Interactive Research Ethics Timeline

Walter Reed was a Major in the U.S. Army appointed to study tropical diseases in Cuba. His research on yellow fever revealed that the disease is transmitted through mosquitoes biting humans rather than from person to person.

The research was conducted with human subjects who were deliberately infected with the disease; two of the subjects died as a result of the yellow fever infection. The subjects were informed that death from yellow fever was a possible risk of their participation. The research was responsible for identifying the mosquito as the vector of disease transmission, and led to a significant decrease in mortality rates from yellow fever.

This first federal directive, issued in 1904 by the Director of the Hygienic Laboratory, the first federal lab of medical bacteriology, marked a significant step in the ethical treatment of non-human animals in laboratory experiments. The directive emphasized that non-human animals should not be subjected to pain during research activities. It reflected a growing awareness and concern for non-human animal welfare within the scientific community, setting a precedent for the humane treatment of non-human animals in research settings.

In 1912, under new authorizing legislation, the Marine Hospital Service was established as the Public Health Service (PHS) to express the enlarged scope of its work.

In 1930, the Hygienic Laboratory was re-designated as the National Institute of Health (NIH). The establishment NIH marked a pivotal moment in medical research and public health. The NIH became a central hub for coordinating biomedical research efforts, laying the groundwork for numerous groundbreaking discoveries and advancements in healthcare.

The US Public Health Service (PHS) Tuskegee Study of Untreated Syphilis in the Negro Male is sometimes called the "Tuskegee Study" because it took place in Tuskegee, Alabama. The press exposure of this study set the stage for the National Research Act, which requires IRB review of all federally-funded studies.

The study began in 1932, when the therapy for syphilis was almost as risky as the disease itself. Six hundred African-American men were recruited – 400 test subjects who had syphilis and 200 controls who did not. The researchers offered free examinations, medical care, and "therapeutic" spinal taps to all men who volunteered for the study.

The initial plan was to study the men for six months, but the subjects were so compliant that the researchers decided to extend the research. The study continued after the discovery of penicillin as an effective and accessible treatment for syphilis. Yet, the researchers continued to withhold penicillin from the study subjects because of the unique scientific opportunity to study the long-term effects of syphilis. The researchers never informed the subjects that they had syphilis or that there was a treatment available.

In 1972, there was a media exposé and in 1973, the surviving subjects finally received penicillin. In 1997, President Bill Clinton issued a formal apology on behalf of the U.S. government to the subjects and their families.

This social science experiment set out to prove that stuttering is a learned behavior that can be induced in children through psychological pressure.

Over a six-month period, Dr. Wendell Johnson, a nationally renowned pioneer in the field of speech pathology, and his staff tested his theory on 22 children who were in the care of the state-run Iowa Soldiers' Orphans' Home. This particular study group was chosen because they formed a convenient sample to abuse and berate. Some were subjected to steady harassment, badgering and other negative therapy in an attempt to get them to stutter; the rest served as a control group.

The Nazi Doctors' Trial began in 1946 following World War II. Criminal proceedings were brought against 23 Germans for participating in war crimes and crimes against humanity. Sixteen were found guilty and seven were sentenced to death because of their participation in experiments on human beings that involved painful and frequently fatal procedures.

In one example, Nazi Doctors were interested in learning about hypothermia that threatened the lives of soldiers fighting at the front. They conducted experiments on prisoners that exposed them to excessively cold temperatures to learn about the core body temperatures at which humans begin to lose consciousness and eventually die.

The Nuremberg Code was adopted following the Nazi Doctors' Trials. It established ten basic principles related to the moral, ethical and legal obligations associated with human subjects research. These principles form the foundation of the Belmont Report that was eventually published in 1979.

Key provisions of the code include: The voluntary consent of the human subject is absolutely essential; Human research should be founded on preliminary results from animal studies; Unnecessary physical and mental suffering should be avoided; Degree of risk to subjects should never exceed the humanitarian importance of the problem to be solved by the experiment; Only sufficiently qualified persons should be allowed to conduct the research; The researcher must stop the experiment if it becomes apparent that injury, disability or death is a likely result of it continuation.

