Human Subjects Protection and the IRB Process
|What we have learned from history...|
The following instances of ethical oversights and unethical treatment of human subjects are only a few of the many abuses alleged by some researchers as “necessary” for the advancement of knowledge. Researchers were either oblivious of or unsympathetic to the risks imposed upon study participants. Such risks were rationalized as minor in contrast to the “greater benefit to society.”
World-Events Leading to Human Subject Protections
The need for ethical standards to protect human subjects in research studies was brought to the forefront during World War II. In the name of medicine and science, Nazi doctors and scientists conducted cruel, harmful, and often deadly experiments on prisoners in war camps.
In 1946, after public awareness and uproar, leading members of the German medical hierarchy were indicted before the war crimes tribunal in Nuremberg, Germany. The trial resulted in the conviction of 16 of the 23 physician defendants, seven of whom were sentenced to death. The tribunal condemned the experiments and classified them as “crimes against humanity.” “Permissible Medical Experiments,” the standards used to judge these German doctors, became known as the Nuremberg Code and remain the basis for ethics codes internationally.
The principles of informed consent and minimizing harm are the focus of the Nuremberg Code.
The U.S. Public Health Service was in the process of conducting the Tuskegee syphilis study when the Nuremberg Code was enacted. Even though minimizing harm and informed consent are the guiding principles of the Nuremberg Code, from 1932 1972 Tuskegee researchers intentionally withheld penicillin treatment from approximately 400 black men who were unaware of their positive diagnosis of late latency stage syphilis and did not inform them about the risks involved in doing so. In 1972, Congress commissioned a Syphilis Ad Hoc Study panel to investigate the Tuskegee study. The panel immediately stopped the research and recommended federal regulation of human research.
Medical records revealed that syphilis was the cause of death in at least 16 of the men; however, because physical damage from syphilis varies among individuals and physical effects often mimic other diseases, the actual number of men whose lives were shortened because treatment was withheld remains unknown. What's more, even though the Tuskegee research protocol required a diagnosis of late latent stage syphilis for all participants, a time when the disease cannot be passed on to others, at the end of the study, 22 wives, 17 children, and 2 grandchildren were infected.
In 1972, The Federal government announced it would compensate the men for all medical expenses until their death and for all medical treatment of spouses and children who had contracted syphilis during the years of the study. In 1997, sixty-five years after the U.S. Public Health Service initiated the Tuskegee syphilis experiments, President William Clinton issued a formal apology to study subjects and their families, calling for renewed emphasis on research ethics.
As recently as September 2011, the Presidential Commission for the Study of Bioethical Issues released the results of its investigation into the U.S. Public Health Service Sexually Transmitted Disease (STD) Inoculation Study carried out from 1946 to 1948 in Guatemala, more than a decade after the Tuskegee experiments began. The U.S. Public Health Service Venereal Disease Research Laboratory and the Pan American Sanitary Bureau collaborated with several Guatemalan government agencies to deliberately expose as many as 1,500 Guatemalan prison inmates, psychiatric patients, solders, and commercial sex workers to syphilis, gonorrhea, or chancroid without the subjects' consent. Experimental logs revealed gruesome details of reprehensible research. One terminally ill female patient was infected with gonorrhea in her eyes and elsewhere to observe the impact of an additional infection. The patient died six months later. Medical records of 497 subjects inoculated with infectious syphilis, indicate that 433 (87%) had evidence of syphilis; of these, adequate penicillin therapy was prescribed for 331 (76%). However, completion therapy was documented for only 85 (26%) subjects. Study records indicate that, at minimum, 83 subjects died, although the relationship of death to the study procedures could not accurately be determined from those records. The Presidential Commission concluded that the Guatemalan experiments were unconscionable basic violations of ethics, even by the ethical standards of the time. Ethical violations include deliberate exposure of subjects to known serious health threats, lack of knowledge of and consent to experimental procedures by study subjects, and the use of highly vulnerable populations.
Researchers in both Tuskegee and in Guatemala ignored the guiding principles of the Nuremberg Code. However, what happened during each study is very different. The Tuskegee men had syphilis prior to the study. There is no evidence that the men were injected or exposed to the bacteria that causes syphilis. Subjects in Guatemala were deliberately infected as part of the study protocol. In Tuskegee, the objective was to prohibit treatment for as long as possible. In Guatemala, almost all of the infected subjects were given some treatment, but at least one-third of them were not cured of the disease.
After the Guatemala STD experiments were publicly disclosed, President Barack Obama apologized to Guatemala's President Alvaro Colom. In addition to the apology, the President ordered his Bioethics Commission to oversee the fact-finding investigation of the study in order to provide full information to Guatemalan officials. President Obama also directed the Commission to review current protections in human subjects research to ensure that national and international research standards effectively protect the health and well-being of human subject participants in U.S. government supported research.In the late 1950s, pregnant women in Europe, Canada, and the United States were given thalidomide, an experimental drug prescribed to control nausea. Thalidomide caused severe birth defects in the fetus that resulted in more than 12,000 deformed and limbless infants. Expectant mothers were not informed of the risks associated with thalidomide or that it was an experimental drug. Additionally, patients did not volunteer nor did they give consent to participate in the research. Once again, the Nuremberg principles of informed consent and minimizing harm were not applied to research practice. In response, the Kefauver-Harris Bill was passed in 1962 to ensure greater drug testing safety.
The Kefauver-Harris Bill requires researchers to inform all subjects about potential risks and benefits of experimental drugs and to obtain consent from participants prior to taking part in the study.
