D
Code of Federal Regulations Title 45: Public Welfare
Part 46: Protection of Human Subjects

This appendix contains the text of Part 46 Protection of Human Subjects of Title 45 Public Welfare of the Code of Federal Regulations (C.F.R.). Part 46 of the C.F.R.s were revised June 23, 2005, and made effective that day. Below is a table of contents listing the sections of Subparts A through D. Following are sections that cover each subpart in turn.



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D Code of Federal Regulations Title 45: Public Welfare Part 46: Protection of Human Subjects This appendix contains the text of Part 46 Protection of Human Sub- jects of Title 45 Public Welfare of the Code of Federal Regulations (C.F.R.). Part 46 of the C.F.R.s were revised June 23, 2005, and made effective that day. Below is a table of contents listing the sections of Subparts A through D. Following are sections that cover each subpart in turn. Subpart A: Basic DHHS Policy for Protection of Human Research Subjects Sec. 46.101 To what does this policy apply? 46.102 Definitions 46.103 Assuring compliance with this policy—research con- ducted or supported by any federal department or agency 46.104– [Reserved] 46.106 46.107 IRB membership 46.108 IRB functions and operations 46.109 IRB review of research 46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk and for minor changes in approved research 46.111 Criteria for IRB approval of research 46.112 Review by institution 205

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206 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS 46.113 Suspension or termination of IRB approval of research 46.114 Cooperative research 46.115 IRB records 46.116 General requirements for informed consent 46.117 Documentation of informed consent 46.118 Applications and proposals lacking definite plans for involvement of human subjects 46.119 Research undertaken without the intention of involving human subjects 46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a federal department or agency 46.121 [Reserved] 46.122 Use of federal funds 46.123 Early termination of research support: evaluation of applications and proposals 46.124 Conditions Subpart B: Additional Protections for Pregnant Women, Human Fetuses, and Neonates Involved in Research Sec. 46.201 To what do these regulations apply? 46.202 Definitions 46.203 Duties of IRBs in connection with research involving pregnant women, fetuses, and neonates 46.204 Research involving pregnant women or fetuses 46.205 Research involving neonates 46.206 Research involving, after delivery, the placenta, the dead fetus, or fetal material 46.207 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women, fetuses, or neonates Subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Sec. 46.301 Applicability 46.302 Purpose

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207 APPENDIX D 46.303 Definitions 46.304 Composition of IRBs where prisoners are involved 46.305 Additional duties of the IRBs where prisoners are involved 46.306 Permitted research involving prisoners Subpart D: Additional Protections for Children Involved as Subjects in Research Sec. 46.401 To what do these regulations apply? 46.402 Definitions 46.403 IRB duties 46.404 Research not involving greater than minimal risk 46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition 46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children 46.408 Requirements for permission by parents or guardians and for assent by children 46.409 Wards The authority for these federal regulations can be found in 5 U.S.C. 301 and 42 U.S.C. 289(a). Note that the Department of Health and Human Services (DHHS) issued a notice of waiver regarding the requirements set forth in Part 46, relating to protection of human subjects, as they pertain to demonstration projects, approved under section 1115 of the Social Security Act, which test the use of cost-sharing, such as deductibles, copayment, and coinsurance, in the Medicaid program. For further information see 47 Federal Register 9208, Mar. 4, 1982. As revised, Subpart A of the DHHS regulations incorporates the Fed- eral Policy for the Protection of Human Subjects (56 FR 28003). Subpart D of the DHHS regulations has been amended at Section 46.401(b) to refer- ence the revised Subpart A.

