DOI: 10.1148/radiol.2363031634
(Radiology 2005;236:748-752.)
© RSNA, 2005
Responsible Conduct of Radiology Research
Part II. Regulatory Requirements 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 900, 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 21, 2004; accepted June 14.
Address correspondence to the author (e-mail: jcooper{at}aahrpp.org).
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ABSTRACT
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The purpose of this series of articles is to explain the ethical and legal basis for responsible conduct of radiology research and the rules that an investigator must follow. In this article (part two of the series), the regulatory requirements to conduct human research are explained. The Food and Drug Administration and Department of Health and Human Services research regulations require two main protections to be in place for the conduct of research involving humans: informed consent and prior review and approval by an institutional review board. Investigators conducting research should know the criteria for institutional review board approval and design their research to meet those criteria. When investigators do not design their research, they should actively work with the sponsor of the research to improve the design in terms of protection of study participants. Investigators should also know the information that must be disclosed when obtaining informed consent and incorporate those requirements into the informed consent process and the documentation of informed consent. Investigators should know about waiver of informed consent and consent documentation and when these situations might be appropriate for their research.
© RSNA, 2005
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INTRODUCTION
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The research regulations of the Food and Drug Administration (FDA) and Department of Health and Human Services (DHHS) require two main protections to be in place for the conduct of research involving humans: informed consent and prior review and approval by an institutional review board (IRB) (1–3). In this article, part two of this series, the criteria for IRB approval of research will be covered, including informed consent and how to prepare for IRB review.
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DEFINITION OF THE IRB
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An IRB is a committee established according to FDA and DHHS regulations. An IRB reviews research and has the authority to approve, require modifications of (to secure approval), or disapprove research (4,5). An IRB also has the authority to suspend or terminate approval of research that has not been conducted in accordance with the requirements of the IRB or that has been associated with unexpected serious harm to participants (6,7). The regulations require IRBs to have at least five members, with at least one member who is not a scientist and one who is not affiliated with the institution where the research is being conducted. Some institutions have their own IRB, while others rely on the IRB of another institution or on an independent review board (8,9).
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CRITERIA FOR IRB APPROVAL OF RESEARCH
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The criteria for IRB approval of research are listed in Figure 1. According to FDA and DHHS regulations, the IRB must determine that research meets all of these criteria before it can be approved (10,11). Investigators can improve the ethical basis for their research by designing studies with these criteria in mind. Investigators can streamline the process of IRB review by providing information to the IRB to show that their research protocol meets these criteria. IRBs can also streamline the process by providing information to investigators to help them design research that meets these criteria.
Minimization of Risks
The first criterion for approval is that risks to participants be minimized. The regulations give two mechanisms to minimize risks. The first mechanism is the use of procedures that are consistent with sound research design and that do not unnecessarily expose participants to risk. The second is the use of procedures already being performed for diagnostic or treatment purposes (10,11).
When imaging research involves noninvasive methods, some investigators incorrectly conclude that risks and discomforts are absent. However, radiologists should consider all possible risks and seek mechanisms to minimize them, including measures that go beyond the standard for clinical care. For example, magnetic resonance (MR) imaging, although noninvasive, can be uncomfortably noisy, and research participants should be provided with and encouraged to use earplugs. However, earplugs should not be used to minimize risk if they interfere with the validity of the scientific design, as might be the case in a functional MR activation study of hearing, where participants need to listen to audio tones through earphones. The use of earplugs would thus interfere with hearing those tones. Similarly, for studies involving exposure to ionizing radiation, radiologists should consider all steps that could be taken to minimize such exposure without jeopardizing the clinical quality of the study. When feasible, radiologists should combine research studies with clinical practice. For example, in a study comparing angiography with a noninvasive imaging procedure, radiologists can minimize risks by enrolling participants who are undergoing angiography for clinical purposes.
Radiologists should understand that informing participants of potential risks does not minimize risk. Radiologists should actively take steps to minimize the risks of their research. For example, merely informing participants that an MR imaging examination might be uncomfortably noisy or that an imaging study will result in exposure to diagnostic radiation does not absolve the radiologist from considering the use of earplugs or reducing radiation exposure.
Risks Reasonable in Relation to Anticipated Benefits and Expected Knowledge
The second criterion for IRB approval is that risks to participants be reasonable in relation both to anticipated benefits, if any, for participants and to the importance of the knowledge that may reasonably be expected to result (10,11). Radiologists should design research that maximizes the likelihood and magnitude of any potential benefits to the individual participants and that maximizes the likelihood that the scientific aims of the research will be achieved. Investigators can often improve their protocol by considering all risks and by implementing procedures that minimize the likelihood and magnitude of each risk. Similarly, investigators can consider all potential benefits and implement procedures that maximize the likelihood and magnitude of each potential benefit. Investigators can also consider issues of scientific design to maximize the likelihood of scientific value from their research. Investigators should consider submission of such a risk–potential benefit analysis to the IRB as part of their application for protocol approval.
