OBJECTIVE:

To describe continuing review requirements and VCU IRB continuing review procedures.

DESCRIPTION:

Except for research protocols determined to be exempt (VCU IRB WPP#: VIII-1), all human research is subject to continuing review based on the level of risk as assessed by the IRB Panel.  The VCU IRB considers the same criteria for consideration of approval under continuing review as under initial review in accordance with 45 CFR 46.111, including, among other things, determinations by the IRB regarding risks, potential benefits, informed consent, and safeguards for human subjects. 

A.     Length (Duration) of Approval (or Other Requirement for Continuing Review):

At initial review and at continuing review (or otherwise as warranted), the VCU IRB will plan for continuing review of research at intervals appropriate to the degree of risk (as per VCU IRB WPP#s: VIII-2 and VIII-3), but not less than once per year, and will exercise the authority to observe or have a third party observe the consent process and the research, as appropriate (given the level or risk, experience of the investigator, vulnerability of subjects, or other concerns) [45 CFR 46.109(e)].

For research receiving full board review, the length of approval is calculated from the date of the full board review.  The primary and secondary reviewers are asked to provide a recommendation for length of approval; if other than annual continuing review will be required.  The appropriate length of approval is considered as part of the full board discussion of known or potential risks.  See also VCU IRB WPP#: VIII-3 for specific information on determining appropriate approval lengths.

For research approved via expedited initial review, the primary reviewer suggests length of approval (see VCU IRB WPP#: VIII-2).  For research reviewed via exempt review, continuing review is not required.

B.     Research Requiring Review More Frequently Than Annually and/or at Other Intervals:

The following issues require that the research receives continuing review by the VCU IRB more frequently than annually and/or at other appropriate intervals, based upon the degree of risk.

1.       Research that involves withdrawal of therapy when there may be significant morbidity or mortality,

2.       Research that involves an invasive surgical procedure,

3.       Research in which there are serious risks to participants and no potential benefits,

4.       More than minimal risk research involving a vulnerable population with no prospect of direct benefit to the individual participants, and/or

5.       Research in which unanticipated problems involving risks to participants or others create new concerns regarding the need for closer project scrutiny.

In cases such as the above, approvals may be granted for time periods less than one year or, as may be more appropriate, for a limited number of subjects over a period not to exceed one year.  The primary reviewer is responsible for recommending these requirements at the time of review or as needed.

C.     Notification of Investigators:

Principal investigators are notified of length of approval and/or limitations of approval in their initial review approval letter.  Reminder notices may be sent by the ORSP as a courtesy to investigators, but are not to be relied upon.

D.     General Continuing Review Notes:

In conducting continuing review of research not eligible for expedited review, all IRB members will receive and review the following:

1.       IRB Continuing Review Form and attachments (if applicalbe)

2.       A status report on the progress of the research (in accordance with VCU IRB WPP#: VII-2), including:

a)      The number of subjects enrolled;

b)      Summary reportable events, including (but not limited to):

i)           A summary of adverse events since the last IRB review.

ii)         A summary of unanticipated problems involving risks to participants or others since last IRB review.

iii)        A summary of complaints about the research since the last IRB review.

c)      A summary of any relevant recent literature, interim findings, and amendments or modifications to the research since the last review;

d)      Any relevant multi-center trial reports; and

e)      Any other relevant information, especially information about risks associated with the research

3.       A copy of the VCU Research Plan/Synopsis and Sponsor's protocol (if applicable).. Furthermore, upon request, any IRB member also should have access to the complete IRB protocol file and relevant IRB minutes prior to or during the convened IRB meeting.

4.       A copy of the current informed consent document

5.       Any proposed amendments

When reviewing the current informed consent document(s), the IRB will ensure the following:

1.       The currently approved or proposed consent document is still accurate and complete;

2.       Any significant new findings that may relate to the subject's willingness to continue participation are provided to the subject in accordance with HHS regulations at 45 CFR 46.116(b)(5).

3.       Review of currently approved or newly proposed consent documents must occur during the scheduled continuing review of research by the IRB, but informed consent documents should be reviewed whenever new information becomes available that would require modification of information in the informed consent document.

The IRB will consider whether verification is needed from sources other than the investigator that no material changes have occurred since previous IRB review.  Examples of when the IRB may require verification from other sources include: (a) investigator has a pattern of submitting the wrong version of the protocol or consent document at time of continuing review, and (b) the investigator has a pattern of submitting reports of unanticipated problems (UPs) past the deadline for reporting UPs.

