unacceptable, to obtain from developing brains.

Already, researchers have deployed brain organoids to investigate neurodevelopmental alterations in people with autism spectrum disorders 8 , 10 or schizophrenia 11 , and to study the unusually small brain size (microcephaly) seen in some babies infected with the Zika virus before birth 12 .

Brain organoids have limitations. They lack certain cell types, such as micro-glia and cells that form blood vessels. Today, the largest organoids are about 4 millimetres in diameter and contain only about 2 million to 3 million cells. An adult human brain measures roughly 1,350 cubic centimetres, and is made up of 86 billion neurons and a similar number of non-neuronal cells. Moreover, so far, brain organoids have received sensory input only in primitive form, and connections from other brain regions are limited.

Given such constraints, the possibility of organoids becoming conscious to some degree, or of acquiring other higher-order properties, such as the ability to feel distress, seems highly remote. But organoids are becoming increasingly complex. Indeed, one of us (P.A.) recorded neural activity from an organoid after shining light on a region where cells of the retina had formed together with cells of the brain. This illustrated that an external stimulus can result in an organoid response 13 .

Ex vivo brain tissue

Another type of model involves slices of brain tissue that have been removed from individuals during some surgical procedure, for example to treat seizures.

For more than a century, researchers have studied brain cells in tissue extracted from patients undergoing surgery, or from people who have died. But technological advances, including in imaging and in the techniques used to preserve the functional properties of brain tissues in the lab ( ex vivo ), could make this approach considerably more powerful.

When tissue from the neocortex or hippocampus regions is removed to treat a pathology, such as epilepsy or cancer, the piece removed is typically the size of a sugar cube (about 1–4 cubic centimetres), although it can sometimes be much bigger. That piece is then generally cut into slices, the functional properties of which can be preserved for weeks.

Using these slices, researchers can measure the synaptic and other properties of neurons in intact brain circuits; map the 3D morphology of circuits; and extract and analyse cellular RNA to probe gene expression. They can also manipulate the firing of specific neurons using optogenetics, which could enable them to analyse in more detail the functional properties of human brain circuits. (Optogenetics uses light to track or selectively activate neurons that have been genetically modified to express a light-sensitive protein.)

Currently, ex vivo brain tissue does not have sensory inputs. And with outbound connections severed, isolated tissues can’t communicate with other regions of the brain, or generate motor outputs. Thus, the possibility of consciousness or other higher-order perceptive properties emerging seems extremely remote.

The third class of experimental brain model involves the transplantation of human cells, derived in vitro from pluripotent stem cells, into the brains of animals such as rodents. This can be done while the animal fetus is developing or after the animal is born. Such chimaeras are generated to provide a more physiologically natural environment in which the human cells can mature.

Neuroscientists have transplanted human glial cells into mice, for instance, and found that the animals perform better in certain tasks involving learning. Researchers have also injected human stem cells into early-stage pig embryos, and then transferred the embryos into surrogate sows, where they’ve been allowed to develop until the first trimester. More than 150 of the embryos developed into chimaeras; in these embryos, about 1 in 10,000 cells in the precursors of hearts and livers were human.

In principle, chimaeras could help researchers to better understand human illnesses and the effects of drug treatments. Labs have developed human–mouse chimaeras to shed light on Parkinson’s disease, for example.

Some groups have even successfully transplanted human brain organoids into rodents, where they have become supported by blood vessels (vascularized) 14 . The provision of a blood supply is an essential step in enabling organoids to grow larger than their current achievable size. But the size of rodent models restricts the degree to which human brain organoids can grow within them.

ISSUES TO CONSIDER

Currently, if research on human tissue occurs outside a living person, only the processes of obtaining, storing, sharing and identifying the tissue fall under the regulations and guidelines that limit what interventions can be conducted on people. As brain surrogates become larger and more sophisticated, the possibility of them having capabilities akin to human sentience might become less remote. Such capacities could include being able to feel (to some degree) pleasure, pain or distress; being able to store and retrieve memories; or perhaps even having some perception of agency or awareness of self.

