3

Determining Minimal Risk in Social and Behavioral Research

The Common Rule1 is frequently described as a risk-based rubric, and a central task of an institutional review board (IRB) is to determine that risks are minimized and that the risks to the subjects are reasonable in relation to the anticipated benefits (45 C.F.R. § 46.111(a)(2)). “Risk” is a word fraught with many connotations, and the way the word is used in a lay context does not necessarily equate with that used in the utilitarian cost-benefit analysis intended by the Common Rule. But there is very little in the Common Rule itself or subsequent guidance that provides help with defining or assessing risk.2 The only definition of risk in the human subjects protection regulations is for minimal risk (45 C.F.R. § 46.102(i)). Over the past 30 years, this definition has guided IRBs in determining the level of review required by a research protocol. At the same time, there has been widespread inconsistency in IRB application of the minimal-risk criteria, due in part to the ambiguity of regulatory language (e.g., Lidz and Garverich, 2013; Shah et al., 2004). Laudable aims of the changes to the Common Rule proposed in the Advance Notice of Proposed Rulemaking (ANPRM; 76 Fed. Reg. 44,512) were to enhance participant protections

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1As explained in Chapter 1, “Common Rule” is used throughout this report to refer to 45 C.F.R. § 46, Subpart A.

2The Office for Human Research Protection Institutional Review Board Guidebook (1993) did define risk as follows: “The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant.” But neither the human-subjects research regulations nor the formal guidance from the Office for Human Research Protections define risk.



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3 Determining Minimal Risk in Social and Behavioral Research The Common Rule1 is frequently described as a risk-based rubric, and a central task of an institutional review board (IRB) is to determine that risks are minimized and that the risks to the subjects are reasonable in relation to the anticipated benefits (45 C.F.R. § 46.111(a)(1) and § 46.111(a)(2)). “Risk” is a word fraught with many connotations, and the way the word is used in a lay context does not necessarily equate with that used in the utili- tarian cost-benefit analysis intended by the Common Rule. But there is very little in the Common Rule itself or subsequent guidance that provides help with defining or assessing risk.2 The only definition of risk in the human subjects protection regulations is for minimal risk (45 C.F.R. § 46.102(i)). Over the past 30 years, this definition has guided IRBs in determining the level of review required by a research protocol. At the same time, there has been widespread inconsistency in IRB application of the minimal-risk criteria, due in part to the ambiguity of regulatory language (e.g., Lidz and Garverich, 2013; Shah et al., 2004). Laudable aims of the changes to the Common Rule proposed in the Advance Notice of Proposed Rulemaking (ANPRM; 76 Fed. Reg. 44,512) were to enhance participant protections 1  As explained in Chapter 1, “Common Rule” is used throughout this report to refer to 45 C.F.R. § 46, Subpart A. 2  The Office for Human Research Protection Institutional Review Board Guidebook (1993) did define risk as follows: “The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant.” But neither the human- subjects research regulations nor the formal guidance from the Office for Human Research Protections define risk. 59

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60 PROPOSED REVISIONS TO THE COMMON RULE and reduce IRB and investigator burden, delay, and ambivalence (Emanuel and Menikoff, 2011; Fisher et al., 2013, p. 4). The committee strongly supports these aims. This chapter considers critical issues related to how best to ensure (a) that the definition of “minimal risk” is appropriate for the full range of current social and behavioral science research; (b) that IRBs and inves- tigators have adequate guidance for avoiding underestimation and over- estimations of minimal risk; and (c) that categories of research that may be reviewed through an expedited review adequately reflect the broad spectrum of social and behavioral science research. The committee’s pro- posed approach to assessing and minimizing participant risk adheres to the Belmont Report’s principles of beneficence, respect, and justice (U.S. De- partment of Health and Human Services, 1979) and to established canons of scientific and professional knowledge. In response to the ANPRM, the Society for Research in Child Devel- opment (SRCD) convened the SRCD Task Force on Proposed Changes to the Common Rule (hereafter, “SRCD Task Force”). In its published report and commentary on the ANPRM, which addresses many of the issues also addressed in this report, the SRCD Task Force viewed research as “a moral endeavor that seeks to ensure that the welfare, autonomy and privacy rights of infant, child and adolescent research participants are adequately protected and that such protections do not prevent them from equitable sharing of the burdens and benefits of research” (Fisher et al., 2013, p. 4). The committee believes its approach is consistent with this view of research, expanded to apply to all research participants. DEFINING MINIMAL RISK As defined at 45 C.F.R. § 46.102(i), “Minimal risk means that the prob- ability 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 exami- nations or tests.” The ANPRM should be applauded for asking the research community to consider whether this definition of “minimal risk” needs revi- sion. In the past 10 years, a number of ethics committees and scholars have grappled with how minimal risk should be delineated, and some consensus has developed (Meyer, 2013; Resnik, 2005; Rid et al., 2010; Wendler et al., 2005). While it is probably impossible—and in fact may be unwise—to completely eliminate variation in interpretation of the term, the regulations and guidance should be revised to reflect the developing consensus.