The IRB will also ensure that the active research plans demonstrate that:

1.       The investigator will obtain the legally effective consent of the participant or the participant’s legally authorized representative.

2.       The circumstances of the consent process provide the prospective participant or the legally authorized representative sufficient opportunity to consider whether to participate.

3.       The circumstances of the consent process minimize the possibility of coercion or undue influence.

4.       The individuals communicating information to the participant or the legally authorized representative during the consent process will provide that information in language understandable to the participant or the representative.

5.       The information being communicated to the participant or the representative during the consent process will not include exculpatory language through which the participant or the legally authorized representative is made to waive or appear to waive any of the participant’s legal rights, or release or appear to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

E.   EXPEDITED Continuing Review Process Notes:

1.       The ORSP provides a form, upon request or on its website, for the submission of continuing review materials.  When an application for continuing review is received, the packet is checked by the ORSP staff for completeness, logged in, and forwarded to the reviewer.

2.       Expedited continuing review submissions are assigned to the original panel that conducted the initial IRB review and to the original primary reviewer (where possible).  If the original primary reviewer is not available, the VCU ORSP staff will make an assignment based upon a list of reviewers designated by the IRB chairperson (including the chairperson and vice chairperson) and by area of experience as documented to the staff.  Assignments are subject to the approval of the Chairperson or designee.  If staff detect that a reviewer may not be available or have the expertise required, they contact the chairperson to obtain a consultation recommendation.

3.       Reviewer's actions are limited to approving research or requiring modifications to secure approval.

4.       Research previously approved via expedited review is considered eligible for expedited review at the time of its regular continuing review, if, during the course of the study, the risks of the study have not increased. 

a)      Expedited initial approvals trigger expedited continuing review unless the investigator proposes changes in the study that cause the review type to be modified to full board review.  At the time of continuing review, the reviewer must verify that the research meets all applicability criteria for one or more approvable categories of research based upon review of the continuing review report.  The Expedited review category must be confirmed and documented .

b)      If the initial review was conducted via Full Board review and is now proposed for Expedited continuing review, the reviewer must verify that the research meets all applicability criteria for the Expedited review category (8 or 9) based upon review of the continuing review report..  The Expedited review category must be confirmed and documented.

5.       If there is any protocol-related information requiring clarification, the reviewer should contact the principal investigator (or appropriate designee directly).

6.       FINAL review comments by the expedited reviewer must be documented in writing and forwarded to the IRB coordinator for processing (email documentation is strongly recommended).

7.       All continuing review reports (reviewed via expedited review) are reported to a convened Panel meeting and are available to all Panel members and alternate members (upon request).

8.       The list of all expedited continuing review reports that were received prior to the next meeting of each panel will be attached to the minutes (or as part of the agenda) of the meetings at which they are reported.

F.   FULL BOARD Continuing Review Notes and Process:

1.       Research previously reviewed via full board review automatically receive a full board continuing review unless the IRB panel, at a convened meeting of the IRB, determines that the study qualifies for expedited continuing review, by meeting category 9 of the Expedited Review Categories 1-9 as published at 63 FR 60364-60367 or the primary reviewer determines that Category 8 (a, b, or c) [of the Expedited Review Categories 1-9 as published at 63 FR 60364-60367].

2.       Full continuing review submissions are assigned to or the original panel that conducted the initial IRB review and to the original primary reviewer (where possible) or a similarly qualified member.  If the original primary reviewer is not available, the VCU ORSP staff will make an assignment based upon a list of reviewers designated by the IRB chairperson (including the chairperson and vice chairperson) and by area of experience as documented to the staff.  Assignments are subject to the approval of the Chairperson or designee.  If staff detect that a reviewer may not be available or have the expertise required, they contact the chairperson to obtain a consultation recommendation.

3.       All members will receive a copy of the VCU Research Plan/Synopsis and Sponsor's protocol (if applicable).  Furthermore, upon request any IRB member, should have access to the complete IRB protocol file, and relevant IRB minutes prior to or during the convened IRB meeting.

4.       Reviewer comments will be prepared prior to the IRB meeting and presented verbally to the panel with the recommendation for action. Changes and/or clarifications requested by the reviewer will be documented in writing and made available to the IRB Coordinator. 

