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Understanding Institutional Review Boards: Practical Guidance to the IRB Review ProcessUniversity of Wisconsin–Madison, Madison, Wisconsin Correspondence: Correspondence: John T. Cejka, MA, University of Wisconsin–Madison, Health Sciences Institutional Review Boards, VA Hospital, Rm B3088, 2500 Overlook Terrace, Madison, WI 53705. Electronic mail may be sent to jtc{at}medicine.wisc.edu. The purpose of this paper is to provide practical guidance to assist investigators in the preparation of materials and obtaining approval for research projects that require oversight by an institutional review board (IRB). The central requirements for IRB approval and core considerations of IRBs are described. Specific suggestions for investigators regarding how to prepare their IRB applications to anticipate and address potential IRB concerns and questions are proposed. When researchers are familiar with these criteria and how they may be interpreted by an IRB, they can avoid deferrals or lengthy requests for protocol modifications or clarifications. General tips regarding the preparation of IRB submission materials that may allow for a smoother IRB review process are also discussed. A brief list of additional resources for investigators is appended. In 1966, a system of local oversight designed to protect human subjects was initiated in the United States after scandals involving troubling, if not necessarily unethical, research studies were published.1 The National Institutes of Health (NIH) Policy for the Protection of Human Subjects established the institutional review board (IRB) as the fundamental component of a system to protect human research subjects. Today, all federally funded or regulated research must be approved by an IRB.2 In practice, especially at academic institutions, such review and approval is often required irrespective of the funding source or use of U.S. Food and Drug Administration (FDA)–regulated drugs and devices. Whether conducting minimal-risk survey research or engaging in a complex multicenter drug trial, researchers must learn to navigate the IRB review process.3 [Federal regulations define minimal risk as any risk where "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."] Unfortunately, many researchers find this process to be frustrating and difficult to understand. Although many factors can contribute to making the review process more difficult than necessary, the complexities and nuances of the IRB review process can contribute to the level of frustration researchers may experience. Better understanding of the primary determinations an IRB is required to make during the review process can help researchers anticipate problematic issues and provide the information relevant to these determinations in their IRB applications. This paper will provide an overview of the central features of IRB review and required determinations, along with practical advice for preparing IRB applications and associated study materials. Although conventions and regulatory interpretations vary among institutions, this paper will describe the most common foundations of IRB review, and provide practical guidance that can minimize the difficulties researchers sometimes encounter during the IRB review and approval process.
Pursuant to the Common Rule (described below) and FDA regulations, specific criteria must be met for an IRB to determine that a protocol can be approved for the involvement of human subjects. When researchers are familiar with these criteria and how they may be interpreted by an IRB, they can craft an IRB application that anticipates many of the questions that arise during IRB deliberations, thus avoiding deferrals or lengthy requests for protocol modifications or clarifications. The primary criteria that IRBs follow are found in what is called the Common Rule, the set of federal regulations governing human subjects research, followed by several federal agencies and codified in 45 CFR 46.4 An overview will follow of the criteria used for IRB approval (as specifically codified in 45 CFR 46.111), as well as an analysis of how IRBs apply them.5 [In accordance with federal regulations, studies may fall into 1 of 3 review categories: full, expedited, or exempt. The focus here is on the criteria IRBs use to conduct full and expedited reviews. The regulatory criteria for review of exempt studies are different and are implemented in a variety of ways among institutions. For guidance on how IRBs review studies that may qualify for exemption, researchers are encouraged to consult with their own IRBs. In addition, suggestions are included for researchers to help ensure their applications demonstrate to the IRB that the proposed research project meets the criteria for approval.]
