Office of Human Subjects Research

Human Subjects Research Advisory Committee

PREAMBLE
DEFINITIONS, APPLICABILITY AND GENERAL INSTITUTIONAL POLICIES
1. Definitions
2. Applicability
  1. Activities covered under this policy
  2. Johns Hopkins Bayview Medical Center
  3. Exemptions to this policy
3. General Institutional Policies
IMPLEMENTATION
1. Responsibilities of the Deputy Director for Intramural Research (DDIR)
2. Responsibilities of the Deputy Director for Extramural Research (DDER)
3. Responsibilities of Research Investigators, Laboratory/Branch Chiefs, Clinical Directors, and Scientific Directors
  1. Determination of human subjects involvement
  2. Determination of human subjects research activities that are exempt from 45 CFR 46
  3. Preparation of a protocol
  4. Review by Laboratory/Branch Chief, Clinical Director, and/or Scientific Director
  5. Submission of protocols to the appropriate IRB
  6. Attending IRB meetings
  7. Complying with IRB decisions
  8. Informed consent
  9. General requirements for informed consent
  10. Providing additional elements of informed consent
  11. Documentation of informed consent
  12. Retention of signed consent documents
  13. Continuing IRB review
  14. Procedures for terminating a protocol
  15. Submission of reports of unanticipated problems and unexpected serious harm
  16. Amendments to approved research activities
  17. Protocols involving Investigational New Drugs or Devices or radiation
  18. Reporting of noncompliance
4. Responsibilities of the Director of the Clinical Center
5. The Human Subjects Research Advisory Committee
6. Institutional Review Boards (IRBs) - Structure
  1. Establishment of IRBs
  2. Composition
7. IRB Authorities and Responsibilities
  1. IRB review of research protocols
  2. Documentation of informed consent
  3. Waiver or alteration of the general requirements of informed consent
  4. Observation of the consent process and the research
  5. Continuing review
  6. Authority to modify, suspend or terminate approval of research
8. General IRB Operating Procedures
  1. Determination of review procedures
  2. Review of collaborative or cooperative research activities
  3. Expedited review
  4. Full IRB review
  5. IRB notification to research investigators in writing of its actions
  6. IRB records
9. The Office of Human Subjects Research (OHSR)
  1. Roles and responsibilities
  2. Institutional determinations concerning exemptions to 45 CFR 46
  3. Conduct of educational activities
  4. Conduct of inquiries/investigations
  5. Review of NIH practices and procedures for the protection of human subjects
  6. Policy formation concerning human subjects research
  7. Collaborative and cooperative research activities
  8. Reporting requirements
10. Cooperative Protocol Research Programs
  1. Appendix A: List of NIH components
  2. Appendix B: List of NIH standing affiliates
  3. Appendix C: Institute IRB rosters
  4. Appendix D: MPA summary and line diagram
  5. Appendix E: The Belmont Report
  6. Appendix F: 45 CFR 46
  7. Appendix G: Activities exempt from coverage under 45 CFR 46
  8. Appendix H: OPRR Reports: Emergency Medical Care
  9. Appendix I: DHHS Policies regarding HIV research
  10. Appendix J: Activities for expedited review procedures
  11. Appendix K: Cooperative Amendment, Johns Hopkins Bayview Medical Center