Equitable Selection of Participants
The third criterion for IRB approval is that selection of participants (subjects) be equitable (10,11). Research studies should not subject one segment of the population to the burdens of research while another gains the benefits, nor should research unfairly exclude populations. For example, research on special populations such as children, adults who cannot provide informed consent for themselves, prisoners, or the economically disadvantaged should be limited to situations where the knowledge gained from the research will directly affect these populations. In addition, populations should not be arbitrarily excluded from research. For example, women of child-bearing potential should not be arbitrarily excluded from research when the risks can be readily managed with pregnancy testing and prevention.
When evaluating the population of participants to be included, radiologists should consider not only the protocol's inclusion and exclusion criteria but also the recruitment process and economic incentives and disincentives. For example, manufacturers of implantable investigational devices commonly charge the participant the cost of the device. Such a requirement may discriminate against those whose health insurance does not cover the investigational device. Investigators should have written procedures for their recruitment process designed to avoid any discriminatory practices. Investigators should consider submission of their recruitment procedures to the IRB as part of their application for protocol approval.
Informed Consent Obtained
The fourth criterion is that informed consent will be sought from each prospective participant or the participant's legally authorized representative (10,11). Investigators need to keep in mind that informed consent is more than a signature on a form. Informed consent is an ongoing process that requires a continuous assessment by the investigator that the participant understands the options and their consequences and has made an informed and voluntary decision (12). Investigators should follow written policies and procedures for informed consent. Some IRBs require submission of such procedures to determine that the informed consent process will be consistent with local legal requirements, as well as ethically appropriate.
The regulations allow permission from a participant's legally authorized representative (13,14). For example, this process might be used to conduct neuroimaging research in adults with Alzheimer disease. According to the federal regulations, "legally authorized representative" means an individual or judicial or other body authorized according to applicable law to consent on behalf of a prospective participant to take part in the procedure(s) involved in the research (15,16). In many states it can be difficult to determine who is a legally authorized representative. Investigators should get clear guidance from the IRB or from legal counsel. Federal regulators have recently cited investigators for obtaining surrogate permission from someone other than the legally authorized representative (17). In addition, permission from a legally authorized representative should not be obtained unless the IRB expressly authorizes the enrollment of participants with limited decision-making capacity.
When conducting an informed consent process, the regulations require the IRB to ensure that certain information be disclosed to the participant or to the participant's legally authorized representative (10,11). Figure 2 lists the information that must be disclosed to participants (13,14). Figure 3 lists additional information that, when appropriate, must be disclosed with every informed consent process (13,14). Although IRBs usually verify these items by reviewing the consent document, the research team must discuss these items with every potential research participant.
Informed Consent Documented
The fifth criterion for IRB approval is that informed consent be appropriately documented (10,11,18,19). Such documentation is usually achieved with a consent document. The consent document does not substitute for the informed consent process but rather documents the information provided in that process. There has been much recent discussion about the high reading level needed for consent documents. (20). Investigators are strongly encouraged to use the readability tools found in most word processors (20). These tools help investigators reduce the reading level for consent documents by means of reduction of sentence length and word size. With such tools, a sixth- to eighth-grade reading level is readily achievable (20).
Monitoring of Data Collected to Ensure Participant Safety
The sixth criterion for IRB approval is that, when appropriate, the research plan makes adequate provision for monitoring of the data collected to ensure the safety of participants (10,11), sometimes called a data-safety-monitoring plan or DSMP. Investigators should design a safety-monitoring plan whenever a research study has the potential to cause serious adverse events. Such safety monitoring can mean periodic review of adverse events by the investigator, medical monitor, or safety review committee. When the research has a double-blinded design, investigators should consider monitoring by a medical monitor, safety review committee, or a committee independent of the sponsor and the investigator, also known as a data-safety-monitoring board (DSMB).
Provisions to Protect Privacy and Maintain Confidentiality
The seventh criterion for IRB approval is that, when appropriate, there are adequate provisions to protect the privacy of participants and to maintain the confidentiality of data (10,11). Such provisions should be in place whenever in-vestigators collect health information. Researchers can help maintain confidentiality by using coded data and by minimizing the distribution of information that can be readily identified. When the research involves illegal or sensitive behavior, such as neuroimaging in active cocaine users, investigators should strongly consider obtaining a Certificate of Confidentiality (21). A Certificate of Confidentiality is designed to allow investigators to refuse to disclose research data with private identifiable information to a civil or judicial authority, even when the data are requested under the authority of a subpoena.
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ROLE OF THE INVESTIGATOR IN INDUSTRY-SPONSORED RESEARCH
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When conducting industry-sponsored research, investigators should provide input to the designs of the research protocol and of the consent documentation. Sponsors routinely have investigator meetings and respond to input from investigators on protocol changes that help a protocol meet the criteria for IRB review. Such suggestions could include additional monitoring for side effects, alteration of the inclusion and exclusion criteria to exclude populations at high risk or to improve scientific validity, or better methods for image acquisition or analysis.
