Types of Determinations

In accordance with HHS regulations at 45 CFR 46.103(b) and 46.109(a), the IRB must review and approve all non-exempt human subject research covered by an assurance before the research can be conducted. We have determined that certain non-exempt human subjects research was conducted without IRB review and/or approval.

HHS regulations at 45 CFR 46.103(f) require that an institution with an approved assurance shall certify that each application or proposal for research covered by the assurance has been reviewed and approved by an IRB designated under the institution's federalwide assurance. We have determined that the IRB consistently failed to review the grant application for proposed research for which the institution is the primary awardee. (see "IRB Review of Applications for HHS Support" http://www.hhs.gov/ohrp/regulations-and-policy/guidance/irb-review-applications-for-hhs-support/index.html)

We have determined that the IRB, when reviewing protocol applications, lacked sufficient information to make the determinations required for approval of research under HHS regulations at 45 CFR 46.111. For example, the IRB reviewed insufficient information regarding (a) risks to subjects and how they are minimized; (b) subject recruitment and enrollment procedures; (c) the equitable selection of subjects; (d) provisions to protect the privacy of subjects and maintain the confidentiality of data; and (e) additional safeguards to protect the rights and welfare of subjects who are likely to be vulnerable.

In accordance with HHS regulations at 45 CFR 46.108(b), review of proposed research must be conducted by the IRB 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, except where expedited review is appropriate under HHS regulations at 45 CFR 46.110(b). We have determined that little substantive review took place at convened meetings. Protocols undergoing initial/continuing review and protocol amendments undergoing review were neither individually presented nor discussed at a convened meeting of the IRB. Furthermore, we have noted little evidence that IRB approval of research was consistently based on consideration of the determinations required under HHS regulations at 45 CFR 46.111. Specifically, the IRB appeared not to have considered systematically and rigorously such issues as risks to subjects and how they are minimized, equitable selection of subjects and subject recruitment, privacy and confidentiality protections, and additional safeguards for subjects likely to be vulnerable to coercion or undue influence.

HHS regulations at 45 CFR 46.107(a) provide, among other things, that each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. In addition, the regulations provide that the IRB be sufficiently qualified through the experience and expertise of its members to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects and be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The convened IRB, when reviewing protocol applications, must have sufficient expertise among the members present at the meeting to make the determinations required for approval of research under HHS regulations at 45 CFR 46.111. We have determined that the members of the IRB present at convened meetings did not have the background and expertise necessary to review the research being proposed.

HHS regulations at 45 CFR 46.113 require that the IRB 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 associated with unexpected serious harm to subjects. In addition, HHS regulations at 45 CFR 46.112 provide that non-exempt human subjects research that has been approved by an IRB may be subject to further appropriate review and approval or disapproval by officials of the institution. However, such officials may not approve non-exempt human subjects research if it has not been approved by an IRB. We have determined that the IRB voted to suspend research, and that an institutional official rescinded or delayed that suspension, in violation of HHS regulations at 45 CFR 46.113 and 112.

We have determined that the IRB frequently approved research contingent upon substantive modifications or clarifications that were directly relevant to the determinations required by the IRB under HHS regulations at 45 CFR 46.111 without requiring additional review by the convened IRB. We have noted that when the convened IRB requests substantive clarifications or modifications regarding the protocol or informed consent documents that the IRB needs in order to make the determinations required by the IRB under HHS regulations at 45 CFR 46.111, IRB approval of the proposed research must be deferred, pending subsequent review by the convened IRB of responsive material, unless the research is eligible for review under an expedited review procedure.

HHS regulations at 45 CFR 46.108(b) require that, except when an expedited review procedure is used, research be reviewed 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 a nonscientific area (hereinafter referred to as "nonscientist"). We have determined that the IRB failed to meet this requirement for certain IRB meetings. Thus, any actions taken at these meetings that required a quorum were not valid under the HHS regulations at 45 CFR part 46. We have emphasized that should the quorum fail during a meeting (e.g., those with conflicts being excused, early departures, absence of a nonscientist member), the IRB may not take further actions or votes that require a quorum unless the quorum is restored.

