IRB review is just one component of the overall review process.
Research on Human Subjects is tightly regulated to protect the health and rights of participants and to ensure the integrity of the research.
There are many steps in the overall review process for a clinical research protocol.
A protocol will need some or all of the following reviews:
1. Completed before IRB Review
2. Completed Concurrent with IRB Review
- Branch or Section Review
- Institute Scientific Review
- Statistical Review (if required by institute)
- Pre-IRB Review by IRB Staff
3. IRB Review Process
- Ethics Review for financial conflict of interest (DEC Review)
- Resource Utilization Review (PRIA form)
- FDA Review
- Radiation Safety Committee or Radioactive Drug Research Committee Review
- Review by Collaborating Sites (Collaborating Site IRB Approval Documentation)
- Review by Recombinant DNA Advisory Committee and/or Institutional Biosafety Committee
4. Completed After IRB Review
- Expedited or Full Board IRB Review
- IRB Actions
- Response to IRB Stipulations
- Final Sign Off
- Office of Protocol Services Review
- Director, Clinical Center Review
The following diagram represents the basic overall review process:
The following provides a brief description of each type of review.
Additional information on required reviews for different submission types can be found under the “Submission Types ” tab.
Branch or Section Review
Some Institutes, Branches or Sections require approval of new protocol submissions by the Principal Investigator’s Branch Chief or Section Head prior to IRB review.
Review of amendments or other submissions may also be required. The process varies between Institutes and branches.
PIs should check with their Branch Chief or Section Head for details.
Institute Scientific Review
NIH requires that every new protocol be reviewed for scientific merit. The process is determined by each Institute.
It may be conducted by an Institute Scientific Review Committee, through outside review, or a combination of both.
Scientific Review approval must be documented before a new protocol can be accepted for review by an IRB.
Contact the PI’s Institute Clinical Director’s office for information on the Scientific Review process.
Some Institutes require a separate statistical review apart from the Scientific Review for each new protocol. Contact the PI’s Institute for information on the Statistical review process.
The pre-IRB review is conducted by the IRB protocol coordinators and is the first step for all submissions to the IRB. The pre-IRB review entails ensuring all required documents have been submitted and that all submitted documents are complete, free of errors, conform to the latest templates and are internally consistent.
If the protocol submission is not on template, incomplete, full of typos or other errors, or internally inconsistent, it cannot be accepted for IRB review. Results of the pre-IRB review are entered into PTMS and the PI is notified via e-mail. The PI must address all issues identified during pre-IRB review, revise/correct the documents and re-submit via PTMS. The pre-IRB review process does not require a point-by-point response memo. Once the pre-IRB review is complete, the submission is accepted and scheduled for IRB review.
Ethics Review for financial conflict of interest (DEC Review)
Some protocol submissions (new protocols, amendments, continuing reviews) must be cleared by the Institute Deputy Ethics Counselor (DEC). During the DEC review, the Institute Ethics Office looks at the financial holdings of certain individuals listed on the protocol to determine if any has an actual or potential financial conflict of interest for that protocol. The DEC office contacts the conflicted investigator to determine how to resolve any actual or apparent conflict.
The process for submitting to the DEC office varies between Institutes. Contact the Institute Ethics office
Resource Utilization Review (PRIA form)
The “Clinical Center Prospective Protocol Resource Impact Assessment (PRIA)” form must be completed for new protocols. The form is used to help assess Clinical Center resource requirements for the protocol. To avoid delays, the PRIA form should be submitted to the CC/OD at the same time it is submitted to the IRB. The completed form is submitted to the Clinical Center, Office of the Director (CC/OD): PRIAsubmission@mail.nih.gov
If the protocol is subject to FDA regulation for a drug requiring an Investigational New Drug (IND) or a device under an Investigational Device Exemption (IDE), then the protocol must be submitted to the FDA for the IND or IDE. The IRB review process cannot be completed until documentation of FDA IND/IDE approval is submitted to the IRB. Documentation of exemption from FDA reporting requirements may also be required.
Radiation Safety Committee (RSC) or Radioactive Drug Research Committee (RDRC) Review
If the protocol involves the use of radiation for research purposes, then it will need approval from the Radiation Safety Committee (RSC). Certain studies with radioactive drugs require review by the Radioactive Drug Research Committee. Contact the RSC or RDRC for more information regarding their review processes.
Review by Collaborating Sites
If the protocol is a multi-site study and NIH is the coordinating site, then approval by each participating site’s IRB must be documented. If NIH is not the coordinating site, then approval by the coordinating site’s IRB must be documented. Protocols with other collaborations may also require review by collaborators’ IRB.
Review by Recombinant DNA Advisory Committee (RAC) and/or Institutional Biosafety Committee (IBC)
If the protocol includes research involving recombinant or synthetic nucleic acid molecules, then it may require review by the RAC and/or IBC.
The IRB is a Federally mandated committee that must review and approve of all research activities involving human subjects.
The primary charge to the IRB is protection of human subjects. IRB review and approval is required for new protocols, at least annually for active protocols, before changes are made to a protocol,
when the protocol is closed, and for other reasons (see “Submission Types ”).
