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2.4 IRB Review of Changes in Previously Approved Research

1.0 Purpose

The purpose of this policy and procedure is to describe the Organization’s requirements for IRB review of changes in previously approved research, including single subject protocol deviations.

2.0 Policy

  • 2.1.

    It is the policy of the Organization thatthat:

    any
    • 2.1. Any proposed change in a research activity must be reviewed and approved by the IRB prior to implementation in accordance with the requirements of 45 CFR 46.103(b)(4) (rev 45 CFR 46.108(a)(3)(iii)); and/or 21 CFR 56.108(a)(4) except when: 1) a change is necessary to eliminate an apparent immediate hazard to the subject(s), or 2) a subject needs to be advised immediately of significant new information. Administrative changes do not require IRB review and can, accordingly, be approved by ORA.
    • 2.2. It is the policy of the Organization that protocolProtocol changes that are minor are eligible for expedited review underin theaccordance provisions of HHS regulations at 45 CFR 46.110(b)(2) (revwith 45 CFR 46.110(b)(1)(ii)) and FDA regulations atand/or 21 CFR 56.110(b)(2), as applicable.
    • 2.3. It is the policy of the Organization that singleSingle subject protocol deviations (SSPDs) represent a change in protocol for a single subject and must be reviewed by the IRB prior to implementation; single subject protocol deviations that are minor may be eligible for expedited review by the Executive Chair, IRB Chairs, or designeedesignee.
      • under
    • 2.4. HHSAdministrative changes do not require IRB review and can be reviewed and approved by IRB analysts and/or FDAstaff, regulationsin consultation with the IRB Executive Chair as above.necessary.

    3.0 Definitions

    • 3.1. Major change in protocol is a change that, in general, adversely affects the risk-benefit relationship by adding appreciably increasing risks, or appreciably decreasing potential benefits, or impacts the process of consent in a manner that might effectaffect a reasonable person’s willingness to participate in the research. SpecificExamples of specific activities which constitute major changes are listed in the appendix to this policy.

      policy.

    • 3.2. Minor change in protocol is a change that is not characterized as major per 3.1as above. SpecificExamples of specific activities which constitute majorminor changes are listed in the appendix to this policy.

      policy.

    • 3.3. Single subject protocol deviation is a change in an IRB-approved protocol which is permitted for an individual subject when it is in the best interest of that subject and/or is necessary for research purposes (e.g., data completion).

      purposes.

    • 3.4. Administrative change is a change where one of the following criteria must be met: 1) the proposed changewhich has no impact on humanthe subject protection,health or 2)welfare of subjects, or on the proposedrisk/benefit changerelationship isof necessarythe toresearch. clarifyAdministrative changes include (but are not limited to) correction of typographical errors, clarification or provide only editorial updates to the protocol and/or ICF. These changes can be reviewed and approved by IRB administrators/staff in consultation with the IRB Executive Chair as necessary.

      Examples of administrative changes include: changes in telephone numbers, deletion of study personnel, correction of typographical errors, or minorICF, administrative changes in the protocol by the sponsor.

      sponsor, changes in telephone numbers or other contact information, and addition or deletion of study personnel other than the Principal Investigator.
      • 3.4.1. Changes to studies for which the Organization is relying on another IRB (CIRB studies) are considered administrative changes.

