Human Subjects Research: Expedited Review and IRB Requirements for Minimal Risk Studies, Exercises of Law

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Code of Federal Regulations TITLE 45 PUBLIC WELFARE Department of Health and Human Services PART 46 PROTECTION OF HUMAN SUBJECTS * * * Revised January 15, 2009 Effective July 14, 2009 SUBPART A— Basic HHS Policy for Protec- tion 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 Depart- ment 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 re- search. 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 in- formed consent. 46.117 Documentation of informed consent. 46.118 Applications and proposals lack- ing 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 re- search to be conducted or sup- ported by a Federal Department or Agency. 46.121 [Reserved] 46.122 Use of Federal funds. 46.123 Early termination of research support: Evaluation of applica- tions and proposals. 46.124 Conditions. SUBPART B— Additional Protections for Pregnant Women, Human Fe- tuses 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 deliv- ery, the placenta, the dead fetus or fetal material. 46.207 Research not otherwise approv- able 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 Involv- ing 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 Insti- tutional Review Boards where prisoners are involved. 46.306 Permitted research involving prisoners. SUBPART D— Additional Protections for Children Involved as Sub- jects 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 pros- pect of direct benefit to individ- ual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condi- tion. 46.407 Research not otherwise ap- provable which presents an op- portunity 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; 42 U.S.C. 289 (a). . SUBPART E — Registration of Institutional Review Boards Sec. 46.501 What IRBs must be registered? 46.502 What information must be provided when registering an IRB? 46.503 When must an IRB be regis- tered? 46.504 How must an IRB be regis- tered? 46.505 When must IRB registration information be renewed or up- dated? Editorial Note: The Department of Health and Human Services issued a notice of waiver regarding the require- ments 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 infor- mation see 47 FR 9208, Mar. 4, 1982. 2 45 CFR 46 §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 depart- ment or agency shall provide written assur- ance 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 Protections, HHS, or any successor office, and approved for federalwide use by that office. When the existence of an HHS- approved assurance is accepted in lieu of requiring submission of an assurance, re- ports (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, HHS, or any successor office. (b) Departments and agencies will conduct or support research covered by this policy only if the institution has an assurance ap- proved as provided in this section, and only if the institution has certified to the depart- ment or agency head that the research has been reviewed and approved by an IRB pro- vided for in the assurance, and will be sub- ject to continuing review by the IRB. Assur- ances applicable to federally supported or conducted research shall at a minimum in- clude: (1)A statement of principles governing the institution in the discharge of its responsi- bilities for protecting the rights and wel- fare of human subjects of research con- ducted at or sponsored by the institution, regardless of whether the research is sub- ject to Federal regulation. This may in- clude an appropriate existing code, decla- ration, or statement of ethical principles, or a statement formulated by the institu- tion itself. This requirement does not pre- empt provisions of this policy applicable to department- or agency-supported or regulated research and need not be appli- cable to any research exempted or waived under §46.101(b) or (i). (2)Designation of one or more IRBs estab- lished 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 re- cordkeeping duties. (3)A list of IRB members identified by name; earned degrees; representative ca- pacity; indications of experience such as board certifications, licenses, etc., suffi- cient to describe each member's chief an- ticipated contributions to IRB delibera- tions; and any employment or other rela- tionship between each member and the institution; for example: full-time em- ployee, part-time employee, member of governing panel or board, stockholder, paid or unpaid 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 exis- tence of an HHS-approved assurance is accepted. In this case, change in IRB membership shall be reported to the Of- fice for Human Research Protections, HHS, or any successor office. (4)Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for re- porting its findings and actions to the in- vestigator and the institution; (ii) for deter- mining 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, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing non- compliance with this policy or the require- ments or determinations 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 institu- tion and to assume on behalf of the institu- tion 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 accor- dance 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 de- partment 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 pro- posed initial and continuing review proce- dures in light of the probable risks, and the size and complexity of the institution. (e) On the basis of this evaluation, the de- partment or agency head may approve or disapprove the assurance, or enter into ne- gotiations to develop an approvable one. The department or agency head may limit the period during which any particular ap- proved assurance or class of approved assur- ances shall remain effective or otherwise condition or restrict approval. (f) Certification is required when the re- search is supported by a federal department or agency and not otherwise exempted or waived under §46.101(b) or (i). An institu- tion with an approved assurance shall certify that each application or proposal for re- search 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 submit- ted. Under no condition shall research cov- ered 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 certify 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 certifica- tion is not submitted within these time lim- its, the application or proposal