PREAMBLE
- The mission of the National Institutes of Health (NIH) is to improve human health through biomedical and behavioral research. The NIH is committed to: (1) conducting biomedical and behavioral research according to high scientific and ethical standards, and (2) administering and regulating these activities in a manner that promotes both the rights and welfare of human subjects and its research mandate.
- In its conduct of research, the NIH is guided by the ethical principles regarding all research involving human subjects in the report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research entitled “The Belmont Report - Ethical Principles and Guidelines for the Protection of Human Subjects of Research” (Appendix E). These ethical principles have been incorporated into Federal regulations 45 CFR 46, entitled Protection of Human Subjects (Appendix F).
- The Deputy Director for Intramural Research (DDIR), on behalf of the Director, NIH, hereby gives assurance, as specified below, that the NIH will comply with the Department of Health and Human Services (DHHS) regulations for the protection of human subjects, 45 CFR
DEFINITIONS, APPLICABILITY, AND GENERAL INSTITUTIONAL POLICIES
1. Definitions
  The following definitions are used in this Assurance.
  1. “Research” means a systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge. (45 CFR 46.102 (d)).
  2. “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. Some clinical and basic research activities with human tissues (i.e., blood and tissue samples, etc.) may also constitute research with human subjects. (45 CFR 46.102 (f)).
  3. “Collaboration ” exists if the NIH participant expects “something in return” as a result of having participated in a research activity. “Something in return” could include data, authorship on a publication, samples, or even patent rights. The NIH views authorship as prima facie evidence of collaboration. Collaborative activities may include but are not limited to : the collection of specimens, visits to institutions to perform research activities or clinical work, exchange of information containing personal identifiers, preliminary data-collection activities involving human subjects, and substantive intellectual contributions to research techniques, protocol design, or interpretation of data. Even remote participation--such as supplying important reagents, performing tests, or analyzing data--may constitute collaboration. Not all collaborations are defined in advance, and there may be subsequent differences of opinion about whether collaboration existed or perhaps developed during the course of research activities. In unclear cases, investigators should contact their IRB Chair or the Office of Human Subjects Research. In some cases further objective third-party review may be necessary (NIH definition not found in 45 CFR 46).
2. Applicability
  1. This Assurance is applicable to all research activities that, in whole or part, involve human subjects if:
    1. the research is conducted or supported by the Intramural Research Program (IRP)* of the NIH, or
    2. the research is conducted by any employee of the NIH in connection with his/her institutional duties, regardless of the site of the activity, or
    3. the research is conducted in a facility of the NIH, or
    4. the research involves the use of any of the NIH IRP non-public information systems or databases to identify or contact human subjects or prospective subjects.
  2. Certain cooperative research, including research conducted at the Johns Hopkins Bayview Medical Center, will be conducted in accordance with amendments attached to this Assurance (Appendix K). Such amendments will be updated as appropriate and submitted to OPRR for approval.
  3. Activities in which the only involvement of human subjects is in one or more of the categories listed in 45 CFR 46.101(b) (Appendix G) are exempt from coverage under this Assurance. Procedures for determination and documentation of exempt status are outlined below (see III.C.2 and III.I.2.)
3. General Institutional Policies
  1. It is the policy of the NIH to respect and safeguard the rights and welfare of human subjects involved in its research activities.
  2. The NIH acknowledges that it bears responsibility for the performance of all research involving human subjects covered by this Assurance, including continuing compliance with pertinent Federal, state or local laws, as they may relate to such research.
  3. The NIH ensures that all researchers newly employed in its Intramural Research Program (IRP), and extramural staff involved in the planning, conduct and program oversight of research involving human subjects, complete the computer-based training program entitled “The Protection of Human Research Subjects at the NIH.”
  4. It is the policy of the NIH that its IRBs will review only research which has been reviewed by the appropriate Institute or Center (IC) and found to be scientifically meritorious, well-designed, and in keeping with ethical guidelines, program relevance and public responsibility.
  5. The DDIR, acting on behalf of the Director, NIH, is the institutional official responsible for implementation of the NIH’s Multiple Project Assurance of Compliance (NIH MPA). The Office of Human Subjects Research (OHSR) develops policies and procedures, and provides education, guidance and assistance to NIH research investigators and others in conducting human subjects research in conformance with the terms and conditions of the NIH MPA and the Federal regulations (45 CFR 46). The Director, OHSR reports to the DDIR.
  6. The NIH, in cooperation with the Institutes and Centers (ICs), establishes and maintains Institutional Review Boards (IRBs). At the NIH, IRBs are responsible for the prospective review and approval of research activities involving human subjects. Their primary mandate is to protect the rights and welfare of human research subjects. The composition and operation of each IRB will conform to the terms and conditions of 45 CFR 46.
  7. Activities in which the only involvement of human subjects is in one or more of the categories listed in 45 CFR 46.101(b) (Appendix G) will be submitted by NIH researchers to NIH’s Office of Human Subjects Research (OHSR) for determination and documentation of exemption from the requirement for IRB review and approval (see III.C.2 and III. I. 2.).
  8. It is the policy of the NIH that, except for those categories of research determined by OHSR to be exempt from the requirement for IRB review and approval (see 7., above), no research activity covered by this Assurance will begin before:
    1. it has been reviewed and approved by an IRB and the DDIR, or his designee (IC Director, Scientific Director, or Clinical Director),
    2. the informed consent of the subject or the subject’s legally authorized representative has been obtained, unless this requirement has been altered or waived by an IRB in accord with 45 CFR 46.116(d), and
    3. IRB review and approval has been documented so that it may be entered into an appropriate NIH database(s).
  9. The NIH will provide appropriate additional safeguards in research that involves: (1) fetuses, pregnant women, or human in vitro fertilization (see 45 CFR 46 Subpart B), (2) prisoners (see 45 CFR 46 Subpart C), (3) children (see 45 CFR 46 Subpart D), (4) the cognitively impaired, or (5) other potentially vulnerable subjects such as those who are economically or educationally disadvantaged.
  10. As a means of safeguarding the rights and welfare of human subjects, the NIH will encourage continuing constructive communication and education among the OHSR, the Director, Clinical Center (CC), the IRBs and their allied administrative personnel, research investigators, clinical care staff, other institutional officials and research subjects.
  11. When research is conducted in the CC, or other NIH clinical research sites, short term medical care will be provided for injury resulting from participation in research.
  12. Each IC will provide appropriate resources to its IRB to assure proper functioning and record-keeping in conformance with the NIH MPA and 45 CFR 46.
  13. The OHSR will periodically assess IRBs’ practices, procedures and record-keeping.
  14. The NIH MPA will be made available to NIH investigators and personnel conducting and/or reviewing human subjects research activities.
  15. The NIH will adhere to the guidelines set forth in the May, 1991 Office for Protection from Research Risks (OPRR) Reports, “Emergency Medical Care” (Appendix H).
  16. The NIH will adhere to applicable DHHS Policies regarding HIV research (Appendix I).
  17. The NIH-IRP will adhere to “The Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research.” (59 Federal Register 11146-11151, efffective March 9, 1994.)
IMPLEMENTATION
1. Responsibilities of theDeputy Director for Intramural Research (DDIR)
  1. The DDIR, on behalf of the Director, NIH, assumes overall responsibility for implementation of this Assurance.
  2. All NIH IRP employees conducting or supporting research involving human subjects are responsible for ensuring that the rights and welfare of human subjects are protected. The DDIR will ensure that NIH intramural staff receive appropriate education and training regarding the requirements of the NIH MPA.
  3. Research approved by an NIH IRB is subject to further review and institutional approval by the DDIR (45 CFR 46.112). In determining if the NIH shall sponsor or support such research, the DDIR will take into account program relevance and public responsibility. The DDIR may delegate this review and approval authority to other appropriate NIH officials (IC Directors, Scientific Directors, or Clinical Directors).
2. Responsibilities of theDeputy Director for Extramural Research (DDER)
  1. The DDER will facilitate compliance with the NIH MPA for all human subject research conducted by NIH extramural program staff.
  2. The DDER will ensure that NIH extramural staff receive appropriate education and training regarding the requirements of the NIH MPA.
  3. The DDER will coordinate extramural human subject policy and education efforts with those of the OHSR, where necessary, to ensure consistent protection for human subjects through the NIH.
3. Responsibilities ofResearch Investigators, Laboratory/Branch Chiefs, Clinical Directors and Scientific Directors
  1. Determination of human subjects involvement
    1. Research investigators are responsible for determining whether their research activities will involve human subjects as defined in 45 CFR 46.102 (see II. A.).
    2. When it is not clear whether their research activities will involve human subjects, investigators shall seek assistance from the OHSR or the Chair of the appropriate IRB in making this determination.
    3. If research activities that were originally determined not to involve human subjects change such that human subjects become involved, research investigators are responsible for obtaining the required official approvals (see III. C. 2. and 3., below).
  2. Determination of human subjects research activities that are exempt from 45 CFR 46
    1. Research investigators make the preliminary determination as to whether or not the proposed human subjects research activity is exempt from 45 CFR 46 (see Appendix G).
    2. If the investigator determines that the activity is exempt, she/he will provide the necessary document (OHSR form “Request for Review of Research Activity”) to the OHSR for the final institutional decision concerning exempt status (see III. I. 2.).
    3. If the investigator or the OHSR determines that the activity is not exempt, the investigator will write, as appropriate, a description of the research or a research protocol (see III. C. 3.) for submission to the appropriate NIH IRB.
  3. Preparation of a protocol
    1. The Principal Investigator (PI) of a research activity is responsible for the design, conduct and monitoring of that activity.
    2. The PI shall provide a complete written description of and rationale for the proposed research design. At the NIH, this document is called a protocol. In addition, the protocol shall include a discussion of the human subjects protection issues that are relevant to the conduct of the study. The protocol shall address, at a minimum, the risks to subjects, any procedures that are experimental, the potential benefits (if any) to subjects, the anticipated number of subjects to be studied, and the consent process to be used. The protocol shall include a copy of the proposed consent form(s). When potentially vulnerable subjects will be enrolled (children, prisoners, cognitively impaired, institutionalized or critically/terminally ill individuals), a discussion of additional safeguards is required.
    3. When appropriate, the PI shall identify in the protocol if any Principal or Associate Investigator involved in the protocol has an equity or consultative relationship with a non-NIH entity related to the protocol which might be considered a real or an apparent conflict of interest.