Federal regulations and IRBs recognize that research often presents risks to subjects. However, it is incumbent on investigators to ensure that the proposed research does not expose subjects to undue risk. Within an IRB application, investigators can specifically describe the scope of the risks of the research, and the steps taken to mitigate or eliminate risks to the degree possible. When reviewing applications to determine whether the risks of the research have been minimized, IRBs must also determine what risks are present. Although physical risks (eg, pain, discomfort, side effects) usually are described in IRB applications, often investigators do not acknowledge other risks, such as those that are social, psychological (suicidality), emotional (invasion of privacy, loss of confidentiality, harassment), economic (damage to reputation, loss of insurance, impact on employability), or legal. The following represent questions that IRBs frequently ask about the risks of research and their expectations of how these risks have been minimized:
Many IRBs refer to this criterion as assessing the risk/benefit ratio of the research study and view this as the most important ethical determination they make. Some of the factors that are considered as part of assessing the risk/benefit ratio of a research study were outlined in the previous section. This section will discuss how an IRB may evaluate the acceptability of risks in relation to the potential benefits of the research. As the IRB Guidebook published by the Office for Human Research Protections describes, the risk/benefit assessment is not a technical one valid under all circumstances, because it is a judgment that often depends on prevailing community standards and subjective determinations of risk and benefit. Due to the nature of the process of the risk/benefit assessment, investigators may find that different IRBs can make different assessments of the risk/benefit ratio for the same study.8 In order to assess the risks in relation to the benefits, IRBs must first identify the risks of the protocol. Once identified, the IRB must determine the degree and likelihood of risks to subjects. Some questions that the IRB considers for identification of the level of risk the research presents to subjects include:
When IRBs have determined the extent and nature of the risks a study presents, they then consider the potential benefits of the study. Benefits of a research study are generally thought of in terms of benefits to subjects and benefits to society. Occasionally, researchers will describe subject remuneration, free healthcare, or the opportunity to help others as benefits of the research. The federal agencies overseeing human subjects research, however, do not view these as factors, which are not part of the study's design, that constitute benefits and thus they do not enter into the IRB's analysis of benefits and risks. According to its assessment of the risks presented by the research and whether the research presents potential benefits directly to subjects or society, the IRB then must determine whether the risks to subjects are justified by the potential benefits and, thus, whether the research can be approved. The following is an outline of the potential outcomes of the IRB's assessment of the risk:benefit ratio of a protocol:
Under this criterion, the IRB must ensure that selection of subjects is equitable. In making this assessment, the IRB takes into account the purposes of the research and the setting in which the research will be conducted. The IRB is particularly cognizant of special concerns that may be raised by research involving vulnerable populations, such as children, prisoners, pregnant women, people with disabilities, or others who are likely to be vulnerable to coercion or undue influence. When reviewing research involving these populations, the IRB must ensure that additional safeguards are provided to protect the rights and welfare of participants. In considering whether the selection of subjects is equitable, the IRB will likely consider a number of questions, including the following:
When preparing their IRB applications, researchers should explain why a particular subject population is appropriate for enrollment in their study. Researchers who plan to enroll populations for which specific federal regulations exist (eg, children, prisoners, pregnant women) should familiarize themselves with those requirements and be sure that their application adequately addresses them. The IRB staff is typically knowledgeable about these requirements, and researchers should contact their IRBs if they have questions about enrolling vulnerable populations and any additional application requirements. Researchers also should make certain that their application includes a robust consent process that is appropriate for the population(s) they wish to enroll. Although providing good informed consent or assent forms is an important part of this, researchers should ensure that the consent process addresses any special concerns raised by their subject population (eg, assessment of capacity to consent for subjects who may have impaired decision-making). Giving the IRB sufficient information about the subject population and the consent process will greatly assist the IRB in its assessment of the equitable selection of subjects and allow for a smoother review process.
Informed consent is a key component of the Common Rule, requiring IRBs to determine that informed consent will be sought from each prospective subject or the subject's legally authorized representative, and that informed consent will be appropriately documented. The Common Rule, as well as FDA regulations, assumes that, with a few exceptions, written informed consent will be obtained before any research procedures commence. IRBs must ensure that requests to waive informed consent or documentation of informed consent are justified and meet the appropriate regulatory requirements. When reviewing studies, IRBs assess the proposed consent process (not just the form), including whether it is appropriate for the subject population. In assessing whether a proposed study meets the regulatory criteria regarding informed consent, the IRB will consider a number of questions, including the following:
Researchers can assist in the IRB's assessment of informed consent by providing a detailed description of the consent process. Stating only that written informed consent will be obtained is generally not regarded as a sufficient consent process. The consent process should ensure that no human subjects are involved in the research before obtaining consent, unless informed consent has been waived by the IRB. The process should be designed to give potential subjects sufficient time and space to make their decision about research participation. A sound consent process should be conducted in a setting that allows a free choice to accept the invitation to participate or to refuse to participate without prejudice or penalty. Individuals who conduct the consent process should be well qualified and able to ensure that any questions potential subjects have are adequately addressed. If any vulnerable populations will be enrolled, the consent process should include additional safeguards as appropriate. (For example, the consent process for studies enrolling children should indicate how a child's assent and parental consent will be obtained.) A good description of a consent process will address these issues in detail, thereby making it easier for the IRB to determine that a sound process is in place. When drafting consent documents, researchers can often rely on resources provided by their own institutions, which may include specific formatting requirements or consent form templates. Some general tips for writing consent documents include keeping the reading level low, usually between a sixth and eighth grade reading level. Using short sentences and subsections to break up information can also assist with making a consent document more accessible to potential subjects. Technical terms should be avoided and simpler words used instead. Using a font that is no smaller than 12 point can help enhance readability (for aging populations, or studies of eye disease, larger font may be appropriate). Consent documents should avoid wording that is, or may seem to be, coercive or overly reassuring to a potential subject. Flowcharts and tables can help convey information about complicated study procedures or study visit schedules. Claims about the safety or efficacy for investigational articles or procedures should be avoided. Giving the consent form a version number and date can be helpful for study personnel, especially when changes need to be made to the form. Some studies may qualify for a waiver of informed consent or waiver of documentation of informed consent. These are 2 different types of waivers that may be granted in different circumstances. Under the Common Rule, an IRB may approve a consent procedure that does not include or that alters some or all of the elements of informed consent, or may waive the requirements to obtain informed consent, provided that:
Research studies that involve prospective, direct interaction with subjects generally do not meet the criteria for a waiver of informed consent. IRBs generally do not accept inconvenience to the researcher as a justification for a waiver of informed consent. In no case should a researcher seek to withhold information about the research or the subject's role solely to reduce the chances of refusal to participate. Requests and justification for a waiver of informed consent or a waiver of some elements of informed consent should be well described in the IRB application. An IRB may waive the requirement for written informed consent (ie, documentation is waived, but the informed consent process is not) if it finds that:
This type of waiver of documentation applies especially to anonymous interviews (including face-to-face and telephone interviews) in which the investigator's sole knowledge of the identity of the interviewee would come from the informed consent document. It is important to note that waivers of documentation of informed consent are not permitted in FDA-regulated research in most cases. In the case when a potential waiver of informed consent documentation may apply, researchers should describe in the IRB application their plan for obtaining informed consent from subjects (eg, providing subjects with an information sheet, obtaining oral consent).
