NIH Investigator Manual for Human Subjects Research

Chapter 10 - Protocol Modification

Overview

Key points

Once a study has received initial IRB approval, any new change to the study or consent form is considered a modification, and the proposed modification must be submitted to the IRB for review.
The NIH IRB must approve the modification before any change can be initiated or before updated materials can be used except when necessary to eliminate apparent immediate hazards to a subject.
You are responsible for ensuring timely submission to the IRB of all modifications.

What are my responsibilities as a Principal Investigator (PI) when submitting documents to the IRB for a modification?

Confirm that all required materials (e.g., the required documentation and information collected in the NIH electronic IRB system), are submitted in a timely manner.
Verify the completeness of all submissions to the NIH IRB consistent with the requirements of NIH Policy 205, Requirements for IRB Submissions. If your submission is incomplete, it will be returned.
Specific information regarding your responsibilities when submitting modifications is found in the following questions, based on whether your protocol is exempt or non-exempt human subjects research.

What are the required materials that I must submit for modifications to my exempt human subjects research study?

For modifications to research determined to be exempt (whether reviewed by exempt procedures or limited IRB procedures), the following materials must be submitted via the NIH electronic IRB system. For any forms or documents being uploaded, include the word "exempt" in the title.

Modification Submission Form including applicable changes
Revised research project
Other revised documents, as applicable:
1. Revised information sheet, verbal script, etc.
2. Revised recruitment material, as applicable (e.g., flyers, posters, scripts, social media ads)
3. Revised study instruments used to collect data from research subjects (e.g., surveys, interview forms, questionnaires, assessments)
Any other documents or information that the IRBO requests

What are the required materials that I must submit for a modification to my non-exempt human subjects research study?

For modifications to previously approved non-exempt human subjects research (whether reviewed by the convened IRB or by expedited procedures), submit the following materials via the NIH electronic IRB system:

Modification Submission Form including applicable changes
Revised protocol, as applicable
Revised informed consent and/or assent documents (e.g., consent, parental permission, information sheets, verbal script), as applicable
If your protocol is a covered protocol and a new NIH investigator is being added, documentation of the Deputy Ethics Counselor (DEC) clearance is required. (See this earlier section of the manual for information on the DEC clearance process.)
Any other documents or information that the IRBO requests

What are the required materials that I must submit for modifications to my non-exempt human subjects research study when adding a participating site to initiate multi-site research or to expand any existing multi-site protocol?

The process for adding non-NIH participating sites (pSites) in the electronic IRB system is described in the manuals available within the PROTECT system's Library tab. When the NIH IRB is the Reviewing IRB, and you are adding a participating site, whether to initiate multi-site research or to expand an existing multi-site protocol, make certain the modification includes the following documentation:

Submit Basic Site Information using the eIRB submission form.
Upload supporting documents in the eIRB system including the following:
1. pSite Protocol Addendum (using the IRBO template);
2. pSite Consents/ Assents (if applicable);
3. pSite Recruitment materials (if applicable) which includes documentation confirming that the pSite’s institutional requirements have been met and that local context information provided has been approved by the relying institution; this can be documented via a letter, email, memo, etc.;
4. pSite HRPP Clearance (via letter or email)
Any other documents or information that the IRBO requests.

If required Human Research Protection Program (HRPP) training is not up to date/current or if I am adding a new AI, will the modification undergo IRB review?

The IRB Coordinator will return modifications if the PI or any investigator is delinquent with their required HRPP training.
If any investigators are added to the study after IRB approval, they need to complete the required training as indicated in Policy 301, Education Program and be added by submitting a modification form.

What format should I use for my protocol and/or consent form when submitting a modification?

The protocol and consent document must be in clean Microsoft Word format. (However, if you are submitting a tracked pdf that the sponsor has provided for IRB submission, this may be included with tracked changes noted.)
When submitting documents to the NIH electronic IRB system, each electronic regulatory file must have a consistent format, including naming of folders and files, to ensure required information is maintained and easily accessible.
For proper nomenclature study teams are required to use when submitting documents to the NIH IRB, refer to the section of the OHSRP website which outlines required nomenclature for protocols, consent forms and other study documents titled How to Name Documents for Submission to the IRB.

What is the process when changes to the protocol require approval by other committee(s) as part of a modification submission?

Identification of which additional ancillary reviews are needed will be based on the modifications you are making to the protocol and/or consent form.
IRB review of your modification may be delayed until such ancillary review approvals are received.
The requirements for each type of ancillary review are set by the specific review committee.
See the section regarding Ancillary Reviews in the Initial Review section of this investigator manual.

What happens after the IRB receives my submission for a modification?

NIH IRBO is responsible for screening all submissions to determine whether the modification needs to be reviewed by the convened IRB or can be processed via expedited review.
Once all documents relevant to the modification get submitted in the NIH electronic IRB system, the internal review process begins:

Analyst Pre-Review: The IRBO Analyst conducts a pre-review of all documents submitted via the NIH electronic IRB system and verifies the submission meets minimum standard to be considered complete for pre-review. The analyst verifies all sections in the modification form are properly completed. All necessary updates to the consent, recruitment documents and questionnaires/data collection instruments should be attached as applicable. Revised documents should be named properly. Ensure there is consistency with all documents submitted.
Potential withdrawal: For any missing or incomplete documents, the submission is considered "incomplete" and will be returned to the study team to address the Pre-review request for clarification. It is the responsibility of the study team to respond to requests for clarification or corrections from the IRBO. At its discretion, the IRBO may administratively withdraw submissions from IRB consideration when the PI is non-responsive to requests from the IRB or from IRBO staff for 30 calendar days. The investigator will be notified by the IRBO if the submission is administratively withdrawn.
Addressing Pre-review Requests for Clarifications: Before your submission is reviewed by the IRB, the Analyst may ask you to make some changes that will be sent as a Request for Clarification.
- When you are responding to these request:
  1. Respond to study information questions directly in the NIH electronic IRB system.
  2. Provide written responses, when appropriate.
  3. If a tracked document is provided by the IRBO Analyst…use it!
  4. Review the changes, accept the changes, and upload a clean version of the document into the application.
  5. If you don't want to accept changes…provide a justification.
  6. Make sure you address/respond to ALL requests for clarifications/changes.
  7. Return to the IRB in a timely manner.
Analyst Pre-Review of Request for Clarification/Study Team Responses - Responses which you submit are reviewed by the IRB Analyst. Once the analyst confirms that required corrections have been made/addressed and all supporting documents are available, the submission is assigned a review level (Expedited or Full Board) review.
IRB Review - When conducting its review, the convened NIH IRB, or expedited reviewer must review the submission materials in order to determine that all regulatory and policy requirements for approval of research are met, or whether more information is needed to make a determination.

What determines whether my modification will get expedited review vs. full board review?

If the proposed change to the research adversely impacts risk/benefit or if the changes are more than a minor change, the modification is sent to full board. This could include research that was previously expedited.
If the proposed change to the research is a minor change that does not adversely impact risk/ benefit, it may be considered for expedited review.
If your level of review does not follow the above parameters, please contact the IRBO Analyst.

Levels of Review:

Expedited	Full Board
Minimal Risk (MR) Analyst Pre-review Reviewed by Chair/Chair Designee	Greater than Minimal Risk (GTMR) Analyst Pre-Review Reviewed and Approved by Convened Board

What happens when my modification to my non-exempt research study undergoes Full Board Review?

At Full Board Review the Board votes as per below:
- Approved
- Modifications required to secure approval
- Deferred
- Disapproved

Chapter 11 - Continuing Reviews (CR)