Human Research Protection Program: Policy

Continuing Review by Full IRB

Adopted By: All Campus IRB

Adoption Date: November 10, 2005

Revised: April 12, 2007

Revised: January 22, 2009

Purpose:  This document describes the policies and procedures of the UW-Madison IRBs in conducting continuing review of research by the full IRB.

Definitions

I.      "Continuing review" of research, as required by federal regulations, refers to regularly scheduled complete reappraisals of an on-going research project to assure that: (i) the risk/benefit ratio is still acceptable, (ii) the measures taken to safeguard subjects are adequate, (iii) the approved protocol is followed, and (iv) the project reflects any changes that have been made in the regulations and institutional policies and procedures for human subjects research since the last approval.

Policy

I.      UW-Madison IRBs conduct continuing review of human subjects research at intervals appropriate to the degree of risk, but not less than once per year.  The IRB determines on a protocol-specific basis whether protocols require more frequent than annual review.  The analysis that supports this requirement depends entirely on the nature of the proposed research.

A.    SBS IRB: In cases where there is uncertainty about the level of risk to subjects or subject response to research activities, the IRB may set a continuing review cycle of less than one year or may limit enrollment and ask the investigator to report back to the IRB when that limit has been reached.

B.    HS IRB and MR IRB: Examples of research that the IRB may review more frequently than once a year are non-therapeutic research that poses more than minimal risk to research subjects, locally investigator-initiated studies, and research that requires special monitoring of its consent procedures to ensure adequate informed consent is obtained.

II.     Continuing review of human subjects research is conducted by the full IRB, except for those protocols that qualify for expedited continuing review. See, Expedited Review Policy.

A.    SBS IRB: Continuing review of research is done by the full IRB if the investigator is asking for substantial change in protocol, problems have occurred in the research or the IRB has determined that continuing review needs to occur earlier than the usual one year period.

III.    Continuing IRB review is required, even when the research is permanently closed to the enrollment of new participants and all participants have completed all research-related interventions, as long as the research remains active for long-term follow-up of participants.

IV.   Continuing IRB review is required even where the remaining research activities are limited to analysis of identifiable data. [See, Protocol Closure Guidance]

V.    Review Criteria

A.  The criteria for approval of research at continuing review are the same as for initial review.  See, Initial Review by Full IRB Policy.  UW-Madison IRBs must determine that all of the following requirements are satisfied:

 

1.  Risks to subjects are minimized.

 

a.  Risks to participants are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose participants to risk, and

 

b.  Whenever appropriate, risks to participants are minimized by using procedures already being performed on the participants for diagnostic or treatment purposes.

 

2.  Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result from the research.

 

3.  Selection of subjects is equitable.

 

4.  Informed consent will be sought from each prospective subject or the subject's legally authorized representative and appropriately documented as required by 45 CFR 46.116 and 46.117

 

5.  When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

 

6.  When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

 

7.       When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects. (45 CFR 46.111)

 

For additional information, see UW-Madison policies on Risk-Benefit Analysis, Equitable Selection, Informed Consent, Review of Data and Safety Monitoring, Protection of Privacy and Confidential Data, Research with Vulnerable Populations.

 

B.  When reviewing the current informed consent documents and/or process on continuing review, the IRB ensures the following:

 

1.  The currently approved or proposed consent document and/or process is accurate and complete, and

 

2.  Any significant new findings that may relate to the participant's willingness to continue participation are provided to the participant in accordance with regulations.

Procedure

VI.   Submission Requirements

 

A.  Sixty days before expiration date of a protocol approval period, the electronic protocol management system automatically sends an email to the principal investigator, co-investigator(s) and point of contact reminding them that, if the research is continuing, an application for continuing review of research must be submitted and approved by the IRB before the existing approval period expires. 

 

1.  “Expiration date” refers to the last date that the protocol is approved and the last date on which research can be conducted.

 

2.  The “expiration date” is calculated in the following manner:

 

a.  For protocols reviewed by the full IRB, the expiration date is one year minus one day from the IRB meeting date at which the protocol was approved or approved pending modifications unless the IRB has required a shorter approval period.

 

b.  For protocols reviewed under the expedited procedure, the expiration date is one year minus one day from the date the approval was granted by the expedited reviewer.