In 1950, the Animal Care Panel was established to address growing concerns about the ethical treatment of non-human animals used in laboratory research. This initiative aimed to ensure that non-human animals received proper care and protection, reflecting a broader societal shift towards greater awareness of animal rights and welfare.

In 1950, NIH Director Dr. Rolla E. Dyer issues "Rules Regarding Animals," covering the ethical treatment and care of non-human animals in research.

During the 1940s and 1950s, researchers fed radioactive cereal to 15 children at the Fernald School, a state home for mentally disabled children in Massachusetts. Small amounts of calcium and iron tagged with radioactive tracers were put in the children's cereal, allowing researchers to track the absorption of those nutrients as the oatmeal was digested.

The researchers enrolled children in the study without their consent or the consent of their guardians. To entice their participation, the children were told they were part of a science club. Some were exposed to more radiation than federal limits allow. However, the children did not suffer any physical harm.

The first federal policy introduced by National Institutes of Health (NIH) (applied only to NIH intramural research) which, in addition to provisions for the protection of research participants, also required prospective review of research protocols. The inclusion of prospective review was consistent with the Nuremberg Code’s emphasis on the protection of healthy volunteers who had little to gain directly from research participation. Another important addition was the review of prospective research protocols by individuals who had no direct involvement with or intellectual investment in the research--marking the beginnings of the research review mechanism known today as Institutional Review Boards (IRBs).

The 1954 NIH Policy on the Care and Treatment of Laboratory Animals for Public Health Service (PHS) funded activities represented a landmark development in animal welfare regulations. This policy set forth guidelines for the humane care and treatment of non-human animals involved in research funded by the PHS, demonstrating a commitment to ethical standards in scientific endeavors.

In 1954, the Rules Regarding Animals were revised and consolidated into the NIH Manual, providing researchers with a comprehensive guide on the ethical and humane treatment of non-human animals in laboratory settings. This manual served as a valuable resource for ensuring the welfare of non-human animals used in biomedical research conducted under the auspices of the NIH.

The Institute of Laboratory Animal Resources (IAR) was renamed as the Institute for Laboratory Animal Research (ILAR) in 1956. This name change reflected a broader scope of activities and a growing emphasis on research related to laboratory animal science. ILAR continued to play a pivotal role in promoting the responsible and ethical use of non-human animals in research.

Researchers at the Willowbrook State School in New York, an institution for mentally disabled children, deliberately infected children with a mild form of hepatitis during a study of the progression, prevention and treatment of viral hepatitis that extended from 1956 to 1972. The results eventually contributed to the development of a successful hepatitis vaccine but were controversial since the study involved healthy, institutionalized children and parental consent issues.

This case along with others contributed to the advancement of federal regulations governing human subjects research.

In the late 1950s, Thalidomide was approved as a sedative in Europe but the Food and Drug Administration (FDA) had not approved it for use in the U.S. At that time, the FDA had only a limited role approving drugs in the U.S., which allowed the manufacturer to give samples to U.S. physicians and pay them to study its safety and efficacy.

By 1961 it became clear that Thalidomide caused significant damage to a fetus if a woman took it during the first trimester of pregnancy. Children were being born severely deformed – without limbs. Although this case did not involve research, it prompted the 1962 amendments to the Food, Drug and Cosmetic Act which required drug manufacturers to establish a drug's effectiveness prior to marketing.

Researchers funded by the National Institutes of Health (NIH) at Sloan-Kettering Cancer Research Institute injected live cancer cells into indigent, chronically ill elderly patients without their consent. The experiment was intended to measure the patients' ability to reject the cells and was not related to their treatment.

Subsequent government hearings revealed that the reason the researchers did not ask the patients for their consent was to ensure that they did not refuse to participate.

This social science study was conducted in an attempt to understand – from a psychological standpoint – the role of obedience to authority: why ordinary people behave in ways that seem inhumane outside a certain context. The research design was to have an authority figure instruct subjects to do something that they would not do under ordinary circumstances.