HHS regulations at 45 CFR 46.108 require that, except when an expedited review procedure is used, the IRB review proposed research at convened meetings at which a majority of the members of the IRB are present. We have determined that the IRB failed to meet this requirement for certain IRB meetings. Thus, any actions taken at these meeting that required a quorum were not valid under the HHS regulations at 45 CFR part 46. We have emphasized that should the quorum fail during a meeting (e.g., those with conflicts being excused, early departures, absence of a nonscientist member), the IRB may not take further actions or votes that require a quorum unless the quorum can be restored.

Continuing review of research must be substantive and meaningful. HHS regulations describe at 45 CFR 46.111 (and at subparts B, C, and D of 45 CFR part 46 when applicable) the criteria that must be satisfied in order for the IRB to approve research. These criteria must be satisfied when the IRB conducts continuing review of research either at a convened meeting or under an expedited review procedure. These criteria include, among other things, determinations by the IRB regarding risks, potential benefits, informed consent, and additional safeguards for subjects likely to be vulnerable to coercion or undue influence.

We have determined that continuing review of research by the IRB was not substantive and meaningful.

HHS regulations at 45 CFR 46.109(e) require that continuing review of research be conducted by the IRB at intervals appropriate to the degree of risk, but not less than once per year. The regulations make no provision for any grace period extending the conduct of the research beyond the expiration date of IRB approval. Additionally, where the convened IRB specifies conditions for approval of a protocol that are to be verified as being satisfied by the IRB chairperson or another IRB member designated by the chairperson, continuing review must occur no later than one year after the date the protocol was reviewed by the convened IRB, not on the anniversary of the date the IRB chairperson or his or her designee verifies that IRB-specified conditions for approval have been satisfied.

We have determined that the IRB failed to conduct continuing review of research at least once per year and that in some cases the IRB has granted extensions beyond the expiration date of IRB approval.

HHS regulations at 45 CFR 46.109(e) state that an IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year.  HHS regulations at 45 CFR 46.102(f) define human subject as 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. Even where (i) the research is permanently closed to the enrollment of new subjects; and (ii) all subjects have completed all research-related interventions, continuing review is required as long as the research remains active for long-term follow-up of subjects and continues to involve non-exempt human subjects research. Furthermore, continuing IRB review of research is required where the remaining research activities are limited to data analysis of individually identifiable private information (see 63 FR 60364-60367, category (8)). We have determined that continuing review did not occur in protocols involving follow-up activities.

HHS regulations at 45 CFR 46.108(b) require that the IRB 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, except where expedited review is appropriate under HHS regulations at 45 CFR 46.110. HHS regulations at 45 CFR 46.110(b)(1) limit the use of expedited review procedures for initial or continuing review to specific research categories published in the Federal Register at 63 FR 60364--60367 (seehttp://www.hhs.gov/ohrp/policy/expedited98.html) when the research is determined to involve no more than minimal risk. We have determined that:

(a) The IRB inappropriately applied expedited review to research that involved minimal risk but did not appear in the categories of research published in the Federal Register.

(b) The IRB inappropriately applied expedited review to research that involved greater than minimal risk.

HHS regulations at 45 CFR 46.108(b) require that the IRB 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, except where expedited review is appropriate under HHS regulations at 45 CFR 46.110. HHS regulations at 45 CFR 46.110(b)(2) permit use of expedited procedures for review of minor changes in previously approved research during the period for which approval is authorized. We have determined that the IRB has employed expedited procedures to review changes that were more than minor.

HHS regulations at 45 CFR 46.110(b) state that under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among the members of the IRB. We have determined that an individual who was not a member of the IRB approved human subject research purportedly under an expedited review procedure, in violation of HHS regulations at 45 CFR 46.103(b), 45 CFR 46.109(a) and 45 CFR 46.110(b).