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DETERMINING MINIMAL RISK 61 Whose “Daily Life” and Which Routine Procedures? One of the most persistent conundrums has been how to compare risks of the research to the risks of daily life or of routine examinations or tests. The question immediately becomes “whose daily life?” Is it the daily life of an average person in the general population or the specific population to be enrolled in the study? Despite recommendations from the National Com- mission for the Protection of Human Subjects of Biomedical and Behavioral Research (U.S. Department of Health and Human Services, 1979) that minimal risk refers to a uniform standard based on the daily life and routine procedures experienced by the general population, in response to public comment the U.S. Department of Health and Human Services (HHS), in the Preamble to the Final Rule, articulated a relative standard describing minimal risk as “those risks encountered in the daily lives of the subjects of the research” (U.S. Department of Health and Human Services, 1981). Unfortunately, the final regulatory definition included neither the “general population” nor the “subjects of the research” language, resulting in the ongoing confusion and wide variations in the determination of minimal risk. The 2003 National Research Council report, Protecting Participants and Facilitating Social and Behavioral Sciences Research, wrestled with this question but was unable to achieve consensus for a solution. But since then, there has been considerable study of this issue and a consensus has devel- oped that the “special population” approach should be rejected because it can result in an unjust distribution of risks. That is, a population-specific definition unjustly permits individuals to be exposed to higher levels of risk under the minimal risk category, simply because their daily lives are filled with greater risk than healthy individuals or those living in safe environ- ments (Briefel et al., 2002; Fisher et al., 2007; Institute of Medicine, 2004; Kopelman, 2004; Oakes, 2002; Snyder et al., 2011; Wendler et al., 2005). Defining the General Population Standard Drawing on recommendations from the Belmont Report and more recent federal committees and independent reviews (Institute of Medicine, 2004; National Human Research Protections Advisory Committee, 2001; Secretary’s Advisory Committee on Human Research Protections, 2005, 2008; U.S. Department of Health and Human Services, 2011), the Secre- tary’s Advisory Committee on Human Research Protections (SACHRP) has noted that the definition of minimal risk based on the risks faced in daily life should “reflect ‘background risks’ that are familiar and part

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62 PROPOSED REVISIONS TO THE COMMON RULE of the routine experience of life for ‘the average person’ in the ‘general population.’”3 Although the definition of “general population” requires additional discussion, one starting point is to harmonize the Common Rule minimal risk definition with the “healthy persons” standard for minimal risk required for Subpart C, Additional Protections Pertaining to Biomedi- cal and Behavioral Research Involving Prisoners (45 C.F.R. § 46.303(d)). While the healthy persons standard is a good start for grounding a general population definition, it may not sufficiently protect from unjust ex- posure to research harms healthy individuals living in unsafe environments in which violence and trauma produced by human or natural causes char- acterize experiences of daily life. Thus, regulators should consider whether the concept of safe environments should be considered along with that of healthy persons in creating a uniform minimal risk definition. An important caveat is that any modification to the definition of mini- mal risk may have substantial implications for the conduct of social and behavioral science research involving children (as well as for biomedical and educational research involving children) because Subpart D, Addi- tional Protections for Children Involved as Subjects in Research, refers to the Common Rule’s minimal risk definition as an anchor for regulations evaluating acceptable research procedures and required human subjects protections (Fisher et al., 2013). For example, the Common Rule mini- mal risk definition informs the conditions, stated in Subpart D (45 C.F.R. § 46.404 and § 46.405), under which an IRB can approve research that has no prospect of direct benefit to child participants. It also anchors IRB approval of a subset of waivers for parental permission and child assent (45 C.F.R. § 46.408). (Informed consent for research with child participants is addressed in detail below, in Chapter 4.) As long as the Common Rule minimal risk definition remains the default criterion for risk categorization of research involving children, the Office for Human Research Protections (OHRP) must ensure that the ap- plication of the recommended general population standard does not result in the inadvertent application of an adult minimal risk standard to child participants. To address this concern, the committee recommends below that OHRP issue guidance on applying age-indexed criteria for application of the minimal risk criteria to risks in daily life and routine examinations (Fisher et al., 2007; Institute of Medicine, 2004; National Human Research Protections Advisory Committee, 2001; Secretary’s Advisory Committee on Human Research Protections, 2005). 3  See the 2008 SACHRP Letter to HHS Secretary at http://www.hhs.gov/ohrp/sachrp/ sachrpletter013108.html [December 2013].

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DETERMINING MINIMAL RISK 63 Which Tests and Which Routine Procedures? Any modifications to the definition of minimal risk also need to recog- nize that social and behavioral research is often conducted in or for educa- tional institutions. Although much educational research involving normal educational practices conducted in educational settings is appropriately exempt from 45 C.F.R § 46, as currently stated under Exemption Category (1), other social and behavioral research conducted outside of educational settings may also include traditional tests of reading, mathematical abilities, problem solving, and other academic skills. For such research, the reference in the current minimal risk definition to routine medical or psychological examinations or tests is insufficient; the definition should be expanded to explicitly include educational examinations or tests. Additionally, the committee believes that restricting the definition of routine “examinations or tests” has caused confusion in IRB evaluation of prevention and inter- vention research in both biomedical and social and behavioral research contexts. Such research may include both routine medical and psychologi- cal examinations and routine medical and mental health procedures. For example, a community-based translational study examining the efficacy of two standard grief counseling techniques for elderly widows and widowers may pose no greater risks than procedures currently available to this popu- lation and should be classified as minimal risk. Similarly, a school-based prevention program to reduce interpersonal conflicts among students may use routine conflict-resolution psycho-educational procedures. To appropri- ately classify minimal prevention and intervention studies, a revised Com- mon Rule could adopt the definition in Recommendation 3.1 below, which includes “procedures” in its definition of minimal risk. Calculating the Probability and Magnitude of Harm An objective assessment of minimal research risk is a calculus involving both the magnitude of a potential harmful outcome and the likelihood that the outcome will occur. In particular, just because a risk of high magnitude is possible does not make it probable. The definition of minimal risk incor- porated into the original 1981 federal regulations was designed to reflect the Belmont Report’s recommendations on the importance of appropriately weighing probability against magnitude of harm. Although identifying the probability and magnitude of harm may have been more objective when re- search sponsored by the National Institutes of Health (NIH) was focused on a narrower range of biomedical disorders, over time the expansion of areas covered by both biomedical and behavioral research has left a vacuum in guidance on the knowledge base from which such estimates may be drawn. Consequently, IRBs often evaluate research as greater than minimal risk if