Could studies involving brain tissue that has been removed from a living person or corpse provide information about the person’s memories, say? Could organisms that aren’t ‘biologically human’ ever warrant some degree of quasi-human or human moral status?

In the light of such possibilities, here we lay out some of the issues that we think civil society, researchers, ethicists, funders and reviewers ought now to be considering.

Is it even possible to assess the sentient capabilities of a brain surrogate? What should researchers measure? If appropriate metrics can be developed, how do investigators decide which capabilities are morally concerning?

Neuroscientists have made considerable progress when it comes to identifying the neural correlates of consciousness 15 . Yet the signals for consciousness or unconsciousness detected in a living adult — using electroencephalography (EEG) electrodes, for example — don’t necessarily translate to infants, animals or experimental brain surrogates. Without knowing more about what consciousness is and what building blocks it requires, it might be hard to know what signals to look for in an experimental brain model 15 .

With regard to human–animal chimaeras, researchers are already dealing with beings that have some form of consciousness. Here, the need to establish what measures to base protections on (both for the animal and the human subject) is more pressing. One possibility is for researchers to use anaesthetics or other methods to maintain comatose-like brain states. Perhaps certain brain functions or a pre-specified level of brain activity, signalling a lack of capacity, could be used to delineate ethically justifiable research.

Human–animal blurring

Researchers have already produced mice with rat pancreases by injecting rat pluripotent stem cells into mouse embryos. The same approach could one day enable the production of human organs in other animals 16 .

How do we define the boundaries of this research? What implications might such boundaries have for vascularizing brain organoids, or for growing neural tissue in animals? Is the production of a human heart in a pig’s body acceptable, for instance, but not the production of a brain from human cells?

We believe that decisions about which kinds of chimaera are permitted, or about whether certain human organs grown in animals make animals ‘too human-like’, should ultimately be made on a case-by-case basis — taking into account the risks, benefits and people’s diverse sensitivities.

Do ex vivo human brain models challenge our understanding of life and death? What implications might such models have for the legal definition of death, and what are the implications for decisions tied to this definition, such as organ donation?

The advent of tracheal positive-pressure ventilation in the 1950s and cardiopulmonary resuscitation (CPR) in the 1960s led to the concept of brain death. Beginning in the 1960s, a person whose brain had completely and irreversibly ceased to function could be declared dead, even if they still had a heartbeat.

Any emerging technologies that could restore lost functionality to a person’s brain could potentially undermine the diagnosis of brain death, because the cessation of brain function might no longer be permanent and irreversible. But a distinction here is important: technologies that would restore a few neurons or certain limited kinds of brain activity would not restore clinical functionality of the brain and so would not raise this concern.

Is the standard process of obtaining informed consent adequate for research using human brain cells or tissue, or developing brain surrogates from induced pluripotent stem cells?

Currently, researchers using pluripotent stem cells or brain tissues generally disclose their plans to donors in broad terms. Given how much people associate their experiences and sense of self with their brains, more transparency and assurances could be warranted. Donors might wish to deny the use of their stem cells for the creation of, say, human–animal chimaeras.

This targeted approach is used in other contexts. When people undergoing in vitro fertilization procedures choose to donate excess embryos to research, for instance, they are assured that these will not be used to create a baby.

Stewardship

Is there a point at which we should be concerned about the welfare of brain surrogates or chimaeras, such that assigning someone loosely akin to a guardian or decision-maker for the brain surrogate might be warranted, beyond the researchers involved? Such an arrangement would be similar to the appointment of a guardian ad litem in custody disputes involving children in the United States (someone besides the parents who can represent the child’s interests).

Who, if anyone, should ‘own’ ex vivo brain tissue, brain organoids or chimaeras?

At present, brain tissue samples are owned by the researchers or organizations collecting the tissue or doing the science. If significant developments in the field one day lead us to regard any of these brain surrogates as having greater moral status than we would currently give them, might greater privileges and protections be appropriate?

Post-research handling

How should human brain tissue be disposed of, or handled at the end of an experiment?

