Attachment 18 PRR REPORTS PROTECTION OF HUMAN SUBJECTS TITLE 45 CODE OF FEDERAL REGULATIONS PART 46 REVISED JUNE 18, 1991 REPRINTED MARCH 15, 1994 PART 46 - PROTECTION OF HUMAN SUBJECTS Subpart A - Federal Policy for the Protection of Human Subjects (Asic 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 conducted or supported by any Federal Department of Agency. 46.104-46.106 [Reserved] 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 risks, and for minor changes in approved research. 46.111 Criteria for IRB approval of research 46.112 Review by institution. 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 DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization Sec. 46.201 Applicability 46.202 Purpose 46.203 Definitions 46.204 Ethical Advisory Boards 46.205 Additional duties of the Institutional Review Boards in connection with activities involving fetuses, pregnant women, or human in vitro fertilization 46.206 General limitations 46.207 Activities directed toward pregnant women as subjects 46.208 Activities directed toward fetuses in vitro as subjects 46.209 Activities directed toward fetuses ex utero including nonviable fetuses, as subjects 46.210 Activities involving the dead fetus, fetal material, or the placenta 46.211 Modification or waiver of specific requirements Subpart C - Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Sec 46.301 Applicability 46.302 Purpose 46.303 Definitions 46.304 Composition of Institutional Review Boards where prisoners are involved 46.305 Additional duties of the Institutional Review Boards were prisoners are involved 46.306 Permitted research involving prisoners. Subpart D - Additional DHHS 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 Authority: 5.U.S.C.301: Sec. 474(a). 88 Stat. 352 (42 U.S.C. 2891-3(a)). Note: As revised, Subpart A of the DHHS regulations incorporates the Common Rule (Federal Policy) for the Protection of Human Subjects (56 FR 28003). Subpart D of the HHS regulations has been amended at Section 46.401(b) to reference the revised Subpart A. The Common Rule (Federal Policy) is also codified at 7 CFR Part 1c Department of Agriculture 10 CFR Part 745 Department of Energy 14 CFR Part 1230 National Aeronautics and Space Administration 15 CFR Part 27 Department of Commerce 16 CFR Part 1028 Consumer Product Safety Commission 22 CFR Part 225 International Development Cooperation Agency, Agency for International Development 24 CFR Part 60 Department of Housing and Urban Development 28 CFR Part 46 Department of Justice 32 CFR Part 219 Department of Defense 34 CFR Part 97 Department of Education 38 CFR Part 16 Department of Veterans Affairs 40 CFR Part 26 Environmental Protection Agency 45 CFR Part 690 National Science Foundation 49 CFR Part 11 Department of Transportation PART 46 - PROTECTION OF HUMAN SUBJECTS Subpart A - Federal Policy for the Protection of Human Subjects (Asic DHHS Policy for Protection of Human Research Subjects) Source: 56 FR 28003, June 18, 1991. Section 46.101 To what does this policy apply? (a) Except as provided in paragraph (b) of this section, those 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 administrative ILLEGIBLE Section 46.207 Activities directed toward pregnant women as subjects. (a) No pregnant woman may be involved as a subject in an activity covered by this subpart unless: (1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal. (b) An activity permitted under paragraph (a) of this section may be conducted only if the mother and father are legally competent and have given their informed consent after having been fully informed regarding possible impact on the fetus, except that the father's informed consent need not be secured if: (1) the purpose of the activity is to meet the health needs of the mother, (2) his identity os whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape. Activities directed toward fetuses in utero as subjects (a) No fetus in utero may be involved as a subject in any activity covered by this subpart unless: (1) the purpose of the activity is to meet the health needs of the particular fetus and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means. (b) An activity permitted under paragraph (a) of this section may be conducted only if the mother and father are legally competent and have given their informed consent after having been fully informed regarding possible impact on the fetus, except that the father's informed consent need not be secured if: (1) the purpose of the activity is to meet the health needs of the mother, (2) his identity os whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape. Section 46.209 Activities directed toward fetuses ex utero, including nonviable fetuses, as subjects Until is has been ascertained whether or not a fetus ex utero is viable, a fetus ex utero may not be involved as a subject in an activity covered by this subpart unless: (1) there will be no added risk to the fetus resulting rom the activity, and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means, or (2) the purpose of the activity is to enhance the possibility of survival of the particular fetus to the point of viability. (b) No nonviable fetus may be involved as a subject in an activity covered by this subpart unless: (1) vital functions of the fetus will not be artificially maintained, (2) experimental activities which of themselves would terminate the heartbeat or respiration of the fetus will not be employed, and (3) the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means. (c) In the event the fetus ex utero is found to be viable, it may be included as a subject in the activity only to the extent permitted by and in accordance with the requirements