 

If research is not continuing, the HS IRB and MR IRB ask the investigator to submit a Protocol Closure Report. 

 

The renewal notice sent out by the SBS IRB and ED IRB includes a statement at the bottom that investigators can return to inform the IRB that the protocol is no longer active and that they won't be requesting a renewal.  In the alternative, the investigator may email the SBS IRB or ED IRB that the protocol is closed.  If no continuing review application is submitted before the expiration date, the protocol is automatically closed.

 

B.  To apply for continuing review of a protocol, the investigator must submit: 

 

1.  For HS IRB and MR IRB protocols:

 

a.  A Progress Report - Continuing Review of Previously Approved Research form.

 

b.  A copy of the current consent form, if currently enrolling subjects,

 

The investigator conducting a clinical research trial must also submit an Adverse Event Reporting Log, which summarizes local adverse events that have occurred since the last continuing review and adverse events that have been previously reported to the IRB that potentially affected the risk benefit ratio of the study. See, HS IRBs Adverse Event Reporting Guidelines. 

 

2.  For ED IRB and SBS IRB protocols:

 

a.  A Continuing Review and Progress Report form.

 

b.  A copy of the consent form (or script for oral consent) that is currently being used. 

 

c.  If changes in the consent form are being proposed, one copy of the consent form with proposed changes underlined and one clean copy. 

 

C.  If the investigator is also making changes to the protocol or consent form at the time of the continuing review, the investigator must indicate on the continuing review form that a change is being proposed. 

 

1.  For HS IRB and MR IRB protocols, the investigator must also submit a Change of Protocol form and copies of the revised consent form or consent process (if applicable).  The continuing review and the change of protocol requests are usually considered simultaneously. See, HS IRB & MR IRB Protocol Progress Report - Continuing Review Form.

 

2.  For SBS IRB and ED IRB protocols, investigators seeking a change in protocol or consent form/process on continuing review do not need to submit a separate change form.   

 

D.  Applications for continuing review are directed to the IRB that conducted the initial review of the research.  See, Review by Expert Policy.

VII.   Screening of Applications for Continuing Review and Progress Reports

 

A.  The IRB Office screens each application for continuing review to determine whether the materials provided by the investigator are complete and contacts the investigator to obtain missing information.  Incomplete submissions may be returned to the investigator. 

 

B.  Once all requested information is received, the IRB Director determines whether the application will be reviewed by the full IRB or is eligible for expedited review.  If the application is eligible for expedited review, the IRB Office will follow UW-Madison procedures applicable to expedited continuing review. See, Expedited Review Policy.

VIII.  Review of Applications for Continuing Review and Progress Reports

 

A.  ED IRB and SBS IRB

 

1.  If the ED/SBS IRB Office (IRB Office) Director determines that an application for continuing review will be reviewed by the full IRB, the review proceeds as follows:

 

a.  Both the ED IRB and the SBS IRB uses a primary reviewer system for all continuing reviews by the full IRB. 

 

b.  For each IRB, at least two primary reviewers, who are members of the reviewing IRB, are assigned to each application for continuing review to be reviewed by that IRB. See, Review by Expert Policy. The assignments are made by the IRB Office and reflect the expertise of the primary reviewers.  The IRB Office also checks for conflicts of interest between primary reviewers and research protocols. See, IRB Conflict of Interest Policy.

    

c.  The IRB Office forwards all of the materials submitted by the investigator to each member of the reviewing IRB, including any alternate substituting for an IRB member, except for the complete protocol file, which is made available to all IRB members through the electronic protocol submission system, and any relevant grant application, which is reviewed by one IRB member.  The grant application and any additional information provided to any primary reviewer are available from the IRB Office to any IRB member who wishes to review it before or during the convened meeting.

    

d.  The assigned primary reviewers and the IRB member who is provided the grant application conduct the in-depth review of the application for continuing review and all provided materials, and lead the discussion of the application at the full IRB meeting.  All other IRB members, including any alternate substituting for an IRB member, are expected to review the provided materials in enough depth to be familiar with them and be prepared to discuss them at the convened meeting.