Today, brain organoids or ex vivo brain tissue are destroyed following standard practices for disposing of all tissues. But if researchers develop mice, say, with some advanced cognitive capacities, should those animals be destroyed or given special treatment at the end of a study? Already certain animals, such as chimpanzees, enter sanctuaries to live out the remainder of their lives after researchers have finished working with them in laboratories.

Should there be special requirements for data sharing, collaboration and legacy use of brain tissue?

The unique benefits and risks of sharing data obtained from such tissues will need to be considered. Ex vivo human brain tissue could reveal sensitive information — for instance, about a person’s memories or disease status. Equally, there could be more value in sharing such information, because of the difficulty of obtaining human brain tissue. In some cases, certain features of the data might need to be stripped out, or the extent of sharing limited.

Geneticists have long grappled with similar issues for people’s genomic information; some of their approaches could be applied to brain research.

ETHICS EFFORTS

Various efforts are already tackling the ethics of advances in neuroscience 17 . When the BRAIN Initiative was announced in 2013, the Presidential Commission for the Study of Bioethical Issues was charged with evaluating ethics, and produced a two-volume report in response 18 , 19 . The European Commission’s Human Brain Project has a major ethics component, and the NIH BRAIN Initiative has a neuroethics division.

But we think more needs to be done. Existing institutional ethics review boards or those for stem-cell research oversight might not yet be equipped to address issues specific to these experimental brain models because they are so new. We recommend that such organizations ask experts in this area to join their boards or serve as consultants. New committees, dedicated to overseeing the use of human-brain surrogates, could also be assembled.

As for the broader societal conversation, various models exist for democratic deliberation that could be applied. One example is the successful consultations between the public, scientists, regulators and bioethicists that preceded the UK government’s decision to permit the clinical use of mitochondrial DNA transfer in 2015.

As these conversations play out, the major funders of biomedical research should strive to provide guidance and, eventually, guidelines. Also, researchers engaged in the development and use of human-brain surrogates should seek ethical guidance, for instance from their funders, review boards or institutions. They should also share their experiences and concerns, as reviewers, in their own papers or at conferences.

We do not think that these difficult questions should halt this research. Experimental models of the human brain could help us to unlock mysteries about psychiatric and neurological illnesses that have long remained elusive. But to ensure the success and social acceptance of this research long term, an ethical framework must be forged now, while brain surrogates remain in the early stages of development.

Simplified 3D brain organoids can be grown in a dish using human stem cells as the starting material.

A researcher dissects slices of human brain tissue.

A 3D human-brain assembloid derived from stem cells.

Contributor Information

Nita A. Farahany, Professor of law and philosophy at Duke University, director of the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA.

Henry T. Greely, Professor of law, director of the Center for Law and the Biosciences, and director of the Stanford Program in Neuroscience and Society at Stanford University, California, USA.

Scientific Research and Experimenting on Human Beings

• First Online: 01 September 2019

Cite this chapter

• Laura Palazzani 2  

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Experimentation is essential in scientific research for the advancement of knowledge. The objective of experimentation is in itself good, insofar as it aims at improving the conditions of human’s health and wellbeing, but it should be adequately justified in relation to the protection of the interests and fundamental rights of the subject being experimented on. The chapter analysis the main ethical requirements of experimentation on human beings in general, focusing on particularly vulnerable categories (minors, women, people in developing Countries). A special focus is dedicated to innovative treatments, early access, unexperimented or not yet experimented drugs and the so called ‘compassionate use’.

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Starting from the Nuremberg Code (1947), through the Declaration of Helsinki (1964 and successive revisions) and the drawing up of the guidelines for clinical practice (Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects , adopted in 1993 with successive revisions; Good Clinical Practice approved by The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use in 2002), up to the documents of international and community importance, with different levels of bindingness. In particular the following deserve mention: UNESCO ( 2005 ); Council of Europe ( 1997 , 2004 ); Regulation of the European Union No. 536/2014 of 16 April 2014 on clinical trials of drugs for human use, which repeals directive 2001/20/EC. In this context see also: European Medicines Agency (EMA) ( 2016 ); World Health Organization (WHO) ( 2002 , 2011 ).

