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Chapter XVIII - Protocol Life Cycle Issues: Amendments, Continuing Review and Closure

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AMENDMENTS
32 CFR 219.103((4)(iii) requires written procedures that the IRB will follow to ensure prompt reporting to the IRB of proposed changes in a research activity and for ensuring that such changes in approved research during the period for which IRB approval has already been given may not be initiated without IRB review and approval, except when necessary to eliminate apparent immediate hazards to the participant.

Any changes (i.e., amendment, modification, revision) to the protocol must be submitted to the GA IRB for review and approval prior to implementation of the change. If the amendment involves changes to the protocol, a revised protocol should be submitted with the amendment.

Responsibilities of Principal Investigator Regarding Proposed Changes in Approved Protocol. The Principal Investigator will obtain approval from the IRB for all proposed changes in previously approved research activities prior to implementing such changes (except when necessary to eliminate apparent immediate hazards to the participant). These include, but are not limited to, any modification or amendment of the protocol, the informed consent process, the test instruments, the recruitment materials, or change of the Principal Investigator. The submission for proposed changes should include a revised protocol, identifying the version by date in the header or footer of each page. A request identifying the proposed changes and the rationale for the modifications must accompany the revised protocol.

Scientific review of proposed changes may be required if the design of the researchstudy has changed significantly by modification of the protocol.

Major Modifications/Amendments to Research Not Eligible for Expedited Review. A major modification to an approved study may impact the risk/benefit ratio in the study, and may alter a participant's choice to remain enrolled. Consequently, for studies not eligible for expedited review, these types of modifications require full Board review. Some common examples of major modifications include the following:

  • Escalation in a drug(s) dosage(s);
  • Introduction of an additional drug(s);
  • Inclusion of a new invasive procedure;
  • Inclusion of more participants; new populations;
  • Inclusion of additional performance sites on a case by case basis.

Minor Modifications to Research Not Eligible for Expedited Review. Minor modifications to a study that was reviewed by full Board may be reviewed and approved by the expedited review process (see 32 CFR 219.110(b)(2)). Some common examples of minor modifications include the following:

  • Changes in study staff members;
  • Changes in contact information;
  • Inclusion of advertisement material.

Modifications to Research Reviewed Via Expedited Procedure For no greater than minimal risk (NGTMR) studies that were previously eligible for expedited review, major or minor modifications may be reviewed by expedited review procedure provided the revised protocol continues to (1) present no greater than minimal risk to participants and (2) comprise one or more of the research categories in the Federal Register list of categories of research that may be reviewed by the IRB through an expedited reviewprocedure.

Protocol Exceptions. A protocol exception is a request made by the Principal Investigator for a deviation from the approved study for a single participant or a small group of participants; it is not a permanent revision to the research protocol. As for all amendments, a protocol exception must be approved by the GA IRB prior to its implementation.

  • A request for a protocol exception must be reviewed and approved by the convened GA IRB (or the IRB Chair for protocols eligible for expedited review) prior to implementation of the planned protocol change. Examples of protocol exception requests include, but are not limitedto:
    • A request to enroll a research participant who fails to meet all of the protocol eligibility criteria. The participant may have been evaluated for all other parameters, and it was determined that not meeting this inclusion criteria or laboratory screening value would not cause harm to the participant or alter the validity of the study;
    • A request to change, add, or delete certain protocol procedures for a participant for reasons that relate to the participants safety andwell-being.
  • The GA IRB will review the request for protocol exception in order to determine that it does not increase the risk to the participant(s), or jeopardize the integrity of the research data. The IRB may request documentation that the study sponsor (and FDA, if applicable) has evaluated the request for protocol exception;
  • The IRB may grant approval, conditionally approve, defer, table, or disapprove the protocol exception;
  • Documentation of sponsor (or FDA) approval and GA IRB approval of the exception should be maintained in the Investigator’s research study file;
  • Multiple requests for exceptions on the same protocol require that the Principal Investigator submit an amendment request.

Instituting Unapproved Changes in Approved Research. Implementing unapproved changes in a GA IRB-approved protocol (except when necessary to eliminate apparent immediate hazards to the participant) is in violation of 32 CFR 219.

If, as a result of verification efforts by the GA IRB, unapproved deliberate changes (as opposed to unintended protocol deviations) are found to have been instituted, the IRB will examine the severity of the non-compliance to determine if it is serious and/or continuing and discuss appropriate sanctions and/or required re-training to prevent future noncompliance.

CONTINUING REVIEW OF RESEARCH
32 CFR 219.109(e) requires 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, and shall have authority to observe or have a third party observe the consent processand the research.” The review criteria for continuing review of protocols are the same as for initial review.

