DOI: 10.1148/radiol.2371031636
(Radiology 2005;237:3-7.)
© RSNA, 2005
Responsible Conduct of Radiology Research
Part III. Exemptions from 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 January 5, 2004; revision received May 6; accepted June 14.
Address correspondence to the author (e-mail: jcooper{at}aahrpp.org).
 |
ABSTRACT
|
|---|
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 needs to follow. In this article (part three of the series), the situations in which human research in radiology is exempt from regulatory requirements are explained. There are several situations in which an activity falls under the regulatory definition of research but is exempt from the research regulations. Investigators who conduct exempt research should know the regulatory criteria for the exemptions. In the case of research that is potentially exempt from the Department of Health and Human Services regulations, the institutional review board or an authority other than the investigator should make the determination of whether a proposed research activity is exempt from the regulations. For research exempt from Food and Drug Administration regulations, investigators should follow institutional guidance and seek input from the institutional review board or Food and Drug Administration for questionable cases.
© RSNA, 2005
|
INTRODUCTION
|
|---|
As discussed in part two of this series (1), 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) (2–4). In select circumstances, IRB review and approval are not required. The purpose of this article, part three of this series, is to explain the situations in which independent review is not required and how to comply with those situations.
|
SITUATIONS IN WHICH IRB REVIEW IS NOT REQUIRED UNDER DHHS REGULATIONS
|
|---|
There are two situations in which IRB review is not required according to the DHHS regulations. The first situation is when the activity does not represent human research (5), and the other situation is when human research falls into a category that is exempt from the DHHS regulations (6).
Activities That Are Not Human Research
The DHHS regulations define research as "a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge" (5). The regulations further define a human participant as "a living individual about whom an investigator ... conducting research obtains 1. data through intervention or interaction with the individual, or 2. identifiable private information" (5). Intervention and interaction may be distinct. For example, randomization is an intervention that does not require interaction. To be subject to DHHS regulations an activity must be research and must involve humans as participants (5).
The definition of research involving humans has been subject to debate (7,8). For example, people have debated whether case reports of a single individual represent research or whether certain quality improvement and peer review activities represent research according to the regulatory definition. Many people consider the intent of the person conducting the activity. Others look at the potential for publication of findings or the novel nature of an activity. The presence or absence of a human participant may or may not be clear. According to the DHHS regulations, cadavers are not human participants because they are not living individuals (5). Research conducted with commercial human cell lines does not involve human participants because there is no interaction or intervention with humans and there is no private identifiable information (5). In other cases, the presence of human participants may be subtle. For example, a survey of department chairs about the performance of individual radiology residents may make those residents human participants of research, depending on the nature of the survey questions.
Radiologists should have a very low threshold for obtaining a written determination from an IRB as to whether an activity represents human research before proceeding with the activity in the absence of IRB review. Radiologists should seek such guidance at the time that they first consider conducting research or publishing findings. This guidance is especially important for quality improvement and peer review activities that may start out as nonresearch but, because of the discovery of generalizable knowledge, may result in publishable findings. There are several advantages to obtaining an independent decision. First, IRBs have more familiarity with the regulations and their interpretation and are therefore more likely to make a correct determination. Second, because some decisions about some activities may be controversial, and investigators have an inherent conflict of interest, IRBs are in a better position to defend controversial decisions than are investigators. Third, journals such as Radiology may require a statement in the text of an article regarding IRB approval and informed consent as a condition of publication.
Human Research That is Exempt from DHHS Regulations
There are six situations in which research involves humans but is not subject to the DHHS regulations. These are listed in Figure 1. The three exemption categories likely to apply to radiology research are categories 1, 2, and 4.
Exemption category 4 is applicable to some radiology research. This category applies to record reviews, image reviews, and research on existing pathology data. There are two important conditions for this exemption category (6). First, the data, documents, or specimens must exist, that is, be "on the shelf," at the time the research is proposed. Thus, research involving the prospective collection of clinical data or the prospective review of pathologic specimens cannot be placed in this category. Second, the data recorded by the investigator must be anonymous. Anonymous data is denoted by the phrase "recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects." In addition to the obvious identifiers of name or social security number, identifiers would include medical record numbers, student identification numbers, and in some cases dates of birth. In a small population of residents, month of birth would likely be a unique identifier. In some populations, the combination of two or more data items represents identifiers. For example, a date of admission, diagnosis, and zip code can readily be used to identify patients in most hospitals. The term "identifiers linked to the subjects" refers to a coded dataset where surveys are coded with a unique identifier, and the research personnel keep a database that links the code to identifying information. If there is a way for investigators to identify participants through such databases, then the exemption category 4 cannot be applied. When authors publish research data that fall under exemption category 4, they should clearly point out in the methods section of the article that the study was a retrospective review of existing data. Misrepresentation of such research as a prospective evaluation may be considered scientific misconduct.
