NIH Investigator Manual for Human Subjects Research

Chapter 11 - Continuing Reviews (CR)

Overview

Key Points

Protocols require periodic review by the IRB to ensure that the protocol continues to meet the criteria for approval.
Depending on the risk of the study, the continuing review process may require approval by a fully convened IRB or may undergo an expedited review process.
Failure to submit a continuing review in a timely matter can result in a lapse in IRB approval.

What is a Continuing Review?

Continuing Review (CR) is the ongoing, scheduled IRB review of a previously approved non-exempt human subjects research study, at intervals appropriate to the degree of risk, but not less than once per year (364 Days), except as described in 45 CFR 46.109(f) for research that is subject to the 2018 Common Rule.
The IRB will look at the progress of a previously approved protocol over the past year. They will also be checking to make sure that the protocol meets current regulations and policies. The fully convened IRB may perform this review, or it may be reviewed by an expedited reviewer under certain circumstances.

Why is Continuing Review required?

Continuing Review (CR) provides an opportunity for the IRB to reassess the totality of the project and ensure that, among other things, risks to subjects are minimized and are still reasonable in relation to anticipated benefits, if any, and the knowledge that is expected to result from the research. At the time of continuing review, the IRB considers whether there is any new information provided by the investigator, or otherwise available to the IRB, that would alter the criteria of IRB approval of the research. The CR provides the IRB with:

The chance to review information from any monitoring entity as well as unanticipated problems that have occurred since the last CR to determine if there is any change in the risk: benefit relationship of the research.
The opportunity for the IRB to ensure investigators are using the most recently approved version of the consent document.
Chance to review any unresolved subject complaints.
Ongoing enrollment data to assess whether enrollment is consistent with what is planned
Information about/reason for any subject withdrawals that might suggest problems related to conduct of the research.

When does a protocol require a Continuing Review?

All research subjected to FDA regulation requires at least an annual CR, regardless of whether the research is subject to the pre-2018 or 2018 Common Rule.
If the study is under the pre-2018 Common Rule, all non-exempt research requires a continuing review.
If the study is under the 2018 Common Rule, all non-exempt research that requires full board review requires a continuing review.
TIP: If your protocol has an expiration date, your protocol requires continuing review. The outcome letter from the approval of the Initial Review will contain the expiration date of the CR.

How often must my protocol go through Continuing Review?

The IRB determines the timeframe of the subsequent CR at time of protocol review. Most protocols will be reviewed every 12 months. However, the timeframe may be shortened by the IRB if the IRB determines that more frequent review is required. Possible reasons the IRB may require more frequent CR is if the protocol is high risk, or the protocol requires prompt modifications. This will be indicated on the outcome letter from the IRB meeting and the exact expiration date will be provided.
The expiration date cannot be extended and there is no grace period.
The time between two CRs can be no more than 364 Days. The expiration date will be set from either the date of the Full Board IRB meeting or the date the submission is approved by the expedited reviewer. The date will be included in the NIH IRB Approval letter.
You will receive a reminder in the eIRB system that the due date for the CR is approaching. It is recommended that you submit the Continuing Review Form in the electronic IRB system at least six weeks before the due date to ensure that the protocol does not expire.

What happens if the Continuing Review is not approved by the expiration date and there is a lapse in IRB approval?

If the CR is not approved by midnight the day the protocol expires, all research activities and enrollment must be stopped until approval is granted by the IRB.
However, when it is in the best interests of already enrolled subjects to continue in the research during the period of lapse in IRB approval, the IRB has the authority to, or the PI may request from the IRB, permission to continue participation of already enrolled subjects during this period.
If a study has lapsed due to the PI's failure to obtain timely CR, the IRB may elect not to review other active or new studies submitted by the PI until the CR is resolved.
If the study lapses more than 45 days, the PI must submit a new initial review in order for the research to continue.
If the study does lapse, this event is not considered noncompliance requiring expedited submission of an event report in the electronic IRB system.

What forms must be submitted in the electronic IRB system for a Continuing Review?

Modifications to the protocol or consent form(s) are permitted as part of the Continuing Review (CR). Whether there are modifications or not, you must complete the Modification/CR Form to submit your continuing review.
Modification/CR Form: the following information is collected via check box format, as applicable
- Information about any subjects who experienced unexpected harm
- Any anticipated adverse events that have taken place with greater frequency or severity than expected
- Subjects who withdrew from the study
- Any unanticipated problems involving risks to subjects or others
- Unresolved complaints about the study
- Publications in the literature relevant to risks or potential benefits
- Any interim findings
- Any multi-center trial reports
- Data safety monitoring reports
- Regulatory actions that could affect safety and risk assessment
- Other relevant information regarding the study, especially information about risks
- Explanation if the PI thinks the risks and potential benefits have changed
- Any modifications to the protocol that have not been submitted to the IRB
- Any problems that require prompt reporting to the IRB have not been submitted
- Information about use of the short form process
- Any non-compliance that has occurred (including minor or major deviations)
Study Information Form
- Double check that the study information is complete.
- For multicenter studies, make sure the information related to the sponsor, the coordinating entity, and other sites is up to date and correct.
Attachments
- Redacted consents
  - The latest consent and/or assent of all available document types. (i.e., Healthy Volunteer, Standard, Screening, Recipient, Donor, etc.)
  - If there has been no enrollment during the Continuing Review period, this is not required.
- DSMB/SMC/IMC Report
- For multicenter studies: If the NIH is the coordinating center and there are sites under local IRB review, provide the CR approval letters from the local IRBs or Ethics Committees.
- Any supporting documentation from sponsors or manufacturers including updated investigational brochures.
- Audit results relevant to the continuation of the research.

What happens after the IRB receives my CR submission?

The submission will undergo a pre-review by one of the IRBO Analysts. They will make sure that the submission is correct and contains all the needed components. They will also anticipate the needs of the IRB and may request additional information by sending back a request for clarification to the research team.
The submission will then be assigned to an IRB meeting or an expedited reviewer.
Once the IRB reviews the submission, the following outcomes will be communicated by an outcome letter in the electronic IRB system:
- Approved
- Modifications required to secure approval
- Deferred
- Disapproved

Chapter 12 - Study closures (routine)