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64 PROPOSED REVISIONS TO THE COMMON RULE there is a very small probability that the research may produce harm of high magnitude or if there is a high probability that research may produce harms or discomfort of small magnitude. The frequency of such misjudgments has heightened the need for guidance specific to research domains on the most appropriate knowledge bases for determining probability of a harm occur- ring and the magnitude of the harm if it occurs. Recommendation 3.1: HHS should adopt the following definition of minimal risk under the Common Rule: “Minimal risk means that the probability and magnitude of physical or psychological harm does not exceed that which is ordinarily encountered in daily life or in the routine medical, psychological, or educational examinations, tests, or procedures of the general population.” Guidance Recommended: OHRP guidance should be issued in the fol- lowing areas to assist in operationalizing the definition of minimal risk in Recommendation 3.1: • Clarify that estimates of risk should be uniformly applied across the general population and should not be indexed to the experi- ence of the study population alone, in order to be certain that the benefits and burdens of research are distributed evenly across populations and to avoid an unjust distribution of risks. • Define the general population standard in terms of healthy persons living in safe environments. • Apply age-indexed criteria for determining the probability and magnitude of harms or discomfort in the daily life of, and in rou- tine medical, psychological, or educational examinations, tests, or procedures of, infants, children, and adolescents (if the Common Rule minimal risk definition remains the default criterion for risk categorization of research involving children). • Clarify how to calculate appropriately both the probability and magnitude of harm and discomfort, when determining whether research meets minimal risk criteria that include examples from domain-specific areas of research. Procedural Improvements Needed: To avoid subjectivity and enhance continuity within and across institutions, IRBs could draw on estab- lished scientific and professional knowledge in their determination of the probability and magnitude of research harms in daily life and in routine medical, psychological, or educational examinations, tests, or procedures of the general population. However, care is needed to avoid confusing evidence-based probability estimates with the subjective

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DETERMINING MINIMAL RISK 65 possibility that harms and discomforts of high magnitude are likely to be produced by the research. For example, IRBs could consider adopting procedures that appropriately balance the probability and magnitude of research harms, in order to avoid subjectively judging research as having a greater than minimal risk in cases where there is a very small probability that the research may produce harm of high magnitude or where there is a high probability that research may pro- duce harms or discomfort of small magnitude. Research Needed: To build a stronger evidence base, research is needed for identifying the probability and magnitude of harms and discomfort in daily life and the nature of age-indexed, routine medical, psychologi- cal, or educational examinations, tests, or procedures of the general population. In addition research is needed to examine appropriate algorithms for determining whether the calculus of probability and magnitude of harms and discomfort meets minimal-risk criteria. AVOIDING OVERESTIMATION AND UNDERESTIMATION OF HARM The definition of minimal risk in the Common Rule has confounded the research community since the human subjects protection regulations were first promulgated. The first comments warned that the vagueness of the definition would cause variability and confusion, and this outcome has certainly come to pass (Ceci and Bruck, 2009; Fisher et al., 2007; Wendler et al., 2005; Westra et al., 2011). And there is evidence that it leads to both overestimation and underestimation of risk (Wendler et al., 2005). This vagueness has been especially problematic for the conduct of research in the social and behavioral sciences, due in large part to (1) the lack of specificity in examples provided for minimal risk under the expedited risk category, (2) difficulty distinguishing research risks from participant vulnerabilities, and (3) the tendency of some IRBs to apply subjective overestimations of the level of harms that may be incurred through social and behavioral sci- ence research methods (Green et al., 2006). Moreover, there may be little awareness by IRBs and investigators of the growing body of published empirical evidence describing participant perspectives on research risks and benefits of social and behavioral re- search, as well as biomedical research (Fendrich et al., 2007; Fisher et al., 2008; Langhinrichsen-Rohling et al., 2006; Lazovski et al., 2009; Leykin et al., 2011; McDonald et al., 2008; Pearlman et al., 2013). This increase is due in part to several NIH-sponsored funding initiatives supporting research on the responsible conduct of research (e.g., the NIH-wide Pro- gram Announcement, Research on Ethical Issues in Biomedical, Social and

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66 PROPOSED REVISIONS TO THE COMMON RULE Behavioral Research) and to the growth of journals in the field, including the Journal of Empirical Research on Research Ethics, Ethics & Behavior, and the American Journal of Bioethics: Primary Research, and Narrative Inquiry in Bioethics. In addition, there is evidence that many IRBs, regardless of whether their purview is mostly biomedical or social and behavioral science, tend to focus more on the magnitude of a harmful outcome, should it occur, and not on the likelihood that it will occur (National Research Council, 2003). This can result in what has been called concern for “the eggshell participant”: an IRB may come to focus on any conceivable risk for any conceivable participant and proceed “as if the risk faced by this ‘eggshell’ participant were the risk faced by all (or even the modal) prospective participant”(Meyer, 2013, p. 39). This tendency to overestimation of risk has important and widespread consequences. It means that much research that currently fits within the current exempt category is subjected to expedited review, while minimal- risk research appropriate for expedited review is sometimes inappropriately viewed by an IRB as requiring full board review (Freundschuh, 2012; Petersen et al., 2012). At a minimum, overestimation of social and be- havioral science research risk has slowed the review process. But more critically it has also resulted in IRBs requiring changes to minimize remote risks—changes that can compromise the scientific validity of the research or pose insurmountable barriers to studies essential for understanding social, behavioral, cognitive, and emotional influences affecting public health and well-being. If not adequately addressed through regulation or OHRP guidance, this problem may persist and extend to IRB evaluation of the ANPRM’s newly proposed “excused” category (76 Fed. Reg. 44,518- 44,520). Indeed, mission creep has persisted in IRB review despite state- ments throughout the Final Regulations Amending Basic HHS Policy for the Protection of Human Research Subjects that the exempt and expedited categories were specifically included to help reduce IRB burden in reviewing social science research that poses no risk, low risk, or minimal risk (U.S. Department of Health and Human Services, 1981). Distinguishing Research Vulnerability from Social Vulnerability One reason for the overestimation of harm in social and behavioral research, as well as in biomedical research, is the vague regulatory require- ment to provide special protections for “vulnerable” populations under 45 C.F.R. § 46.111(b): When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally

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DETERMINING MINIMAL RISK 67 disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects. The current wording of § 46.111(b), while well intentioned, is too broad to provide a useful metric for determining when and under what cir- cumstances research would pose greater than minimal risk for any specific population. At the same time, this wording inadvertently encourages IRBs to apply subjective estimations of the nature, magnitude, and probability of the research harms faced by any population assumed to be vulnerable. In the absence of guidance to distinguish social vulnerability from research vulnerability, this wording appears to have inadvertently led IRBs to over- estimate research risks for these populations, a particular problem for social and behavioral research studies. For example, there is an abundance of investigator reports of survey studies for research on sexuality, drug use, and other health-relevant behaviors in which IRBs have created barriers to research implementation based on the empirically unsupported claim that surveys or interviews on such topics may harm participants by encouraging them to engage in the behaviors being studied (Fendrich et al., 2007; Fisher, 2002, 2003; Fisher et al., 2013, p. 5; Langhinrichsen-Rohling et al., 2006; Mustanski, 2011). Many social and behavioral science studies are designed to observe, survey, assess, or evaluate prevention or intervention programs designed to address vulnerabilities and protective factors associated with health disparities among socially vulnerable populations: for example, individuals with learning problems, substance abuse disorders, sexual and other health compromising behaviors, or a history of interpersonal violence or racial or sexual discrimination. However, just because the life histories of these indi- viduals are characterized by higher levels of psychological and other harms than the general population does not mean that they are more susceptible to research risks (DuBois et al., 2012). As proposed in her model of Goodness- of-Fit Ethics, Fisher has argued that research vulnerability should be defined not by participant characteristics but as the joint product of the fit between participant characteristics and the specific research context (Fisher, 2002; Fisher and Goodman, 2009; Fisher and Ragsdale, 2006; Masty and Fisher, 2008). Thus, in assessing risk, it is crucial to distinguish between harm that may be caused by the research participation itself and harms that may be caused by the life situation or characteristics of the research participants. The latter harms, while real, are not caused by the research. For example, members of historically oppressed racial/ethnic minority groups in the United States may be subject to higher levels of psychological stress associ- ated with explicit and implicit social, economic, and other forms of dis- crimination. But that fact alone does not raise to above minimal risk levels

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68 PROPOSED REVISIONS TO THE COMMON RULE of psychological harm their participation in a survey study on frequency of, and their emotional responses to, everyday discrimination. Failure to distinguish between vulnerabilities in participants’ lives and their vulnerability to research risks can also lead to erroneous greater-than- minimal-risk classifications in IRB evaluations of prevention programs based on social and behavioral research results. Take, for example, a study designed to use a peer-education model to increase participants’ knowledge about, and motivation to get tested at, local clinics for HIV, in which the participants are economically disenfranchised persons who inject drugs. The outcome measures include pre- and post-intervention surveys and indi- vidual interviews on drug use, HIV risk behavior, frequency of HIV testing, and, with written permission of participants, access to clinic information on their HIV testing. Although there are health risks of potentially high magni- tude associated with injection drug use, HIV risk behaviors, and reactions to HIV testing, these risks are not produced by the educational prevention format; the survey and interview questions; or the adequacy of HIV test- ing, counseling, and treatment provided by local clinics. No evidence-based rationale exists for assuming the study procedures themselves exacerbate or create the risks faced by the study population. In addition, since Subparts B, C, and D of Part 46 are specifically designed to provide adequate additional protections for pregnant women, prisoners, and children, respectively, asking IRBs to consider these popu- lations at risk not covered by these subparts places an undue barrier to research critical in enhancing understanding and promotion of health and well-being in these populations. The committee believes the regulatory language of § 46.111 should be eliminated and replaced by guidance (dis- cussed in greater detail below) on (a) distinguishing between vulnerabilities in participants’ lives and their vulnerability to research risks and (b) pro- cedures for assessing the extent to which the fit between participant char- acteristics and research procedures adequately minimizes research harms and discomforts. With respect to a related issue, even though considering the long-range effects of applying knowledge gained in research is currently outside an IRB’s purview (45 C.F.R. § 46.111(a)(2)), some IRBs have included in their evaluation of social harm the consequences for the entire group of conduct- ing social and behavioral research studies involving members of populations suffering from current and historical discrimination, if the study includes collection of data on socially stigmatizing topics such as substance abuse or antisocial behavior. The ethical relevance of considering group conse- quences will differ depending on the extent to which an individual person or a community is the focus of research. Risks to groups in community- engaged research may arise from transferring, for example, disease study results for an individual to a group, or stigma from a group causing harm

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DETERMINING MINIMAL RISK 69 to an individual (Anderson et al., 2012). For example, in some instances the needs of the community may not coincide with the needs of less power- ful individuals who are the focus of an investigation (Fisher et al., 2002). Investigator and IRB decision making regarding research involving indi- vidual members of social minorities’ communities and that involving the community itself will benefit from identifying and communicating with the stakeholders to whom human subjects protections are directly applicable (DuBois et al., 2012). The committee believes that Subpart D of Part 46 already includes suf- ficient provisions for protecting the rights and welfare of child populations, and we endorse the recommendation of the SRCD Task Force that OHRP provide explicit guidance indicating that research involving children as a class should not by default be required to undergo full board review (Fisher et al., 2013, p. 4). Consideration of Steps Taken to Reduce Risk in the Assessment of Minimal Risk Under current OHRP guidance, research posing what in the current ANPRM is labeled “informational risk” can be considered minimal-risk research if reasonable and appropriate protections are implemented so that disclosure risks are no greater than minimal.4 The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. In its response to the ANPRM, SACHRP noted that an IRB’s evalua- tion of whether the harms and discomforts of research subject to expedited review meet minimal risk standards should take into account steps taken to minimize risk.5 The committee agrees with this SACHRP recommendation that regulations harmonize criteria for evaluating the level of risk for infor- mational and other types of research harms by requiring consideration of the adequacy of steps taken to minimize risk in the calibration of magnitude and probability of harm. In Recommendation 3.3, below, we recommend 4  Quoted text is from “Categories of Research That May be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure,” condition 3 under “Applicabil- ity.” See http://www.hhs.gov/ohrp/policy/expedited98.html [November 2013]. 5  See the 2011 SACHRP Letter to the HHS Secretary at http://www.hhs.gov/ohrp/sachrp/ commsec/sachrpanprmcommentsfinal.pdf.pdf [November 2013].