After the initial review and approval of proposed research involving human participants, the GA IRB retains responsibility for oversight of the project, including review of periodic reports, safety, and other updates, and monitoring for compliance with the protocol and applicable human participants protection regulations. The IRB can withdraw or continue its approval of the research or require modifications to ensure that the original criteria for approval are still satisfied, namely, determinations as to the risks, potential benefits, adequate informed consent, and safeguards in the conduct of the protocol. The major issues to be considered at each periodic review as well as at the time of each safety or other update are whether, in light of the latest information, the risk/benefit ratio is still acceptable and if the informed
consent is still adequate for the protection of the rights and welfare of the participating individuals. One key criterion to be examined is whether the consent process provides all the information that participants would reasonably want or need to know in light of the issues identified during the protocol’s previous approval period.

CONTINUING REVIEW REPORT
The Principal Investigator will regularly prepare and submit reports tothe GA IRB summarizing the progress of the research at intervals designated in the IRB’s approval of the research, but no less often than annually, as required at 32 CFR 219.109(e)

Pursuant to 32 CFR 219.103(b)(4) and 21 CFR 56.108(a) investigators must submit a protocol summary and status report on the progress of the research to the IRB for periodic continuing review that includes (1) the number of participants accrued, withdrawn, or discontinued, and the reasons; (2) a summary of any unanticipated problems involving risks to participants or others, any AEs and any complaints about the research; (3) a summary of any recent literature, findings obtained thus far, amendments or modifications to the research since the last review, multi-center trial reports, especially any from Data Safety Monitoring Boards (DSMBs) or Data Monitoring Committees (DMCs), and any other relevant information, especially information about risks associated with the research; and (4) any statements of significant new findings provided to participants, the current and any proposed new informed consent document, and the current Investigators’ brochure, if there is one (for all IND and Investigational Device Exemption (IDE)) studies) (see 21 CFR 312.33)

CONTINUING REVIEW OF RESEARCH BY THE GA IRB
Research that was initially approved via expedited review may be reviewed for continuation through an expedited review procedure provided it still (1) presents no greater than minimal risk to participants and (2) comprises one or more of the research categories in the Federal Register list of categories of research that may be reviewed by the IRB through an expedited review procedure. The investigator must submit to the IRB office a continuing review report as outlined above, along with a current version of the protocol and consent form(s). These submissions should arrive approximately 21 calendar days prior to the protocol’s expiration date.

Research identified to pose GTMR to participants and research that poses NGTMR but does not appear in the categories of research that can be reviewed via an expedited review procedure will be reviewed and approved by the convened GA IRB prior to continuation. These submissions should arrive approximately 21 calendar days prior to the protocol’s expiration date.

Research reviewed and approved for continuation may retain the previously established expiration date for its next continuing review. For example, if a protocol’s expiration date is 1 February, and the protocol is reviewed and approved for continuation for a one-year period on 15 January, the new expiration date may be set at 1 February of the following year (rather than resetting the date to 15January). Keeping the same anniversary date aids investigators in planning for continuing review at the same time each year. 

Review Criteria for Continuing Review. The review criteria for continuing review of human research protocols are the same as those for initial review (i.e., 32 CFR219.111).

  • The review of the protocol must be substantive and meaningful. In conducting continuing review of research not eligible for expedited review, the same primary reviewer system as for initial convened GA IRB reviews will be employed as previously described. The IRB office provides all Board members with a complete read-ahead packet for continuing reviews. The IRB members receive and review the Principal Investigator’s continuing review report, along with a current version of the protocol and consent form(s) prior to the IRB meeting. The minutes of the GA IRB meetings will record separate deliberations, actions, and votes for each protocol undergoing continuing review and identify the period of re-approval;
  • At the time of re-approval, the GA IRB may limit the approval for a term of less than one year if the IRB determines there is reason to do so. The date when approval expires will be noted in the notification letter.

“Full-Board” Initial Review Followed by “Expedited” Continuing Review. Categories (8) and (9) in the Federal Register list of categories of research permit an IRB to conductexpedited continuing review, subsequent to a full Board initial review.

  • Category (8): Continuing review of research previously approved by the convened IRB as follows:
    • Where the research is permanently closed to the enrollment of new participants, all participants have completed all research-related interventions, and the research remains active only for long-term follow-up of participants; OR
    • Where no participants have been enrolled and no additional risks have been identified; OR
    • Where the remaining research activities are limited to dataanalysis.

Note: Category (8) identifies three situations in which research that is GTMR and was initially reviewed by the convened IRB may undergo subsequent continuing review by an expedited review procedure.

  • Category (9): Continuing review of research, not conducted under an IND application or IDE where categories (2) through (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves NGTMR and no additional risks have been identified. Thus, for research not conducted under an IND or IDE, category (9) specifically permits continuing review to be done by expedited procedure, subsequent to a full Board initial review, where the following three conditions aremet:
    • Categories (2) – (8) in the list of categories of research do not apply; AND
    • No additional risks have been identified in research during the initial approval period; AND
    • The IRB determines that research presents NGTMR to participants.