All actions for CNS IRB review must be submitted via PTMS . All submission types generally follow the same pathway:
Expedited or Full Board IRB Review
Once a submission has been accepted for IRB review, it is assigned either to expedited or full board review. The determination is based on regulatory criteria for expedited review and issues specific to the study.
Expedited IRB Review:
Initial Review, Continuing Reviews and Amendments that meet certain regulatory criteria (45 CFR 46.110
) may be eligible for expedited review. Not all submissions that meet these criteria are assigned for expedited review. The IRB Chair makes the determination of expedited or Full Board review based on the regulatory criteria and study-specific issues. Expedited review is conducted by the IRB Chair or designees of the Chair who exercise all of the authorities of the Board, except that disapproval requires full IRB review.
Expedited review is not necessarily faster than full board review because:
- All Protocol and Consent requirements, including NIH review standards, apply
- All Investigator requirements apply
- IRB Chair, Deputy Chair and staff carefully review all documents
Full Board IRB Review:
The CNS IRB is comprised of three independent, duly constituted IRBs (panels) with common processes and under common management. New protocols are assigned to the panel with the expertise that best suits the protocol. Once a protocol is assigned to a panel, it stays with that panel throughout the life of the protocol.
Each panel meets once a month (see Meetings schedule). The due date for completing pre-review in order that the submission is placed on the agenda of a full board IRB meeting is approximately two weeks before the meeting. The 2 week period allows time for the IRB meeting review material to be finalized, distributed to IRB members and reviewed by IRB members prior to the meeting.
An IRB may take one of the following actions when reviewing a submission:
- Unconditional Approval
The IRB may approve as is and without adding stipulations (conditions).
- Approval with Stipulations (conditions)
The IRB may approve research with stipulations (conditions) if, given the scope and nature of the stipulations, the IRB is able, based on the assumption that the stipulations are satisfied, to make all of the determinations required for approval under regulation/policy. Review of the PI response to IRB stipulations is delegated to the IRB Chair or designee.
The IRB may defer approval. This term is used when the IRB has any stipulation (condition) which requires more than mere concurrence on the part of the PI. Deferred approval is required if the IRB needs additional information to make all of the determinations required for approval under applicable regulations. For submissions that receive deferred approval, the response to IRB stipulations must go back to the full board for review. Approval will be granted by the IRB if the stipulations have been met.
The IRB may table a submission if it determines that it does not have sufficient information for approval. If a submission is tabled, the IRB will provide recommendations for a re-write of the submission. The recommendations may be incomplete as formal IRB review stops once it is clear a submission cannot be approved. For submissions that are tabled, the investigators must address the issues raised and revise the documents for Full Board reconsideration.
This term is used when the IRB has determined that a submission cannot be approved. A disapproved protocol may not be re-submitted to a different IRB at NIH or elsewhere. The IRB decision cannot be appealed to Institute or NIH leadership. The PI may appeal the IRB’s decision to the same IRB that previously reviewed the action.
Response to IRB Stipulations
The PI is required, per NIH policy, to respond to stipulations within 30 days.
The response must be via formal written memo. The memo must address each stipulation point-by-point and note where changes made in response can be found. The CNS IRB has a response to stipulations template that provides directions for responding to IRB stipulations.
Document revisions in response to IRB stipulations must be made using “Track Changes”. Tracking the changes enables the IRB to easily identify what has been edited and to verify that all stipulated changes have been made. When submitting a response to stipulations, prior versions of any revised documents should not be deleted or replaced in PTMS . The revised documents should be added to PTMS as a separate document and labeled clearly (e.g., “Protocol – Revised per Response to IRB Stipulations”).
Please note that NO UNSTIPULATED CHANGES can be made when responding to stipulations.
Final Sign Off
Submissions must meet all the relevant regulatory and NIH policy requirements before they can receive final approved by the IRB.
Once all stipulations, if any, have been met, the IRB Chair signs to indicate final IRB approval.
All required non-IRB reviews must be completed and documented before IRB staff can forward documentation for “Reviews completed after IRB review.”
Office of Protocol Services (OPS)
When IRB Approval is complete, Initial Review, Continuing Review, Amendment and Study Closure submissions are sent to OPS by the IRB Office. OPS will review submissions to ensure all the information they require is present. OPS will contact the IRB office and the PI to resolve any issues prior to signing off. OPS sign off is the last step in the approval process. Upon completion, OPS will post or update the consent form(s) on the Clinical Center consent website
as necessary and email the latest watermarked consent documents and the OPS completion documentation to the PI and IRB office.
The watermarked consent documents received from OPS are a Microsoft word version of the informed consent with a “Revision” watermark. OPS provides the watermarked consent document so that the PI will have an editable version of the latest approved consent form to use for future submissions. It is not used for obtaining participant consent.
The consent form to be used for participant signature must be downloaded from the Clinical Center consent website
on the day that the participant arrives to begin the research study.
Director, Clinical Center Review
OPS forwards Initial Review submissions to the Director, Clinical Center for research conducted at the Clinical Center. OPS provides their final sign off for Initial Reviews after the Director of the Clinical Center signature has been obtained.