The Office for Human Research Protections (OHRP) is a small office within the United States Department of Health and Human Services (DHHS), specifically the Office of the Assistant Secretary for Health in the Office of the Secretary of DHHS, that deals with ethical oversights in clinical research conducted by the Department, mostly through the National Institutes of Health (NIH).
The United States of America (USA), commonly known as the United States or America, is a country comprising 50 states, a federal district, five major self-governing territories, and various possessions. At 3.8 million square miles, the United States is the world's third or fourth largest country by total area and is slightly smaller than the entire continent of Europe's 3.9 million square miles. With a population of over 327 million people, the U.S. is the third most populous country. The capital is Washington, D.C., and the largest city by population is New York City. Forty-eight states and the capital's federal district are contiguous in North America between Canada and Mexico. The State of Alaska is in the northwest corner of North America, bordered by Canada to the east and across the Bering Strait from Russia to the west. The State of Hawaii is an archipelago in the mid-Pacific Ocean. The U.S. territories are scattered about the Pacific Ocean and the Caribbean Sea, stretching across nine official time zones. The extremely diverse geography, climate, and wildlife of the United States make it one of the world's 17 megadiverse countries.
Clinical research is a branch of healthcare science that determines the safety and effectiveness (efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease. Clinical research is different from clinical practice. In clinical practice established treatments are used, while in clinical research evidence is collected to establish a treatment.
The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1870s and is now part of the United States Department of Health and Human Services. The majority of NIH facilities are located in Bethesda, Maryland. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program.
The office's primary duty is the implementation of 45 C.F.R. 46 , a set of regulations for Institutional Review Boards (IRB) that mirrors the U.S. Food and Drug Administration (FDA) regulation that covers clinical research conducted by pharmaceutical companies as well as other regulations under the guidance of the Federal Policy for the Protection of Human Subjects, which is also known as the "Common Rule".
CFR Title 45 - Public Welfare is one of fifty titles comprising the United States Code of Federal Regulations (CFR). Title 45 is the principle set of rules and regulations issued by federal agencies of the United States regarding public welfare. It is available in digital and printed form, and can be referenced online using the Electronic Code of Federal Regulations (e-CFR).
The Common Rule is a 1981 rule of ethics in the United States regarding biomedical and behavioral research involving human subjects. It governed Institutional Review Boards for oversight of human research and followed the 1975 revision of the Declaration of Helsinki; it is encapsulated in the 1991 revision to the U.S. Department of Health and Human Services Title 45 CFR 46 Subparts A, B, C and D. Subpart A. The Common Rule is the baseline standard of ethics by which any government-funded research in the US is held; nearly all U.S. academic institutions hold their researchers to these statements of rights regardless of funding.
Institutions that conduct DHHS-sponsored research must have a "Federal-Wide Assurance" (FWA), an agreement with OHRP regarding ethical oversight. OHRP also provides education for IRBs, gives guidance on research ethics, and advises the HHS Secretary on issues of medical ethics.
Medical ethics is a system of moral principles that apply values to the practice of clinical medicine and in scientific research. Medical ethics is based on a set of values that professionals can refer to in the case of any confusion or conflict. These values include the respect for autonomy, non-maleficence, beneficence, and justice. Such tenets may allow doctors, care providers, and families to create a treatment plan and work towards the same common goal. It is important to note that these four values are not ranked in order of importance or relevance and that they all encompass values pertaining to medical ethics. However, a conflict may arise leading to the need for hierarchy in an ethical system, such that some moral elements overrule others with the purpose of applying the best moral judgement to a difficult medical situation.
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Unethical human experimentation in the United States has been practiced in the United States for a long time prior to creation of the OHRP.[ citation needed ] A major characteristic of experimentation done during this time was the disregard for suffering inflicted on patients. In the 1840s, J. Marion Sims performed hundreds of surgical operations on enslaved African women without using anesthesia. Robert Bartholow applied electric currents into the exposed brain matter of patients. One egregious example was in 1874 when a lady came in for treatment of a cancerous ulcer on her skull that made a 2-inch hole. Bartholow inserted electrodes into her brain and caused her great distress. The lady went into a coma and died 4 days later. Another theme of human experimentation in the 19th and early 20th century was the unjust treatment of ethnic minority patients. At the turn of the 20th century, US Army doctors infected 34 Filipino prisoners with bubonic plague and beriberi. Between 1932 and 1972, the Tuskegee syphilis experiment observed the natural progression of syphilis in 600 African American males (399 of which had syphilis and 201 control subjects who did not have syphilis). In exchange for their participation, the men were promised free medical exams, hot meals and a burial fund. The men were never told that they had syphilis nor were they provided treatment when penicillin became available as an effective cure in 1947. By the end of the study in 1972, only 74 of the test subjects were alive. Of the original 399 men with syphilis, 28 had died of the disease, 100 had died of syphilis-related complications. Additionally, 40 wives had been infected and 19 children had been born with congenital syphilis. A common misconception of the Tuskegee Syphilis Experiment is that subjects were injected with syphilis.