On this topics see the Opinions of the Italian Committee for Bioethics ( 1992a , b , 2009 , 2010a , c ).

On this topics see Emanuel et al. ( 2011 ); Council of Europe, Committee on Bioethics (DH-BIO) ( 2012 ).

See documents on the topics on an European level: European Medicines Agency (EMA) ( 2008 , 2012 ); European Commission ( 2013 ); European Commission ad hoc group ( 2008 ). The main Opinions on the topics in Europe: Nuffield Council on Bioethics ( 2015 ); U.K. Medical Research Council ( 2004 ); Italian Committee for Bioethics ( 2012 ); Working Party of Research Ethics Committees in Germany ( 2010 ). On an international level: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ( 2000 ); International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ( 2016 ). In USA: American Academy of Paediatrics – Committee on Bioethics ( 2016 ); U.S. National Academy of Sciences (Committee on Clinical Research Involving Children) ( 2004 ); U.S. National Academy of Sciences (Committee on Paediatric Studies-Institute of Medicine) ( 2012 ); U.S. National Institutes of Health ( 2016 ); U.S. Presidential Commission for the Study of Bioethical Issues ( 2013 ).

Wendler ( 2006 ), pp. 229–234.

Miller and Nelson ( 2006 ), pp. S25–S30.

The regulation on international level: UN Convention of the Rights of the Child , 1989; Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine , 1997; Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research , 2005. Regulation on European level: Charter of Fundamental Rights of European Union , 2000 (2000/C 364/01); Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data; Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance); Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (Text with EEA relevance); Regulation (EU) 679/2016 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation); European Parliament Resolution of 15 December 2016 on the regulation on paediatric medicines (2016/2902(RSP)).

While in 1977 the Food and Drug Administration (FDA) in its General Considerations for the Clinical Evaluation of Drugs and in 1982 the World Health Organisation in its Proposed International Guidelines recommended the exclusion of women from experimentations, it is in 1988 that the FDA in its Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Application recommends the analysis of data differentiated according to sex in clinical trials. In 1993 once again the Food and Drug Administration issues the Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs , expressing the hope for the inclusion of women in the experimentation protocols so as to guarantee an equal representation. Along the same line are the International Ethical Guidelines for Biomedical Research Involving Human Subjects (1993, revised in 2002), which recommend researchers, sponsors and ethics committees to not exclude women of child bearing age from experimentation, not considering the potential of pregnancy a sufficient reason to limit their participation and recognising women the capacity to take a “rational decision” in taking part in research.

Wizemann and Pardue ( 2001 ); Mattison ( 2004 ), pp. 112–117.

Franconi et al. ( 2007 ), pp. 81–97.

This is the theory maintained by feminists. Cfr. DeBruin ( 1994 ), pp. 117–146; Sherwin ( 1994 ), pp. 533–538; Sherwin ( 1992 ), pp. 158–175; and Merton ( 1996 ).

On the topics see the Opinion of the National Ethics Council in Europe: Austrian Bioethics Commission at the Federal Chancellery ( 2009 ); Belgian Advisory Committee on Bioethics ( 2004 , 2015 ); European Medicines Agency (EMA) ( 2005 , 2005 ); Italian National Bioethics Committee ( 2008 ). In USA: Columbia University Institutional Review Board ( 2012 ); John Hopkins University Center for Communication Programs ( 2003 ); The American College of Obstetricians and Gynecologists ( 2015 ); The Society for Women’s Health Research – United States Food and Drugs Administration Office of Women’s Health ( 2011 ); U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Office of Research on Women’s Health ( 2011 ); U.S. Government Accountability Office ( 1992 ); U.S. Government Accountability Office ( 2001 ); U.S. Food and Drug Administration ( 1993 ); U.S. National Institute of Health ( 2001 ). In other countries and on international level: Health Canada ( 2013 ); International Conference on Harmonisation (ICH) ( 2004 ); World Health Organization (WHO) ( 1995 , 1998 , 2010 ).