Exemption category 2 is applicable to some radiology research. This category applies to educational tests, survey procedures, interview procedures, or observation of public behavior (6). Most often in radiology this applies to survey research. When disclosure of the collected data outside the research reasonably places participants at risk of criminal or civil liability or damage to their financial standing, employability, or reputation, then the data must be recorded anonymously (6). Examples of such data would include information about illegal behavior (eg, marijuana use) or unethical behavior (eg, cheating).
Exemption category 1 deals with research in established or commonly accepted educational settings that involves normal educational practices and might occasionally be used for radiology research. This category would cover research on typical training programs for medical students, residents, and fellows that are conducted in the usual hospital or imaging center settings. This category would also cover patient education in typical settings, such as research on postangiography care instructions. Research on atypical training or education methods or research on training or education that takes place outside the usual setting would not be covered.
Technically, research projects that fall under one of the categories that are exempt from the DHHS regulations do not require any prior review. However, the Office of Human Research Protections or OHRP, which enforces the DHHS regulations, recommends that institutions adopt procedures by which the IRB or an authority other than the investigator determines whether proposed research is exempt from the human subjects regulations (9). Before proceeding with an exempt research activity, radiologists should always obtain a determination by an IRB or other independent review entity.
|
HUMAN RESEARCH THAT IS EXEMPT FROM FDA REGULATIONS
|
|---|
The FDA regulations apply whenever research is conducted with an FDA-regulated item. Most important, research that may be exempt from the DHHS regulations may still be subject to IRB review because the research remains subject to the FDA regulations.
There are four situations in which human research conducted with an FDA-regulated item is not subject to the FDA regulations (10). These situations are listed in Figure 2. The exemption category most likely to apply to radiology research is category 3—the emergency use of a test article.
The use of any unapproved FDA-regulated drug, device, or biologic product is considered to be a research study that is subject to FDA regulations. However, the FDA recognizes that occasionally patients are in life-threatening situations in which the only treatment available is an investigational drug or device, and waiting for IRB review would put patients' lives in danger. In this situation, physicians are allowed a one-time exemption from the requirement of obtaining IRB review. This situation is often referred to as "emergency use of a test article" (11–13). In radiology, this situation most often arises with invasive therapeutic procedures. An example would be the use of an unapproved intravascular stent (where "unapproved" means not FDA-approved for any indication) when there are no approved stents that have a reasonable chance of success.
Radiologists commonly need to use an approved drug or device in an unapproved manner. The regulations regarding emergency use of a test article do not apply to the use of an approved drug or device for an indication that is not contained in the approved labeling ("off-label use") (14). More information on "off-label use" will be presented in part four of this article series.
There are several criteria that must be met for the emergency use of a test article without IRB review (10–13). These criteria are listed in Figure 3. "Life-threatening" means that the likelihood of death is high unless the course of the disease is interrupted or that the disease has a potentially fatal outcome. The situation does not need to be immediately life-threatening or to immediately result in death. Rather, the participant must be in a life-threatening situation that requires intervention before review at a convened IRB meeting is feasible (12,13). "Severely debilitating" refers to diseases that cause major irreversible morbidity, such as blindness; loss of arm, leg, hand, or foot; loss of hearing; or paralysis or stroke (12,13).
Before emergency use of a test article, investigators must obtain the informed consent of the participant or of the participant's legally authorized representative (10). This informed consent must be documented in writing. Informed consent can be waived if all the criteria in Figure 4 can be met (12,13,15). The treating physician and an independent physician must document that these criteria are met. If the test article must be used on such an emergent basis that the opinion of an independent physician cannot be obtained, the treating physician should document that the criteria are met, use the test article, and obtain a written independent determination within 5 days (15). The emergency use and the independent determination must be reported to the IRB within 5 days of the emergency use. Federal law does not specify how the documentation requirements for emergency use are to be met, and IRBs may simply request a letter to the chair of the IRB as documentation. However, state law may require this information to be documented in the medical record.
The emergency use regulations must be applied in the context of clinical care, where the goal is to provide an investigational article as the only available treatment for a life-threatening situation. Therefore, these regulations cannot be used to enter a participant in a randomized trial without prior IRB review and approval. Radiologists should not use these regulations when their intent is to conduct research. Specifically, data obtained through the emergency use of a test article cannot be used for prospectively planned research (9). In addition, no interventions should be performed beyond those required to provide medical care for the participant. Investigators who want to report findings from an emergency use should report them in a retrospective review.