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78 PROPOSED REVISIONS TO THE COMMON RULE orphans,” unable to accrue the benefits derived from scientific advances (Leonard et al. 1996). (Fisher et al., 2013, pp. 3-4) To help remove these unsupported obstacles to valuable research, the committee has recommended, in its Guidance Recommended, that OHRP underscore the applicability of the expedited categories to research involv- ing children and provide specific age-indexed examples. Risk Equivalence and Expedited Review No list can adequately include all the variations in minimal-risk re- search procedures that should be eligible for expedited review. And waiting for the list to be updated may result in unnecessary barriers to responsible science. There are many ways to judge the risk equivalence of research pro- cedures including the duration and frequency of the procedure, the cumula- tive risk posed by a set of procedures, and the degree to which any harms, if they do occur, are transient and reversible. OHRP thus needs to make clear that the list of expedited review categories is an example rather than an exhaustive, limited set of procedures. Further, procedures not specifically listed in the expedited categories should be considered minimal risk if their risks can be determined to be functionally equivalent or less in probability and magnitude of harms and discomforts to listed procedures. Ensuring Adequate Classification of Excused and Expedited Categories The committee welcomes the current ANPRM proposal to classify surveys, educational tests, interviews, focus groups, and specified types of benign interventions used in social and behavioral research as excused if they only present informational risk (see Chapter 2). However, additional guidance is needed to help investigators and IRBs appropriately distinguish between minimal risk procedures that are appropriately classified under the excused versus the expedited review categories. For example, under current conditions IRBs have had difficulty distinguishing social and behavioral research procedures, such as surveys that meet criteria for exemption, from those that should undergo expedited review. Without explicit guidance, this confusion may extend to instances in which research that should be clas- sified under the new proposed category of excused research is erroneously subjected to expedited review. In its response to the ANPRM, SACHRP noted that evaluation of the harms and discomforts of the research should take into account (a) the nature of the study procedures; (b) other study characteristics; (c) charac- teristics of subjects to be enrolled in the research, including an evaluation of subject susceptibility, vulnerability, resilience, and experience in relation to

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DETERMINING MINIMAL RISK 79 the procedures; and (d) steps taken to minimize risk.8 Research appropriate for expedited review includes studies that, because of the specific nature of the research procedures and/or the characteristics of the subject population, require consideration of human subjects protections beyond those normally applied, in order to ensure that harm or discomfort created solely by the research procedures are not greater than minimal risk. Recommendation 3.4: HHS should clarify in regulations the conditions under which research methods, that might otherwise be classified under the new excused category, are appropriate for expedited review because the specific nature of the research procedures and/or the characteris- tics of the subject population require consideration of human subjects protections beyond those normally applied for excused research, in order to ensure that harm or discomfort created solely by the research procedures are not greater than minimal risk. Guidance Recommended: The committee offers below elements of a guidance statement that would help investigators, IRBs, and research and academic institutions understand when studies implementing the methods described under the excused category require expedited re- view. Such guidance, if issued by OHRP, would assist investigators and IRBs in developing risk-minimizing human subjects protections appropriate for the following special situations, in which protections are needed beyond those required to minimize informational risk: a. The participant population is known to have decisional vulnerabili- ties empirically established to require enhanced informed consent protections for the type of study to be conducted. b. The study is designed to produce clinical changes in health, health- related behaviors or symptomology, and includes identifiable information. c. Public awareness of recruitment procedures can jeopardize partici- pant physical safety or reveal criminal behavior. d. The nature of the research data collected requires specific plans for reporting illegal behaviors, providing emergency treatment, or protecting a participant or third party from physical harm. e. Use of deceptive techniques includes procedures that are specifically designed to induce psychological, social, or physical discomfort. 8  Seethe 2011 SACHRP Letter to the HHS Secretary at http://www.hhs.gov/ohrp/sachrp/ commsec/sachrpanprmcommentsfinal.pdf.pdf [November 2013].

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80 PROPOSED REVISIONS TO THE COMMON RULE f. Additional protections are necessary to avoid harms produced by an existing professional or service relationship with research staff that would compromise voluntary participation. Below are some examples of research, keyed to the special situations listed in the Guidance Recommended above, for which it would be appro- priate to assign the research protocol to expedited review: a. A study involving individuals diagnosed with obsessive-compulsive disorder and a nonclinical population designed to assess the valid- ity of a scale to detect malingering. b. A survey study asking adults with intellectual disabilities about their adaptation to independent living housing. c. Research comparing the effectiveness of a peer- versus counselor-led education program to reduce alcohol consumption among college students found in violation of institutional rules against drinking on campus. d. A study recruiting street-drug users in public spaces that has the potential to alert local police to prospective participants’ illegal behaviors. e. A focus group study on parenting styles that asks for specific ex- amples of physical discipline that may elicit reports meeting criteria of child abuse that an investigator is required by law to report. f. A deception study using a confederate to assess participants’ emo- tional reactions to peer rejection. g. A study on nursing aides’ attitudes toward patients hospitalized for HIV-related infections, conducted by a senior psychologist on staff. Guidance Recommended: The following actions would facilitate the adequate classification of excused and expedited risk categories: • OHRP should expand the list of research eligible for expedited review to include additional specific examples of social and behav- ioral research to assist investigators and IRBs in identifying when a protocol should be submitted for expedited review. • The standing committee appointed by OHRP to review and update categories for expedited review should have sufficient representa- tion from researchers with expertise in social and behavioral re- search involving a wide range of populations. • OHRP should take steps to ensure that investigators and IRBs appropriately apply categories for expedited review to research involving children and adolescents and do not by default require research involving children to undergo full board review.