We have determined that unanticipated problems involving risks to subjects or others or serious or continuing noncompliance or suspensions or terminations of IRB approval were not reported to appropriate institutional officials or the IRB or OHRP or the head of the sponsoring Federal department or agency as required by HHS regulations at 45 CFR 46.103(a) and 46.103(b)(5).

HHS regulations at 45 CFR 46.103(b)(4)(iii) require that the IRB review and approve all proposed changes in a research activity, during the period for which IRB approval has already been given, prior to initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subjects. We have found no documentation that the IRB reviewed and approved protocol changes prior to initiation or we determine that certain protocol changes were initiated without IRB approval and/or approval, in circumstances where the changes were not necessary to eliminate apparent immediate hazards to the subjects.

HHS regulations at 45 CFR 46.103(b)(4)(iii) require that the IRB review and approve all proposed changes in a research activity, during the period for which IRB approval has already been given, prior to initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subjects. We have determined that the IRB's procedures for reviewing protocol modifications was inadequate. In some cases, the IRB chairperson or designated IRB reviewer from among the IRB members approved such modifications in the absence of a complete description of the proposed changes.

We note that when reviewing proposed changes to research, the IRB must also receive sufficient information to make the determinations required for approval of research under HHS regulations at 45 CFR 46.111 and, when applicable, under subparts B, C, and D of 45 CFR part 46, although we did not cite these regulatory provisions when making this determination in the past.

HHS regulations at 45 CFR 46.101(b) delineate six specific categories of research that are exempt from the requirements of 45 CFR part 46. We have determined that the institution applied an exemption to research activities that exceed these categories.

HHS regulations at 45 CFR 46.101(b)(4) exempt research that only involves the collection or study of existing data, documents, records, pathologic specimens, or diagnostic specimens provided specified conditions are met. We have noted that such materials must already exist at the time the research is proposed. We have determined instances where this exemption was applied to research involving data, documents, pathologic specimens, or diagnostic specimens that were not existing at the time the research was proposed.

HHS regulations at 45 CFR 46.401(b) stipulate that the exemption at 45 CFR 46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by 45 CFR part 46, subpart D (Additional Protections for Children Involved as Subjects in Research), except for research involving observation of public behavior when the investigators do not participate in the activities being observed. We have determined that exemption 2 was inappropriately applied to survey and observational research involving children.

HHS regulations at 45 CFR 45.116 state that no investigator may involve a human being as a subject in research covered by the regulations unless (a) the investigator has obtained the legally effective informed consent of the subjects or the subject's legally authorized representative, or (b) the IRB has waived the requirements to obtain informed consent in accordance with 45 CFR 46.116(c) or (d), or in accordance with the provisions for waiver of informed consent for research in emergent settings published in the Federal Register, Vol. 61, pp. 51531-51533. We have determined that the investigator initiated human subject research without obtaining legally effective informed consent of subjects and without the IRB appropriately waiving these requirements.

HHS regulations at 45 CFR 46.117(a) require that informed consent be documented by the use of a written consent form approved by the IRB and that is signed by the subject, or the subject's legally authorized representative, unless the IRB waives this requirement in accordance with 45 CFR 46.117(c). We have determined that informed consent was not documented by a written consent form signed by the subject(s) for this research and there was no IRB waiver of this requirement.

HHS regulations at 45 CFR 46.117(a) require that informed consent be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative unless the requirement for documentation of informed consent has been waived by the IRB in accordance with HHS regulations at 45 CFR 46.117(c). The regulations further require that a copy of the informed consent document shall be given to the person signing the form. We have determined that a copy of the informed consent document was not provided to the person signing the informed consent form.

HHS regulations at 45 CFR 46.116 require that informed consent information be in language understandable to the subject or the subject's legally authorized representative. We have determined that the informed consent information provided to subjects would not be understandable to some subjects.

HHS regulations at 45 CFR 46.116 prohibit the inclusion of any exculpatory language in informed consent through which the subject is made to waive, or appear to waive, any of the subject's legal rights. We have determined certain language in the IRB-approved informed consent documents was exculpatory.

