SUBJECT:  Written Procedures Governing the Committee

 HHS regulations at 45 CFR 46.103(b)(4) and (5) require written procedures for each of the following:

1.   Conducting initial review of research.

2.   Conducting continuing review of research.

3.   Reporting findings and actions to investigators and the institution.

4.   Determining which projects require review more often than annually.

5.   Determining which projects need verification from sources other than the investigators

6.   Ensuring that no material changes have occurred since previous HRAC review.

7.   Ensuring prompt reporting to the HRAC of proposed changes in a research activity, and for ensuring that such changes in approved research, during the period for which HRAC approval has already been given, may not be initiated without HRAC review and approval except when necessary to eliminate apparent immediate hazards to the subject.

8.   Ensuring prompt reporting to the HRAC, appropriate institutional officials, any Department or Agency head, and OHRP of:

(a) any unanticipated problems involving risks to subjects or others;

(b) any serious or continuing noncompliance with 45 CFR Part 46 or the requirements or determinations of the HRAC; and

(c)   any suspension or termination of HRAC approval.

A.              Initial Review  (See HRAC policy 7.4)

1.   Requirement for Review of Research by the HRAC at Convened Meetings. In accordance with HHS regulations at 45 CFR 46.108(b), initial and continuing reviews of research must be conducted by the HRAC at convened meetings at which a majority of the members of the HRAC are present, including at least one member whose primary concerns are in nonscientific areas (i.e., a quorum), except where expedited review is appropriate [45 CFR 46.110(b)(1)]. Approval of research is by a majority vote of this quorum (see HRAC policy 3.2).  Should the quorum fail during a meeting (e.g., loss of a majority through recusal of members with conflicting interests or early departures, or absence of a nonscientist member), the HRAC may not take further actions or votes unless the quorum can be restored.

2.   Research Review Materials

Initial Review Materials. HHS regulations at 45 CFR 46.111 set forth the criteria that must be satisfied in order for the HRAC to approve research. These criteria include determinations by the HRAC regarding risks, potential benefits, informed consent, and safeguards for human subjects. In conducting the initial review of proposed research, HRACs must obtain information in sufficient detail to make the determinations required (45 CFR 46.111). Materials should include the full protocol, a proposed informed consent document, any relevant grant application(s), the investigator's brochure (if one exists), and any recruitment materials, including advertisements intended to be seen or heard by potential subjects. 

The primary reviewer(s) should do an in-depth review of all pertinent documentation (see previous paragraph). All other HRAC members should receive and review a protocol summary (of sufficient detail to make the determinations required under HHS regulations at 45 CFR 46.111), the proposed informed consent document, and any recruitment materials, including advertisements intended to be seen or heard by potential subjects. In addition, the complete documentation should be available to all members for review.

B.             Continuing Review  (See HRAC policy 7.6)

1.   HRAC members should receive and review a protocol summary and a status report on the progress of the research, including: (i) the number of subjects accrued; (ii) a summary of adverse events and any unanticipated problems involving risks to subjects or others and any withdrawal of subjects from the research or complaints about the research since the last HRAC review; (iii) a summary of any relevant recent literature, interim findings, and amendments or modifications to the research since the last review; (iv) any relevant multi-center trial reports; (v) any other relevant information, especially information about risks associated with the research; and (vi) a copy of the current informed consent document and any newly proposed consent document.

2.   At least one member of the HRAC (i.e., a primary reviewer) also should receive a copy of the complete protocol including any modifications previously approved by the HRAC. Furthermore, upon request, any HRAC members also should have access to the complete HRAC protocol file and relevant HRAC minutes prior to or during the convened HRAC meeting.

3.   The minutes (see HRAC policy 6.3) of HRAC meetings should document separate deliberations, actions, and votes for each protocol undergoing continuing review by the convened HRAC.

4.   When reviewing research under an expedited review procedure, the HRAC Chair (or designated HRAC member(s)) should receive and review all of the above-referenced documentation, including the complete protocol

C.            HRAC Review in Emergency Situations.  (See HRAC policy 18.3, 18.4, 18.5

Human subject research activities can not be started, even in an emergency, without prior HRAC review and approval (see 45 CFR 46.103(b) and 46.116(f). When emergency medical care is initiated without prior HRAC review and approval, the patient may not be considered a research subject under 45 CFR Part 46. Such emergency care may not be claimed as research, nor may any data regarding such care be included in any report of a prospectively conceived research activity. When emergency care involves investigational drugs, devices, or biologics, U.S. Food and Drug Administration (FDA) requirements must be satisfied.