5.       If there were pertinent changes to the research protocol submitted at the time of continuing review, the reviewer’s comments must include the following (only required if any changes to the research protocol include the addition of vulnerable populations, waiver of consent, or reasons for reconsideration of approval periods):

a)      Comments on review of consent process and document (unless waiver of consent was requested).

i)           If a waiver of consent (45 CFR 46.116(c-d)) or waiver of documentation of informed consent (45 CFR 46.117(c)(1-2)) is requested/approved, the required determinations must be included along with protocol specific findings justifying each of those determinations.  [The VCU IRB requires that the protocol include the precise information that justifies the findings of the IRB and that this information be part of the IRB application].

b)      If children are involved newly requested to include as research participants (in Virginia, individuals under the age of 18 years unless emancipated), (or if the protocol has undergone signification modification that affects the determinations made at initial review) the following information must be documented:

i)           The category or children's research (under 45 CFR 46 Part D);

ii)         The unique determinations required by the regulations (for the children's category or categories of research) must be documented.  This documentation must include protocol specific findings justifying each of those determinations.  [The VCU IRB requires that the protocol include the precise information that justifies the findings of the IRB and that this information be part of the IRB application].

iii)        The requirements for ASSENT and documentation of assent;

iv)       The determination of whether permission of both parents is required (unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child), or whether the permission of one parent is sufficient.

c)      If pregnant women and/or fetuses are involved as research participants, confirmation of determinations required under 45 CFR 46 Part B along with protocol specific findings justifying each of those determinations must be included.  [The VCU IRB requires that the protocol include the precise information that justifies the findings of the IRB and that this information be part of the IRB application].

d)      If prisoners are involved as research participants, confirmation of determinations required under 45 CFR 46 Part C along with protocol specific findings justifying each of those determinations must be included.  Note:  The VCU IRB requires that the principal investigator submit a written justification that serves as the foundation for this documentation. 

e)      Approval period dates (if less than annual continuing review is recommended) or detailed limitations to approval periods (such as limitations to enrollment numbers prior to reporting back for continuing review). 

6.       The Chairperson will encourage discussion prior to requesting a motion of the IRB, requesting a second to the motion, and then calling for a final vote.  An individual vote is taken for each continuing review.

7.       Full board continuing reviews are recorded as part of the minutes of the IRB meeting in which they are conducted (as separate deliberations, actions, and votes for each protocol undergoing continuing review by the convened IRB).

EXPEDITED CATEGORIES 8 AND 9

G.  DMSB, DMC, and Other Boards:

When the IRB is conducting continuing review in multi-center trials monitored by a DSMB, DMC, or other similar body or sponsor where relevant data/information may not be readily available to local investigators, the VCU IRB may request/require and rely upon a current statement from the DSMB or sponsor indicating that it has reviewed study-wide adverse events, interim findings, and any recent literature that may be relevant to the research (in lieu of requiring that this information be submitted directly to the IRB and in addition to reports of local, on-site events and unanticipated problems).

H. Lapse in Continuing Review

When continuing review of a research protocol does not occur prior to the end of the approval period specified by the IRB, IRB approval expires automatically, and all research activities must stop (including recruitment, enrollment, interactions and interventions on current participants, and data analysis).  Investigators who believe that current participants will be placed at risk by stopping research procedures should immediately contact the IRB chairperson and/or prepare a written justification for continuation (in accordance with the VCU IRB approval letter), whichever is the most necessary immediate action based upon the research schedule.  The IRB chairperson (or designee) will review the justification, and notify the investigator in writing whether current participants can continue.  The ORSP will provide a formal notice of expiration of approval on the date that expiration occurs as a clear alert to principal investigators of the situation.   Such expiration of IRB approval does not need to be reported to OHRP as a suspension of IRB approval under HHS regulations, as per OHRP guidance.

RESPONSIBILITY:

It is the responsibility of the IRB to determine approval periods.  It is the responsibility of the principal investigator to monitor approval periods and to ensure that continuing review reports are filed in ample time to allow for IRB review.

REFERENCES:

HHS 45 CFR 46.109(e)

FDA 21 CFR 56.109(f)  

OHRP Guidance on Continuing Review (July 11, 2002)

VCU IRB WPP#: VII-2

VCU IRB WPP#: VIII-1