Unethical human experimentation in the United States describes numerous experiments performed on human test subjects in the United States that have been considered unethical, and were often performed illegally, without the knowledge, consent, or informed consent of the test subjects. Such tests have occurred throughout American history, but particularly in the 20th century. The experiments include: the exposure of humans to many chemical and biological weapons, human radiation experiments, injection of toxic and radioactive chemicals, surgical experiments, interrogation and torture experiments, tests involving mind-altering substances, and a wide variety of others. Many of these tests were performed on children, the sick, and mentally disabled individuals, often under the guise of "medical treatment". In many of the studies, a large portion of the subjects were poor, racial minorities, or prisoners.
James Marion Sims was an American physician and a pioneer in the field of surgery, known as the "father of modern gynecology". His most significant work was the development of a surgical technique for the repair of vesicovaginal fistula, a severe complication of obstructed childbirth. He is also remembered for inventing Sims' speculum, Sims' sigmoid catheter, and the Sims' position. However, "one would be hard pressed to find a more controversial figure in the history of medicine."
Before the founding of the OHRP, the United States went through several precursory entities whose goals were to handle ethics in human experimentation. Many were transitory committees that lasted no more than a year or two, such as the Advisory Committee on Human Radiation Experiments and the Ethics Advisory Board.One of the early and longstanding groups concerned with experimental subject safety was the American Psychological Association (APA), who first published their “Ethical standards of psychologists” in 1953. The APA has since published many versions of their Ethics Code and currently operate under the code passed in 2002 The National Research Act then established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was the first national commission whose entire focus was the protection of experimental subjects. In 1978, the Food and Drug Administration added their first regulations protecting human research subjects, which were revised in 1981. The National Bioethics Advisory Commission was signed into existence by President Bill Clinton in October 1995 and was terminated in October 2001.
The Advisory Committee on Human Radiation Experiments was established in 1994 to investigate questions of the record of the United States government with respect to human radiation experiments. The special committee was created by President Bill Clinton in Executive Order 12891, issued January 15, 1994. Ruth Faden of The Johns Hopkins Berman Institute of Bioethics chaired the committee.
The American Psychological Association (APA) is the largest scientific and professional organization of psychologists in the United States, with around 118,000 members including scientists, educators, clinicians, consultants, and students. The APA has an annual budget of around $115m. There are 54 divisions of the APA—interest groups covering different subspecialties of psychology or topical areas.
The National Research Act was enacted by the 93rd United States Congress and signed into law by President Richard Nixon on July 12, 1974 after a series of congressional hearings on human-subjects research, directed by Senator Edward Kennedy. The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to develop guidelines for human subject research and to oversee and regulate the use of human experimentation in medicine. The National Research Act issued Title 45, Part 46 of the Code of Federal Regulations: Protection of Human Subjects. The National Research Act is overseen by the Office of Human Research Protections. The Act also formalized a regulated IRB process through local institutional review boards, also overseen by the Office of Human Research Protections.
On June 13, 2000, the United States Secretary of Health and Human Services, Donna Shalala created the OHRP as a component of the Office of Public Health and Science, with the main function of overseeing research done on human test subjects and ensuring its compliance with regulations set forth by the US Department of Health and Human Services.The OHRP replaced the Office for Protection from Research Risks, and Greg Koski was named as the first director. The director of the OHRP was to report to the United States Assistant Secretary for Health under the Department of Health and Human Services (then David Satcher).
The United States Secretary of Health and Human Services is the head of the United States Department of Health and Human Services, concerned with health matters. The Secretary is a member of the President's Cabinet. The office was formerly Secretary of Health, Education, and Welfare.