Investigators should understand that the FDA never dictates specific language to be included in the consent document. Statements by sponsor representatives to the contrary are in error. The FDA does require language to comply with the regulatory requirements for disclosure (Figs 2, 3). However, the FDA defers to the IRB with regard to how that language should be composed. An FDA requirement for verbatim language would be a violation of its own regulations, because it would prevent IRBs from ensuring that the language of the informed consent was understandable to the local population being recruited into the study.
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WAIVER OF INFORMED CONSENT
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Under limited circumstances, DHHS regulations permit an IRB to waive or alter the requirement for informed consent (13). The criteria most relevant to radiology research for such a waiver are listed in Figure 4. These criteria cannot be used when research is subject to FDA regulation, because the FDA regulations have no comparable provisions:
1. The research must be of minimal risk, which is defined in the regulations as meaning that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (15). There is variability in how IRBs interpret the definition of minimal risk. In general, ultrasonography, MR imaging, and blood drawing are considered to present minimal risk in most individuals, although there are exceptions. For example, MR imaging in an individual with a metal implant and blood drawing in a person with severe bleeding diatheses would not represent minimal risks. In general, any procedure involving sedation or moderate radiation exposure would be considered more than minimal risk. The opinion of an IRB may vary with regard to whether conventional radiography constitutes a minimal risk.
2. The waiver of consent must not have any adverse effects on rights and welfare. An evaluation of this should consider whether the waiver would violate any state or federal statute, customary practice, or entitlement.
3. The research could not practicably be carried out without the waiver or alteration. Impracticable does not require that the research would be impossible without the waiver, but it does require something stronger than the research would be difficult to perform. A reasonable definition of impracticable would be that the time and expense that society would have to invest to obtain informed consent would be prohibitive and a potentially poor use of limited resources.
4. Finally, whenever appropriate the participants will be provided with additional pertinent information after participation. This is commonly done in situations where informed consent cannot be obtained at the start of the research but participants can later be informed of the research.
There are several situations in radiology research where a waiver of consent might be considered appropriate by an IRB (Fig 5). Waiver of consent may be appropriate for activities that represent both quality improvement and research. Radiologists often make a prospective decision to follow up certain radiologic findings associated with pathologic or clinical findings. Waiver of consent may be appropriate when prospective identification of the patients who will be followed up is impracticable. Radiologists who study individuals who are unable to provide consent may be in a state where there is no legally authorized representative for medical procedures without direct medical benefit. An example of this would be serial functional MR imaging examinations in patients with dementia. If the procedures are of minimal risk, an IRB can grant a waiver of consent. IRBs and investigators should require permission of another involved adult, such as the next of kin, to minimize the possibility of coercion or undue influence.
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WAIVER OF CONSENT DOCUMENTATION
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Under limited circumstances, the IRB can waive the requirement to document informed consent (18,19). In such situations, the investigator remains obligated to obtain informed consent but is not required to obtain the participant's signature on a written consent document. There are two situations in which an IRB may waive the documentation of informed consent. The most common situation is when the research presents no more than minimal risk of harm to participants and involves no procedures for which written informed consent is normally required outside of the research context. This waiver would typically be used when consent will be obtained by phone. This waiver can be used for research subject to FDA regulations. A second situation is when the only record linking the participant to the research would be the signed consent document and the principal risk is a breach of confidentiality. In such situations, participants must be given the option to sign a written consent document. This situation might arise when imaging data are anonymously collected from patients with acquired immunodeficiency syndrome or who are active drug abusers. This waiver cannot be used for research subject to FDA regulations.
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CONCLUSION
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Research regulations of the FDA and DHHS require two main protections to be in place for the conduct of research involving humans: informed consent and prior review and approval by an IRB (1–3). Investigators conducting research should know the criteria for IRB approval and design their research to meet those criteria to maximize the ethical basis for their research. Even when investigators do not design their research, they should actively work with the sponsor to improve research design in terms of the protection of research participants. Investigators should also know the information that must be disclosed when obtaining informed consent and incorporate those requirements into both their informed consent process and their documentation of informed consent. Investigators should know about waivers of informed consent and of consent documentation and the circumstances in which these situations might be appropriate for their research.
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FOOTNOTES
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Abbreviations: DHHS = Department of Health and Human Services • FDA = Food and Drug Administration • IRB = institutional review board
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References
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- 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).
- Protection of human subjects: IRB review of research. 45 CFR 46.109 (1991).
- IRB review of research: institutional review boards. 21 CFR 56.109 (2002).
- Protection of human subjects: suspension or termination of IRB approval of research. 45 CFR 46.113 (1991).
- Institutional review boards: suspension or termination of IRB approval of research. 21 CFR 56.113 (2002).
- Protection of human subjects: IRB membership. 45 CFR 46.107 (1991).
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- Protection of human subjects: criteria for IRB approval of research. 45 CFR 46.111 (1991).
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- Levine RJ. Informed consent: ethics and regulation of clinical research. 2nd ed. New Haven, Conn: Yale University Press, 1986.
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- Weil CJ. Human research protections under multiple project assurance (MPA) M-115: Office for Human Research Protections—letter to Dr Neal Nathanson, June 10, 2002. Available at: http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jun02b.pdf. Accessed March 14, 2004.
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ABSTRACT
INTRODUCTION