LAPSED APPROVAL
Unless extraordinary circumstances have been brought to the attention of the IRB office and a remedy made, the GA IRB cannot consider reinstatement of a study past its expiration date. If a study is not re-approved by its expiration date, the Principal Investigator will immediately be notified by the IRB office, and all study activities must cease except for those activities required to prevent placing participants atrisk.

Once a protocol lapses approval, it must undergo approval by either expedited or full Board as is appropriate to its risk level and whether or not it is eligible for expedited review before any further study activities (including participant enrollment, data collection and/or data analysis) may resume. The Principal Investigator must submit the full protocol, consent form(s) and all supporting documents as well as the continuing review report for the previous approval period for consideration by the GA IRB.

PROTOCOL CLOSURE/FINAL STUDY REPORT
32 CFR 219.103(b)(4)(iii) states, “Assurances applicable to federally supported or conducted research shall at a minimum include: ... written procedures which the IRB will follow…for ensuring prompt reporting to the IRB of proposed changes in a research activity...” One of these procedural requirements (32 CFR 219.103(b)(4)) is ensuring “prompt reporting to the IRB of changes in a research activity.” The completion of the study is a change in activity and must be reported to the IRB. A final report/notice to the IRB allows it to close its files and provides information that may be used by the IRB in the evaluation and approval of related studies.

When a project is terminated or completed, the Principal Investigator will submit to the GA IRB a protocol summary and a final report of the results of the research (no later than the end of the current approval period). The final report must include a summary of what was learned, and to what extent the project met its goals. In addition, the report must include: (a) the date of proposed study closure (b) the reason for closure (e.g., completed, terminated) (b) the number of participants (or specimens/data) accrued; (c) a summary of AEs and any unanticipated problems involving risks to participants or others; (c) a summary of any withdrawal of participants from the research or complaints about the research since the last IRB review; (e) a summary of all protocol amendments implemented during the study period; (f) a summary of relevant recent literature, interim findings, and amendments or modifications to the research since the last review; (g) any relevant multi-center trial reports; (h) any other relevant information, especially information about newly discovered risks associated with the research; and (i) a copy of the last informed consent document (if applicable). The final report should address the plans for retention, disposal or future use of any research materials generated in the course of the study (e.g., data collected for the study, biologic, or chemical samples,etc.).

Completion shall mean the end of participant recruitment and all participant interactions and the completion of any planned experiments, analyses, or manipulations of research materials. Any retention of research materials or planned, contemplated, or potential uses of them not already specified and approved in a current project must be reviewed and approved by the GA IRB as a new protocol.

WHEN TO CLOSE A RESEARCH PROTOCOL TO CONTINUING GA IRB REVIEW
For a protocol to be closed from continuing IRB review, it is essential that, in that protocol, the research activity has indeed ended. This includes completion of data analyses and reporting of study findings. Studies that have not reached that stage of completion may not be closed.

Prior to conclusion of the study, the Principal Investigator must coordinate any required medical follow-up and/or debriefing of volunteers. Principal Investigators need to be aware that once a protocol is closed, it must be formally reopened only as a new protocol.

Three Distinct Closure Categories Defined:

  • Protocol Withdrawal. A study is defined as withdrawn if it is closed voluntarily by the Principal Investigator in the early phase when:
    • The protocol has been received by the IRB office but has not yet been reviewed;
    • Protocol is currently under review by the IRB but has not yet been approved; OR
    • Protocol has been approved, but no study procedures involving human participants have beeninitiated.
  • Protocol Termination. A study is defined as terminated if it is closed voluntarily or involuntarily by the Principal Investigator or the IRB for reasons such as:
    • Due to human participant protection issues, such as the occurrence of events that raise safety concerns about the study;
    • Due to non-compliance issues;
    • If the Principal Investigator started a research project pending award of funding support, then learns that funding will not be made available and as a result is forced to terminate the project;
    • Because of participant recruitment problems;
    • Termination by the Sponsor; AND/OR
    • When early data analysis leads to determination that further research would be futile or that the study intervention is successful and no further study is necessary.
  • Protocol Completion. A study is defined as completed if it is closed voluntarily by the Principal Investigator when: (a) the study is closed to further enrollment of participants and all participants have completed all research-related interventions and follow-up; (b) the research team has completed all of the specific aims including data collection and analyses as identified in the research protocol; and (c) the Principal Investigator has submitted the finalreport(s).

Note: Certain studies previously approved by full-Board review that do not yet qualify for closure as described above may qualify for an expedited review. A protocol may be approved by expedited continuing review (a) where the research is permanently closed to the enrollment of new participants; all participants have completed all research-related interventions; and the research remains active only for long-term follow-up of participants; or (b) where no participants have been enrolled and no additional risks have been identified; or (c) where the remaining research activities are limited to data analysis.

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