    4.0 ProceduresInvestigator forResponsibilities

    • 4.1. A Change Request in Protocol (other than Single Subject Protocol Deviation)Deviations)
      • 4.1.must Thebe submitted by the PI mustthru submit a Change RequestRSS in accordance with HRPP policy 2.1 (Submission of Items for Review by the IRB).
      • 4.2. A Single Subject Protocol Deviation Request must be submitted by the PI thru RSS to the ORA and be approved by either the IRB Executive Chair, IRB Chair or designee or the full IRB prior to the initiation of the deviation.
        • 4.2.1. The PI or designee is responsible for requesting approval for the single subject protocol deviation from the study sponsor (if appropriate) in advance of submission to the ORA.
        • 4.2.2. Initiation of a single subject protocol deviation without IRB approval (unless necessary to eliminate an apparent immediate hazard to the subject, or to provide significant new information as above) represents noncompliance and will be addressed in accordance with HRPP policy 8.4 (Review of Noncompliance Involving the PI and Study Personnel).
      • 4.3. Changes required to eliminate an apparent, immediate hazard to the subject(s) may be implemented without prior IRB approval in accordance with 45 CFR 46.108(a)(3)(iii)) and/or 21 CFR 56.108(a)(4).
        • 4.3.1. The ORA must be notified of the action as soon as possible, but no later than two business days from the time the change was initiated.
        • 4.3.2. If the change was initiated for all subjects, a Change Request (including a revised IRB application and other required documents) must be submitted in accordance with this policy.
        • 4.3.3. If the change was initiated for a single subject, the Single Subject Protocol Deviation Request must be completed and submitted.
      • 4.4. Changes involving immediate disclosure of significant new information (for example, an important new risk) which would likely affect a subject’s decision to continue participating in research, may be implemented without prior IRB approval in accordance with 45 CFR 46.108(3)(iii)) and/or 21 CFR 56.108(a)(4) and HRPP policy 5.1 (Obtaining Informed Consent from Research Subjects).
        • 4.4.1. The ORA must be notified of the action as soon as possible, but no later than two business days from the time the change was initiated.
        • 4.4.2. No new subjects may be accrued without IRB approval of a revised ICF that includes the relevant information.

      5.0 IRB and/or ORA Responsibilities

      • 5.1. Change Requests will be processed for review in accordance with HRPP policy 2.1 (Submission of Items for Review by the IRB).

      • 5.2. Change Requests (including SSPDs) that are minor may be reviewed and approved thru an expedited process in accordance with HRPP Policy 2.3 (Expedited Review) and 2.5 (Criteria for IRB Approval)

      • 5.3. Change Requests (including SSPDs) that are major will be reviewed by the convened IRB (if the protocol was initially reviewed and approved by the convened IRB) or by the expedited process (if the protocol is eligible for expedited review per HRPP 2.3 (Expedited Review) in accordance with HRPP 2.5 (Criteria for IRB Approval).

      • 5.4.3. Administrative changes aremay be reviewed and processed by an IRB AdministratorAnalyst or ORA staff.

      • 4.4. The procedure for review via full IRB review or expedited review is in accordance with HRPP policies 2.2 (Full IRB Review) and 2.3 (Expedited Review), respectively.
      • 4.

        5. The criteria for approval via full IRB review or expedited review is in accordance with HRPP policies 2.2 Section 3.9 (Full IRB Review) and 2.3, Section 5.4 (Expedited Review), respectively.

      • 4.6. The date of continuing review is not changed based on the date of IRB approval of a Change Request.

      • 4.7.

        5.6. Changes in protocol for research classified as exempt per HRPP policy 2.6 (Exempt Research) do not need to be submitted to the ORA provided the changes do not:

        • 4.7.5.6.1. Affect the risk-benefit relationship of the research

        • 4.7.5.6.2. Pose new risks which are greater than minimal

        • 4.7.5.6.3. Constitute a new risk to privacy or confidentiality

        • 5.6.4.7.4. Involve sensitive topics (including but not limited to personal aspects of the subject’s behavior, life experiences or attitudes)

        • 4.7.5.6.5. Involve deception

        • 4.7.5.6.6. Target a vulnerable population (as defined in HRPP Policy 4.1; Additional Protections for Vulnerable Populations)

        • 4.5.6.7.7. Include prisoners or children

        • 4.7.5.6.8. Otherwise suggest loss of the exempt status of the research.

        Note: Investigators are encouraged to contact the ORA to discuss whether changes to exempt research requires review by ORA.

    5.07. ProcedureChanges to studies for Single Subject Protocol Deviation*

    • 5.1. A Single Subject Protocol Deviation Request must be submitted towhich the ORAOrganization andis berelying approvedon by either theanother IRB Executive(CIRB Chair,studies) IRBare Chairreviewed oradministratively.

      designee or the full IRB prior to the initiation of the deviation.

    • 5.2.8. The PI/authorized study personnel should request approval for the single subject protocol deviation from the study sponsor (if appropriate) in advance of submission to the ORA.