  4. Review by Laboratory/Branch Chief, Clinical Director and/or Scientific Director
    Laboratory/Branch Chiefs, Clinical Directors and/or Scientific Directors, through appropriate procedures established within their respective ICs, are responsible for the review of protocols, taking into account scientific merit, ethical considerations, program relevance and public responsibility. Protocols without prior IC certification of such review will not be accepted by an NIH IRB for consideration.
  5. Submission of protocols to the appropriate IRB
    After recommendation by the Laboratory/Branch Chief, and the Clinical Director and/or Scientific Director, and/or other IC officials as appropriate, the Principal Investigator (PI) is responsible for submitting the protocol with an NIH-1195-1 form to the IRB in his/her IC, except as follows:
    1. If the intramural or extramural NIH PI who is conducting research is an employee of the CC, or an IC which does not have an IRB, she/he shall submit the protocol to the IRB most closely related to the subject matter of the protocol.
    2. Protocols involving investigators from more than one IC shall be reviewed by at least one IRB, generally that of the PI’s IC.
    3. IRBs shall take care to review protocols submitted by Clinical Directors, Scientific Directors and IC Directors in a manner that will avoid real or apparent conflict of interest. IRBs have the option to request that such protocols be reviewed by an IRB of another IC.
  6. Attending IRB meetings
    When invited by the IRB Chair, investigators are encouraged to attend IRB meetings in order to facilitate the review of their protocols.
  7. Complying with IRB decisions
    Research investigators are responsible for complying with all IRB decisions and stipulations and for responding in writing to IRB stipulations and recommendations within 30 days.
  8. Informed consent
    1. Research investigators are responsible for fully informing the subject or the subject’s legally authorized representative in accordance with 45 CFR 46.116, and for ensuring that no human subject will be involved in the research before giving informed consent.
    2. Unless otherwise authorized by an IRB, research investigators are responsible for ensuring that legally effective informed consent shall:
      1. be obtained from the subject or the subject’s legally authorized representative;
      2. be explained in a language and a manner understandable to the subject or the representative;
      3. be obtained in circumstances that offer the subject or the representative sufficient opportunity to consider whether the subject should participate; and
      4. not include exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights; nor to release or appear to release the research investigators, the sponsor, the institution or its agents from liability.
  9. General requirements for informed consent
    Unless otherwise authorized by an IRB (see III. G. 3.), research investigators shall provide the following information 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 that are experimental.
    2. A description of any reasonably foreseeable risks or discomforts to the subject, an estimate (if available) of their likelihood, and, if appropriate, a description of the steps that will be taken to prevent, mitigate, or treat them.
    3. A description of any benefits to the subject or to others that 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. When appropriate, the statement shall include who may have access to research records (e.g., FDA, non-NIH research sponsor).
    6. For research involving more than minimal risk, an explanation regarding any compensation and any medical treatments that are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
    7. An explanation of whom to contact for answers to pertinent questions about the research and the research subject’s rights, and whom to contact in the event of a research-related injury to the subject.
    8. A statement that participation is voluntary and that refusal to participate or discontinuing participation at any time will involve no penalty or loss of benefits to which the subject is otherwise entitled.
  10. Providing additional elements of informed consent
    When deemed appropriate by an IRB, the research investigators shall provide one or more of the following additional elements of information to each subject:
    1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) that are currently unforeseeable.
    2. Anticipated circumstances in which the subject’s participation may be terminated by the research investigator without regard to the subject’s consent.
    3. Any additional costs to the subject that may result from participation in the research.
    4. The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject.
    5. A statement that significant new findings developed during the course of the research that may relate to the subject’s willingness to continue participation will be provided to the subject.
    6. The approximate number of subjects involved in the study, and
    7. When appropriate, a statement concerning an investigator’s potential financial or other conflict of interest in the conduct of the research protocol.
  11. Documentation of informed consent.
    1. Research investigators shall be responsible for ensuring that informed consent is recorded by the use of a written consent document approved by an IRB and signed by the subject or the subject’s legally authorized representative, unless this requirement is specifically waived by an IRB in accord with 45 CFR 46.117(c) (see III. G. 3.).
    2. Research investigators shall ensure that each person signing the written consent document is given a copy.
    3. Research investigators may use one of two consent documents;
      1. A written consent document that embodies the elements of informed consent required by 45 CFR 46.116 (see III. C. 8. and 9.). This form may be read to the subject or the subject’s legally authorized representative, but in any event, the research investigators shall give either the subject or the representative adequate opportunity to read the document before signing it, or;
      2. A “short form” written consent document stating that the elements of informed consent required by 45 CFR 46.116 have been presented orally to the subject or the subject’s legally authorized representative. When the “short form” is used, research investigators shall ensure that:
        