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208 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS The Federal Policy for the Protection of Human Subjects is also codi- fied at the following: 7 C.F.R. Part 1c Department of Agriculture 10 C.F.R. Part 745 Department of Energy 14 C.F.R. Part 1230 National Aeronautics and Space Administration 15 C.F.R. Part 27 Department of Commerce 16 C.F.R. Part 1028 Consumer Product Safety Commission 22 C.F.R. Part 225 International Development Cooperation Agency, Agency for International Development 24 C.F.R. Part 60 Department of Housing and Urban Development 28 C.F.R. Part 46 Department of Justice 32 C.F.R. Part 219 Department of Defense 34 C.F.R. Part 97 Department of Education 38 C.F.R. Part 16 Department of Veterans Affairs 40 C.F.R. Part 26 Environmental Protection Agency 45 C.F.R. Part 690 National Science Foundation 49 C.F.R. Part 11 Department of Transportation Subpart A: Basic DHHS Policy for Protection of Human Research Subjects Authority: 5 U.S.C. 301; 42 U.S.C. 289(a); 42 U.S.C. 300v-1(b). Source: 56 FR 28003, June 18, 1991; 70 FR 36325, June 23, 2005. §46.101 To what does this policy apply? (a) Except as provided in paragraph (b) of this section, this policy applies to all research involving human subjects conducted, supported, or otherwise subject to regulation by any federal department or agency which takes appropriate administrative action to make the policy applicable to such research. This includes research conducted by federal civilian employees or military personnel, except that each department or agency head may adopt such procedural modifications as may be appropriate from an administra- tive standpoint. It also includes research conducted, supported, or other- wise subject to regulation by the federal government outside the United States. (1) Research that is conducted or supported by a federal department or agency, whether or not it is regulated as defined in §46.102(e), must com- ply with all sections of this policy.

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209 APPENDIX D (2) Research that is neither conducted nor supported by a federal depart- ment or agency but is subject to regulation as defined in §46.102(e) must be reviewed and approved, in compliance with §46.101, §46.102, and §46.107 through §46.117 of this policy, by an institutional review board (IRB) that operates in accordance with the pertinent requirements of this policy. (b) Unless otherwise required by department or agency heads, research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from this policy: (1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, cur- ricula, or classroom management methods. (2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or obser- vation of public behavior, unless: (i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects’ responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation. (3) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or obser- vation of public behavior that is not exempt under paragraph (b)(2) of this section, if: (i) the human subjects are elected or appointed public officials or candi- dates for public office; or (ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter. (4) Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through iden- tifiers linked to the subjects. (5) Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs. (6) Taste and food quality evaluation and consumer acceptance studies, (i)

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210 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS if wholesome foods without additives are consumed or (ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. (c) Department or agency heads retain final judgment as to whether a particular activity is covered by this policy. (d) Department or agency heads may require that specific research activities or classes of research activities conducted, supported, or otherwise subject to regulation by the department or agency but not otherwise covered by this policy, comply with some or all of the requirements of this policy. (e) Compliance with this policy requires compliance with pertinent federal laws or regulations which provide additional protections for human sub- jects. (f) This policy does not affect any state or local laws or regulations which may otherwise be applicable and which provide additional protections for human subjects. (g) This policy does not affect any foreign laws or regulations which may otherwise be applicable and which provide additional protections to human subjects of research. (h) When research covered by this policy takes place in foreign countries, procedures normally followed in the foreign countries to protect human subjects may differ from those set forth in this policy. [An example is a foreign institution which complies with guidelines consistent with the World Medical Assembly Declaration (Declaration of Helsinki amended 1989) issued either by sovereign states or by an organization whose function for the protection of human research subjects is internationally recognized.] In these circumstances, if a department or agency head determines that the procedures prescribed by the institution afford protections that are at least equivalent to those provided in this policy, the department or agency head may approve the substitution of the foreign procedures in lieu of the proce- dural requirements provided in this policy. Except when otherwise required by statute, Executive Order, or the department or agency head, notices of these actions as they occur will be published in the Federal Register or will be otherwise published as provided in department or agency procedures.