may be re- turned to the institution. (Approved by the Office of Management and Budget under Control Number 0990-0260.) [56 FR 28012, 28022, June 18, 1991; 56 FR 29756, June 28, 1991, as amended at 70 FR 36328, June 23, 2005] §§46.104--46.106 [Reserved] 45 CFR 46 5 §46.107 IRB membership. (a) Each IRB shall have at least five mem- bers, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the insti- tution. The IRB shall be sufficiently quali- fied 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 pro- mote respect for its advice and counsel in safeguarding the rights and welfare of hu- man subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB shall be able to ascertain the acceptability of pro- posed research in terms of institutional com- mitments and regulations, applicable law, and standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowl- edgeable about and experienced in working with these subjects. (b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the institution's consideration of qualified per- sons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession. (c) Each IRB shall include at least one mem- ber whose primary concerns are in scientific areas and at least one member whose pri- mary concerns are in nonscientific areas. (d) Each IRB shall include at least one mem- ber who is not otherwise affiliated with the institution and who is not part of the imme- diate family of a person who is affiliated with the institution. (e) No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a con- flicting interest, except to provide informa- tion requested by the IRB. (f) An IRB may, in its discretion, invite indi- viduals with competence in special areas to assist in the review of issues which require expertise beyond or in addition to that avail- able on the IRB. These individuals may not vote with the IRB §46.108 IRB functions and operations. In order to fulfill the requirements of this policy each IRB shall: (a) Follow written procedures in the same detail as described in §46.103(b)(4) and, to the extent required by, §46.103(b)(5). (b) Except when an expedited review proce- dure is used (see §46.110), review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas. In order for the research to be ap- proved, it shall receive the approval of a majority of those members present at the meeting. §46.109 IRB review of research. (a) An IRB shall review and have authority to approve, require modifications in (to se- cure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that information given to subjects as part of informed con- sent is in accordance with §46.116. The IRB may require that information, in addition to that specifically mentioned in §46.116, be given to the subjects when in the IRB's judg- ment the information would meaningfully add to the protection of the rights and wel- fare of subjects. (c) An IRB shall require documentation of informed consent or may waive documenta- tion in accordance with §46.117. (d) An IRB shall notify investigators and the institution in writing of its decision to ap- prove or disapprove the proposed research activity, or of modifications required to se- cure IRB approval of the research activity. If the IRB decides to disapprove a research activity, it shall include in its written notifica- tion a statement of the reasons for its deci- sion and give the investigator an opportunity to respond in person or in writing. (e) An IRB shall conduct continuing review of research covered by this policy at inter- vals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the re- search. (Approved by the Office of Management and Budget under Control Number 0990-0260.) [56 FR 28012, 28022, June 18, 1991, as amended at 70 FR 36328, June 23, 2005] §46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (a) The Secretary, HHS, has established, and published as a Notice in the FEDERAL REGISTER, a list of categories of research that may be reviewed by the IRB through an expedited review procedure. The list will be amended, as appropriate, after consultation with other departments and agencies, through periodic republication by the Secre- tary, HHS, in the FEDERAL REGISTER. A copy of the list is available from the Of- fice for Human Research Protections, HHS, or any successor office. (b) An IRB may use the expedited review procedure to review either or both of the following: (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chair- person or by one or more experienced re- viewers designated by the chairperson from among members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non- expedited procedure set forth in §46.108(b). (c) Each IRB which uses an expedited re- view procedure shall adopt a method for keeping all members advised of research proposals which have been approved under the procedure. (d) The department or agency head may restrict, suspend, terminate, or choose not to authorize an institution's or IRB's use of the expedited review procedure. [56 FR 28012, 28022, June 18, 1991, as amended at 70 FR 36328, June 23, 2005] §46.111 Criteria for IRB approval of re- search. (a) In order to approve research covered by this policy the IRB shall determine that all of the following requirements are satisfied: (1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. 6 45 CFR 46 (2) Risks to subjects are reasonable in rela- tion to anticipated benefits, if any, to sub- jects, and the importance of the knowl- edge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. (3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the re- search and the setting in which the re- search will be conducted and should be particularly cognizant of the special prob- lems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled per- sons, or economically or educationally disadvantaged persons. (4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accor- dance with, and to the extent required by §46.116. (5) Informed consent will be appropriately documented, in accordance with, and to the extent required by §46.117. (6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. (7) When appropriate, there are adequate provisions to protect the privacy of sub- jects and to maintain the confidentiality of data. (b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, preg- nant women, mentally 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. §46.112 Review by institution. Research covered by this policy that has been approved by an IRB may be subject to further appropriate review and