Published online before print June 21, 2005, 10.1148/radiol.2362031633
(Radiology 2005;236:379-381.)
© RSNA, 2005
Responsible Conduct of Radiology Research
Part I. The Regulatory Framework for Human Research1
Jeffrey A. Cooper, MD, MMM
1 From the Association for the Accreditation of Human Research Protection Programs, 915 15th St NW, Suite 400, Washington, DC 20005-2315, and the Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa. Received October 8, 2003; revision requested December 23; revision received April 19, 2004; accepted September 7.
Address correspondence to the author (e-mail: jcooper{at}aahrpp.org).
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ABSTRACT
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The purpose of the articles in this series is to explain the ethical and legal basis for responsible conduct of radiology research. In the current article, the regulatory framework of human research is explained. There is no overall regulatory process for protecting the rights and welfare of humans participating in research. Instead, legal protections in the United States are an amalgam of regulations from multiple federal and state agencies. The key regulations are from the Department of Health and Human Services, the Food and Drug Administration, and the Federal Privacy Rule of the Health Insurance Portability and Accountability Act. Which of these apply in any situation depends on many factors, including the funding source of the research, the site of the research, and the items being tested. Radiologists conducting human research need to know which regulations apply and how to comply with them. The regulations represent a set of rules based on the ethical principles of respect for persons, beneficence, and justice. Radiologists should understand these ethical principles for situations when the regulations are silent, ambiguous, or incomplete.
© RSNA, 2005
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INTRODUCTION
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During the past 5 years, the regulatory environment for research involving humans has been turbulent, with the federal government (1), academia (2), and the lay press (3) criticizing the current oversight system. Investigators feel as though they face increased scrutiny and new rules every day. Institutions and their institutional review boards feel threatened by lawsuits and government sanctions. Editorial policies of Radiology and other journals require institutional review board approval of research protocols and informed consent of participants before manuscripts are accepted for publication.
How did we get to this state? What are the rules that an investigator needs to follow? The purpose of the first in this series of articles is to explain the answers to these questions and to give guidance to investigators, with an eye to the specific issues that occur in radiologic research.
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THE LEGAL AND ETHICAL BASIS FOR RESPONSIBLE HUMAN RESEARCH
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For the conduct of research to be responsible, it must meet two tests: It must comply with legal requirements, and it must comply with ethical requirements. Because the legal requirements have a basis in ethics, there tends to be a strong concordance between research that is legal and research that is ethical. However, investigators should know both the legal and the ethical requirements, because the legal requirements represent a set of rules for responsible behavior, while the ethical requirements represent a set of principles that can be applied when these rules are silent, ambiguous, or incomplete. Most important, knowledge of ethics can guide investigators to choose a responsible course of action for situations not covered by the law.
The Legal Basis for Responsible Human Research
The legal requirements of research come from an amalgam of regulations. There are two main categories of federal regulations that govern medical research with humans: The Department of Health and Human Services (DHHS) regulations (Title 45 of the Code of Federal Regulations, part 46 [4]) and the Food and Drug Administration (FDA) regulations (Title 21 of the Code of Federal Regulations, parts 50, 56, and others [5,6]). The Federal Privacy Rule regulations from the Health Insurance Portability and Accountability Act (HIPAA) also influence the conduct of human research (7). This article will focus on the DHHS and FDA research regulations. The HIPAA regulations will be discussed in a subsequent article in this series. One or both of these regulations may cover any given research protocol. In addition, there is a body of research not covered by any federal regulations (Fig 1), as will be discussed later.
In the DHHS regulations, research is defined as a systematic investigation designed to yield generalizable knowledge, and a human subject (also referred to in this article as a human participant) is defined as a living individual about whom an investigator conducting research obtains data by means of intervention or interaction with the individual or obtains identifiable private information (8). Note that intervention or interaction with research participants is not required to fulfill the definition of research involving humans. Thus, according to this definition research that uses methods such as chart reviews, interviews, surveys, and databases may be subject to regulation.
The DHHS regulations cover all research with human participants that is conducted, supported, or overseen by DHHS (9), and the regulations are enforced by the Office of Human Research Protections. Other federal agencies that support biomedical research, such as the National Science Foundation, the Department of Defense, the Department of Veterans Affairs, and the National Aeronautics and Space Administration, have adopted regulations that follow the main provisions of DHHS regulations (10).