The researcher, Stanley Milgram, and an associate duped the subjects into thinking they were causing the associate to be shocked with an electrical charge. They did this by connecting the associate to a device that appeared to administer electrical shocks. Milgram told the subjects that another research subject (the associate) would be completing a memory task and should be given an electrical shock if he answered incorrectly. The subjects were told to push a button and increase the "electrical charge" to shock the associate when instructed by the researcher. The researcher instructed the subjects to increase the "electrical charge" often. Eventually the associate pretended to convulse with the shock and lapse into unconsciousness.

The research taught Milgram about human behavior at the expense of the unwitting subjects, who had no idea that their associates were not actually being shocked. Some of the subjects suffered emotional distress after witnessing the responses they thought they had inflicted.

The first edition of "The Guide for the Care and Use of Laboratory Animals" was published in 1963 by the Institute of Laboratory Animal Resources (ILAR). This groundbreaking document set forth guidelines and recommendations for the proper care, housing, and humane treatment of non-human animals used in biomedical research. The Guide served as a foundation for the development of standardized practices and policies governing the use of laboratory non-human animals in scientific studies.

The Declaration of Helsinki was developed in 1964 by the World Medical Association as an international statement of ethical principles to guide medical professionals conducting research involving human subjects.

The incorporation of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) in 1965 marked a significant milestone in the establishment of accreditation standards for laboratory animal care programs. AAALAC's mission was to promote the humane treatment of non-human animals in research by accrediting institutions that adhered to high standards of animal care and welfare.

Surgeon General's Directive: First Public Health Service (PHS) Policy - required review of prospective research taking into account rights and welfare of the subjects, appropriateness of the methods used to obtain informed consent; risks and potential benefits of the research had to be weighed; also instituted assurance requirement for grantee institutions.

Public Law 89-544, enacted in 1966, established the Animal Welfare Act (AWA) in the United States. This landmark legislation aimed to regulate the treatment of non-human animals in research, exhibition, transportation, and commerce, setting minimum standards for their care and housing. The AWA represented a major step forward in protecting the welfare of non-human animals used in various settings, including laboratories.

As a result of the Nazi Doctors' Trials, many American researchers held the belief that ethical abuses only happened in Europe. They were unaware that many of the same abuses were happening in the U.S.

Dr. Thomas Beecher published an article in the New England Journal of Medicine that cited 22 published studies with serious ethical flaws. Examples included one study in which researchers assigned some patients with acute streptococcal infections to a "control group" and did not allow them to receive effective treatment. More than 70 of these patients developed rheumatic fever. In another study of immune response, researchers injected live cancer cells into subjects without their informed consent. Many of them died.

Beecher concluded that:

"If suitably approached, patients will accede, on the basis of trust, to about any request from their physicians." "There is a belief prevalent in some sophisticated circles that attention to [informed consent] would block progress." New England Journal of Medicine 274 (1966): 1354-60.

In 1967, the Animal Care Panel (ACP) underwent a name change and became known as the American Association for Laboratory Animal Science (AALAS). This renaming reflected the organization's evolving focus on promoting professionalism and best practices in the field of laboratory animal science, emphasizing the importance of animal welfare and ethical standards.

In 1971, researcher Philip Zimbardo conducted a study of the psychology of imprisonment by setting up a mock prison using volunteer college student subjects to assume the roles of prisoners and guards. The student "guards" brutalized the student "prisoners."

Ethical concerns about the research include underestimation of the likelihood and severity of psychological harm to the subjects, and that the researcher himself played a role (prison director) in the research rather than safeguarding the welfare of the research subjects.

In 1971, the United States Department of Agriculture (USDA) promulgated Subpart F of the Animal Welfare Act (AWA), addressing the issue of stolen non-human animals. This regulatory provision aimed to prevent the acquisition and use of stolen non-human animals in research, strengthening safeguards to ensure the ethical sourcing and treatment of non-human animals involved in scientific studies.

The 1971 NIH Policy on the Care and Treatment of Laboratory Animals represented a significant advancement in promoting ethical standards for animal research funded by the National Institutes of Health (NIH). This policy outlined requirements for the humane care, handling, and treatment of laboratory non-human animals, emphasizing the responsibility of researchers to prioritize animal welfare in their work.

The Office for Protection from Research Risks (OPRR), was created in 1972 as part of the National Institutes of Health (NIH). (OPRR was later replaced by OHRP).