Donna Edna Shalala is an American politician who is currently the U.S. Representative for Florida's 27th congressional district, which includes just over half of Miami as well as many of its eastern suburbs. She previously served as the United States Secretary of Health and Human Services under President Bill Clinton from 1993 to 2001. She was the president of the University of Miami, a private university in Coral Gables, Florida, from 2001 through 2015. Previously she was the chancellor of the University of Wisconsin–Madison from 1988 to 1993. Shalala served as Trustee Professor of Political Science and Health Policy at the University of Miami, and was President of the Clinton Foundation from 2015 to March 2017. Shalala was elected to the U.S. House of Representatives in November 2018.
Since its founding, the OHRP has interfered in several cases involving human subject research experiments in which violations were made to the health and rights of the participants, as well as the regulations put in place for human research. In 2001, the OHRP temporarily suspended the research license of Johns Hopkins University and its associated research facilities following the death of a participant in a hexamethonium inhalation experiment.The experiment was found to be violating regulations in that the researchers failed to inform the participants of the possible dangers of hexamethonium as well as obtain proper information on the effect of hexamethonium prior to experimentation. In another case that occurred in 2013, the OHRP challenged the practice of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT), a research project in which 1300 premature infants were used as subjects to test the optimum levels of oxygenation to be used for proper care of premature infants in hospitals. This experiment was determined to be in violation of federal regulations in that the parents of these infants were not informed of the possible effects of the experiment on their child, which included blindness or death, and were therefore unable to give informed consent.
As a leader in the DHHS, the Office of the Director oversees all functions of the OHRP and works closely with DHHS officials including the Secretary of Health and Human Services and the Assistant Secretary for Health to ensure that human research policies, plans, and procedures meet ethical standards. The committees that fall under the Office of the Director include International Activities and the Secretary’s Advisory Committee on Human Research Protections (SACHRP).
A committee within the Office of the Director, the SACHRP consists of mainly researchers and lawyers who aid the Secretary of Health and Human Services with their expert advice. The Assistant Secretary for Health acts as a middleman presenting the committee's advice to the Secretary for consideration. In addition, the SACHRP also holds three annual meetings which are open for public audience and questions.
This committee works to enhance ethical policies and procedures that protect human research subjects around the world. These global efforts ensure that the people who participate in any research funded and or conducted by the DHHS are given protection equal to those participating in the United States.
The Division of Compliance Oversight is in charge of evaluating substantive noncompliance reports based on the Health and Human Services (HHS) regulations. Based on written investigation reports, the office determines whether regulatory actions will be needed to protect the human research subjects. Both for-cause compliance and not-for cause surveillance evaluations are conducted.
The DED is responsible for much of OHRP's publicity. Its tasks include hosting events, advising researchers involved in affiliated experiments, and propagating educational materials about human research subject protections. Education materials are also presented online via the official OHRP website.
Division of Policy and Assurances prepares the policies, guidelines, and requirements for human subject protection and provides the information to the research community. It is also in charge of the administration of the Federal-wide Assurances of Compliance and registration of institutional review boards.
The Office for Human Research Protections adheres to the principles of the Belmont Report in order to carry out its responsibilities. The Belmont Report is a set of guidelines created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.Intended to serve as ethical parameters for those conducting research involving human subjects, the Belmont Report has three main aspects: boundaries between practice and research, basic ethical principles, and application of these principles.
There is major difference between regulations for practice of approved procedures and research. As such, the Belmont Report defines each term in order to help determine what constitutes as what. Practice is defined as an established methodology designed to improve an individual’s condition with confidence for success.Research is defined as a procedure designed to test a hypothesis and draw conclusions in an experimental style. The OHRP only reviews activity categorized as research.
The three basic ethical principles outlined in the Belmont Report are respect for persons, beneficence, and justice.Respect for persons incorporates emphasis on the subjects and their autonomy, meaning their ability to make decisions in the research. To have autonomy, subjects must give informed consent. This means they must be mature enough to and mentally capable of self-determination, must fully understand their role in the procedures, and must be completely voluntary to participate. Beneficence requires that the research have intentions to produce benefits, or potential for benefits, for the individual or others with similar conditions that outweigh any risk that may be involved. Justice delineates a need for fair distribution in the selection of subjects, meaning bias in participants is minimized. Participant cannot be all from a vulnerable or easily accessible population without violating the justice principle.
Subpart A, or more commonly known as the “Common Rule”, of the 45 C.F.R. 46 is the fundamental guidelines for ethics of all human research. Any establishment that wants to do research involving humans must submit a document that states they will comply with this policy and all pertinent policies to the federal department or agency with authority. The IRB must initially review and approve the research and in the case the study is approved, the IRB will then continue to monitor the research. If at any point the research does not follow the guidelines approved by the IRB, then the IRB has the authority to suspend or terminate the research. The department or agency in charge also has the power to suspend the research. During the course of the study, the IRB must document all meetings and activities.