CIOMS 2016, Commentary on Guideline 19.

On the topics see: French National Consultative Ethics Committee for Health and Life Sciences ( 2003 ); Italian Committee for Bioethics ( 2011 , 2017 ); European Group on Ethics in Science and New Technologies (EGE) ( 2003 ); Nuffield Council on Bioethics ( 2005 ); U.S. Food and Drug Administration ( 2013 , 2016 ); U.S. National Bioethics Advisory Commission ( 2001 ); U.S. National Institute of Health ( 2001 ); Marshall ( 2007 ); Neves ( 2009 ).

In the context of international guidelines the ethical criteria of experimentation with particular reference to developing Countries have been elaborated in International Ethical Guidelines for Biomedical Research Involving Human Subjects 2002, which updated the 1993 guidelines of the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization; Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, in its most recently developed form by the World Medical Association (adopted in 1964, revised in 1975, 1983, 1989, 1996, 2000 and 2008), Working Party for the Elaboration of Guides for Research Ethics Committee Members (CDBI, 2010 , Rev. 1. 2).

Italian Committee for Bioethics ( 1992a , b ).

See art. 37 of the Declaration of Helsinki (updated in October 2013) that provides for the possibility of “unproven interventions in clinical practice”. It allows the use, under the responsibility of the doctor and with the consent of the patient or his legal representative, of “an unproven intervention”, when there are no proven treatments or other known interventions have proved ineffective, and after seeking expert opinion on the subject. The doctor must be convinced that this drug could “constitute a hope to save the life, restore the physical integrity or alleviate the suffering of the patient”. The article adds that “this intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and made publicly available when appropriate”. In one of the many drafts of the Universal Declaration on Bioethics and Human Rights of UNESCO, art. 16 of Scientific and Rational Method , after pointing out that every decision and practice should be based on the best scientific information available, stressed that (v) “be considered individually, allowing for the possibility of exceptions to general rules and practices”. The article was then removed from the final version, but it is the sign of a debate within the international community itself.

‘Expanded access’ refers to treatment offered to patients in the absence of other effective treatment, emergency for individual and public health. Nevertheless, the spread of contagion cannot be sufficient to allow compassionate treatment only in these circumstances and thus result as being an advantage for these patients. If one considers the point of view of the person affected by a rare disease, with high mortality but not contagious, the lack of danger of its spread would paradoxically deprive these patients of an opportunity that others instead have in trying a treatment.

The expression “compassionate use” can be traced in art. 83 of EC Regulation no. 726/2004, that authorizes individual states to derogate from the Community rules for the marketing of drugs in the event that a group of patients with a chronic, seriously debilitating or life-threatening illness, cannot be treated satisfactorily with an authorized medicinal product. EC Regulation no. 726/2004 was amended by Regulation no. 1394/2007. The latter introduces for the first time the definition of “advanced therapies”, including not only gene therapy and somatic cell therapy, as well as tissue engineered products. The main innovations introduced by the Regulation include: the establishment of an expert committee (Committee for Advanced Therapies), within the European Medicines Agency (EMA); the adoption of new requirements for quality, safety and traceability of the donation, procurement and control; the adoption of new regulatory procedures for classification and certification; support for small and medium businesses with incentives to promote entrepreneurship. In addition, Regulation stipulates that each Member State should standardize the production and use of advanced therapies for individual patients, treated in national public facilities, and therefore not aimed at placing on the market and commercialization.

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• 25 April 2018

The ethics of experimenting with human brain tissue

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Nita A. Farahany is professor of law and philosophy at Duke University, director of the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA.

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Christof Koch is the chief scientist and president at the Allen Institute for Brain Science, Seattle, Washington, USA.

Christine Grady is chief of the Department of Bioethics at the National Institutes of Health Clinical Center, Bethesda, Maryland, USA.

Sergiu P. Pașca is assistant professor of psychiatry and behavioural sciences at Stanford University, Palo Alto, California, USA.