In 1973, the NIH Policy on the Care and Treatment of Laboratory Animals was expanded to become the first Public Health Service (PHS) Policy on laboratory animal care and treatment. This expansion broadened the scope of regulatory oversight to include all PHS-funded activities involving non-human animals, reinforcing the commitment to ethical standards and humane treatment in scientific research.

This directive, which was spearheaded by Senator Ted Kennedy and represented one of his earliest achievements, created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission spent five years developing the Belmont Report and ultimately mandated IRB review of all federally-funded research.

In 1974, the Office for Protection from Research Risks (OPRR) was established, signaling a commitment to safeguarding the welfare of human subjects involved in research funded by the Department of Health, Education, and Welfare (DHEW), which later became the Department of Health and Human Services (HHS). OPRR played a crucial role in developing policies and guidelines to ensure the ethical conduct of research and the protection of research participants.

Human Subjects of Biomedical and Behavioral Research was established by the National Research Act of 1974 and met from 1974 to 1978. In accord with its charge, the Commission issued reports and recommendations identifying the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects.

In 1981 the Department of Health and Human Services (DHSS), and the Food and Drug Administration (FDA) promulgated new regulations on human subjects research published at 45 CFR 46 and 21 CFR 50 respectively.

The U.S. Food and Drug Administration (FDA) proposed Good Laboratory Practice (GLP) regulations in 1976, aiming to ensure the quality and integrity of non-clinical laboratory studies conducted for the evaluation of pharmaceuticals, food additives, and medical devices. These proposed regulations outlined standards for the conduct, documentation, and reporting of studies to support the safety and efficacy of regulated products, enhancing the reliability of preclinical research.

This guidance recommended that women of childbearing potential be excluded from participation in Phase I and early Phase II clinical trials.

Even though it was later reversed, this policy (and similar practices in non-Food and Drug Administration (FDA) clinical research) led to the widespread exclusion of women from clinical and scientific trials, resulting in a lack of information about the effects of many therapies and drugs on women.

The publication of the 5th edition of the Guide for the Care and Use of Laboratory Animals in 1978 represented a significant update to the guidelines established by the Institute for Laboratory Animal Research (ILAR) and the National Research Council (NRC). This revised edition provided updated recommendations for the housing, care, and use of laboratory non-human animals, reflecting advancements in scientific knowledge and evolving standards of animal welfare.

The Ethical Principles and Guidelines for the Protection of Human Subjects of Research, called the Belmont Report after the conference center where it was created, was published. It evolved from the National Research Act and the Nuremberg Code. It defined three fundamental ethical principles for using human subjects for research:

1. Respect for persons: protecting the autonomy of all people, treating them with courtesy and respect, and allowing for informed consent

2. Beneficence: maximizing benefits of the research while minimizing risks of harm to the research subjects

3. Justice: ensuring fair recruitment of subjects and fair distribution of both the costs and benefits of research.

These principles form the ethical foundation for the Common Rule, the uniform set of rules followed by many federal agencies for the protection of human subjects, and identical to subpart A of 45 CFR part 46 of the federal regulations.

In 1979, the U.S. Food and Drug Administration's (FDA) Good Laboratory Practice (GLP) regulations became law, establishing requirements for the conduct of non-clinical laboratory studies supporting the safety and efficacy of FDA-regulated products. This regulatory milestone standardized procedures for study conduct, data documentation, and quality assurance, ensuring the reliability and integrity of research submitted to the FDA for product approval.

The United States Department of Agriculture (USDA) promulgated Subpart E of the Animal Welfare Act (AWA) in 1979, focusing on the identification of non-human animals used in research settings. This regulatory provision established requirements for the proper identification of non-human animals involved in covered activities, facilitating traceability and accountability in research involving animal subjects.

The revision of the Public Health Service's (PHS) Animal Welfare Policy and the requirement for PHS Assurance emphasized the commitment to the humane care and use of non-human animals in research funded by the PHS. This development highlighted the importance of ethical oversight and responsible conduct in research involving non-human animals, promoting the well-being of research subjects and the integrity of scientific inquiry.