HHS regulations at 45 CFR 46.116 require that investigators seek the legally effective informed consent of subjects under circumstances that minimize the possibility of coercion or undue influence. We have determined that informed consent was not sought from prospective subjects under circumstances that minimized the possibility of coercion or undue influence.

HHS regulations at 45 CFR 46.107(d) require that each IRB include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution. We have determined that the IRB did not include any such member.

HHS regulations at 45 CFR 46.304 require that at least one member of an IRB that reviews research involving prisoners 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 IRB only one IRB need satisfy this requirement. When the convened IRB reviews research involving prisoners (including initial review, continuing review, review of protocol modifications, and review of unanticipated problems involving risks to subjects or others), the prisoner or prisoner representative must be present as a voting member. We have determined that the IRB failed to meet this requirement when reviewing research projects involving prisoners.

HHS regulations at 45 CFR 46.107(a) provide, among other things, that the IRB shall be sufficiently qualified through the experience and expertise of its members to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects and shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. We have determined that the IRB chairperson and/or IRB members lacked a detailed understanding of the specific requirements of the HHS regulations for the protection of human subjects. As a result, IRB determinations sometimes deviated from these requirements.

HHS regulations at 45 CFR 46.103(b)(2) require that institutions provide meeting space and sufficient staff to support the IRB's review and recordkeeping duties. We have determined that the IRB lacked sufficient meeting space and/or staff to support the IRB's review and recordkeeping duties.

We have determined that IRB records fail to include all the documentation required by HHS regulations at 45 CFR 46.115(a).

HHS regulations at 45 CFR 46.115(a) require that the institution prepare and maintain adequate documentation of IRB activities. We found that in numerous instances among the IRB files examined by OHRP, it was difficult to reconstruct a complete history of all IRB actions related to the review and approval of the protocol. In some instances, we could not determine what the IRB actually approved.

HHS regulations at 45 CFR 46.404-407 require specific findings on the part of the IRB for approval of research involving children. We have determined that the IRB did not make the required findings when reviewing research involving children.

HHS regulations at 45 CFR 46.116(c) and (d) require that the IRB find and document specific criteria when approving waiver or alteration of some or all of the required elements of informed consent. We have determined that the IRB failed to satisfy these requirements.

HHS regulations at 45 CFR 46.117(c) requires specific findings on the part of the IRB for waiver of the requirements for the investigator to obtain a signed consent form from all subjects. We have determined that the IRB failed to make the required findings when approving such waivers.

HHS regulations at 45 CFR 46.115(b) require that IRB records be retained for at least 3 years, and records relating to research which is conducted be retained for at least 3 years after completion of the research. All records must be accessible for inspection and copying by authorized representatives of HHS at reasonable times and in a reasonable manner. We have determined that the institution failed to retain IRB records OR records relating to research for at least 3 years after completion of the research at that study site.

HHS regulations at 45 CFR 46.109(d) require that an IRB notify investigators and the institution in writing of its decision to approve or disapprove the proposed research activity, or of modifications required to secure IRB approval of the research activity. If the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. We have determined that the IRB did not notify investigators and the institution in writing of its decision to approve or disapprove proposed research or of modifications required to secure IRB approval of the research.

HHS regulations at 45 CFR 46.103(c) require that an institution's assurance of compliance with the regulations for the protection of human subjects shall be executed by an individual authorized to act for the institution and to assume on behalf of the institution the obligations imposed by the regulations. We have determined that the Signatory Official failed to fulfill his or her obligations imposed by the HHS regulations for the protection of human subjects and the institution's FWA.

We note that HHS regulations at 45 CFR 46.103(a) require that each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in the regulations, although we did not cite this regulatory provision when making this determination in the past. Similarly, Public Law 99-158 Sec. 491(a) requires that the Secretary shall by regulation require that each entity which applies for a grant, contract, or cooperative agreement under this Act for any project or program which involves the conduct of biomedical or behavioral research involving human subjects submit in or with its application for such grant, contract, or cooperative agreement assurances satisfactory to the Secretary.