Toxicological Research Involving Humans: Ethical and Regulatory Considerations

Bernard A. Schwetz*,1, Lois Lehman-McKeeman{dagger} and Linda S. Birnbaum{ddagger}

* Department of Health and Human Services, Office of Public Health and Science, Office for Human Research Protection, Rockville, Maryland 20852; {dagger} Discovery Toxicology, Bristol Myers Squibb Company, Princeton, New Jersey 08543; and {ddagger} U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Research Triangle Park, North Carolina 27709

1 To whom correspondence should be addressed at 1101 Wootton Parkway, Suite 200, Rockville, MD 20852. E-mail: bschwetz{at}osophs.dhhs.gov.

Received March 3, 2005; accepted March 3, 2005


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 APPENDIX 1: RESOURCES
 
This paper discusses the need for the Society of Toxicology (SOT) to develop a policy for ethical research in humans, and a review for publication of these studies. Observations on human beings have been the foundation upon which toxicologic knowledge has been built since the inception of toxicology as a science that developed information on cause-and-effect relationships between exposures to substances and subsequent undesired health effects. Observations by Sir Percival Pott and others in the 1700s were instrumental in creating an understanding between occupational exposures and cancer. In the 20th century, many sources of exposure from the workplace, foods, drugs, and environment were found to contribute to the human disease load based on observations on humans.

During this same span of time, humans came to be the subjects of research in many countries throughout the world in areas of basic and applied research, including both biomedical and social/behavioral studies. The research related to development of new medical products, improved surgical and medical procedures, and enhancements to our knowledge of physiology, biochemistry, pharmacology, behavior, and many other areas of science and medicine. There are numerous examples that involve abuse of humans through failure to disclose the purpose of the studies, failure to inform subjects of risks, coercion, undisclosed personal gain by researchers, unethical intentions of nations, and many other situations that are frequently cited as atrocities committed against humans.

Research conducted on humans by Nazi physicians during World War II led to the formulation of a code for human subjects research known as the Nuremberg Code (1947). While not enforceable as law, the Code and later the Declaration of Helsinki (1964, latest revision in 2004) provided the first international guidelines for the ethical treatment of human subjects in research.

Unethical research continued, however, as U.S. researchers tested the effects of radiation on hospital patients, children, and soldiers without obtaining consent or permission. In a study widely known as the Tuskegee syphilis study, conducted by the U.S. Public Health Service on African American males, the course of the untreated disease was tracked over several decades, well after antibiotics were discovered that were effective in treating the disease. Several unethical studies involved children, such as one conducted at New York's Willowbrook State School (1956 to 1972) where researchers infected children with a mild form of hepatitis to study the natural history and prevention of viral hepatitis.

These and many other studies raised questions about the ethics of involving humans as subjects of research. As a result, Congress created a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974. Over the next four years, the National Commission issued several reports, including the report widely know as the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects. These reports eventually became the basis of U.S. regulations for the protection of humans involved in research, including vulnerable groups of subjects such as pregnant women, fetuses, neonates, children, and prisoners. In 1991, many federal agencies that conduct or support research involving human subjects adopted the Federal Policy for the Protection of Human Subjects, known as the "Common Rule" (45 CFR 46, Subpart A). Additional regulations and numerous guidances have been issued since then, providing a foundation for protections of human subjects of domestic and international research. The authority for enforcing the regulations of the Department of Health and Human Services (DHHS) for protection of human subjects involved in research conducted or supported by HHS has been delegated to the Office for Human Research Protections (OHRP) within the Office of Public Health and Science, Office of the Secretary, DHHS.

Research that is conducted or supported by agencies outside of HHS may also come under the purview of the HHS regulations if the institution conducting the research has agreed to comply with the HHS regulations, regardless of the source of funding, through the required Federal Wide Assurance, Multiple Project Assurance, or other assurance agreement. Having an assurance agreement with OHRP is a condition of receiving HHS funds for research involving humans. Thus, research involving humans may be unregulated, one extreme, may be regulated by the funding agency, such as HHS, or may be regulated by multiple agencies in the other extreme.


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 INTRODUCTION
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 APPENDIX 1: RESOURCES
 
The SOT has a history of ethics policies and positions dating back several decades. The Society adopted the SOT Code of Ethics on January 31, 1985. Adherence to the code is a condition of membership in the Society, assuring that each member is personally committed to a high standard of ethics. The SOT has been aggressively involved in issues that relate to the ethical use of laboratory animals in research. The Animals in Research Committee was formed in 1982 as a standing committee of the Society. The Committee focuses on the effective and humane use of animals in research, as well as the development of valid alternatives to animal testing.

The SOT has also posted several position statements on its Web site, www.toxicology.org. "Use of Animals in Toxicology" was added to the Web site in January, 1986. Two additional statements were posted in March, 1999: "Animals in Research Public Policy Statement" and "Guiding Principles in the Use of Animals in Toxicology."


    HUMAN RESEARCH POLICIES
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Until this year, there has been no specific policy of the Society on the ethics of research conducted on human subjects. It is timely for the Society to now have positions on the ethical considerations for members who conduct research involving humans, and to have a policy for publication of reports of research on human subjects. Such policies have now been developed and approved by the Council and Board of Publications of the Society. These are available at http://www.toxicology.org/Information/generalpublic/public.html.