The Interagency Research Animal Committee (IRAC) was formed in 1983 to address issues related to the care and use of laboratory non-human animals across federal agencies involved in research. Comprising representatives from various agencies, IRAC aimed to harmonize policies, share expertise, and coordinate efforts to enhance the welfare of non-human animals used in research while ensuring scientific rigor and regulatory compliance.

In 1984, the Food and Drug Administration (FDA) proposed amendments to the Good Laboratory Practice (GLP) regulations. These proposed changes aimed to enhance the quality and integrity of non-clinical laboratory studies conducted for regulatory submissions, including those involving animal testing.

In 1984, the US Government Principles Regarding the Care and Use of Animals in Testing, Research, and Training were promulgated. These principles provided overarching guidance for the ethical treatment of non-human animals involved in research, emphasizing the importance of minimizing pain and distress, ensuring appropriate housing and care, and considering alternatives to animal use whenever possible.

In 1985, amendments to the Animal Welfare Act (AWA) were passed by Congress, requiring all registered research institutions to establish Institutional Animal Care and Use Committees (IACUCs) to oversee non-human animal research and approve proposed protocols. The revised Public Health Service (PHS) policy on non-human animal research also mandated the creation of IACUCs for institutions receiving PHS funds. These amendments emphasized the importance of minimizing pain and distress in non-human animal subjects and encouraged the exploration of alternatives to potentially painful research procedures.

The Humane Research and Experimentation Act (HREA) was passed by Congress in 1985, introducing further regulations to promote the ethical treatment of non-human animals in research. This legislation aimed to establish clear standards for the care and use of non-human animals in scientific studies, emphasizing the importance of minimizing pain and distress, providing appropriate housing and veterinary care, and considering alternatives to animal experimentation whenever feasible.

In 1985, the sixth edition of the Guide for the Care and Use of Laboratory Animals was revised. This widely recognized guide provided comprehensive recommendations for the proper care, housing, and use of non-human animals in research, education, and testing.

In 1986, the Animal Welfare Information Center (AWIC) was established to facilitate access to information related to the humane care and use of non-human animals in research, testing, and teaching. Operating within the National Agricultural Library of the United States Department of Agriculture (USDA), AWIC serves as a valuable resource for researchers, educators, and regulatory agencies seeking guidance on animal welfare issues.

In 1986, the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals was revised to incorporate provisions of the Humane Research and Experimentation Act (HREA). This revision aimed to align PHS policy with legislative requirements, ensuring that institutions receiving PHS funding adhered to established standards for the ethical treatment of non-human animals in research.

In 1987, the Food and Drug Administration (FDA) issued a final rule amending the Good Laboratory Practice (GLP) regulations. These amendments represented the culmination of regulatory efforts to enhance the quality and reliability of non-clinical laboratory studies conducted for regulatory purposes.

In 1986, the American Veterinary Medical Association (AVMA) released a report from its Panel on Euthanasia, addressing best practices for the humane euthanasia of non-human animals in various settings, including research laboratories. The report provided guidance on appropriate methods and techniques for euthanasia, emphasizing the importance of minimizing pain and distress while achieving a rapid and peaceful death.

In 1989, the United States Department of Agriculture (USDA) promulgated Parts 1 and 2 of the Animal Welfare Act (AWA) regulations, implementing key provisions of the 1985 AWA Amendments. These regulations established licensing and registration requirements for research facilities, dealers, exhibitors, and other entities covered by the AWA.

In 1990, the United States Department of Agriculture (USDA) promulgated Subparts B and C as part of the regulations governing the Animal Welfare Act (AWA). Subpart B focused on the registration of research facilities that use non-human animals for experimentation, teaching, or testing purposes, requiring them to provide detailed information about their animal care and use programs. Subpart C outlined specific standards and requirements for research facilities to ensure the well-being and humane treatment of non-human animals under their care, covering aspects such as housing, veterinary care, and environmental enrichment.

In 1990, the Office for Protection from Research Risks (OPRR) established the Animal Welfare Division to oversee and enforce compliance with animal welfare regulations in research settings. Tasked with ensuring the humane care and use of non-human animals in projects funded by the Public Health Service (PHS), the Animal Welfare Division played a critical role in promoting ethical conduct and regulatory compliance among research institutions.