 

2.  After the IRB discusses the continuing review application, the IRB makes the determination whether to approve the application, require modifications in the application, defer the application until additional information is obtained, or disapprove the application.  [See, Section IV, below.]

 

3.  If, after discussion by the IRB, questions remain unanswered, the IRB may request additional written information from the investigator and may invite the investigator to meet with the IRB during the next review to answer questions. 

 

4.  In reviewing an application for continuing review, the IRB may also consult with individuals representing areas of expertise not represented on the IRB. 

 

B.  HS IRB and MR IRB

 

1.  The HS IRB and MR IRB use both a staff reviewer and primary reviewer system. 

 

a.  Continuing reviews that need review by the full IRB are first assigned to staff reviewers by the IRB Director.

 

b.  The IRB Office forwards to the assigned staff reviewer all of the materials submitted by the investigator and the complete protocol file, which contains all minutes, correspondence between the IRB and researcher, consent documents (if applicable), and all prior submissions for IRB review (e.g., prior changes, progress reports, the Initial Review Application and supporting materials)

 

c.  Staff reviewers prepare a summary and detailed analysis of each application for continuing review.  As part of this review, the staff reviewers evaluate the appropriateness of any consent forms.  The staff reviewer’s report generally contains the following:

 

•          Summary of the protocol’s purpose or objectives.

•          Information about the subject population, recruitment strategy, treatment arms, or other details of the protocol, if relevant, particularly if a change is proposed in addition to the request for continuing review.

•          Summary of changes in research since last review

•          Summary of activities completed and current and future activities

•          Summary and analysis of serious adverse events

•          Description of participant withdrawals and reasons for them

•          Whether a Data Safety Monitoring Board or Data Monitoring Committee report was included or needed.

•          Recommendation as to whether the progress report raises any ethical, safety, or regulatory concerns; if concerns are raised, the staff reviewer generally makes further recommendations regarding how the concerns can be addressed

 

d.  The HS IRB and MR IRB use a preliminary review system (PRS) to evaluate applications for continuing review.  See, Review by Expert Policy.  The IRB Director assigns each application for continuing review to primary reviewers, who are IRB members and who review the application in a preliminary review session (PRS) held prior to a scheduled meeting of the full IRB.  The IRB Director screens for conflicts of interest between primary reviewers and research protocols when making these assignments. See, IRB Conflict of Interest Policy.

 

e.  The assigned primary reviewers are provided the following information:

 

•          The complete protocol file

•          Copy of the continuing review progress report and any other relevant supporting materials the researcher has submitted for IRB review

•          A staff review that provides a detailed summary and expert analysis of the continuing review, continuing review progress report, and/or adverse event reports to be reviewed by the primary reviewer

 

f.   In the preliminary review session (PRS), the assigned primary reviewers conduct an in-depth review of the protocol file, staff reviewer report and progress report for each continuing review application.  The primary reviewers prepare written assessments of each application and make recommendations to the full IRB regarding whether the application should be (a) approved without modification/clarification, (b) approved after modifications/clarifications have been obtained, or (c) deferred due to the inadequacy of the submission.  As part of their assessment, primary reviewers may request additional review by someone with a specific expertise (e.g., review by an individual with a different medical expertise).

 

2.  The Continuing Review Protocol Progress Report and supporting materials, including consent documents and Data Safety Monitoring Board reports, as well as a Continuing Review - Staff and Primary Reviewer Worksheet will be posted on a secure website for IRB members to access.  The Continuing Review - Staff and Primary Reviewer Worksheet includes the criteria for IRB approval and documents any concerns, questions, and recommendations to the full committee raised by the primary reviewers and IRB staff.  IRB members will be reminded via email that these materials are posted so that they can review them in sufficient depth to make an informed decision at the convened IRB meeting regarding whether the study continues to meet the criteria for IRB approval pursuant to 45 CFR 46.111 and, if applicable, 21 CFR 56.111, and 38 CFR 16.111.

 

3.  The assigned primary reviewers conduct the in-depth review of the application for continuing review and all provided materials, and lead the discussion of the application at the full IRB meeting.  All other IRB members, including any alternate substituting for an IRB member, are expected to review the provided materials in enough depth to be familiar with them and be prepared to consider them at the convened meeting.