Nenad Sestan is professor of neuroscience, of genetics, of psychiatry, and of comparative medicine at the Yale School of Medicine, New Haven, Connecticut, USA.

Paola Arlotta is professor of stem cell and regenerative biology at Harvard University, Cambridge, Massachusetts, USA.

James L. Bernat is professor of neurology and medicine (active emeritus) at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, USA.

Jonathan Ting is assistant investigator at the Allen Institute for Brain Science, Seattle, Washington, USA.

Jeantine E. Lunshof is research scientist-ethicist at MIT Media Lab in Cambridge, Massachusetts; ethics consultant to the Department of Genetics at Harvard Medical School, Boston, Massachusetts, USA; assistant professor in the Department of Genetics, University of Groningen, Groningen, the Netherlands.

Eswar P. R. Iyer is a postdoctoral fellow at Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Insoo Hyun is associate professor of bioethics and philosophy at Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Beatrice H. Capestany is a postdoctoral fellow at the Science, Law, and Policy Lab at the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA.

George M. Church is professor of genetics at Department of Genetics, Harvard Medical School, and Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA.

Hao Huang is associate professor of radiology at University of Pennsylvania, Philadelphia, USA.

Hongjun Song is Perelman professor of neuroscience at University of Pennsylvania in Philadelphia, USA.

If researchers could create brain tissue in the laboratory that might appear to have conscious experiences or subjective phenomenal states, would that tissue deserve any of the protections routinely given to human or animal research subjects?

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How the Experimental Method Works in Psychology

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The Experimental Process

Types of experiments, potential pitfalls of the experimental method.

The experimental method is a type of research procedure that involves manipulating variables to determine if there is a cause-and-effect relationship. The results obtained through the experimental method are useful but do not prove with 100% certainty that a singular cause always creates a specific effect. Instead, they show the probability that a cause will or will not lead to a particular effect.

At a Glance

While there are many different research techniques available, the experimental method allows researchers to look at cause-and-effect relationships. Using the experimental method, researchers randomly assign participants to a control or experimental group and manipulate levels of an independent variable. If changes in the independent variable lead to changes in the dependent variable, it indicates there is likely a causal relationship between them.

What Is the Experimental Method in Psychology?

The experimental method involves manipulating one variable to determine if this causes changes in another variable. This method relies on controlled research methods and random assignment of study subjects to test a hypothesis.

For example, researchers may want to learn how different visual patterns may impact our perception. Or they might wonder whether certain actions can improve memory . Experiments are conducted on many behavioral topics, including:

The scientific method forms the basis of the experimental method. This is a process used to determine the relationship between two variables—in this case, to explain human behavior .

Positivism is also important in the experimental method. It refers to factual knowledge that is obtained through observation, which is considered to be trustworthy.

When using the experimental method, researchers first identify and define key variables. Then they formulate a hypothesis, manipulate the variables, and collect data on the results. Unrelated or irrelevant variables are carefully controlled to minimize the potential impact on the experiment outcome.

History of the Experimental Method

The idea of using experiments to better understand human psychology began toward the end of the nineteenth century. Wilhelm Wundt established the first formal laboratory in 1879.

Wundt is often called the father of experimental psychology. He believed that experiments could help explain how psychology works, and used this approach to study consciousness .

Wundt coined the term "physiological psychology." This is a hybrid of physiology and psychology, or how the body affects the brain.

Other early contributors to the development and evolution of experimental psychology as we know it today include:

• Gustav Fechner (1801-1887), who helped develop procedures for measuring sensations according to the size of the stimulus
• Hermann von Helmholtz (1821-1894), who analyzed philosophical assumptions through research in an attempt to arrive at scientific conclusions
• Franz Brentano (1838-1917), who called for a combination of first-person and third-person research methods when studying psychology
• Georg Elias Müller (1850-1934), who performed an early experiment on attitude which involved the sensory discrimination of weights and revealed how anticipation can affect this discrimination

Key Terms to Know

To understand how the experimental method works, it is important to know some key terms.