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DETERMINING MINIMAL RISK 81 • OHRP should clarify that the types of research listed in the ex- pedited category are examples rather than an exhaustive, limited set of procedures. Further, it should be clarified that procedures not specifically listed in the expedited categories should be con- sidered minimal risk if their risk can be determined to be func- tionally equivalent or less in probability and magnitude of harms and discomforts to listed procedures. In addition, to ensure equal protection and opportunities for participation for all populations, equivalent risk evaluations should not be based solely on the con- tent area covered by an examination or test (e.g., health behaviors) but on whether the content, method, and language of inquiry is population-appropriate and whether the investigator has the train- ing required to treat participants with sensitivity and respect. Procedural Improvements Needed: Investigators and IRBs might con- sider for expedited review research protocols whose risks can be de- termined to be functionally equivalent to research methods specifically described in current expedited review categories. Estimates of risk equivalence can include the duration and frequency of the procedure, the cumulative risk posed by a set of procedures, and the degree to which any harms, if they do occur, are transient and reversible. Individuals who are vulnerable to risks in their daily lives should not be considered by default to be more susceptible to greater than minimal research risks than other populations. Rather, established sci- entific knowledge or professional expertise should be considered that indicates which specific types of research procedures are associated with an increase in the probability and/or magnitude of harms for specific participant populations. RESEARCH INVOLVING GREATER THAN MINIMAL RISK AND REQUIRING FULL BOARD REVIEW As discussed above, the majority of social and behavioral science re- search methods pose harms of no greater than minimal risk either in and of themselves or once appropriate human subjects protections are instituted that ensure the probability and magnitude of harm posed by research par- ticipation are minimal. Rare instances of greater-than-minimal-risk social and behavioral research might occur, for example, when a psychological or behavioral intervention study involving individuals with serious mental health disorders includes treatments that have a reasonable possibility of exacerbating distressful or maladaptive psychological or behavioral symp- toms (for instance, a study testing effectiveness of exposure therapy for

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82 PROPOSED REVISIONS TO THE COMMON RULE severe phobias). A second example might include the potential for physical harm indirectly associated with assertiveness training for victims of inter- personal violence who are still living with their abusive partners. A third example might include studies involving institutionalized individuals with declining or persistent neurocognitive or affective disorders whose ability to understand or assert their right to refuse or withdraw from participation may be compromised by the research context. Guidance Recommended: To avoid overestimation of risk, OHRP guidance is recommended to clarify that expedited review should be considered the default procedure for evaluating social and behavioral science research that is not excused. In addition, decisions to require full board review should be based on established scientific or profes- sional knowledge indicating a significant probability that participants will experience a magnitude of risk that is greater than minimal and that cannot be adequately reduced through risk-minimizing procedures. OHRP guidance is also recommended to clarify that research involving children, prisoners, persons from economically or socially disenfranchised groups, individuals with mental disorders, those engaged in illegal activities, or other social groups traditionally labeled as “vulnerable” should not by default require full board review. IRBs should be directed to only assign such studies for full board review if the research procedures pose greater than minimal risk and appropriate human subjects protections may not be sufficient to reduce such risks to the level of minimal risk. Procedural Improvements Needed: In determining whether research poses greater than minimal risk, investigators and IRBs should draw on established scientific or professional knowledge to help determine whether the probability and magnitude of harms associated with the research procedures themselves pose greater than minimal risk and that appropriate human subjects protections may not be sufficient to reduce them to minimal risk levels. STREAMLINING EXPEDITED AND FULL BOARD REVIEW The committee endorses the ANPRM recommendation that research approved under expedited review should not require continuing review (76 Fed. Reg. 44,517). However, this recommendation alone does not ad- equately address the problem of lengthy delays for IRB review of research in the expedited category (Gordon, 2003; Koski, 2002). We therefore recom- mend below that OHRP guidance to IRBs specify time limits in processing research under expedited review.

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DETERMINING MINIMAL RISK 83 There will be instances in which a protocol submitted includes new research methodologies, population characteristics, or research contexts for which established scientific and professional evidence, the investiga- tor’s previous research experience, or clear guidance on human subjects protections may require full board review to ascertain whether or not the research presents no greater than minimal risk. To ensure appropriate hu- man subjects protections, flexibility in assignment to expedited or full board review is required in such situations. Timeliness of review is also required to ensure that the need for IRB deliberation does not cause delays that create undue barriers to the conduct of socially significant research and ethically responsible research. Consequently, regulations should specify time limits on the IRB processing of research under full board review, the time permit- ted to elapse before communicating a decision to the investigator, and, if the protocol is not approved, the specific nature of information communicated to the investigator to facilitate timely re-review. Recommendation 3.5: To streamline expedited and full board review and procedures, HHS should eliminate the requirement for continuing review for expedited research. Guidance Recommended: OHRP should offer specific guidance on time limits for conducting expedited reviews and processing research under full board review. For example, with rare exception, a decision on ex- pedited review by the IRB should be communicated to the investigator within 2 business weeks. If the review does not result in an approval, the IRB should provide a specific rationale and directives for the spe- cific information required for the review to proceed in a timely manner via deferral, specific directive comments, or a decision to submit the protocol for full board review. Full board meetings would reasonably be scheduled approximately once a month to ensure timely review of research protocols. With rare exception, a decision by the IRB should be communicated to the investiga- tor within 10 business days of the full board meeting. If the review does not result in an approval, the IRB should provide a specific rationale and directives for the specific information required for the review to proceed in a timely manner. ESTABLISHING AN EMPIRICAL KNOWLEDGE BASE FOR LEVEL OF RISK IRBs should recognize that daily life is not a risk-free affair. For ex- ample, car trips and sports have risk and are a part of daily life (Wendler