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211 APPENDIX D (i) Unless otherwise required by law, department or agency heads may waive the applicability of some or all of the provisions of this policy to specific research activities or classes or research activities otherwise covered by this policy. Except when otherwise required by statute or Executive Order, the department or agency head shall forward advance notices of these actions to the Office for Human Research Protections, Department of Health and Human Services (DHHS), or any successor office, and shall also publish them in the Federal Register or in such other manner as provided in department or agency procedures.1 §46.102 Definitions. (a) Department or agency head means the head of any federal department or agency and any other officer or employee of any department or agency to whom authority has been delegated. (b) Institution means any public or private entity or agency (including federal, state, and other agencies). (c) Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) in- volved in the research. (d) Research means a systematic investigation, including research develop- ment, testing, and evaluation, designed to develop or contribute to general- izable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities. 1Institutions with DHHS-approved assurances on file will abide by provisions of Title 45 C.F.R. Part 46 Subparts A-D. Some of the other departments and agencies have incorporated all provisions of Title 45 C.F.R. Part 46 into their policies and procedures as well. However, the exemptions at 45 C.F.R. § 46.101(b) do not apply to research involving prisoners, Sub- part C. The exemption at 45 C.F.R. § 46.101(b)(2), for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, Subpart D, except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed. [56 FR 38012, 28022, June 18, 1991; 56 FR 29756, June 28, 1991; 70 FR 36325, June 23, 2005]

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212 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS (e) Research subject to regulation and similar terms are intended to encom- pass those research activities for which a federal department or agency has specific responsibility for regulating as a research activity, (for example, investigational new drug requirements administered by the Food and Drug Administration). It does not include research activities which are inciden- tally regulated by a federal department or agency solely as part of the department’s or agency’s broader responsibility to regulate certain types of activities whether research or nonresearch in nature (for example, wage and hour requirements administered by the Department of Labor). (f) Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains: (1) Data through intervention or interaction with the individual, or (2) Identifiable private information. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject’s environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects. (g) IRB means an institutional review board established in accord with and for the purposes expressed in this policy. (h) IRB approval means the determination of the IRB that the research has been reviewed and may be conducted at an institution within the con- straints set forth by the IRB and by other institutional and federal require- ments. (i) Minimal risk means that 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. (j) Certification means the official notification by the institution to the supporting department or agency, in accordance with the requirements of

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213 APPENDIX D this policy, that a research project or activity involving human subjects has been reviewed and approved by an IRB in accordance with an approved assurance. §46.103 Assuring compliance with this policy-research conducted or sup- ported by any federal department or agency. (a) Each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy. In lieu of requiring submission of an assurance, individual department or agency heads shall accept the existence of a current assurance, appropriate for the research in question, on file with the Office for Human Research Protec- tions, DHHS, or any successor office, and approved for federal-wide use by that office. When the existence of an DHHS-approved assurance is ac- cepted in lieu of requiring submission of an assurance, reports (except certification) required by this policy to be made to department and agency heads shall also be made to the Office for Human Research Protections, DHHS, or any successor office. (b) Departments and agencies will conduct or support research covered by this policy only if the institution has an assurance approved as provided in this section, and only if the institution has certified to the department or agency head that the research has been reviewed and approved by an IRB provided for in the assurance, and will be subject to continuing review by the IRB. Assurances applicable to federally supported or conducted re- search shall at a minimum include: (1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to federal regulation. This may include an appropri- ate existing code, declaration, or statement of ethical principles, or a state- ment formulated by the institution itself. This requirement does not pre- empt provisions of this policy applicable to department-supported, agency-supported, or regulated research and need not be applicable to any research exempted or waived under §46.101 (b) or (i). (2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB’s review and recordkeeping duties. (3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses,