        the written summary of what is to be said to the subject or the representative receives the prior approval of the IRB;
        
        the short form is signed by the subject or the representative;
        
        a witness attends the oral presentation;
        
        the witness signs both the short form and a copy of a written summary of the oral presentation;
        
        the person obtaining consent signs a copy of the summary, and
        
        a copy of both the short form and summary is given to the subject or the representative.
  12. Retention of signed consent documents
    1. For research conducted in the CC, research investigators are responsible for placing original, signed consent documents into each subject’s permanent CC medical record.
    2. In cases where subject accrual occurs elsewhere, signed consent documents will be retained according to the collaborating institution’s Multiple Project Assurance or other OPRR-approved assurance covering the research to be conducted.
  13. Continuing IRB review
    1. Each IRB shall conduct continuing review of approved research activities at least once per year or at shorter intervals appropriate to the degree of risk (see III. G. 5.).
    2. To facilitate continuing review, the PI is responsible for timely submission of requested forms/reports to the Chair of the IRB that previously reviewed the protocol. Each PI shall submit (i) the necessary forms, including the current consent document, (ii) a brief narrative to the IRB indicating the experience with the research, including subject demographics, and (iii) the reason(s) for continuing the study.
    3. The IRB may require that a protocol be rewritten to consolidate amendments.
    4. On the due date, if IRB approval of continuing review has not been completed, subject accrual into the protocol is suspended. If the PI fails to submit the continuing review materials to the IRB within one month after the due date, the protocol may be terminated. Reactivation of the protocol requires submission of a new protocol to the IRB.
  14. Procedures for terminating a protocol
    When a PI terminates a protocol, the appropriate forms (NIH-1195-1) should be submitted to the IRB accompanied by a short narrative explanation of the reasons for termination, the research results of the protocol, and the demographics of the enrolled subjects.
  15. Submission of reports of unanticipated problems and unexpected serious harm
    The PI is responsible for reporting promptly (1) any unanticipated problems involving risks to subjects or others, or (2) unexpected serious harm to subjects and others. Written reports shall be submitted for evaluation to:
    1. the appropriate IRB (see III. G. 6. a., b.),
    2. the IC Clinical Director,
    3. the Director, CC, if the protocol is conducted in the CC, and
    4. the FDA and/or non-NIH sponsor, as necessary.
    5. OHSR
  16. Amendments to approved research activities
    1. Changes in research activities during the period for which IRB approval has already been given shall not be initiated by research investigators without prior IRB review and approval, except where necessary to eliminate apparent immediate hazards to the subject.
    2. Research investigators are responsible for reporting proposed changes in previously approved research activities through the Laboratory/Branch Chief, Clinical Director and/or Scientific Director to the appropriate IRB.
  17. Protocols involving Investigational New Drugs or Devices or radiation
    1. Protocols using test articles (i.e., drugs, devices, biologics) or proposing new uses for approved test articles must comply with the Food and Drug Administration requirements for Investigational New Drugs/Devices (INDs/IDEs).
    2. Research activities requiring the administration of radiation to human subjects must be approved by a Radiation Safety Committee before final institutional approval of a protocol.
  18. Reporting of noncompliance.
    Research investigators, Laboratory/Branch Chiefs, Clinical Directors and/or Scientific Directors are responsible for reporting promptly to the OHSR and the appropriate IRB any serious or continuing noncompliance with the requirements of 45 CFR 46, this Assurance or the determinations of an IRB. Such reports shall also be made to the Director, CC if the research activity is conducted in or by an employee of the CC.
4. Responsibilities of theDirector of the Clinical Center 1. As an IC Director, the Director of the CC exercises all protocol review and approval authorities delegated to him/her by the DDIR per III. A. 3. and III. C. 5. a. 2. Protocols to be conducted in the CC that have been approved by an IRB and the appropriate IC official (III. A. 3.), are subject to further administrative review and approval by the Director, CC. This review will take into account the in-house resources necessary to implement the study and assures review and approval by other appropriate groups (e.g., NIH Radiation Safety Committee). 3. The Director, CC will assure maintenance of a central database of all approved CC research protocols and files relating to the IRBs. The central files shall include but are not limited to official file copies of protocols and their approval sheets, documentation of continuing review, and IRB meeting minutes. 4. The Clinical Center (CC) administrative review and approval is generally completed in a timely fashion. However, there may be exceptional circumstances (e.g., a subject is waiting to be enrolled in the research study) in which any further delay would cause unwarranted hardship. In such circumstances, the Director, CC may delegate to the Deputy Director for Clinical Care, CC the authority to approve enrollment of a subject. Such approval may be given only when a protocol has received all other necessary approvals (e.g., IRB, IC Clinical Director, Radiation Safety Committee) except that of the Director, CC.
5. The Human Subjects Research Advisory Committee (HSRAC) 1. The primary responsibility of the HSRAC is to advise the DDIR on policies and procedures regarding the conduct of human subjects research in the NIH IRP. 2. Membership shall include: the DDIR (Chair), the Director, OHSR (Executive Secretary), all IRB Chairs, the Director, CC, and the Chief of the Department of Clinical Bioethics, CC. 3. At the discretion of the DDIR, the HSRAC may serve as the IRB of record for the review, approval and oversight of any research activity involving human subjects covered by this Assurance. In the event that the HSRAC shall serve as an IRB, its membership shall be appropriately augmented to meet the requirements of 45 CFR 46, and a membership list will be provided to the OPRR for approval. 4. HSRAC membership lists and meeting minutes will be maintained by the OHSR.
6. Institutional Review Boards (IRBs) - Structure
  1. Establishment of IRBs
    1. Subject to the approval of the DDIR, it is the responsibility of each IC having a significant volume of research activity involving human subjects to establish an IRB of persons with varying backgrounds to promote complete review and approval of such IC research activities. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members’ backgrounds, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to foster respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review and approve specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in light of (1) ethical principles set forth in The Belmont Report (Appendix E), (2) requirements of Federal regulations for the protection of human subjects (45 CFR 46, Appendix F), (3) applicable Federal, local and state law, and (4) standards of professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas.
    2. Investigators from the Clinical Center and other NIH components that generate an insufficient quantity of research protocols to warrant their own IRB shall submit their protocols to the IRB most closely related to the subject matter of the proposed study.
  2. Composition
    1. Each IRB shall have at least 5 members.
    2. No IRB shall consist entirely of men, entirely of women or entirely of members of one profession.
    3. Each IRB shall include at least one member (e.g., lawyer, ethicist, cleric) whose primary concerns are in nonscientific areas, and at least one member who is not otherwise affiliated with the Public Health Service, and who is not part of the immediate family of an affiliated person.
    4. The Chair of the IRB shall be recommended by the IC Clinical Director, in consultation with the IC Scientific Director, and appointed by the DDIR. IC, Scientific and Clinical Directors may not serve as IRB Chairs. Ordinarily, the IRB Chair shall serve for two years, but the appointment may be renewed.
    5. IRB members shall be recommended by the IC Clinical Director, in consultation with the IC Scientific Director, and appointed by the DDIR for one- to three-year renewable terms.
    6. An IRB Chair may appoint ad hoc members with competence in special areas to assist in the review of complex issues that require expertise beyond that available on the IRB. These individuals may not vote with the IRB.
7. IRB Authorities and Responsibilities
  1. IRB review of research protocols.
    1. The IRB has the responsibility and authority to review and approve, require modification in, or disapprove new protocols, or amendments to previously approved protocols.
    2. The IRB shall approve research based on its determination that the following requirements are satisfied:
      1. Risks to subjects are minimized
        