    • 5.3. Theconvened IRB Executive Chair, IRB Chair or designee will obtain any additional information required for the review.
    • 5.4. Single subject protocol deviation requests that are more than minor cannot be approved by the IRB Executive Chair, IRB Chair, or designee and will be referrednotified toof (1) changes in protocol, including SSPDs, approved thru the fullexpedited IRBprocess, by(2) thechanges designated IRB Administrator for review and approval.
    • 5.5. Single subject protocol deviation requests that are minor will be reviewed and approved by the IRB Executive chair, IRB Chair, or designee.
    • 5.6. All minor single subject protocol deviation requests approved by IRB Executive Chair, IRB Chair, or designee will be submitted to the IRB for their notification.
    • 5.7. Initiation of a single subject protocol deviationimplemented without prior IRB approval represents noncompliance and addressed in accordance with HRPP policy 8.4 (Review of Noncompliance Involving the PI and Study Personnel).

    6.0 Changes in a research activity requiring immediate implementation

    • 6.1. If the change is required to eliminate an apparent, immediate hazard to the subject(s), the PI may implement the change without prior IRB approval in accordance with 45 CFR 46.103(b)(4)or (rev3) 45changes CFRinvolving 46.108(3)(iii));immediate 21 CFR 56.108(a)(4).
    • 6.2. The ORA must be notified as soon as possible, but no later than two business days from the time the change was initiated.
      • 6.2.1. If the change was initiated for all subjects, a Change Request, the revised IRB application and other required documents must be submitted in accordance with this policy.
      • 6.2.2. If the change was initiated for a single subject, the Single Subject Protocol Deviation Request must be completed and submitted.
    • 6.3. The full IRB will be notifieddisclosure of allsignificant changesnew implemented without prior IRB approvalinformation, and will take any additional actions necessary to protect human subjects.

    7.0 Provision of new information to subjects which requires immediate implementation

    • 7.1. If a change involves immediate disclosure of significant new information (e.g., an important new risk) which is essential to a subject’s decision to continue participating in research, the investigator is authorized to implement the change without IRB approval in accordance with 45 CFR 46.103(b)(4) (rev 45 CFR 46.108(3)(iii)); 21 CFR 56.108(a)(4) and HRPP policy 5.1 (Obtaining Informed Consent from Research Subjects).
    • 7.2. The ORA must be notified as soon as possible, but no later than two business days from the time the change was initiated. No new subjects can be accrued without IRB approval of a revised ICF that includes the relevant information.
    • 7.3. If a Change Request is submitted to the ORA which includes a revised ICF or an addendum ICF containing significant new information involving risk which is germane to a subject’s decision to continue participating in the research and the change is not eligible for expedited review, the ORA will submit the RFC for review at the earliest possible full Board meeting.
    • 7.4. The full IRB will be notified of all changes implemented without prior IRB approval and will take any additional actions necessary to protect human subjects.

    Appendix to HRPP Policy 2.4 (Changes in Previously Approved Research)

    Examples of Major and Minor Changes in Protocol or Single Subject Protocol Deviations (per Sections 3.1 and 3.2)

    Examples of Major Changes:

    • Changes in inclusion or exclusion criteria that broaden eligibility (i.e., broadening the range of the inclusion criteria or narrowing the range of the exclusion criteria) when risks to new subjects will be different than to previously eligible subjects

    • Addition of a vulnerable population (e.g., children, cognitively impaired, prisoners, socially or educationally disadvantaged, students)

    • Increase in target accrual of subjects in studies where UNMC. CHMCCN and/or UNO are the only sites

    • Increase in study wide accrual of subjects in a multi-institution study

    • Increase in subject payment amount that exceeds criteria in HRPP Policy

    • Change in study design, where such change might affect risk, potential benefit to subject or scientific value or validity

    • Alterations in the dosage or route of administration of an administered drug

    • Addition of research activities that carry greater than minimal risk

    • Change in research activities where the change might negatively impact the potential benefit of the research (e.g.,for example, change from one questionnaire to another which is not substantively similar, or to a non-validated questionnaire; change from CT-based staging to clinically based staging of a tumor)