In 1991, the United States Department of Agriculture (USDA) promulgated Part 3 of the Animal Welfare Act (AWA) regulations, establishing comprehensive standards for the humane care and treatment of non-human animals in research, exhibition, and commercial settings. These standards covered various aspects of animal care, including housing, feeding, veterinary care, and environmental enrichment, with the aim of ensuring the well-being and welfare of non-human animals under human care.

In 1992, the United States Congress passed the Animal Enterprise Protection Act (AEPA), legislation aimed at preventing and punishing acts of animal rights extremism and terrorism targeting animal enterprises, including research institutions, farms, and businesses involved in animal-related industries. The AEPA provided law enforcement agencies with expanded authority to investigate and prosecute individuals or groups engaged in activities such as vandalism, harassment, or intimidation against animal facilities or personnel.

In 1996, the seventh edition of the Guide for the Care and Use of Laboratory Animals was published, providing updated guidelines and recommendations for the ethical and humane treatment of non-human animals in research, testing, and teaching environments. Developed by the Institute for Laboratory Animal Research (ILAR) and endorsed by the National Research Council (NRC), the Guide served as a foundational resource for researchers, veterinarians, and institutional animal care and use committees (IACUCs) responsible for overseeing animal welfare.

The NIH Revitalization Act of 1993, PL 103-43. The Food and Drug Administration (FDA) Guidance and National Institutes of Health (NIH) Policy, both released in 1993, sought to rectify the exclusion of women from clinical research.

The U.S. government published a report entitled, "Human Radiation Experiments: The Department of Energy Roadmap to the Story and Records ("The DOE Roadmap") in 1995. It discusses human radiation experiments that were conducted on thousands of United States citizens during and after World War II, including the injection of plutonium into hospital patients without their consent and the intentional release of radiation into the environment.

The studies were conducted for a variety of reasons, among them, the advancement of biomedical science and national defense. Most of the studies did not result in serious harm to subjects, but some did result in increased risk of thyroid cancer, and several deaths occurred that were associated with acute radiation effects.

The ethical issues raised by these experiments include lack of informed consent, lack of fairness in the selection of subjects, failure to report the existence or results of the experiments, and failure to maintain proper records of the experiments.

A healthy 19-year-old college student died after volunteering for a medical research study in which University of Rochester researchers performed a bronchoscopy under general anesthesia. An investigation revealed that researchers exceeded the maximum dosage of lidocaine established by the research protocol.

In 1997, the National Aeronautics and Space Administration (NASA) established Principles for the Ethical Care and Use of Animals, outlining ethical guidelines and responsibilities for the use of non-human animals in NASA-funded research and spaceflight missions. These principles emphasized the importance of minimizing animal pain and distress, providing appropriate veterinary care, and ensuring the humane treatment of non-human animals throughout their involvement in research activities.

OPRR, on behalf of the federal government, suspended federally-funded human subjects research at 15 institutions due to various lapses in human subjects research oversight. In many cases, the violations involved failure to obtain adequate informed consent from research subjects.

Jesse Gelsinger was an 18-year-old research subject who died as a result of taking part in a clinical experiment using gene transfer. He suffered from ornithine transcarbamylase deficiency, a genetic disease that disrupts metabolism. His disease was not severe and he was able to live a relatively normal life.

During the experiment conducted at the University of Pennsylvania, Gelsinger developed a massive immune response after being injected with the study substance. He died four days later.

An Food and Drug Administration (FDA) investigation concluded that the informed consent provided to Gelsinger was inadequate for a number of reasons including the fact that it failed to fully describe the risks of the research study, and did not reveal the financial conflict of interest of the researcher.

In 2000, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICVAM) was established to coordinate federal efforts in the development, validation, and acceptance of alternative methods to animal testing. Comprising representatives from multiple government agencies, including the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and the Environmental Protection Agency (EPA), ICVAM aimed to advance the use of scientifically valid alternative methods that reduce, refine, or replace the use of non-human animals in toxicological and biomedical research.