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214 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS etc., sufficient to describe each member’s chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution; for example: full-time employee, part-time employee, member of governing panel or board, stockholder, paid or un- paid consultant. Changes in IRB membership shall be reported to the de- partment or agency head, unless in accord with §46.103(a) of this policy, the existence of an DHHS-approved assurance is accepted. In this case, change in IRB membership shall be reported to the Office for Human Research Protections, DHHS, or any successor office. (4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (ii) for determining which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review; and (iii) for ensuring prompt reporting to the IRB of proposed changes in a research activity, and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. (5) Written procedures for ensuring prompt reporting to the IRB, appro- priate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or deter- minations of the IRB; and (ii) any suspension or termination of IRB approval. (c) The assurance shall be executed by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by this policy and shall be filed in such form and manner as the department or agency head prescribes. (d) The department or agency head will evaluate all assurances submitted in accordance with this policy through such officers and employees of the department or agency and such experts or consultants engaged for this purpose as the department or agency head determines to be appropriate. The department or agency head’s evaluation will take into consideration the adequacy of the proposed IRB in light of the anticipated scope of the institution’s research activities and the types of subject populations likely to be involved, the appropriateness of the proposed initial and continuing review procedures in light of the probable risks, and the size and complex- ity of the institution.

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215 APPENDIX D (e) On the basis of this evaluation, the department or agency head may approve or disapprove the assurance, or enter into negotiations to develop an approvable one. The department or agency head may limit the period during which any particular approved assurance or class of approved assur- ances shall remain effective or otherwise condition or restrict approval. (f) Certification is required when the research is supported by a federal department or agency and not otherwise exempted or waived under §46.101 (b) or (i). An institution with an approved assurance shall certify that each application or proposal for research covered by the assurance and by §46.103 of this policy has been reviewed and approved by the IRB. Such certification must be submitted with the application or proposal or by such later date as may be prescribed by the department or agency to which the application or proposal is submitted. Under no condition shall research covered by §46.103 of the policy be supported prior to receipt of the certification that the research has been reviewed and approved by the IRB. Institutions without an approved assurance covering the research shall cer- tify within 30 days after receipt of a request for such a certification from the department or agency, that the application or proposal has been approved by the IRB. If the certification is not submitted within these time limits, the application or proposal may be returned to the institution. (Approved by the Office of Management and Budget under control number 0990-0260.) [56 FR 38012, 28022, June 18, 1991; 56 FR 29756, June 28, 1991; 70 FR 36325, June 23, 2005] §§46.104–46.106 [Reserved] §46.107 IRB membership. (a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the mem- bers, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human sub- jects. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and

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228 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means; (c) Any risk is the least possible for achieving the objectives of the research; (d) If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with the informed consent provisions of Subpart A of this part; (e) If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of Subpart A of this part, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest; (f) Each individual providing consent under paragraph (d) or (e) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate; (g) For children as defined in §46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of Subpart D of this part; (h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy; (i) Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and (j) Individuals engaged in the research will have no part in determining the viability of a neonate. §46.205 Research involving neonates. (a) Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met: (1) Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates. (2) Each individual providing consent under paragraph (b)(2) or (c)(5) of

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229 APPENDIX D this section is fully informed regarding the reasonably foreseeable impact of the research on the neonate. (3) Individuals engaged in the research will have no part in determining the viability of a neonate. (4) The requirements of paragraph (b) or (c) of this section have been met as applicable. (b) Neonates of uncertain viability. Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions have been met: (1) The IRB determines that (i) The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viabil- ity, and any risk is the least possible for achieving that objective, or (ii) The purpose of the research is the development of important biomedical knowl- edge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and (2) The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained in accord with Sub- part A of this part, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest. (c) Nonviable neonates. After delivery nonviable neonate may not be in- volved in research covered by this subpart unless all of the following addi- tional conditions are met: (1) Vital functions of the neonate will not be artificially maintained; (2) The research will not terminate the heartbeat or respiration of the neonate; (3) There will be no added risk to the neonate resulting from the research; (4) The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and (5) The legally effective informed consent of both parents of the neonate is obtained in accord with Subpart A of this part, except that the waiver and alteration provisions of §46.116(c) and (d) do not apply. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the requirements of this paragraph (c)(5), ex- cept that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representa- tive of either or both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph (c)(5).