The guidelines that a research study must follow before being approved involves: informed consent of the subjects, minimal risk to the subjects, and no abuse of “vulnerable subjects”.Informed consent must include all aspects of the research which include the overall premise, risks, benefits, alternative procedures, confidentiality, and any compensations that may be available. The subject must officially state that they voluntary choose to participate in the experiment under all the circumstances provided by the establishment. This informed consent is documented by the IRB and signed by the test subject.
The U.S. Department of Health & Human Services sets required conditions for any research is done on pregnant women or fetuses.
For research on pregnant women and fetuses, condition topics include preclinical risk studies, minimizing risk, no money (or other benefits) given to terminate pregnancy, direct potential benefit to pregnant women and fetuses (otherwise special consent provisions are required), pregnant children (requires special consent provisions), and research participants inability to choose neither how a pregnancy is terminated nor if a neonate (an infant under 4 weeks old) is viable.
For research specifically on neonates, regulations differ based on whether the infant has certain viability, certain unviability, or uncertain viability. For uncertain viability, research must maximize the probability of viability and abide by parental consent provisions. For non-viable neonates, the research cannot terminate heartbeat or respiration, nor can they artificially maintain vital functions; there can be no risk added to the neonate, and parental consent is required. Viable neonates have a consent procedure.
There are also specific conditions for research involving post-delivery placenta, dead fetus, or fetal material. These require studies to comply with federal, state, and local laws. In addition, if individuals from the research can be in any way identified, those individuals are research subjects and must be treated with all necessary legal requirements.
If a study cannot be approved by these conditions but offers great potential for the health of pregnant women, fetuses, or neonates, there is a special process by which The Secretary may or may not approve the study; this process involves consultation with a panel of experts, as well as ethical and consent codes.
The Guidance on Involvement of Prisoners in Research provides protection to prisoners. It is important to note that prisoners can be involved in biomedical or behavioral research if and only if the research is specifically authorized. "Prisoner" is defined by HHS regulations at 45 CFR part 46.303(c) as "any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing." It also applies to the situation where a person becomes a prisoner after the research has started.
The subpart B points out that if a prisoner’s ability of giving consent is affected, i.e., this prisoner’s decision is not truly voluntary and uncoerced, then additional safeguards should be provided for the purpose of safety. In addition, the members of the IRB should (1) generally have no association with the prison(s) involved, and (2) have at least one of them to be a prisoner. In general, the protection for prisoners is similar to the ones for other minority groups, and the research itself should receive permission from OHRP.
In the case of human research, “‘Children’ are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” For the most part, the protections for minors are mostly the same as they are for any other human subject. However, Subpart D of 45 CFR 46 marks several distinctions about obtaining consent/assent and the nature of the research involving children. According to the actual rules of informed consent given by the IRB for the research in question, child assent and parental consent may both be required to conduct research on minors. Depending on IRB regulations, should either party fail to give their assent, then research may not be conducted on the child.
In general, research may only be done on children if it will offer no significant risk to the child. This rule may be circumvented if the child stands to gain a direct benefit to his/her health even if the procedure may have greater than minimal risk. Even if there is no direct benefit to the minor and there may be greater than minimal risk, the IRB may approve the research if generalized knowledge about the subject’s condition or if knowledge pertaining to the health of children may come out of research on the child.
IRB, institutional review board, is a type of committee that reviews human based bio-research. Under 45 C.F.R 46, Each IRB that is designated by an institution must be registered with Office for Human Research Protections(OHRP) of Department of Health and Human Services(HHS).When registering an IRB,the following information must be provided to OHRP: the information of the institution, including its name and mailing address, the personal information of the person in charge of the IRB, the estimated number of active protocols that the IRB has conducted an initial review or is going to conduct a review, and the number of full-time positions of the IRB. All the registration process must be done electronically through the official website of OHRP. After registration, all the information provided will be reviewed by OHRP. The IRB will remain effective for three years after being officially approved and accepted. The information must be renewed for every three years. In addition, should there is any change of the chairperson’s information, an update must be submitted to OHRP within 90 days. If the institution or organization decides to disband a currently operating and functioning IRB, a report must be sent to OHRP within 30 days.