 

4.  The full IRB makes the determination whether to approve the application, require modifications in the application, defer the application until additional information is obtained, or disapprove the application.  [See, Section IV, below.]

 

5.  If, after discussion, questions remain unanswered, the IRB may request additional written information from the investigator and may invite the investigator to meet with the IRB during the next review to answer questions. 

 

6.  In reviewing an application for continuing review, the IRB may also consult with individuals representing areas of expertise not represented on the IRB. 

 

C.  Verification of No Material Changes

 

1.  The IRB may decide to obtain verification from sources other than the investigator that no material changes have occurred since the previous IRB review in certain instances, for example, when:

 

a.  The information provided by the investigator has inconsistencies that cannot be resolved through discussions with the investigator

 

b.  The IRB doubts the accuracy of the information provided by the investigator, or

 

c.  The investigator has a history of non-compliance.

 

2.  When the IRB determines that protocols need verification from sources other than the investigators that no material changes have occurred since the previous IRB review, the IRB may arrange for an audit of the investigator’s records.

IX.    IRB Determinations on Applications for Continuing Review

 

A.  On application for continuing review, the full IRB may:

 

1.  approve the application

2.  require modifications in the application for continuing review

3.  defer the application until additional information is obtained, or

4.  disapprove the application.

 

     In each case, the IRB Office notifies the investigator of the action taken and the reasons for that action.  Where necessary, the IRB Office also reports the IRB action to appropriate University officials or, where the protocol is submitted by an investigator from another institution for whom the IRB acts as the IRB of record (e.g., the Veterans Administration), to appropriate officials within that institution.

 

B.  To approve a protocol pending resolution of requested modifications:

 

1. IRB members may agree during an appropriately convened meeting of the full IRB to approve a protocol pending resolution of requested modifications (contingent approval) if the requested modifications are non-substantive changes that are not relevant to the determinations required by the IRB under the Common Rule or its subparts (45 C.F.R. part 46) or, as applicable, FDA regulations (21 C.F.R. part 56).

 

Contingent approval also is permitted in situations where the IRB stipulates specific revisions requiring simple concurrence from the investigator.

 

If substantive clarifications or modifications regarding the protocol or informed consent documents are required as a condition of approval, approval must be deferred pending subsequent review by the convened IRB of responsive material (See, Section IV.C, below)

 

2.  If a protocol is approved pending resolution of requested modificiations, the IRB office will notify the investigator of those modifications and instruct the investigator that he or she must respond to these requests according to IRB directions.

 

3.  For the protocol to be approved, the investigator must comply with the request for modifications according to the IRB’s directions.

 

4.  An IRB member(s) reviews the investigator’s response and either

 

a.  approves it, or

 

b.  if the investigator’s response is not consistent with the IRB’s directions, sends the response back to the full IRB.

 

     If a staff reviewer process is used to review an IRB’s request for modifications, the staff reviewer works with the investigator to obtain the modifications requested by the IRB.  The staff reviewer then forwards the investigator’s response to an IRB member(s) for review along with a staff report and recommendation as to whether the investigator’s response has satisfied the IRB’s request for modifications. The IRB member(s) reviews both the investigator’s response and the staff report and recommendation before deciding to approve the protocol or to send it back to the full IRB as per Section IV.B.4.

 

5.  The full IRB will be provided, on a routine basis, a list of research protocols approved by the full IRB pending resolution of requested modifications that were subsequently granted final approval by an IRB director or IRB member(s) designated by the IRB chair to conduct expedited reviews. All IRB members shall be provided access to the IRB files for any research study in which they may have a concern.

 

6.  Notice to investigators of requested modifications.

 

a.  SBS IRB and ED IRB: At intervals of 60 and 120 days from the date the modification request was first sent to the investigator, the electronic protocol management system automatically sends a reminder to the investigator of the need to respond to modification requests and obtain IRB approval of the research before research can continue.  If a response is not received from the investigator within 180 days of the first request for modifications, the electronic protocol management system automatically sends a notice to the investigator that the protocol has been closed and will need to be re-submitted for reconsideration before the research to proceed.

