IRB Review of Changes to Previously Approved Research

During the course of study conduct, most research involving human participants will require some form of planned modification or revision. This includes amendments involving changes to institutional review board (IRB)-approved protocols.

The investigator is responsible for ensuring changes receive IRB review prior to implementation; the IRB is responsible for reviewing the changes to ensure everything continually approves the regulatory criteria.

There are various IRB review requirements for amendments involving changes to IRB-approved protocols and other study modifications. Additionally, researchers must be mindful of IRB considerations as they review study changes.

Changes in Research Requiring IRB Review

Prior to implementation, the IRB must review and approve any modification to research activities or amendments involving changes to an IRB-approved protocol or document. These changes can range from minor (e.g., updating the site’s phone number) to significant (e.g., amending the IRB-approved protocol to change the dosing schedule or add a new research objective).

The exception to this rule is when changes are necessary to eliminate immediate hazards to subjects. In these cases, the IRB must receive these after implementation. Many IRBs require such reporting within 10 business days of the change; however, it may vary between different IRBs.

Researcher Considerations for IRB Review of Study Changes

Modification or amendment information should include sufficient detail for IRB assessment. This includes noting any implications for participants currently enrolled in the research.

Providing context – such as rationale for the change, enrollment status of the study, and the investigator’s plan for participant notification – are critical details. Depending on the nature of the modification or amendment, research participants may need notification of changes through a letter or be required to re-consent. The more information researchers provide in the IRB submission, the easier it is for the IRB to consider implications for the research, researcher, and current and future research participants.

The Secretary’s Advisory Committee on Human Research Protections (SACHRP) provides examples of instances where modifications and amendments to IRB-approved protocols may affect a research participant’s willingness to participate. These changes should be disclosed to them.

Examples of study changes SACHRP recommends be disclosed to participants may include:

• Identifying new research-related risks
• Increase in the frequency or magnitude of previously described risks (e. g., severe allergic reaction)
• Unanticipated problem exposing participants or others to new risks (e.g., a data breach)
• Decrease in expected benefits to participation (e.g., limited efficacy of experimental therapy)
• Change to the research resulting in increased burden or discomfort
• New alternative therapy availability (e.g., FDA approval of a new drug for the condition under study)
• Impact of participation on alternative therapies (e.g., investigational agent reduces effectiveness of standard of care therapy)

IRB Considerations for Amendments and Study Modifications

When sites submit study amendments and modifications for review, the IRB will determine whether the change is minor or significant. The outcome of this assessment will determine the specific IRB review pathway for any given modification.

Typically, “minor” changes may be reviewed using expedited review procedures, which means an individual reviewer conducts the review, rather than the fully convened board. “Significant” changes are sent for review by a convened IRB meeting.

The IRB considers several factors when making this review triage determination:

1. Are the changes made to the study no more than a minor change to the previously approved research?
2. Do these changes increase risk to participants or otherwise alter the risk/benefit assessment?
3. Would these changes impact a participant’s willingness to participate – and if so, how/to what extent should they be informed of the changes?

IRB Review of Minor Study Changes

Federal regulations and guidance do not provide a singular definition for “minor” changes to research.

Generally, IRBs have policies and procedures to identify if a modification is minor. The IRB also relies on their board members’ experience and expertise to evaluate those changes within the context of the research.

Some examples of “minor” modifications to previously approved research may include:

• Updated site contact information
• Spelling corrections or wordsmithing revisions
• Addition of new recruitment or subject-facing materials
• Adding a new research location or site

IRB Review of Significant Study Changes

Significant changes to IRB-approved protocols are typically defined as those reflecting more than a minor change to previously approved research, increasing risk to participants or otherwise altering the IRB’s risk/benefit assessment.

Some examples generally considered as more than a minor change to previously approved research may include:

• New cohort addition, including a new drug and/or new intervention
• New risks identified potentially impacting subjects’ willingness to participate in the research
• Removal of previously approved safety monitoring procedures
• Investigator’s brochure (IB) update to add a new section on an immune system response (immunogenicity) not described in the previously reviewed version

Other Considerations

The IRB also evaluates whether participants should be notified, how, and under what circumstances. Investigators must include a clear plan for when, how, and if consent (or participant notification) is required to help the IRB make clear, actionable review determinations.

The IRB gives additional scrutiny to amendments involving changes in the research precipitated by (or identifying) an unanticipated problem involving risks to subjects or others, serious or continuing noncompliance, or a serious adverse event. When such changes are identified, the IRB may be required to report findings to federal oversight agencies – in addition to other requirements the IRB may impose on the research, up to and including study suspension or termination.

Modifications are sometimes more difficult for the IRB to review than a new research study. If participants have already started the research, there are additional considerations. This includes examining when and how to provide participants with sufficient information so they can adequately assess whether to continue participating.

In some situations, the IRB may determine the study risks outweigh the benefits and impose further modifications (or restrictions) to protect participants. The more information the investigator provides the IRB, the easier it is for the IRB to deliberate over the changes, with a goal of providing a clear, actionable review outcome.

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