The vulnerability of medical journals from publication of study or trial results that could subsequently be found to involve some unethical practice has driven those journals to require authors to certify that they have complied with all applicable regulations. Because any journal of the SOT is similarly vulnerable, it is appropriate that the Society has now expanded the instructions for authors to cover studies that involve research in humans.

What are the regulatory authorities of federal agencies to oversee protection of human subjects of research, and how do they relate to the new policies of the SOT? As mentioned earlier, many federal agencies have adopted the "Common Rule." The codification for each agency is shown in Table 1. While all of these agencies/departments have adopted Subpart A, the part of the regulation known as the "Common Rule," not all agencies/departments have adopted the other subparts: Subpart B—Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research, Subpart C—Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects, and Subpart D—Additional Protections for Children Involved as Subjects in Research.


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TABLE 1 Code of Federal Regulations References for Departments and Agencies That Have Adopted the Common Rule

 
Certain aspects of Subpart A are most relevant to the new SOT ethics policy on research involving humans. Investigators who are contemplating a study involving humans but are uncertain whether or not the protocol must be reviewed by an Institutional Review Board (IRB) sometimes have trouble answering two basic questions: Does the study meet the definition of research? Does the study involve humans? The answer is sometimes less obvious than it would seem to most people. To get assistance with the definitions and a decision tree to determine whether the regulations apply, readers are referred to the OHRP website at www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm. The charts are useful to determine whether the activity is research that must be reviewed by an IRB, whether the review may be performed by expedited procedures, and whether informed consent or its documentation may be waived.

If the activity under consideration is research, is research involving humans, and is not exempt, the regulations apply. The protocol must be reviewed and approved by an IRB; the IRB composition and procedures are defined by the regulations, as are the requirements for informed consent and annual continuing review.


    CONCLUSIONS ON A SOT POLICY FOR HUMAN RESEARCH
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 INTRODUCTION
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 APPENDIX 1: RESOURCES
 
The SOT has recognized the importance of having a policy to assure that manuscripts published in journals of the Society that report results of research studies involving humans must be accompanied by certification by the authors that the protocol for the research was reviewed and approved by an appropriately constituted IRB and that all applicable regulations (federal, state, and local) were followed. Compliance with the policy for involvement of humans in research is a requirement for compliance with the ethics policy of the Society. Compliance with the ethics policy is a condition of membership in the SOT.

The toxicology community has long recognized that observations in humans are a critical part of the knowledge base of the field of toxicology. As with research involving various species of laboratory animals, research studies and clinical trials involving humans as subjects are critical to new product development, development of new medical and clinical procedures, as well as new occupational and environmental standards of exposure. Public trust is a requisite for continuation of the right to conduct research in the future that involves laboratory animals or humans. Unethical behavior of any member of the SOT or by authors of papers published in a journal of the Society could seriously jeopardize the credibility of toxicologists and the SOT and thereby undermine the trust of the public in this field of science. A human research policy will go a long way in helping to prevent unethical behavior in research by members of the SOT.

Disclaimer: The views represented here are those of the authors and are not intended to represent those of the Department of Health and Human Services. The information in this document has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency.


    APPENDIX 1: RESOURCES
 TOP
 INTRODUCTION
 SOT INVOLVEMENT IN HUMAN...
 HUMAN RESEARCH POLICIES
 CONCLUSIONS ON A SOT...
 APPENDIX 1: RESOURCES
 
Policies, Reports, and Policy Statements
Directives for Human Experimentation: Nuremberg Code (1949). http://ohsr.od.nih.gov/guidelines/nuremberg.html.

Federal Policy for the Protection of Human Subjects, 45 CFR 46, Subpart A (2001). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

National Institutes of Health (1995). Guidelines for the Conduct of Research Involving Human Subjects at the National Institutes of Health. http://www.nihtraining.com/ohsrsite/guidelines/graybook.html.

National Institutes of Health (2000). Required Education in the Protection of Human Research Participants. http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, DHHS, Washington, DC. http://ohsr.od.nih.gov/guidelines/belmont.html.

World Medical Association. (1964, 2002). Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. World Medical Association, Helsinki, Finland. http://www.wma.net/e/policy/b3.htm.

General Information Web Sites
National Institutes of Health (2000). Standards for Clinical Research within the NIH Intramural Research Program. http://www.cc.nih.gov/ccc/clinicalresearch/.

National Institutes of Health (2003). Bioethics Resources on the Web. http://www.nih.gov/sigs/bioethics/.

National Institutes of Health (no date). OHSR—Office of Human Subjects Research. http://206.102.88.10/ohsrsite/.

Office for Human Research Protections, U.S. Department of Health and Human Services (no date). HHS—Office for Human Research Protections. http://www.hhs.gov/ohrp/.

U.S. Food and Drug Administration (1998). Guidance for Institutional Review Boards and Clinical Investigators: 1998 Update. http://www.fda.gov/oc/ohrt/irbs/default.htm.





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