Even though there is no regulatory requirement for IRB review in order to use an investigational article in an emergency, radiologists should consult with an IRB chair or administrator before such use, if at all possible. This consultation can help ensure that all regulatory criteria have been met. After the emergency use of a test article, radiologists should document that criteria 1–5 in Figure 3 were met. Some sponsors ask investigators to provide "an IRB approval letter" before shipping the test article. According to the definition of an emergency use, the IRB cannot provide such approval (11). However, sponsors generally accept a letter from the IRB chair that he or she has reviewed the situation and found compliance with FDA requirements.
|
CUSTOM DEVICES
|
|---|
Physicians occasionally need to make custom modifications in devices for the purpose of treating a single patient. Such devices are not subject to FDA regulation provided that they fall under the regulatory definition of a custom device (Figure 5) and are not being used to determine safety or effectiveness for commercial distribution (16). Prosthetics and dental implants are classic custom devices. However, radiologists may need to modify a catheter, a support device, or an imaging probe to make it work for a specific patient. Custom devices may be subject to local institutional oversight, so radiologists should check with their department head or medical director. If a device does not clearly fulfill the requirements for a custom device, physicians should contact the FDA for guidance about whether FDA clearance is required.
|
CONCLUSION
|
|---|
There are several situations in which an activity falls under the regulatory definition of research but is exempt from the research regulations. Investigators who conduct exempt research should know the regulatory criteria for the exemptions. In the case of research that is exempt from the DHHS regulations, the IRB or an authority other than the investigator should make the determination of whether a proposed research activity is exempt from the regulations. For research that is exempt from the FDA regulations, investigators should follow institutional guidance and seek input from the IRB or FDA in questionable cases.
|
FOOTNOTES
|
|---|
Abbreviations: DHHS = Department of Health and Human Services • FDA = Food and Drug Administration • IRB = institutional review board
|
References
|
|---|
- Cooper JA. Responsible conduct of radiology research. II. Regulatory requirements for human research. Radiology 2005;236:748–752.
- Protection of human subjects: federal policy for the protection of human subjects. 45 CFR
46 (1991).
- Protection of human subjects. 21 CFR 50 (2002).
- Institutional review boards. 21 CFR 56 (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 (1991).
- Pritchard IA. Searching for "research involving human subjects": what is examined? what is exempt? what is exasperating? IRB 2001; 23(3):5–13.[Medline]
- Amdur RJ, Speers MA. Identifying research intent. In: Amdur RJ, Bankert E, eds. Institutional review board: management and function. Sudbury, Mass: Jones & Bartlett, 2002.
- Office of human research protections compliance activities: common findings and guidance. Department of Health and Human Services, Offices for Human Research Protections (OHRP) Web site. http://ohrp.osophs.dhhs.gov/references/findings.pdf. Published July 10, 2002. Accessed May 19, 2005.
- Exemptions from IRB requirement: protection of human subjects. 21 CFR 56.104 (2002).
- Definitions: protection of human subjects. 21 CFR 56.102 (2002).
- Information sheets: guidance for institutional review boards and clinical investigators—emergency use of an investigation drug or biologic. U.S. Food and Drug Administration Web site. http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency. Updated 1998. Accessed May 19, 2005.
- Information sheets: guidance for institutional review boards and clinical investigators—emergency use of unapproved medical devices. U.S. Food and Drug Administration Web site. http://www.fda.gov/oc/ohrt/irbs/devices.html#emergency. Updated 1998. Accessed May 19, 2005.
- Information sheets: guidance for institutional review boards and clinical investigators—"off-label" and investigational use of marketed drugs, biologics, and medical devices. U.S. Food and Drug Administration Web site. http://www.fda.gov/oc/ohrt/irbs/offlabel.html. Updated 1998. Accessed March 14, 2004.
- Exception from general requirements: institutional review boards. 21 CFR 50.23 (2002).
- Definitions: investigational device exemptions. 21 CFR 812.3 (2002).
This article has been cited by other articles:
|
|
|
|
 
A. B. Wolbarst and W. R. Hendee
The National Institute of Biomedical Imaging and Bioengineering and NIH Grant Process: An Overview
Radiology,
January 1, 2007;
242(1):
32 - 55.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Cooper
Responsible Conduct of Radiology Research Part IV. The Boundary of Research and Practice
Radiology,
November 1, 2005;
237(2):
383 - 384.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