The adoption of regulations similar to the DHHS regulations by multiple federal agencies is commonly referred to as the Common Rule. Institutions that agree to accept federal funding for human research must sign a document with the government in which they agree to abide by DHHS regulations (11). This document is called a "Federalwide Assurance," previously known as a "Multiple Project Assurance." Through this assurance process, most organizations that receive any federal funding for human research voluntarily agree to apply and allow federal enforcement of the DHHS regulations to all research under their oversight, regardless of the source of funding (12). An assurance must be approved by the Office of Human Research Protections (OHRP) for an organization to receive funding from the National Institutes of Health or other DHHS subunit. So called shutdowns of research occur when OHRP withdraws its approval of an institution's assurance. For practical purposes, radiologists should assume that all research involving humans that is conducted, supported, or overseen by the federal government is subject to the DHHS regulations. Radiologists affiliated with organizations that receive federal funding should check to see whether all research involving humans is subject to the DHHS regulations.
The FDA regulations cover all research with human participants that involves any FDA-regulated item (Figure 2), without regard to sponsorship or purpose (13,14). Although most investigators know that the FDA regulates human research involving unapproved drugs, devices, and biologic products, few understand that the FDA applies its regulations regarding both the protection of human participants in research (Title 21 of the Code of Federal Regulations, part 56) and institutional review boards (Title 21 of the Code of Federal Regulations, part 56) to human research studies of approved drugs and devices (13–16). For example, the FDA has the authority to regulate research on magnetic resonance (MR) imaging of a neurodegenerative disease or doses of an approved contrast agent, even if a drug company does not sponsor the research and the information will not be used for marketing purposes or be submitted to the FDA. The FDA also has the authority to regulate human research on foods for which a health care claim has been made: for example, a research study of the effectiveness of blueberry juice as an MR imaging contrast agent (17).
In general, the FDA has exercised its discretionary authority to limit its regulation to human research involving unapproved drugs, devices, or biologic products or to human research in which data are gathered for submission to the FDA. However, if participants are seriously harmed during research with FDA-approved drugs or devices, the FDA might exercise its full authority. To ensure compliance with the regulations and protection of participants, radiologists should assume that human research studies of any imaging device, contrast agent, or other FDA-regulated item must comply with FDA regulations.
HIPAA covers all research involving the use or disclosure of protected health information by a covered entity (7). Covered entities include all health care organizations except those that do not bill insurance providers. With few exceptions, most radiology research is covered by HIPAA. These exceptions are limited to research performed outside covered entities where there is no overlap of the health care and the research. For example, imaging studies in healthy volunteers performed at manufacturing facilities would not be covered by HIPAA. Research at hospitals that provide only charity care (eg, Shriners Hospitals) is also not covered by HIPAA. Biomedical researchers should generally assume that all research with human participants that they conduct is subject to HIPAA unless advised otherwise.
Occasionally, human research is subject to additional federal, state, or local laws. For example, the Departments of Defense, Energy, Justice, Education, and Veterans Affairs have specific regulations that apply whenever they conduct, fund, or oversee research (10). Radiologists need to be aware of these additional requirements whenever human research is funded by these federal agencies. Some states have laws that provide additional protections to humans participating in research, and radiologists also need to be aware of these laws.
The research regulations are not exhaustive, and there exists a body of research that is not subject to regulation. Research is not subject to any federal regulations if it is conducted by a private organization that is not a health care entity, is not funded by the federal government, and does not involve FDA-regulated items. For example, a nonfunded controlled comparison of two surgical interventions in a private setting conducted without institutional review board approval or informed consent does not violate any federal regulation governing human research (18). However, because the DHHS regulations represent a set of rules that help ensure the ethical conduct of research, radiologists who conduct research not subject to any regulation should voluntarily comply with the DHHS regulations.
The Ethical Basis for Responsible Research
The current ethical basis for research in the United States was first codified in the Report of the National Commission for Subjects of Biomedical and Behavioral Research, commonly referred to as the Belmont Report (19). The Belmont Report serves as the ethical basis for federal regulations governing research with human participants. Researchers should read and be familiar with the Belmont Report, because this report can provide guidance for the responsible conduct of research when regulations are silent or unclear.
The authors of the Belmont Report list three ethical principles: respect for persons, beneficence, and justice (19). Respect for persons requires researchers to treat individuals as autonomous agents and not use people as a means to an end. The principle of respect for persons gives rise to the concepts of informed consent, respect for privacy, and maintenance of confidentiality. Beneficence requires researchers to affirmatively seek what is good for their participants and avoid what is bad. The principle of beneficence gives rise to concepts of minimizing risks, seeking a favorable risk-benefit ratio, and protecting research participants from harm. Justice refers to distributive justice and requires researchers to treat people fairly. The principle of justice gives rise to the concept that one should not take advantage of one group by letting that group take on the risks of research while another group receives the benefits.