Most IRBs require the presentation of a data and safety monitoring plan (DSMP) when the research presents more than minimal risk to subjects. A DSMP is a description of how the investigator or study sponsor will monitor research data and respond to adverse events and unanticipated problems that occur during the course of the research to ensure the safety of participants and the validity and integrity of data collection. Monitoring research is important because preliminary data may signal the need to change the research design, change the information presented to subjects or provide them with information that may affect their willingness to continue their participation, or even to terminate the project before the scheduled end date. Both the timing and adequacy of the plan for data analysis are important, especially to detect when the data suggest a need for early termination due to evidence of efficacy or futility, high mortality rates, accrual problems, or previously unrecognized safety problems. For long-term studies involving a significant number of subjects (eg, phase III clinical trials), IRBs tend to prefer that formal data and safety monitoring boards be established to review study data. If such a board will not be formed, it is especially critical to describe how adverse event trends will be identified, who will review unblinded or aggregate data, and that IRBs will be informed of adverse findings promptly. Concerns about data and safety monitoring are not limited to biomedical research and, depending on the nature of the study, researchers conducting sociobehavioral research should also be prepared to provide a plan for monitoring subject safety. A sound safety monitoring plan is often essential for an IRB to approve higher-risk sociobehavioral studies, such as research on child abuse, drug use, or mental health issues. Survey or interview research that may reveal suicidality, potential for harm to self or others, or illegal behaviors should include provisions for handling such situations. This is particularly important because local or state law may require reporting of these events, and a certificate of confidentiality (COC; discussed below) may be needed to protect both the researcher and study participants.
For research to be approved by an IRB, the protocol generally must include adequate provisions to protect the privacy interests of research participants and the confidentiality of research data. Privacy refers to a person's desire to control the access of others to him or herself. For example, research participants may not want to be seen entering a place that might stigmatize them, such as a pregnancy counseling center that is clearly identified as such by signs on the front of the building. Confidentiality refers to the researcher's agreement with the participant about how the research participant's identifiable private information will be handled, managed, and disseminated. An invasion of privacy or breach of confidentiality has the potential to present significant risk to subjects. Some information may, if a breach of confidentiality occurs, have an adverse effect on the subjects' employability or economic status, insurability, social relationships, legal status, or psychological wellbeing. In addition, breaches of confidentiality can undermine the perceptions participants may have of the researcher or institution at which the study is conducted. Thus, the protection of subject data should be well considered by the researcher. As the IRB Guidebook notes, researchers usually seek informed consent from subjects in order to obtain information from them for research purposes.14 When informed consent has been obtained, there is little reason for concern about privacy. However, researchers are still expected to assure that appropriate confidentiality of research data is maintained. Privacy issues are more likely to arise when information is obtained for research purposes without the consent of subjects. For example, the majority of the complaints the University of Wisconsin–Madison IRBs have received from research subjects over the last 10 years, although these have been few, are related to perceptions that an individual's privacy has been breached. In their review of a research protocol, IRBs must ensure that subjects' privacy and the confidentiality of study data are adequately protected. Generally, the same levels of protections in place to help ensure the privacy of patients' medical records are expected to be in effect for research records. In certain cases, such as when a potential breach of confidentiality could put subjects at significant legal, social, or economic risks, IRBs may require researchers to deidentify (anonymize) study data (ie, remove all direct or indirect identifiers from the data collected). If the data cannot be deidentified, an IRB may require an investigator to obtain a COC. COCs are particularly warranted when the data being collected could be sought by others outside of the research study personnel and research oversight agencies, such as by law enforcement agencies that may subpoena the research data. Researchers obtain COCs from federal agencies that are under the auspices of the NIH, such as the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), or the National Institute of Mental Health (NIMH), which, in 1991, became components of NIH. COCs are generally granted when the research involves the collection of information relating to sexual attitudes, preferences, or practices; the use of alcohol, drugs, or other addictive products; illegal conduct; or an individual's psychological well-being or mental health. In addition, a COC would be warranted if the release of the information could reasonably be damaging to an individual's financial standing, employability, or reputation within the community, or the disclosure of medical information could reasonably lead to social stigmatization or discrimination. There are other conditions in which COCs can be granted, such as in the case of tissue or data banks that are being maintained for unspecified future use. Generally, IRBs will ask at least some of the following questions when assessing the adequacy of the measures in place to protect subject confidentiality:
Subject populations that are vulnerable to coercion or undue influence require special consideration by the IRB, as noted in the equitable selection of subjects and informed consent sections. Investigators who will enroll vulnerable groups in research, such as children, prisoners, mentally disabled people, or economically or educationally disadvantaged people, should explicitly describe what measures are in place to ensure that the subjects' rights and welfare are adequately protected. Because the types of protections needed tend to be group- and protocol-specific, it is generally best to consult with the IRB office for advice of how to address this issue in the IRB application.