Dependent Variable

The dependent variable is the effect that the experimenter is measuring. If a researcher was investigating how sleep influences test scores, for example, the test scores would be the dependent variable.

Independent Variable

The independent variable is the variable that the experimenter manipulates. In the previous example, the amount of sleep an individual gets would be the independent variable.

A hypothesis is a tentative statement or a guess about the possible relationship between two or more variables. In looking at how sleep influences test scores, the researcher might hypothesize that people who get more sleep will perform better on a math test the following day. The purpose of the experiment, then, is to either support or reject this hypothesis.

Operational definitions are necessary when performing an experiment. When we say that something is an independent or dependent variable, we must have a very clear and specific definition of the meaning and scope of that variable.

Extraneous Variables

Extraneous variables are other variables that may also affect the outcome of an experiment. Types of extraneous variables include participant variables, situational variables, demand characteristics, and experimenter effects. In some cases, researchers can take steps to control for extraneous variables.

Demand Characteristics

Demand characteristics are subtle hints that indicate what an experimenter is hoping to find in a psychology experiment. This can sometimes cause participants to alter their behavior, which can affect the results of the experiment.

Intervening Variables

Intervening variables are factors that can affect the relationship between two other variables. 

Confounding Variables

Confounding variables are variables that can affect the dependent variable, but that experimenters cannot control for. Confounding variables can make it difficult to determine if the effect was due to changes in the independent variable or if the confounding variable may have played a role.

Psychologists, like other scientists, use the scientific method when conducting an experiment. The scientific method is a set of procedures and principles that guide how scientists develop research questions, collect data, and come to conclusions.

The five basic steps of the experimental process are:

• Identifying a problem to study
• Devising the research protocol
• Conducting the experiment
• Analyzing the data collected
• Sharing the findings (usually in writing or via presentation)

Most psychology students are expected to use the experimental method at some point in their academic careers. Learning how to conduct an experiment is important to understanding how psychologists prove and disprove theories in this field.

There are a few different types of experiments that researchers might use when studying psychology. Each has pros and cons depending on the participants being studied, the hypothesis, and the resources available to conduct the research.

Lab Experiments

Lab experiments are common in psychology because they allow experimenters more control over the variables. These experiments can also be easier for other researchers to replicate. The drawback of this research type is that what takes place in a lab is not always what takes place in the real world.

Field Experiments

Sometimes researchers opt to conduct their experiments in the field. For example, a social psychologist interested in researching prosocial behavior might have a person pretend to faint and observe how long it takes onlookers to respond.

This type of experiment can be a great way to see behavioral responses in realistic settings. But it is more difficult for researchers to control the many variables existing in these settings that could potentially influence the experiment's results.

Quasi-Experiments

While lab experiments are known as true experiments, researchers can also utilize a quasi-experiment. Quasi-experiments are often referred to as natural experiments because the researchers do not have true control over the independent variable.

A researcher looking at personality differences and birth order, for example, is not able to manipulate the independent variable in the situation (personality traits). Participants also cannot be randomly assigned because they naturally fall into pre-existing groups based on their birth order.

So why would a researcher use a quasi-experiment? This is a good choice in situations where scientists are interested in studying phenomena in natural, real-world settings. It's also beneficial if there are limits on research funds or time.

Field experiments can be either quasi-experiments or true experiments.

Examples of the Experimental Method in Use

The experimental method can provide insight into human thoughts and behaviors, Researchers use experiments to study many aspects of psychology.

A 2019 study investigated whether splitting attention between electronic devices and classroom lectures had an effect on college students' learning abilities. It found that dividing attention between these two mediums did not affect lecture comprehension. However, it did impact long-term retention of the lecture information, which affected students' exam performance.

An experiment used participants' eye movements and electroencephalogram (EEG) data to better understand cognitive processing differences between experts and novices. It found that experts had higher power in their theta brain waves than novices, suggesting that they also had a higher cognitive load.

A study looked at whether chatting online with a computer via a chatbot changed the positive effects of emotional disclosure often received when talking with an actual human. It found that the effects were the same in both cases.