of other subparts of this part. (d) An activity permitted under paragraph (a) or (b) of this section may be conducted only if the mother and father are legally competent and have given their informed consent, except that the father's informed consent need not be secured if: (1) the purpose of the activity is to meet the health needs of the mother, (2) his identity os whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape. Section 46.210 Activities involving the dead fetus, fetal material, or the placenta. Activities involving the dead fetus, macerated fetal material, or cells, tissue, or organs excised from a dead fetus shall be conducted only in accordance with any applicable State or local laws regarding such activities. Section 46.211 Modification or waiver of specific requirements Upon the request of an applicant or offeror (with the approval of its Institutional Review Board), the Secretary may modify or waive specific requirements of this subpart, with the approval of the Ethical Advisory Board after such opportunity for public comment as the Ethical Advisory Board considers appropriate in the particular instance. In making such decisions, the Secretary will consider whether the risks to the subject are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to warrant such modification or waiver and that such benefits cannot be gained except through a modification or waiver. Any such modifications or waivers will be published as notices in the Federal Register. Subpart C -Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Source: 43 FR 53655, Nov. 16, 1978. Section 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 prisoners as subjects, to the extent such research is limited or barred by applicable State or local law. (c) The requirements of this subpart are in addition to those imposed under the other subparts of this part. Section 46.302 Purpose Inasmuch as prisoners may be under constraints because of their incarceration 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. Section 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. (d) "Minimal risk" is the probability and magnitude of physical or psychological examination of healthy persons. Section 46.304 Composition of Institutional Review Boards where prisoners are involved. In addition to satisfying the requirements in Section 46.107 of this part, an Institutional 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. Section 46.305 Additional duties of the Institutional Review Boards where prisoners are involved (a) In addition to all the responsibilities prescribed for Institutional Review 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 Section 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 conditions, 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 justification in writing for following some other procedures, control subjects must 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 provision has been made for such examination or care, taking into account the varying lengths of individual prisoners' sentences, and for informing participants 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. Section 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 research under Section 46.305 of this subpart; and (2) in the judgment of the Secretary the proposed research involves solely the following: (A) 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; (B) 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; (C) research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that 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 his intent to approve such research; or (D) 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 by DHHS shall not involve prisoners as subjects. Subpart D - Additional DHHS Protections for Children Involved as Subjects in Research Source: 48 FR 9818, March 8, 1983: 56 FR 28032, June 18, 1991 Section 46.401 To what do these regulations apply? (a) This subject applies to all research involving children as subjects, conducted 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 appropriate circumstances, the Secretary may, under paragraph (i) of Section 46.101 of Subpart A, waive the applicability of some or all of the requirements of these regulations for research of this type. (b) Exemptions at Section 46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at Section 46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at Section 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 Section 46.101 of Subpart A are applicable to this subpart. Section 46.402 Definitions The definitions in Section 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 construed as assent. (c) "Permission" means the agreement of parent(s) or guardian to the participation 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. Section 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 research which satisfies the conditions of all applicable sections of this subpart. Section 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 adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in Section 46.408. Section 46.405 Research involving greater than minimal risk but presenting the prosect 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 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 Section 46.408. Section 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalized knowledge 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 Section 46.408. Section 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 Section 46.404, Section 46.405, or Section 46.406 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 children; and (b) the Secretary, after consultation with a panel of experts in pertinent