Although some researchers may argue otherwise, the majority of IRBs consider themselves to be facilitators of ethically sound research that protects the rights and welfare of human subjects. When possible, prospective investigators (especially those new to the IRB review process) should discuss their project with an IRB representative for assistance in identifying and addressing potentially problematic issues before submitting it. In addition to consulting with their local IRB, the following general guidelines may assist researchers in providing IRBs with the information they need to make the required determinations and therefore provide for a smooth review process:
A quick call or e-mail to the IRB can save researchers time and effort, so when in doubt, investigators should consult with their IRB.
Even in the best of circumstances, the IRB review process can sometimes be frustrating and time consuming for both researchers and IRBs. Closer working relationships between researchers and their IRBs can help mitigate some of these frustrations and create a smoother and more efficient IRB review process for all. A central feature of this relationship is a better understanding of the requirements of IRB approval as delineated in the Common Rule. A more complete grasp of the determinations IRBs are required to make during the review process can greatly assist researchers in preparing applications that anticipate the questions IRBs are likely to raise during their deliberations and thereby avoid delays caused by deferrals or lengthy requests for additional information. Good lines of communication between researchers and their IRBs are critical not only to ensuring a smooth review process but also to protect the rights and welfare of human research participants.
Federal Certificates of Confidentiality Kiosk http://grants1.nih.gov/grants/policy/coc/ FDA Information Sheets http://www.fda.gov/oc/ohrt/irbs/ Investigator 101 CD-ROM http://www.hhs.gov/ohrp/references/cdrom.pdf Office for Human Research Protections IRB Guidebook http://www.hhs.gov/ohrp/irb/irb_guidebook.htm
Selected IRB Websites Featuring Investigator Guidance Johns Hopkins University (School of Medicine) http://irb.jhmi.edu/ Stanford University http://humansubjects.stanford.edu/ University of California–San Francisco http://www.research.ucsf.edu/chr/about/hsppWhatIsChr.asp University of Minnesota http://www.research.umn.edu/irb/ University of Pittsburgh http://www.irb.pitt.edu/ University of Wisconsin–Madison (School of Medicine and Public Health) http://info.gradsch.wisc.edu/research/compliance/humansubjects/hsirbs/index.html 1 Beecher HK. Ethics and clinical research. N Engl J Med. 1966; 274:1354 –1360.[Web of Science][Medline] [Order article via Infotrieve] 2 Amdur R, Bankert E. Preface. In: Institutional Review Board: Management and Function. Sudbury, MA: Jones and Bartlett Publishers; 2002: xxv.3 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.102). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.4 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.5 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.6 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[1]). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.7 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[2]). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.8 Office for Human Research Protections. IRB Guidebook. Available at: http://www.hhs.gov/ohrp/irb/irb_guidebook.htm. Accessed May 24, 2007.9 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[3]). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.10 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[4-5]). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.11 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.116). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.12 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[6]). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.13 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111[7]). Revised June 23,2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.14 Penslar RL, Porter JP. IRB guidebook [Office of Human Research Protections website]. 1993. Available at: http://www.hhs.gov/ohrp/irb/irb_guidebook.htm. Accessed July 25, 2007.15 U.S. Department of Health and Human Services. Regulations for the protection of human subjects (45 CFR 46.111). Revised June 23, 2005. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. Accessed August 3, 2007.
Nutrition in Clinical Practice, Vol. 22, No. 6,
618-628 (2007)
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