The Tuskegee Study of Untreated Syphilis in the Negro Male was an infamous and unethical clinical study conducted between 1932 and 1972 by the U.S. Public Health Service. The purpose of this study was to observe the natural history of untreated syphilis; the African-American men in the study were told they were receiving free health care from the United States government.
Human subject research is systematic, scientific investigation that can be either interventional or observational and involves human beings as research subjects. Human subject research can be either medical (clinical) research or non-medical research. Systematic investigation incorporates both the collection and analysis of data in order to answer a specific question. Medical human subject research often involves analysis of biological specimens, epidemiological and behavioral studies and medical chart review studies. On the other hand, human subject research in the social sciences often involves surveys which consist of questions to a particular group of people. Survey methodology includes questionnaires, interviews, and focus groups.
The regulation of science refers to use of law, or other ruling, by academic or governmental bodies to allow or restrict science from performing certain practices, or researching certain scientific areas.
An institutional review board (IRB), also known as an independent ethics committee (IEC), ethical review board (ERB), or research ethics board (REB), is a type of committee that applies research ethics by reviewing the methods proposed for research to ensure that they are ethical. Such boards are formally designated to approve, monitor, and review biomedical and behavioral research involving humans. They often conduct some form of risk-benefit analysis in an attempt to determine whether or not research should be conducted. The purpose of the IRB is to assure that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study. Along with developed countries, many developing countries have established national, regional or local Institutional Review Boards in order to safeguard ethical conduct of research concerning both national and international norms, regulations or codes.
The Belmont Report is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Its full title is the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.
An ethics committee is a body responsible for ensuring that medical experimentation and human research are carried out in an ethical manner in accordance with national and international law.
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was the first public national body to shape bioethics policy in the United States.
A Clinical Research Coordinator (CRC) is a person responsible for conducting clinical trials using good clinical practice (GCP) under the auspices of a Principal Investigator (PI).
Public Responsibility in Medicine and Research (PRIM&R) is a 501(c)(3) nonprofit organization based in Boston, Massachusetts. The organization was formed in 1974 by a group of researchers who sought to ensure that the concerns and experiences of those working in biomedical research would be reflected in the growing body of federal regulations governing the field.
In health care, a clinical trial is a comparison test of a medication or other medical treatment, versus a placebo, other medications or devices, or the standard medical treatment for a patient's condition.
Throughout history, prisoners have been frequent participants in scientific, medical and social human subject research. Some of the research involving prisoners has been exploitative and cruel. Many of the modern protections for human subjects evolved in response to the abuses in prisoner research. Research involving prisoners is still conducted today, but prisoners are now one of the most highly protected groups of human subjects
Human subject research legislation in the United States can be traced to the early 20th century. Human subject research in the United States was mostly unregulated until the 20th century, as it was throughout the world, until the establishment of various governmental and professional regulations and codes of ethics. Notable – and in some cases, notorious – human subject experiments performed in the US include the Tuskegee syphilis experiment, human radiation experiments, the Milgram obedience experiment and Stanford prison experiments and Project MKULTRA. With growing public awareness of such experimentation, and the evolution of professional ethical standards, such research became regulated by various legislation, most notably, those that introduced and then empowered the institutional review boards.
The Collaborative Human Tissue Network was established in 1987 by the National Cancer Institute in response to an increase in the demand for high quality biospecimens for cancer research. The purpose of the CHTN is to stimulate, for the good of the public, cooperative efforts to collect and distribute human biospecimens and to thereby facilitate research utilizing those specimens. These activities are expected to encourage basic and developmental studies in many areas of cancer research, including molecular biology, immunology and genetics. The CHTN is not intended to be a human tissue bank, but instead procures tissue at the request of an investigator. Limited banking was to be done as needed to meet specific requests and longer-term banking of targeted specimens to assure availability of rare and hard to obtain materials. It is funded under a UM1 NIH grant.
Various organizations have created guidelines for human subject research for various kinds of research involving human subject research and for various situations.
Respect for persons is the concept that all people deserve the right to fully exercise their autonomy. Showing respect for persons is a system for interaction in which one entity ensures that another has agency to be able to make a choice.
Celia B. Fisher, is an American developmental psychologist. She is the Marie Ward Doty University Chair and Professor of Psychology, and founding director of the Fordham University Center for Ethics Education. In addition, she is currently the director of the Fordham HIV Prevention Research Ethics Training Institute, which provides training on research ethics issues and offers financial support for a mentored research project that will contribute to evidence- based research ethics practices.