        by using procedures that are consistent with sound research design and that do not unnecessarily expose subjects to risk, and
        
        whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
      2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB shall 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). Future applications of the knowledge gained from the research are not among those research risks that fall within the purview of the IRB’s responsibility.
      3. Selection of subjects is equitable. In making this assessment the IRB shall take into account the purposes of the research, the setting in which the research will be conducted, and the population from which subjects will be recruited. IRBs shall place special emphasis on the inclusion of minorities and both genders in study populations so that research findings can be applied to all persons at risk for the disease, disorder or condition under study. The IRB shall review and approve advertisements and recruitment letters for subjects.
      4. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by 45 CFR 46.116 (see III. G. 2.).
      5. Informed consent will be appropriately documented, in accordance with, and to the extent required by 45 CFR 46.117 (see III. C. 11.).
      6. Where appropriate, the research plan makes adequate provisions for monitoring the data collected to ensure the safety of subjects including, if necessary, by establishment of a Data and Safety Monitoring Board.
      7. Where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
      8. When appropriate, review and approval by other required groups (e.g., NIH Radiation Safety Committee) is under way.
  2. Documentation of informed consent
    1. The IRB shall require documentation of informed consent consistent with 45 CFR 46.117 (see III. C. 11) by use of a written consent document approved by the IRB and signed by the subject or the subject’s legally authorized representative.
    2. In accord with 45 CFR 46.117(c), an IRB may waive the requirement for a signed consent document for some or all subjects, if the IRB determines that:
      1. The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern; or
      2. The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context.
        
        When the documentation requirement is waived, the IRB may require the research investigator to provide subjects with a written statement regarding the research.
  3. Waiver or alteration of the general requirements of informed consent
    
    The IRB may approve a consent procedure which does not include, or which alters, some or all of the general requirements for informed consent set forth in 45 CFR 46.116 (see III. C. 8., 9.) or waive the requirements to obtain consent provided the IRB finds and documents that:
    1. The research involves no more than minimal risk to the subjects (as defined in 45 CFR 46);
    2. The waiver or alteration will not adversely affect the rights and welfare of the subjects;
    3. The research could not practicably be carried out without the waiver or alteration; and
    4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.
  4. Observation of the consent process and the research
    