D.            "Conditional" Approvals.  (See HRAC policy 7.1)

When the convened HRAC requests substantive clarifications or modifications regarding the protocol or informed consent documents that are directly relevant to the determinations required by the HRAC under HHS regulations at 45 CFR 46.111, HRAC approval of the proposed research should be deferred, pending subsequent review by the convened HRAC of responsive material.

Only when the convened HRAC stipulates specific revisions requiring simple concurrence by the investigator may the HRAC Chair or another HRAC member designated by the Chair subsequently approve the revised research protocol on behalf of the HRAC under an expedited review procedure.

E.             Conflicting Interest.  (See HRAC policy 3.3) 

HHS regulations at 45 CFR 46.107(e) stipulate that no HRAC member may participate in the HRAC’s initial or continuing review of a project in which the member has a conflicting interest, except to provide information requested by the HRAC. OHRP recommends that except when requested by the HRAC to be present to provide information, HRAC members absent themselves from the meeting room when the HRAC reviews research in which they have a conflicting interest, and such should be noted in the HRAC meeting minutes. 

F.             Expedited Review. (See HRAC policy 7.5)

G.              Records and Documentation   [45 CFR 46.115(a)(1), (3), (4), and (7)]

 1.    Minutes of HRAC Meetings. The minutes of HRAC meetings should document, among other things:

a.   Separate deliberations, actions, and votes for each protocol undergoing initial or continuing review by the convened HRAC.

b.   The vote on all HRAC actions including the number of members voting for, against, and abstaining. In order to document the continued existence of a quorum, 45 CFR 46.115(a)(2)

2.   Documentation of Findings. HHS regulations at 45 CFR 46.116(d) require that the HRAC make and document findings when approving a consent procedure which does not include, or which alters, some or all of the required elements of informed consent or when waiving the requirement to obtain informed consent. OHRP recommends that when approving such a waiver for research reviewed by the convened HRAC, these findings be documented in the minutes of the HRAC meeting, including protocol-specific information justifying each HRAC finding.

Similarly, where HHS regulations require specific findings on the part of the HRAC, such as (a) approving a procedure which waives the requirement for obtaining a signed consent form [see 45 CFR 46.117(c)]; (b) approving research involving pregnant women, human fetuses, or neonates (see 45 CFR 46.204-207); (c) approving research involving prisoners (see 45 CFR 46.305-306); or (d) approving research involving children (see 45 CFR 46.404-407), the HRAC should document such findings. OHRP recommends that for research approved by the convened HRAC, all required findings be fully documented in the minutes of the HRAC meeting, including protocol-specific information justifying each HRAC finding.

For research reviewed under an expedited review procedure, these findings should be documented by the HRAC Chairperson or other designated reviewer elsewhere in the HRAC record.

3.   Documentation of Risk and Approval Period. HRACs must determine which protocols require continuing review more often than annually, as appropriate to the degree of risk [see HRAC policy 16.1 and  45 CFR 46.103(b)(4) and 46.109(e).  The minutes of HRAC meetings should clearly reflect these determinations regarding risk and approval period (review interval).

4.   Retention of HRAC Records. HHS regulations at 45 CFR 46.115(b) require that HRAC 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 (see HRAC policy 5.1).

H.              Review of Protocol Changes

1.   Review of Proposed Protocol Changes by the HRAC at Convened Meetings. In accordance with HHS regulations at 45 CFR 46.108(b), review of proposed protocol changes must be conducted by the HRAC at convened meetings at which a majority of the members of the HRAC 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)(2).

2.   Expedited Review of Minor Changes. Institutions should adopt policies describing the types of minor changes in previously approved research which can be approved under an expedited review procedure in accordance with HHS regulations at 45 CFR 46.110(b)(2).

3.   Protocol Revisions. Each revision to a research protocol should be incorporated into the written protocol. This practice ensures that there is only one complete protocol with the revision dates noted on each revised page and the first page of the protocol itself. This procedure is consistent with the procedure used for revised and approved informed consent documents which then supersede the previous one.