approval or disapproval by officials of the institution. However, those officials may not approve the research if it has not been approved by an IRB. §46.113 Suspension or termination of IRB approval of research. An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associ- ated with unexpected serious harm to sub- jects. Any suspension or termination of ap- proval shall include a statement of the rea- sons for the IRB's action and shall be re- ported promptly to the investigator, appro- priate institutional officials, and the depart- ment or agency head. (Approved by the Office of Management and Budget under Control Number 0990-0260.) [56 FR 28012, 28022, June 18, 1991, as amended at 70 FR 36328, June 23, 2005] §46.114 Cooperative research. Cooperative research projects are those pro- jects covered by this policy which involve more than one institution. In the conduct of cooperative research projects, each institu- tion is responsible for safeguarding the rights and welfare of human subjects and for complying with this policy. With the ap- proval of the department or agency head, an institution participating in a cooperative project may enter into a joint review ar- rangement, rely upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort. §46.115 IRB records. (a) An institution, or when appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities, including the following: (1) Copies of all research proposals re- viewed, scientific evaluations, if any, that accompany the proposals, approved sam- ple consent documents, progress reports submitted by investigators, and reports of injuries to subjects. (2) Minutes of IRB meetings which shall be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of con- troverted issues and their resolution. (3) Records of continuing review activities. (4) Copies of all correspondence between the IRB and the investigators. (5) A list of IRB members in the same detail as described in §46.103(b)(3). (6) Written procedures for the IRB in the same detail as described in §46.103(b)(4) and §46.103(b)(5). (7) Statements of significant new findings provided to subjects, as required by §46.116(b)(5). (b) The records required by this policy shall be retained for at least 3 years, and records relating to research which is conducted shall be retained for at least 3 years after comple- tion of the research. All records shall be accessible for inspection and copying by authorized representatives of the depart- ment or agency at reasonable times and in a reasonable manner. (Approved by the Office of Management and Budget under Control Number 0990-0260.) [56 FR 28012, 28022, June 18, 1991, as amended at 70 FR 36328, June 23, 2005] §46.116 General requirements for in- formed consent. Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this pol- icy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the repre- sentative sufficient opportunity to consider whether or not to participate and that mini- mize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. (a) Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject: (1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental; (2) A description of any reasonably fore- seeable risks or discomforts to the subject; (3) A description of any benefits to the subject or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained; 45 CFR 46 7 (b) The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the re- search is the development of important bio- medical knowledge which cannot be ob- tained by any other means; (c) Any risk is the least possible for achiev- ing 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 preg- nant 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 devel- opment 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 in- formed consent provisions of subpart A of this part, except that the father's consent need not be obtained if he is unable to con- sent 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 foresee- able 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 tim- ing, method, or procedures used to termi- nate 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 non- viable neonates may be involved in research if all of the following conditions are met: (1) Where scientifically appropriate, pre- clinical and clinical studies have been con- ducted and provide data for assessing po- tential risks to neonates. (2) Each individual providing consent un- der paragraph (b)(2) or (c)(5) of this sec- tion is fully informed regarding the rea- sonably 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 appli- cable. (b) Neonates of uncertain viability. Until it has been ascertained whether or not a neo- nate 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 viability, and any risk is the least possible for achieving that objective, or (ii) The purpose of the research is the de- velopment of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the re- search; and (2) The legally effective informed consent of either parent of the neonate or, if nei- ther parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent's legally author- ized representative is obtained in accord with subpart A of this part, except that the consent of the father or his legally author- ized representative need not be obtained if the pregnancy resulted from rape or incest. (c) Nonviable neonates. After delivery non- viable neonate may not be involved in re- search covered by this subpart unless all of the following additional 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 neo- nate resulting from the research; (4) The purpose of the research is the de- velopment 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, ex- cept that the waiver and alteration provi- sions of §46.116(c) and (d) do not apply. However, if either parent is unable to con- sent because of unavailability, incompe- tence, or temporary incapacity, the in- formed consent of one parent of a nonvi- able neonate will suffice to meet the re- quirements of this paragraph (c)(5), except that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph (c)(5). (d) Viable neonates. A neonate, after deliv- ery, that has been determined to be viable may be included in research only to the ex- tent permitted by and in accord with the requirements of subparts A and D of this part. §46.206 Research involving, after deliv- ery, the placenta, the dead fetus or fetal material. (a) Research involving, after delivery, the placenta; the dead fetus; macerated 