    Each IRB shall have the authority to observe or to have a third party observe the consent process and the research.
  5. Continuing review
    1. Each IRB shall conduct continuing review of approved research at least once a year or at shorter intervals appropriate to the degree of risk (see III. C. 13. a., b.)
      1. Each PI will submit (i) the necessary forms, including the current consent document, (ii) a brief narrative to the IRB indicating the experience with the research, including subject demographics, and (iii) the reason(s) for continuing the study.
      2. In addition, each IRB may require that a protocol be rewritten to consolidate amendments. The frequency of this consolidation will be mandated by the IRB.
    2. Research protocols that required full IRB review initially shall require full IRB review for continuation.
    3. The PI has 30 days to respond to the IRB’s recommendations and/or stipulations.
  6. Authority to modify, suspend or terminate approval of research
    1. Each IRB shall have the authority to modify, suspend or terminate approval of research that:
      1. has been associated with unexpected serious harm to subjects, or
      2. is not being conducted in accordance with 45 CFR 46 or the IRB’s decisions, conditions and requirements.
    2. Whenever an IRB suspends or terminates approval of research for reasons listed in a. above, the IRB Chair shall report the decision in writing to:
      1. the PI,
      2. the IC Clinical Director, or Scientific Director, as appropriate,
      3. the OHSR, and,
      4. the Director, CC, if the research is conducted in or by an employee of the CC.
8. General IRB Operating Procedures
  1. Determination of review procedures
    1. The IRB Chair shall determine whether the research protocol meets the criteria necessary for an expedited review process.
    2. The IRB Chair refers all research protocols to either full committee review or expedited review.
  2. Review of collaborative or cooperative research activities
    1. Documentation of non-NIH IRB approval for collaborative or cooperative human research activities being conducted at NIH and other institutions holding Multiple Project Assurances (MPAs) will be maintained by the IRB and will be available to the OHSR on request.
    2. OPRR negotiation of a Single Project Assurance (SPA) or other appropriate assurance shall be requested by the IRB Chair through the OHSR.
    3. The IRB Chair shall obtain the approval of OHSR if she/he determines that another institution’s OPRR-approved IRB is better suited to serve as the primary review body (see III. I. 7.). OHSR will determine whether reliance on the non-NIH IRB is appropriate and will obtain the required documentation and OPRR approval.
  3. Expedited review
    1. The IRB Chair may use the expedited review procedure:
      1. to review minor changes in previously approved research during the period for which approval is authorized, or
      2. to review research which involves no more than minimal risk to subjects and in which the only involvement of human subjects will be in one or more of the categories listed in Appendix J.
    2. Expedited review may be conducted by the IRB Chair or by one or more of the experienced IRB members designated by the Chair.
    3. The IRB Chair or member(s) conducting the expedited review may:
      1. exercise all the authorities of an IRB except that the reviewer(s) may not disapprove the research. Any research that would have been disapproved shall be referred to the full committee.
      2. refer research protocols to the full committee whenever the reviewer(s) judges that full committee review is warranted.
    4. Protocols reviewed and approved by the expedited review procedure:
      1. require subsequent approval by the appropriate IC official consistent with III. A. 3.;
      2. must be entered into the appropriate IRP NIH database(s) (see II. C.8.c., and III. D. 3.);
      3. are subject to continuing review by the IRB (see III. C. 13. and III. G. 5.).
    5. When the expedited review procedure is used, the IRB Chair, or member(s) conducting the review, shall, at the next convened meeting, inform the IRB members of, and document in the IRB minutes, research protocols which have been approved by the expedited review procedure.
  4. Full IRB review
    1. Meetings shall be called by the Chair as often as required to accomplish the business of the IRB. The meetings shall be open to the public except for those discussions which deal with private or confidential information.
    2. A quorum shall be defined as a majority of the voting members (fifty percent plus one) including at least one member whose primary concerns are in nonscientific areas. The Chair shall vote only to break a tie.
    3. No IRB member shall participate in an IRB’s initial or continuing review of any protocol in which the member has a real or an apparent conflict of interest, except to provide information requested by an IRB.
    4. Possible IRB Actions
      1. Protocol approval
        Protocol approval requires the approval of a majority of the IRB’s quorum. If the vote of the IRB is not unanimous, the minority opinion must be recorded in or attached to the minutes and accompany the majority decision when forwarded for final institutional review and approval. A copy of each approved protocol together with all the correspondence and approval cover sheet will be forwarded for institutional approval and signature to the DDIR or his/her IC designee (see III. A. 3.). Protocols conducted in the CC are then forwarded to the Director, CC for review and approval as per III. D. 2. Copies of protocols not conducted in the CC shall be forwarded to OHSR for entry into its database (III. I. 7.b(2)).
      2. Protocol approval with recommendations
        The IRB may approve a protocol with non-binding recommendations. PIs must respond in writing to IRB recommendations.
      3. Protocol approval with stipulations
        An IRB may approve a protocol with stipulations which must be met in writing by a PI before initiation of the research. The IRB may (i) authorize the IRB Chair to approve the response to the stipulations and forward the protocol as described in d. (1) above; (ii) authorize an IRB subcommittee to review the response to the stipulations, or (iii) request that the response be reviewed at a convened meeting of the IRB.
      4. Tabling of protocol
        Approval cannot be granted until further information is provided or specific changes are made. When the new information is submitted the protocol is reviewed by the full IRB again.
      5. Disapproval
        Notice of the disapproval is sent to the PI and includes the reasons for the disapproval and information about reconsideration.
  5. IRB notification to research investigators in writing of its actions
    