Simply having these three ethical principles does not lead to an easy solution to all ethical problems. Instead, the principles form a structure for analysis and decision making. When making ethical decisions, investigators should consider each ethical principle to have moral force; no one principle should automatically discount another. For example, one error that clinical researchers make is to assert that informed consent is unimportant because the benefits of research are so great. This error ignores the moral force of the principle of respect for persons relative to the principle of beneficence. Because the application of the three ethical principles can involve a difficult balance, ethical decisions are delegated to an institutional review board for deliberation, with the assumption that such a committee process is more likely to result in decisions that are morally acceptable to the community than are decisions made by a single person.
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RECENT CHANGES IN THE ETHICAL AND REGULATORY REQUIREMENTS
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The general perception among investigators is that there has been a rapid acceleration in the level of regulation of human research. However, the DHHS and FDA regulations have remained essentially unchanged over the past 2 decades. Instead, the perceived changes are related to increased enforcement actions. In response to several instances of injuries to human research participants and to a DHHS Office of the Inspector General 1998 report that indicated that the research regulatory system was in jeopardy (1), federal regulators dramatically increased their level of enforcement. These enforcement actions uncovered many cases of serious regulatory noncompliance, usually related to misunderstanding and ignorance, and resulted in shutdowns of human research at major academic institutions (2). As a result, many organizations then realized their vulnerability to similar enforcement actions unless they greatly strengthened their programs for regulatory compliance (2).
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CONCLUSION
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The responsible conduct of research involving humans requires compliance with applicable regulations and adherence to ethical principles. The main regulations governing research are the DHHS, FDA, and HIPAA Federal Privacy Rule regulations. The next article in this series will discuss the regulatory requirements of the DHHS and FDA regulations. Radiologists should have both a general understanding of when each regulation applies and a low threshold for seeking guidance. The ethical principles governing research are respect for persons, beneficence, and justice. The regulations are founded on ethical principles. Radiologists should understand these ethical principles and apply them to the conduct of their research at all times, including in circumstances where the regulations are silent, ambiguous, or incomplete.
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FOOTNOTES
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Abbreviations: DHHS = Department of Health and Human Services • FDA = Food and Drug Administration • HIPAA = Health Insurance Portability and Accountability Act
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References
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- Brown JG. Institutional review boards: a time for reform. Report no. OEI-01-97-00193. Washington, DC: Department of Health and Human Services Office of Inspector General, 1998.
- Steinbrook R. Protecting research subject: the crisis at Johns Hopkins. N Engl J Med 2002; 346:716–720. [Published correction appears in N Engl J Med 2002; 346:1678.][Free Full Text]
- Lemonick MD, Goldstein A. At your own risk. Time. April 22, 2002:46–56.
- Protection of human subjects: federal policy for the protection of human subjects. 45 CFR
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- Protection of human subjects. 21 CFR 50 (2002).
- Institutional review boards. 21 CFR 56 (2002).
- Standards for privacy of individually identifiable health information. 21 CFR 160 and 164 (2002).
- Definitions: protection of human subjects—federal policy for the protection of human subjects. 45 CFR 46.102 (1991).
- To what does this policy apply? protection of human subjects: federal policy for the protection of human subjects. 45 CFR 46.101(a) (1991).
- National Bioethics Advisory Commission. The current oversight system: history and description. In: Ethical and policy issues in research involving human participants. Vol I. Report and recommendations of the National Bioethics Advisory Commission. National Bioethics Advisory Commission Web site. http://www.georgetown.edu/research/nrcbl/nbac/human/overvol1.pdf. Accessed May 17, 2005.
- Assuring compliance with this policy: protection of human subjects—federal policy for the protection of human subjects. 45 CFR 46.103 (1991).
- Question 4 of sample domestic FWA application form. Department of Health and Human Services, Offices for Human Research Protections (OHRP) Web site. http://www.hhs.gov/ohrp/humansubjects/assurance/filasur.htm. Accessed May 17, 2005.
- Protection of human subjects: scope. 21 CFR 50.1 (2002).
- Investigational new drug application: applicability. 21 CFR 312.2 (2002).
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- Office of the Secretary. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. 1979. Department of Health and Human Services, Offices for Human Research Protections (OHRP) Web site. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm. Accessed May 17, 2005.
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ABSTRACT
INTRODUCTION