In 2000, the Office of Laboratory Animal Welfare (OLAW) was established within the National Institutes of Health (NIH) to oversee and monitor compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals. Tasked with ensuring the ethical treatment of non-human animals in research funded by the PHS, OLAW provided guidance, oversight, and educational resources to research institutions and their Institutional Animal Care and Use Committees (IACUCs).

The Office for Human Research Protections (OHRP) was established in the Office of the Assistant Secretary for Health to elevate its stature and effectiveness. OHRP replaced the Office for Protection from Research Risks (OPRR).

The National Human Research Protections Advisory Committee (NHRPAC) was established to advise DHHS on human subject protection. The NHRPAC was later replaced by SACHRP.

In 2000, the American Veterinary Medical Association (AVMA) released a comprehensive report on euthanasia methods for non-human animals, providing guidance on humane euthanasia practices across various species and settings. Developed by a panel of veterinary experts, the report outlined recommended techniques, considerations, and criteria for selecting euthanasia methods based on factors such as species, size, and intended use.

Ellen Roche was a healthy 24-year-old lab technician at the Johns Hopkins Asthma Center. She volunteered to take part in an experiment to understand the natural defenses of healthy people against asthma. Roche was part of a group that inhaled hexamethonium, a drug that induced a mild asthma attack. Within 24 hours of inhaling the drug, Roche had lost one-third of her lung capacity; she died within a month. The consent form she signed warned of coughing, dizziness, and tightness in the chest, but not death. It called hexamethonium a "medication" although its approval by the Food and Drug Administration (FDA) (as a treatment for high blood pressure) had been withdrawn in 1972.

In 2002, the definition of non-human animals under the Animal Welfare Act (AWA) was modified to exclude certain categories of non-human animals, specifically rats, mice, and birds bred for research purposes. This modification resulted in these non-human animals being excluded from the regulatory protections afforded to other covered species under the AWA.

In 2002, the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals was modified to include Just-in-Time (JIT) procedures for the submission of Institutional Animal Care and Use Committee (IACUC) approvals. This modification streamlined the process for grant applicants by allowing them to submit IACUC approvals after peer review but before award issuance, reducing administrative burden and expediting the funding process for animal research projects.

In 2002, a Memorandum of Understanding (MOU) was established between the National Institutes of Health (NIH) and the Department of Veterans Affairs (VA) to facilitate collaboration and coordination in animal research activities. The MOU outlined areas of mutual interest, such as the exchange of scientific information, resources, and expertise related to biomedical research involving non-human animals.

The HIPPAA Privacy Rule, originally issued in 2000, was modified in 2002. The Privacy Rule addresses uses and disclosures of private health information (PHI) for research purposes.

The Secretary's Advisory Committee on Human Research Protection (SACHRP) replaces the NHRPAC. SACHRP is charged with providing advice to the DHHS on matters relating to the responsible conduct of research involving human subjects. This includes research issues involving special populations, such as children, neonates, prisoners and the decisionally impaired; pregnant women, embryos and fetuses; individuals and populations in international studies; populations in which there are individually identifiable samples, data or information; and investigator conflicts of interest.

The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) was an early example of comparative effectiveness research (CER) to determine the optimum oxygen therapy protocol for premature infants. The National Institutes of Health (NIH)-sponsored multicenter trial randomly assigned approximately 1,300 premature infants to either a low or high oxygen treatment protocols. Considerable controversy about this study has been raised, focusing on several issues. OHRP found that the parents in the study were insufficiently informed of the risks involved, a conclusion that has been disputed by some in the medical research community. Other controversial issues include the random assignment of infants to treatment groups, rather than assignment by a physician based on the infants' best interests; and whether there was already sufficient medical knowledge at the time, making a randomized trial inappropriate.

In 2006, the Animal Enterprise Terrorism Act (AETA) was passed by the United States Congress, aiming to address acts of terrorism and violence targeting animal enterprises, including research institutions, agricultural facilities, and businesses involved in animal-related industries. The AETA expanded federal law enforcement's authority to investigate and prosecute individuals engaged in activities that cause economic damage, disruption, or fear to animal enterprises through illegal acts such as vandalism, harassment, or intimidation.