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230 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS (d) Viable neonates. A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of subparts A and D of this part. §46.206 Research involving, after delivery, the placenta, the dead fetus or fetal material. (a) Research involving, after delivery, the placenta; the dead fetus; macer- ated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accord with any applicable federal, state, or local laws and regulations regarding such activities. (b) If information associated with material described in paragraph (a) of this section is recorded for research purposes in a manner that living indi- viduals can be identified, directly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent sub- parts of this part are applicable. §46.207 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women, fetuses, or neonates. The Secretary will conduct or fund research that the IRB does not believe meets the requirements of §46.204 or §46.205 only if: (a) The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of pregnant women, fetuses or neonates; and (b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, ethics, law) and following op- portunity for public review and comment, including a public meeting an- nounced in the Federal Register, has determined either: (1) That the research in fact satisfies the conditions of §46.204, as appli- cable; or (2) The following: (i) The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of pregnant women, fetuses or neonates; (ii) The research will be conducted in accord with sound ethical principles; and (iii) Informed consent will be obtained in accord with the informed consent provisions of Subpart A and other applicable subparts of this part.

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231 APPENDIX D Subpart C: Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Source: 43 FR 53655, Nov. 16, 1978, unless otherwise noted §46.301 Applicability. (a) The regulations in this subpart are applicable to all biomedical and behavioral research conducted or supported by the Department of Health and Human Services involving prisoners as subjects. (b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth herein will authorize research involving pris- oners as subjects, to the extent such research is limited or barred by appli- cable state or local law. (c) The requirements of this subpart are in addition to those imposed under the other subparts of this part. §46.302 Purpose. Inasmuch as prisoners may be under constraints because of their incarcera- tion which could affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide additional safeguards for the protection of prisoners involved in activities to which this subpart is applicable. §46.303 Definitions. As used in this subpart: (a) Secretary means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom authority has been delegated. (b) DHHS means the Department of Health and Human Services. (c) Prisoner means any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing.

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232 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS (d) Minimal risk is the probability and magnitude of physical or psychologi- cal harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. §46.304 Composition of institutional review boards where prisoners are involved. In addition to satisfying the requirements in §46.107 of this part, an insti- tutional review board, carrying out responsibilities under this part with respect to research covered by this subpart, shall also meet the following specific requirements: (a) A majority of the board (exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership on the board. (b) At least one member of the board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one board only one board need satisfy this requirement. [43 FR 53655, Nov. 16, 1978, as amended at 46 FR 8366, Jan. 26, 1981] §46.305 Additional duties of the institutional review boards where prison- ers are involved. (a) In addition to all other responsibilities prescribed for institutional re- view boards under this part, the board shall review research covered by this subpart and approve such research only if it finds that: (1) The research under review represents one of the categories of research permissible under §46.306(a)(2); (2) Any possible advantages accruing to the prisoner through his or her participation in the research, when compared to the general living condi- tions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired; (3) The risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers; (4) Procedures for the selection of subjects within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the principal investigator provides to the board justifica- tion in writing for following some other procedures, control subjects must

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233 APPENDIX D be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project; (5) The information is presented in language which is understandable to the subject population; (6) Adequate assurance exists that parole boards will not take into account a prisoner’s participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole; and (7) Where the board finds there may be a need for follow-up examination or care of participants after the end of their participation, adequate provi- sion has been made for such examination or care, taking into account the varying lengths of individual prisoners’ sentences, and for informing par- ticipants of this fact. (b) The board shall carry out such other duties as may be assigned by the Secretary. (c) The institution shall certify to the Secretary, in such form and manner as the Secretary may require, that the duties of the board under this section have been fulfilled. §46.306 Permitted research involving prisoners. (a) Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects only if: (1) The institution responsible for the conduct of the research has certified to the Secretary that the institutional review board has approved the re- search under §46.305 of this subpart; and (2) In the judgment of the Secretary the proposed research involves solely the following: (i) Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; (ii) Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; (iii) Research on conditions par- ticularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than else- where; and research on social and psychological problems such as alcohol- ism, drug addiction, and sexual assaults) provided that the study may pro- ceed only after the Secretary has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research; or (iv)