Both the Nuremberg Code and Kefauver-Harris Bill established the requirements that all research participants be fully informed about potential risks or harm that may result from taking part in a study and that, based on this information, they voluntarily agree to participate. These requirements did not address the capacity of minors or adults with limited decision-making skills to make an informed decision. To address this issue, the World Medical Association issued the Declaration of Helsinki in 1964, requiring surrogate consent when the participant is incapable of decision-making. Parental consent is required for all youth under the legal age limit. Youth assent is required if a child has the cognitive and emotional maturity to understand the conditions of the research and to decide whether to participate. Parental consent can only overrule the child’s refusal to assent when the research condition is therapeutic.
The Declaration of Helsinki requires surrogate consent for minors and adults who lack cognitive ability or emotional maturity to understand potential risk or harm associated with research participation.
The Evolution of the IRB
While the 1947 Nuremberg Code was the world’s reaction to Nazi war crimes, the 1974 National Research Act (Public Law 93-348) is the response of the United States to the Tuskegee Study of Untreated Syphilis. Once again, informed consent is a fundamental principle on which human subject protection is established.
The National Research Act established the IRB process that requires formal peer review and approval of all Department of Health and Human Services (HHS) research involving human subjects.
The legislation also created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research that, in 1979, issued the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects Research. The IRB process, formalized by the Commission, remains the present-day peer review method to ensure compliance with the basic principles of the Belmont Report.
The ethical principles in the Belmont Report, Respect for Persons, Beneficence, and Justice, are the standards on which current federal laws and regulations governing human subjects research are based and ethical practices of research studies are evaluated.
In 1974, the Department of Health and Human Services instituted formal IRB procedures as part of the regulations for the Protection of Human Subjects of Biomedical Research (Title 45 Code of Federal Regulations (CFR) 46, Subpart A).
Title 45 CFR 46 which was adopted by 17 Federal agencies is known as the Common Rule because the rules are “common” to a wide range of federal departments and agencies conducting human subjects research.
As with all federal departments and agencies that adopted the Common Rule, the Department of Justice regulations (28 CFR 46) are identical to the core regulations in 45 CFR 46, Subpart A. The purpose of these regulations is to ensure that recipients of federal funding for research involving human subjects have appropriate procedures in place to protect such subjects from undue or unnecessary risks. The regulations address protection of privacy and the assurance of confidentiality along with detailed procedures to establish and operate an Institutional Review Board (IRB). The IRB is responsible for determining whether proposed research projects contain adequate protections for the subjects involved. Accordingly, all recipients of federal funds must submit to IRB review and approval for all research about or directly involving human subjects.
The Department of Justice policy to protect human subjects research establishes the essential rules that all juvenile justice professionals must follow when conducting Federally funded research activities.
Proposed Changes to the Common Rule
Since the Common Rule took effect in 1991, the conduct of research has been transformed by a number of contributing factors. Key changes include a marked increase in the volume of federal and industry-sponsored biomedical research, rapid growth and expansion of social science methodologies in areas such as education, sociology, criminology, national security, and social policy, along with the development of sophisticated computer software and database capabilities, the Internet, and mobile technology. In addition, the Food and Drug Administration (FDA) regulations and the HIPAA Privacy Rule also regulate certain types of human subjects research. Human subjects protection requirements of the Common Rule, FDA regulations, and the Privacy Rule sometimes overlap, but sometimes are inconsistent. Investigators and IRBís may have to comply with all, some, or none of these federal requirements, resulting in confusion, frustration, and criticism.
Failures of the current system for protecting human subjects have resulted in fatal outcomes for some human volunteers in clinical trials and government shutdown of research at the universities involved. High profile cases, such as the 1996 death of Nicole Wan at the University of Rochester, the 1999 death of Jesse Gelsinger at the University of Pennsylvania, and the 2001 death of Ellen Roche at Johns Hopkins University were each carried out with insufficient safeguards to adequately minimize risks and protect healthy volunteers.
In response to these events and other inadequacies of the existing safeguards, a variety of government agencies and federal panels as well as behavioral and biomedical scientists and scholars are advocating revisions to the current human subjects protection regulations. A number of critics of the Common Rule, including the National Bioethics Advisory Commission, the Institute of Medicine, and the National Science Foundation, have put forth recommendations and proposed legislative initiatives.
On July 22, 2011, the U.S. Department of Health and Human Services (HHS) announced that the federal government is considering changes to the regulations overseeing research on human subjects. The proposed revisions are based on decades of experience with and critical evaluations of the Common Rule. The changes under consideration focus on issues related to the ethics, safety, and oversight of human research and are designed to strengthen protections for human research subjects.
The Juvenile Justice Professional's Guide to Human Subjects Protection and the IRB Process represents a general framework for integrating Federal human subject protection requirements into juvenile justice practice and research. Federal human subjects protection laws are supplemented by other Federal, state, and local regulations. This guide also reviews relevant youth-related protection regulations in situations related to information sharing.
Please note: For further developments in the proposed revisions to the Common Rule as well as all other specific issues related to the ethics, safety, and oversight of human research, visit http://www.hhs.gov/ohrp/humansubjects/anprm2011page.html
Juvenile justice professionals who are uncertain about their legal responsibilities for human subject protection should seek advice from local legal authorities and from experts at federal, state, and local government offices. Once changes to the Common Rule are finalized, the Juvenile Justice Professional's Guide to Human Subjects Protection and the IRB Process will be updated to incorporate those revisions.
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