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84 PROPOSED REVISIONS TO THE COMMON RULE et al., 2005). But even those normal daily risks may be context-specific, and the related benefits of the activities in context must be considered in assessing the risk. Moreover, there is limited empirical data about the risks of daily life (Fisher et al., 2007). Thus, even if there is consensus that a “general population” standard should be used for assessment of minimal risk, there will be continued disagreement as to what constitutes “routine experiences ordinarily encountered.” For much research, a better standard for comparison may be routine tests and examinations, especially when those routine tests are contextually similar to the research under consider- ation (Fisher et al., 2007; Resnik, 2005). The committee does not take a position on whether the daily-life risks or those of routine tests or examinations should take precedence. Both aspects can help IRBs consider levels of risk. What is clear, however, is that those standards alone are not sufficient to guide IRBs. More empirical research is needed on the relative risks of the various bases used to assess a minimal level of risk. IRBs need concrete contextual examples to guide their deliberation. While greater clarity in regulatory language would no doubt be helpful, it does not eliminate the need for continued research and guidance. Research Needed: Research is needed to study the effects of social and behavioral science research on research participants so that evidence- based assessments of “known and foreseeable” risk are more feasible. In particular, research is needed to properly address nonphysical risks of research and the methods that create them, rather than having IRBs rely on anecdote or moving to make drastic changes based on efficiency. Research is also needed on the effectiveness of confidentiality strategies in reducing risks of physical, social, economic, and legal harm. REFERENCES Anderson, E., Solomon, S., Heitman, E., DuBois, J.M., Fisher, C.B., Kost, R.G., Lawless, M.E., Ramsey, C., Jones, B., Ammerman, A., and Ross, L.F. (2012). Research ethics education for community-engaged research: A review and research agenda. Journal of Empirical Research on Human Research Ethics, 7(2):3-19. Briefel, G., Stiff, J., and Nelson, R. (2002). Nontherapeutic research and minimal risk. IRB: Ethics and Human Research, 24(3):14-15. Ceci, S.J., and Bruck, M. (2009). Do IRBs pass the minimal harm test? Perspectives in Psy- chological Science, 4(1):28-29. DuBois, J.M., Beskow, L., Campbell, J., Dugosh, K., Festinger, D., Hartz, S., James, R., and Lidz, C. (2012). Restoring balance: A consensus paper on the protection of “vulnerable” research participants. American Journal of Public Health, 102(12):2220-2225. Emanuel, E.J., and Menikoff, J. (2011). Reforming the regulations governing research with human subjects. New England Journal of Medicine, 365(12):1145-1150.

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DETERMINING MINIMAL RISK 85 Fendrich, M., Lippert, A., and Johnson, T.P. (2007). Respondent reaction to sensitive ques- tions. Journal of Empirical Research on Human Research Ethics, 2(3):31-37. Fisher, C.B. (2002). Participant consultation: Ethical insights into parental permission and confidentiality procedures for policy relevant research with youth. Pp. 371-396 in R.M. Lerner, F. Jacobs, and D. Wertlieb (Eds.), Handbook of Applied Developmental Science Vol. 4. Thousand Oaks, CA: Sage. Fisher, C.B. (2003). A goodness-of-fit ethic for child assent to nonbeneficial research. American Journal of Bioethics, 3(4):27-28. Fisher, C.B., and Goodman, S.J. (2009). Goodness-of-fit ethics for non-intervention research involving dangerous and illegal behaviors. Pp. 25-46 in D. Buchanan, C.B. Fisher, and L. Gable (Eds.), Research with High-Risk Populations: Balancing Science, Ethics, and Law. Washington, DC: APA Books. Fisher, C.B., and Ragsdale, K. (2006). A goodness-of-fit ethics for multicultural research. Pp. 3-26 in J. Trimble and C.B. Fisher (Eds.), The Handbook of Ethical Research with Ethnocultural Populations and Communities. Thousand Oaks, CA: Sage. Fisher, C.B., Hoagwood, K., Boyce, C., Duster, T., Frank, D.A., Grisso, T., Macklin, R., Levine, R.J., Spencer, M.B., Takanishi, R., Trimble, J.E., and Zayas, L.H. (2002). Re- search ethics for mental health science involving ethnic minority children and youth. American Psychologist, 57(12):1024-1040. Fisher, C.B., Kornetsky, S.Z., and Prentice, E.D. (2007). Determining risk in pediatric research with no prospect of direct benefit: Time for a national consensus on the interpretation of federal regulations. American Journal of Bioethics, 7(3):5-10. Fisher, C.B., Oransky, M., Mahadevan, M., Singer, M., Mirhej, G., and Hodge, G.D. (2008). Marginalized populations and drug addiction research: Realism, mistrust, and miscon- ception. IRB: Ethics and Human Research, 30(3):1-9. Fisher, C.B., Brunnquell, D.J., Hughes, D.L., Liben, L.S., Maholmes, V., Plattner, S., Russell, S.T., and Sussman, E.J. (2013). Preserving and enhancing the responsible conduct of research involving children and youth: A response to proposed changes in federal regula- tions. Social Policy Report, 27(1):1, 3-15. Freundschuh, S.M. (2012). Institutional review for research in the social sciences from the federal perspective. Professional Geographer, 64(1):43-48. Gordon, E. (2003). Trials and tribulations of navigating IRBs: Anthropological and bio­ edical m perspectives of ‘risk’ in conducting human subjects research. Anthropological Quarterly, 76(2):299-320. Green, L.A., Lowery, J.C., Kowalski, C.P., and Wyszewianski, L. (2006). Impact of institu- tional review board practice variation on observational health services research. Health Services Research, 41(1):214-230. Hoagwood, K., Jensen, P.S., and Fisher, C.B. (1996). Towards a science of scientific ethics in research on child and adolescent mental disorders. Pp. 3-14 in K. Hoagwood, P. Jensen, and C.B. Fisher (Eds.), Ethical Issues in Mental Health Research with Children and Adolescents. Hillsdale, NJ: Lawrence Erlbaum Associates. Institute of Medicine. (2004). Ethical Conduct of Clinical Research Involving Children. M.J. Field and R.E. Behrman (Eds). Washington, DC: The National Academies Press. Klitzman, R. (2011). The myth of community differences as the cause of variations among IRBs. AJOB Primary Research, 2(2):24-33. Kodish, E. (2005). Ethics and Research with Children: A Case-Based Approach. New York: Oxford University Press. Kopelman, L. (2004). Minimal risk as an international ethical standard in research. Journal of Medicine and Philosophy, 29(3):351-358. Koski, G. (2002, April 17). An Open Letter to the Human Research Community. Available: http://archive.hhs.gov/ohrp/humansubjects/qip/oltr.pdf [December 2013].