    • Modification of research questionnaires or data collection instruments/processes to collect sensitive information (e.g.,for example, depression, sexuality, illegal activities)

    • Addition of an element that may affect subject confidentiality (e.g.,for example, specimen banking or genetic testing; addition of focus groups or identifiable surveys)

    • Extending substantially the duration of exposure to the test material or intervention

    • Deletion of laboratory tests, monitoring procedures, or study visits directed at the collection of information for safety evaluations

    • Addition of serious adverse events, serious UADEs or other significant risks to the Informed Consent process or form

    • Addition of a new (additional) consent form

    • Addition of a qualified investigator with a disclosable conflict of interest

    • Changes, which, in the opinion of the IRB chairperson or his/hertheir designee, do not meet the criteria or intent of a minor modification

    Note: Multiple minor changes in the protocol, instruments, and/or consent may, together, be considered a major change subject to convened IRB reviewreview.

    Examples of Minor Changes:

    • Changes in inclusion or exclusion criteria that narrow eligibility (i.e.,that is, narrowing the range of the inclusion criteria or broadening the range of the exclusion criteria).

      Note: such changes should not appreciably reduce the likelihood that the research can be completed in a timely manner

    • Changes in inclusion or exclusion criteria that broaden eligibility (i.e.,that is, broadening the range of the inclusion criteria or narrowing the range of the exclusion criteria) when the investigator provides evidence that risks to the new subjects will not be different than to previously eligible subjects

    • Increase in local enrollment of subjects in a multi-institution study without a change in the overall study wide enrollment target

    • Addition of research activities that constitute no more than minimal risk.

      Note: addition of clinically indicated procedures where data will be used for research purposes (i.e.,that is, where the incremental risk is no more than minimal) are considered a minor changechange.

    • Addition of research activities that would be eligible for expedited IRB review (per §_.110(b)(ii)) under categories 1-7 (unless specifically defined as “major” above)

    • Alterations in the dosage form (e.g.,for example, tablet to capsule or oral liquid) of an administered drug, provided the dose and route of administration are unchanged

    • Decrease in the number or volume of biological samples collection, provided that such a change does not affect the collection of information related to safety evaluations;evaluations

    • Decrease in the length of hospitalization or number of study visits, provided such a decrease does not affect the collection of information related to safety evaluations

    • Alternations subject payment schedule, provided such payments remain fairly pro-rated

    • Increase in subject payment amount provided such amounts are within criteria in HRPP Policy

    • Changes to improve the clarity of statements or to correct typographical errors in the protocol, CF or any questionnaire, provided that such a change does not alter the content or intent of the statement

    • Changes in recruitment materials and advertising, provided such items continue to satisfy criteria in HRPP Policy

    • Revision of subject identification and recruitment strategy to include use of the NebraskaNM Medicineor CN Conditions of Treatment Opt-In database.database

    • Consent form modifications that add or remove information from the consent form so that it is consistent with an already approved IRB requirement

    • Updating a consent form using IRB approved boiler plate language

    • Addition or deletion of qualified investigators orstudy personnel

    • Change in Principal Investigator, provided the new PI is qualified by education, training, experience and licensure (as applicable) to assume overall responsibility for the safe and proper conduct of the research

    • Addition of study sites (that have a valid FWA and Reliance agreement as appropriate);appropriate; or that serve as performance sites where informed consent will not be obtained; or that serve as performance sites where informed consent will be obtained by a UNMC, CHMCCN or UNO investigator.

    DOCUMENT HISTORY:

     Written: 1/5/2016 (Approved: 1/5/2016) - original author not recorded

     Revised: 1/24/2018 - revision not documented

     Revised: 10/4/2018 - revision not documented

     Revised 1/18/2025 – clarified level of review associated with changes in PI and/or research personnel; clarified that changes to CIRB protocols are considered administrative changes; removed references to pre-2018 HHS regulations; stylistic changes {Approved Rusty McCulloh (Institutional Official), Bruce Gordon (Assistant Vice Chancellor for Regulatory Affairs, Executive Chair)}

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