In 2007, the American Veterinary Medical Association (AVMA) released updated guidelines on euthanasia methods for non-human animals, providing evidence-based recommendations and best practices to ensure the humane and ethical euthanasia of non-human animals across various species and settings. The guidelines addressed considerations such as the selection of appropriate euthanasia agents, techniques, and procedures based on species-specific factors, as well as the importance of trained personnel and compassionate care during the euthanasia process.

In 2010, the Guide for the Care and Use of Laboratory Animals, published by the National Research Council (NRC), underwent its eighth edition revision, providing updated standards and recommendations for the housing, care, and use of non-human animals in research, testing, and teaching environments. The revised edition incorporated new scientific knowledge, advancements in animal welfare practices, and changes in regulatory requirements to ensure the continued improvement of animal care and research standards.

The Havasupai tribe settled with Arizona State University (ASU) concerning their claim that blood collected in the 1990s by ASU researchers to study the genetic origins of diabetes among tribal members was used for unrelated projects including studies of schizophrenia, inbreeding, and theories of the tribe's geographical origins that contradict their traditional stories. The Havasupai had consented to the diabetes study, but the other studies were performed without their knowledge or consent.

In 2010, Dr. Susan Reverby, a medical historian, announced her discovery of a syphilis study conducted in Guatemala from 1946 to 1948. In the study, funded by the U.S. government, nearly 700 Guatemalans — prison inmates, mental patients and soldiers — were deliberately infected with venereal diseases in what was meant as an effort to test the effectiveness of penicillin. Representatives of the U.S. government apologized to the government of Guatemala and the survivors and descendants of those infected, calling the experiments "clearly unethical."

Rebecca Skloot publishes The Immortal Life of Henrietta Lacks, a book that describes the short life of Henrietta Lacks, who died in 1951 from cervical cancer at age 31. Her cancer cells were the originators of the HeLa cell line, an incredibly robust line that has contributed to countless scientific advances over the years. Her descendants' realization of their mother's 'immortality' (for which she received no compensation or recognition) is the focus of the book. The book sparked a national dialogue about the ethics of collection and subsequent use of biological tissue for research purposes.

In 2011, DHHS announced an Advanced Notice of Proposed Rulemaking (ANPRM), signaling that the government was considering various ways of enhancing the regulations overseeing research on human subjects.

In 2015, DHHS and fifteen other federal departments and agencies announced proposed revisions to the Common Rule. The Notice of Proposed Rulemaking (NPRM) sought comment on proposals to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators.

The revised Common Rule was published in the Federal Register on January 19, 2017. It implements new steps to reach the goals described in the NPRM.

On January 17, 2018 an Interim Final Rule to delay implementation of the Common Rule was released. Until July 19, 2018, regulated entities are required to comply with the pre-2018 Common Rule with some exceptions, such as incorporating new elements of consent.

The outbreak of the Ebola virus in West Africa killed over 11,000 people across six countries in just under two years. The urgent need to treat the disease led to rapid approval of clinical trials in affected areas, raising novel ethical questions about researching unproven therapies in public health emergencies.

The social media platform Facebook conducted a massive experiment in which the news feeds of over 600,000 Facebook users were manipulated. The experiment found that emotional contagion, a well-characterized phenomenon in offline environments, also occurs online. The study, published by the Proceedings of the National Academy of Sciences in 2014, raised widespread ethical concerns around the ideas of privacy, industry-academic partnerships, and the nature of informed consent.

The 21st Century Cures Act was signed into law, providing broad support for biomedical research and implementing measures to reduce administrative burden. Impacts to human research protections included allowances for waiver or alteration of informed consent for Food and Drug Administration (FDA)-regulated minimal risk studies, and for use of a single IRB for multisite medical device studies, as well as a call for harmonization of FDA regulations and the Common Rule. Provisions to support increased diversity among clinical research subjects, protect vulnerable populations in research, and enhance privacy protections for subjects' sensitive data, were also included.

The National Institutes of Health (NIH) mandated that all multi-site cooperative research funded by NIH must rely upon ethical review and approval conducted by a single IRB of record. The revised Common Rule followed suit and included a requirement for single IRB review of cooperative research to take effect in 2020.