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86 PROPOSED REVISIONS TO THE COMMON RULE Langhinrichsen-Rohling, J., Arata, C., O’Brien, N., Bowers, D., and Klibert, J. (2006). Sensi- ������ tive research with adolescents: Just how upsetting are self-report surveys anyway? Vio- lence and Victims, 21(4):425-444. Lazovski, J., Losso, M., Krohmal, B., Emanuel, E. Z., Grady, C., and Wendler, D. (2009). Benefits and burdens of participation in a longitudinal clinical trial. Journal of Empirical Research on Human Research Ethics, 4(3):89-97. Leonard, H., Jensen, P.S., Vitiello, B., Ryan, N., March, J., Riddle, M., and Biederman, J. (1996). Ethical issues in psychopharmacological treatment research with children and adolescents. Pp. 73-88 in K. Hoagwood, P. Jensen, and C.B. Fisher (Eds.), Ethical Issues in Mental Health Research with Children and Adolescents. Hillsdale, NJ: Lawrence Erlbaum Associates. Leykin, Y., Christopher, P.P., Holtzheimer, P.E., Appelbaum, P.S., Mayberg, H.S., Lisanby, S.H., and Dunn, L.B. (2011). Participants’ perceptions of deep brain stimulation research for treatment-resistant depression: Risks, benefits, and therapeutic misconception. AJOB Primary Research, 2(4):33-41. Lidz, C., and Garverich, S. (2013). What the ANPRM missed: Additional needs for IRB re- form. Journal of Law, Medicine and Ethics, 41(2):390-396. Masty, J., and Fisher, C.B. (2008). A goodness-of-fit approach to parent permission and child assent pediatric intervention research. Ethics and Behavior, 18(2-3):139-160. McDonald, M., Townsend, A., Cox, S., Paterson, N., and Lafrenière, D. (2008). Trust in health research relationships: Accounts of human subjects. Journal of Empirical Research on Human Research Ethics, 3(4):35-47. Meyer, M.N. (2013). Regulating the production of knowledge: Research risk-benefit analy- sis and the heterogeneity problem. Administrative Law Review, 65(237). Available: http://ssrn.com/abstract=2138624 or http://dx.doi.org/10.2139/ssrn.2138624 [December 2013]. Mustanski, B. (2011). Ethical and regulatory issues with conducting sexuality research with LGBT adolescents: A call to action for a scientifically informed approach. Archives of Sexual Behavior, 40(4):673-686. National Human Research Protections Advisory Committee. (2001). Children’s Workgroup Report: April 2001 Meeting. Available: http://www.hhs.gov/ohrp/archive/nhrpac/ mtg04-01/child-workgroup4-5-01.pdf [December 2013]. National Research Council. (2003). Protecting Participants and Facilitating Social and Be- havioral Sciences Research. Panel on Institutional Review Boards, Surveys, and Social Science Research. C.F. Citro, D.R. Ilgen, and C.B. Marrett (Eds.). Committee on National Statistics and Board on Behavioral, Cognitive, and Sensory Sciences. Washington, DC: The National Academies Press. Oakes, J.M. (2002). Risks and wrongs in social science research: An evaluator’s guide to the IRB. Evaluation Review, 26(5):443-479. Office for Human Research Protection. (1993). Protecting Human Research Subjects: Insti- tutional Review Board Guidebook. Washington, DC: U.S. Government Printing Office. Available: http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm [December 2013]. Pearlman, R.A., Cohen, J.H., Foglia, M., and Fox, E. (2013). Perceptions of research ethics practices: Integrated ethics™ staff survey data from the VA health care system. AJOB Primary Research, 4(1):34-43. Petersen, L.A., Simpson, K., SoRelle, R., Urech, T., and Chitwood, S.S. (2012). How variabil- ity in the institutional review board review process affects minimal-risk multisite health services research. Annals of Internal Medicine, 156(10):728-735. Pritchard, I.A. (2011). How do IRB members make decisions? A review and research agenda. Journal of Empirical Research on Human Research Ethics, 6(2):31-46.

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DETERMINING MINIMAL RISK 87 Resnik, D.B. (2005). Eliminating the daily life risks standard from the definition of minimal risk. Journal of Medical Ethics, 31(1):35-38. Rid, A., Emanuel, E.J., and Wendler, D. (2010). Evaluating the risks of clinical research. Journal of the American Medical Association, 304(13):1472-1479. Secretary’s Advisory Committee on Human Research Protections. (2005, April 18-19; Novem- ber 1). Meeting Presentations and Reports. Available: http://www.hhs.gov/ohrp/archive/ sachrp/mtgings/mtg04-05/present.htm [December 2013]. Secretary’s Advisory Committee on Human Research Protections. (2008, January 21). SACHRP Letter to HHS Secretary. Available: http://www.hhs.gov/ohrp/sachrp/sachrpletter013108. html [October 2013]. Shah, S., Whittle, A., Wilfond, B., Gensler, G., and Wendler, D. (2004). How do institutional review boards apply the federal risk and benefit standards for pediatric research? Journal of the American Medical Association, 291(4):476-482. Snyder, J., Miller, C.L., and Gray, G. (2011). Relative versus absolute standards for everyday risk in adolescent HIV prevention trials: Expanding the debate. American Journal of Bioethics, 11(6):5-13. U.S. Department of Health and Human Services. (1979). The Belmont Report: Ethical Prin- ciples and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Re- search. Washington, DC: U.S. Department of Health and Human Services. Available: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html [October 2013]. U.S. Department of Health and Human Services. (1981). Final regulations amending basic HHS policy for the protection of human research subjects. Federal Register, 46(16):8366-8391. U.S. Department of Health and Human Services. (2011). Department’s recent Advance Notice of Proposed Rulemaking (ANRM) protection subjects and reducing burden, delay, and ambiguity for investigators. Federal Register, 76(143):44512-44531. Available: http:// www.gpo.gov/fdsys/pkg/FR-2011-07-26/html/2011-18792.htm [December 2013]. Wendler, D., Belsky, L., Thompson, K., and Emanuel, E. (2005). Quantifying the federal minimal risk standard: Implications for pediatric research without a prospect of direct benefit. Journal of the American Medical Association, 294(7):826-832. Westra, A.E., Wit, J.M., Sukhai, R.N., and de Beaufort, I.D. (2011). How best to define the concept of minimal risk. The Journal of Pediatrics, 159(3):496-500.

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