 

b.  HS IRB or MR IRB: The HS IRB and MR IRB do not send out automatic reminders.  However, if they fail to receive a response from the principal investigator to any modification requests, then the protocol is terminated.

 

C.  To defer a protocol until additional information is obtained:

 

1.  The IRB must defer approval of a protocol if, to approve the protocol, the IRB requires substantive clarifications or modifications of the protocol or informed consent documents that are relevant to the determinations required by the IRB under the Common Rule or its subparts (45 C.F.R. part 46) or, as applicable, FDA regulations (21 C.F.R. part 56).

 

2.  The IRB will notify the investigator of the substantive clarifications or modificationsnecessary to allow approval of the research.

 

3.  The investigator may supply the substantive clarifications or modifications or provide a rationale for not doing so.  The protocol will then be re-reviewed by the full IRB.

 

Ÿ         For SBS IRB and ED IRB protocols, if the full IRB determines on initial review that the protocol is eligible for expedited review, review of additional information supplied by the investigator may be done by an IRB subcommittee.

 

·         If a staff reviewer process is used to review an investigator’s response to an IRB’s request for substantive clarifications or modifications, the staff reviewer works with the investigator to obtain the substantive clarifications or modifications requested by the IRB.  The staff reviewer then forwards to the  IRB the investigator’s response along with a staff report and recommendation as to whether the investigator’s response has satisfied the IRB’s request for substantive clarifications or modifications. The IRB reviews both the investigator’s response and the staff report and recommendation before deciding whether to approve the protocol.

 

4.Notice to investigators of requested substantive clarifications or modifications .

 

a.  SBS IRB and ED IRB: At intervals of 60 and 120 days from the date the modification request was first sent to the investigator, the electronic protocol management system automatically sends a reminder to the investigator of the need to respond to modification requests and obtain IRB approval of the research before research can continue.  If a response is not received from the investigator within 180 days of the first request for modifications, the electronic protocol management system automatically sends a notice to the investigator that the protocol has been closed and will need to be re-submitted for reconsideration before the research to proceed.

 

b.  HS IRB or MR IRB: The HS IRB and MR IRB do not send out automatic reminders.  However, if they fail to receive a response from the principal investigator to any modification requests, then the protocol is terminated.

 

D.  If an IRB decides to disapprove an application, the IRB gives the investigator an opportunity to respond in person or in writing.

 

E.  An IRB decision to disapprove or defer an application for continuing review may be addressed by the investigator by re-submission of the application for continuing review to the original IRB, accompanied by a cover letter detailing changes made or a justification of why recommended revisions were not made.  The full IRB will approve or disapprove all responses.

 

F.  An application for continuing review of a protocol that has been disapproved, deferred or for which modifications have been requested by an IRB cannot be resubmitted to a different IRB for review as an alternative to following the procedures as set forth in this Section.

X.     IRB Records on Continuing Review

 

A.  The full IRB’s action on each Application for Continuing Review is documented in the minutes for each meeting. 

 

B.  Votes for and against approval of each Application for Continuing Review and the name of any IRB member abstaining from the vote on each protocol or leaving the room before the vote due to a conflict of interest with a protocol are recorded in the meeting minutes.   IRB meeting minutes are available from the IRB office for review by the Institutional Official at his or her request.

XI.    Failure to Apply for Continuing Review

 

A.  If an investigator fails to provide continuing review information to the IRB, or the IRB has not reviewed and approved a research study by the continuing review date specified by the IRB, research activities must stop, unless there is an overriding safety concern involved such that it is in the best interests of individual participants to continue participating in the research interventions or interactions based on the investigator’s clinical judgment.

 

1.  Such expiration of IRB approval does not need to be reported to OHRP as a suspension of IRB approval under DHHS regulations.

 

2.  Enrollment of new participants cannot occur after the expiration of IRB approval.

 

B.  If it is a VA research study, the expiration of approval is reported to the VA Chief of Staff, and the IRB consults with the VA Chief of Staff on the issue of continuation of interventions or interactions on current participants, if applicable.

 

C. The IRB Office notifies the Pharmaceutical Research Center of all expired protocols.

 

D.  Continuation of research activities or enrollment of participants after lapse of protocol approval may constitute noncompliance.  See, Noncompliance Policy.