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 individuals can be identified, di- rectly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent subparts of this part are applicable. §46.207 Research not otherwise approv- able which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women, fe- tuses, 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 10 45 CFR 46 a reasonable opportunity to further the un- derstanding, prevention, or alleviation of a serious problem affecting the health or wel- fare of pregnant women, fetuses or neo- nates; and (b) The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, ethics, law) and following opportunity 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 applicable; or (2) The following: (i) The research presents a reasonable op- portunity 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 ac- cord with sound ethical principles; and (iii) Informed consent will be obtained in accord with the informed consent provi- sions of subpart A and other applicable subparts of this part. Subpart C Additional Protections Pertaining to Biomedical and Behavioral Re- search Involving Prisoners as Subjects Source: 43 FR 53655, Nov. 16, 1978, unless otherwise noted. §46.301 Applicability. (a) The regulations in this subpart are appli- cable to all biomedical and behavioral re- search conducted or supported by the De- partment of Health and Human Services involving prisoners as subjects. (b) Nothing in this subpart shall be con- strued 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. §46.302 Purpose. Inasmuch as prisoners may be under con- straints because of their incarceration which could affect their ability to make a truly vol- untary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide addi- tional safeguards for the protection of pris- oners 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 involuntar- ily confined or detained in a penal institu- tion. 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 stat- utes or commitment procedures which pro- vide alternatives to criminal prosecution or incarceration in a penal institution, and indi- viduals detained pending arraignment, trial, or sentencing. (d) Minimal risk is the probability and magni- tude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychologi- cal 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 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. [43 FR 53655, Nov. 16, 1978, as amended at 46 FR 8366, Jan. 26, 1981] §46.305 Additional duties of the Institu- tional Review Boards where prison- ers are involved. (a) In addition to all other responsibilities prescribed for Institutional Review Boards under this part, the Board shall review re- search 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 permissi- ble under §46.306(a)(2); (2) Any possible advantages accruing to the prisoner through his or her participa- tion 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 char- acteristics needed for that particular re- search project; (5) The information is presented in lan- guage which is understandable to the sub- ject population; (6) Adequate assurance exists that parole boards will not take into account a pris- oner's participation in the research in mak- ing 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 partici- pation, 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 Secre- 45 CFR 46 11 tary, in such form and manner as the Secre- tary 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 con- ducted or supported by DHHS may involve prisoners as subjects only if: (1) The institution responsible for the con- duct of the research has certified to the Secretary that the Institutional Review Board has approved the research under §46.305 of this subpart; and (2) In the judgment of the Secretary the proposed research involves solely the fol- lowing: (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 sub- jects; (ii) Study of prisons as institutional struc- tures or of prisoners as incarcerated per- sons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects; (iii) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepati- tis which is much more prevalent in pris- ons than elsewhere; and research on social and psychological problems such as alco- holism, drug addiction, and sexual as- saults) 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 REG- ISTER, of his intent to approve such re- search; or (iv) 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 con- sistent 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 con- sulted 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 re- search conducted or supported by DHHS shall not involve prisoners as subjects. Subpart D Additional Protections for Chil- dren Involved as Subjects in Re- search 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 in- volving 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 De- partment may adopt such nonsubstantive, procedural modifications as may be appro- priate 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 subpart A, waive the applicabil- ity 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 inter- view procedures or observations of public behavior does not apply to research covered by this subpart, except for research involv- ing observation of public behavior when the investigator(s) do not participate in the ac- tivities 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 ap- plicable to this subpart. [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 addi- tion, as used in this subpart: (a) Children are persons who have not at- tained the legal age for consent to treat- ments or procedures involved in the re- search, under the applicable law of the juris- diction in which the research will be con- ducted. (b) Assent means a child's affirmative agree- ment 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 adop- tive parent. (e) Guardian means an individual who is au- thorized 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 re- view research covered by this subpart and approve only research which satisfies the conditions of all applicable sections of this subpart. §46.404 Research not involving greater than minimal risk. HHS 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 §46.408. §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the indi- vidual subjects. HHS 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 solicit- ing the assent of the children and permission of their parents or guardians, as set forth in §46.408. 12 45 CFR 46