One experimental study evaluated whether exercise timing impacts information recall. It found that engaging in exercise prior to performing a memory task helped improve participants' short-term memory abilities.

Sometimes researchers use the experimental method to get a bigger-picture view of psychological behaviors and impacts. For example, one 2018 study examined several lab experiments to learn more about the impact of various environmental factors on building occupant perceptions.

A 2020 study set out to determine the role that sensation-seeking plays in political violence. This research found that sensation-seeking individuals have a higher propensity for engaging in political violence. It also found that providing access to a more peaceful, yet still exciting political group helps reduce this effect.

While the experimental method can be a valuable tool for learning more about psychology and its impacts, it also comes with a few pitfalls.

Experiments may produce artificial results, which are difficult to apply to real-world situations. Similarly, researcher bias can impact the data collected. Results may not be able to be reproduced, meaning the results have low reliability .

Since humans are unpredictable and their behavior can be subjective, it can be hard to measure responses in an experiment. In addition, political pressure may alter the results. The subjects may not be a good representation of the population, or groups used may not be comparable.

And finally, since researchers are human too, results may be degraded due to human error.

What This Means For You

Every psychological research method has its pros and cons. The experimental method can help establish cause and effect, and it's also beneficial when research funds are limited or time is of the essence.

At the same time, it's essential to be aware of this method's pitfalls, such as how biases can affect the results or the potential for low reliability. Keeping these in mind can help you review and assess research studies more accurately, giving you a better idea of whether the results can be trusted or have limitations.

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Schumpe BM, Belanger JJ, Moyano M, Nisa CF. The role of sensation seeking in political violence: An extension of the significance quest theory . J Personal Social Psychol . 2020;118(4):743-761. doi:10.1037/pspp0000223

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Human research protections

Research with human participants has proven invaluable in advancing knowledge in the biomedical, behavioral, and social sciences. Such research is strictly regulated, with laws at the federal, state, and local levels. Further, professional societies have developed discipline-specific standards, policies, and guidelines for ensuring that the rights and welfare of research participants is protected.

In the early 1970s, following widely publicized cases of research abuse, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was created to study issues surrounding the protection of humans in research. In 1979 the Commission issued a report entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research (commonly called the Belmont Report), which provided the ethical framework on which current federal regulations for the protection of human participants in research are based.

Legislation and regulations

Legislation and regulations that affect the conduct of research with human participants:

• Department of Health and Human Services - 45CFR46
• Food and Drug Administration - 21CFR50 and 21CFR56
• The privacy rule
• Mandatory reporters: Summary of state laws (PDF, 493KB)
• NIH policy and compliance: Human subjects research

Resources that provide additional guidance on various human research protection issues:

Institutional review boards (IRBs)

• IRB guidebook
• Expedited review categories
• IRBs and psychological science (APA report)
• Recommendations of the 2007 APA Presidential Task Force on IRBs and psychological science (PDF, 36KB)
• Protecting personal health information in research: Understanding the HIPAA privacy rule (PDF, 3.59MB)
• HIPAA frequently asked questions

Research on the internet

• Psychological research online: Opportunities and challenges

Federal offices

U.S. federal agency offices charged with regulating research with human participants:

• Office for Human Research Protections (DHHS)
• Policy and compliance: Human subjects research (NIH)

Training resources

• Ethical and policy issues in research involving human participants (PDF, 2MB) (NBAC report)
• National Library of Medicine bibliography
• Protecting participants and facilitating social and behavioral sciences research (NRC report)
• Research involving persons with mental disorders that might affect decision-making capacity (NBAC report)
• Resources for research ethics education: Human subjects
• Responsible research: A systems approach to protecting research participants (IOM report)
• University of Minnesota consent module

APA resources

• Guidelines for ethical conduct of behavioral projects involving human participants by high school students
• Researchers and regulators hammer out guidelines for research risk ( Monitor on Psychology , 2005)
• Ethics in research with human participants (APA book)
• Committee on Human Research (CHR)
• Conducting research

Contact APA