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234 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the intent to approve such research. (b) Except as provided in paragraph (a) of this section, biomedical or behavioral research conducted or supported by DHHS shall not involve prisoners as subjects. Subpart D: Additional Protections for Children Involved as Subjects in Research Source: 48 FR 9818, March 8, 1983, unless otherwise noted §46.401 To what do these regulations apply? (a) This subpart applies to all research involving children as subjects, con- ducted or supported by the Department of Health and Human Services. (1) This includes research conducted by department employees, except that each head of an operating division of the department may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint. (2) It also includes research conducted or supported by the Department of Health and Human Services outside the United States, but in appropriate circumstances, the Secretary may, under paragraph (i) of §46.101 of Sub- part A, waive the applicability of some or all of the requirements of these regulations for research of this type. (b) Exemptions at §46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at §46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at §46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed. (c) The exceptions, additions, and provisions for waiver as they appear in paragraphs (c) through (i) of §46.101 of Subpart A are applicable to this subpart.

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235 APPENDIX D [48 FR 9818, Mar.8, 1983; 56 FR 28032, June 18, 1991; 56 FR 29757, June 28, 1991.] §46.402 Definitions. The definitions in §46.102 of Subpart A shall be applicable to this subpart as well. In addition, as used in this subpart: (a) Children are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. (b) Assent means a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be con- strued as assent. (c) Permission means the agreement of parent(s) or guardian to the partici- pation of their child or ward in research. (d) Parent means a child’s biological or adoptive parent. (e) Guardian means an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care. §46.403 IRB duties. In addition to other responsibilities assigned to IRBs under this part, each IRB shall review research covered by this subpart and approve only re- search which satisfies the conditions of all applicable sections of this sub- part. §46.404 Research not involving greater than minimal risk. DHHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that ad- equate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in §46.408. §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that

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236 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being, only if the IRB finds that: (a) The risk is justified by the anticipated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in §46.408. §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowl- edge about the subject’s disorder or condition. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well- being of the subject, only if the IRB finds that: (a) The risk represents a minor increase over minimal risk; (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and (d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. DHHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, or §46.406 only if:

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237 APPENDIX D (a) The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and fol- lowing opportunity for public review and comment, has determined either: (1) That the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or (2) the following: (i) The research presents a reasonable opportunity to further the understanding, prevention, or allevia- tion of a serious problem affecting the health or welfare of children; (ii) The research will be conducted in accordance with sound ethical principles; (iii) Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408. §46.408 Requirements for permission by parents or guardians and for assent by children. (a) In addition to the determinations required under other applicable sec- tions of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. If the IRB deter- mines that the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure in- volved in the research holds out a prospect of direct benefit that is impor- tant to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condi- tion for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under circumstances in which consent may be waived in ac- cord with §46.116 of Subpart A. (b) In addition to the determinations required under other applicable sec- tions of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by §46.116 of Subpart A, that adequate provisions are made for soliciting the permission of each child’s parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted

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238 ETHICAL CONSIDERATIONS FOR RESEARCH INVOLVING PRISONERS under §46.404 or §46.405. Where research is covered by §46.406 and §46.407 and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibil- ity for the care and custody of the child. (c) In addition to the provisions for waiver contained in §46.116 of Subpart A, if the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mecha- nism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsis- tent with federal, state, or local law. The choice of an appropriate mecha- nism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition. (d) Permission by parents or guardians shall be documented in accordance with and to the extent required by §46.117 of Subpart A. (e) When the IRB determines that assent is required, it shall also determine whether and how assent must be documented. §46.409 Wards. (a) Children who are wards of the state or any other agency, institution, or entity can be included in research approved under §46.406 or §46.407 only if such research is: (1) Related to their status as wards; or (2) Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. (b) If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child’s participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.