    The IRB shall notify research investigators in writing of its decisions.
  6. IRB Records
    1. Each IRB shall maintain copies of protocols and samples of consent documents that it has reviewed; scientific evaluations, if any, that accompany protocols, including, when appropriate, a copy of the relevant clinical investigator’s brochure; minutes of its meetings in accord with 45 CFR 46.115(a)(2); a current approved membership list; progress reports submitted by investigators; reports of injuries to subjects; copies of all correspondence between the IRB and investigators, statements of significant new findings provided to subjects; and documentation of collaborative and cooperative research activities occurring at other institutions with MPAs, SPAs, or other OPRR-approved assurances.
    2. These records and documents shall be retained for at least three years after completion of the research. The records shall be accessible for inspection and copying by OHSR and authorized representatives of DHHS at reasonable times and in a reasonable manner.
    3. The IRB shall notify the OHSR of any change in its membership.
9. The Office of Human Subjects Research (OHSR)
  1. The OHSR is administratively situated in the Office of Intramural Research, NIH and the Director reports to the Deputy Director for Intramural Research (DDIR). The OHSR coordinates and oversees NIH’s activities to which this MPA applies involving the protection of human research subjects.
  2. Institutional determinations concerning exemptions to 45 CFR 46
    The OHSR is responsible for reviewing the preliminary determinations of research investigators (see III. C. 2.) and for making final institutional determinations of whether research activities qualify for exemption from coverage under 45 CFR 46.101 (Appendix C).
    1. Documentation of research activities that do qualify for exemption will be kept on file in the OHSR.
    2. Documentation of research activities that are determined not to be exempt will be returned to the investigator for incorporation into a protocol and submission to the appropriate IRB for review.
  3. Conduct of educational activities
    The OHSR plans, organizes and conducts educational programs, as appropriate, for all NIH IRP scientists conducting research with human subjects.
  4. Conduct of inquiries/investigations
    At the request of the DDIR, the OHSR shall conduct inquiries and/or investigations concerning allegations of noncompliance with this Assurance and/or other policies and procedures covering the conduct of human subjects research.
  5. Review of NIH practices and procedures for the protection of human subjects
    OHSR will provide to the DDIR ongoing review and evaluation of NIH practices and procedures for the protection of human subjects to which this MPA applies.
  6. Policy formation concerning human subjects research
    1. The OHSR interprets and formulates policies consistent with 45 CFR 46.
    2. In this activity, it coordinates its efforts with other appropriate groups including, but not limited to, the CC Medical Executive Committee, the HSRAC, the Office of the Director, CC, and the IRBs.
  7. Collaborative and cooperative research activities
    1. The NIH will comply with the requirements set forth in 45 CFR 46.114 regarding cooperative research projects.
    2. When collaborative or cooperative research activities are being conducted with other entities that do not have assurances established with OPRR, the OHSR will consult with the OPRR and will, on behalf of the NIH, request that the OPRR negotiate assurances of compliance, as warranted.
    3. OHSR will establish and maintain the NIH database for which this MPA applies of all collaborative and cooperative research activities for which SPAs or other OPRR approved assurances are required.
    4. The NIH may accept, for the purposes of meeting IRB review requirements, the review of an IRB established under another MPA or other OPRR-approved assurance covering the research to be conducted.
      1. In the case of multiple-protocol, long-term collaborative agreements, such acceptance must be approved by OHSR and the corresponding official(s) of the other cooperating institution(s), and kept on file in the OHSR.
      2. In the case of a single protocol, one-time-only collaboration, OHSR may approve a written request by an NIH investigator for deferral to another OPPR-assured institution when the following conditions have been met:
        
        Research subjects are to be enrolled only at OPRR-assured performance sites and not at NIH,
        
        for each site, a research protocol that includes a description of the activity to be conducted by the NIH investigator has been reviewed and approved by the collaborating institution’s IRB, and
        
        documentation of IRB approval at the collaborating site(s) is provided by the NIH investigator to OHSR.
      3. When OHSR approves a deferral to another OPRR-assured institution, the investigator and IRB at that institution will be informed by copy of the OHSR memo of approval to the NIH investigator.
      4. Documentation of OHSR activities taken at (1), (2), and (3) above will be forwarded to OPRR for written approval prior to involvement of subjects.
      5. OHSR will maintain appropriate documentation of deferral requests and actions.
  8. Reporting requirements
    The OHSR, on behalf of the DDIR, shall report promptly to the OPRR:
    1. any unanticipated problems involving risks to subjects or others;
    2. any suspension or termination of IRB approval as a result of unexpected serious harm to research subjects or others;
    3. any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB (III. G. 6. b.);
    4. any changes in IRB membership, including IRB membership changes to meet 45 CFR 46.304(b) for research involving prisoners.
10. NIH recognizes that certain Cooperative Protocol Research Programs (CPRPs) may require additional reporting and record-keeping related to the protection of human subjects.

NATIONAL INSTITUTES OF HEALTH

Human Subjects Research Advisory Committee

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