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IRB-HSR > Managing Protocol After Initial Approval > Continuing Review Process

 

 

 

 

 

 

Continuing Review Process

Background Information:  Establishing Continuing Review

  • Except for studies determined to be exempt from IRB oversight, all human subject's studies are required to undergo continuing review based on the level of risk as assessed by the IRB. This review takes place no less than annually, and may require more frequent review or reports as determined by the IRB. For projects receiving full board review, the length of approval is calculated from the date of the full board review. When a primary reviewer has been assigned, that reviewer is asked to provide a recommendation for the length of approval. The appropriate length of approval is considered as a part of the full board discussion. That review may take place up to thirty (30) days prior to expiration.
  • Continuing review of expedited or full board approved research will be conducted with the same diligence as utilized with the initial review of the research. The review should be substantial and complete. Reviewers have access to the original submission, all documents submitted since the beginning of the research and any new documentation submitted with the continuing review application.
  • For projects approved via the expedited process, the chair, vice chair or experienced member designee conducts the review and determines the length of approval but, the approval time is still no greater than annual.
  • For research where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions, continuing IRB review is required as long as the research remains active only for long-term follow-up of subjects. Furthermore, continuing IRB review of research is required where the remaining research activities are limited to data analysis (see 63 FR 60364-60367, category (8)).

Projects requiring review more frequently than annually may include:

  • Experimental therapies in which the clear potential for significant adverse experiences have been identified at the time of review;
  • Non-therapeutic projects based on risk information provided at the time of initial review;
  • Projects in which new information provided during the duration of the study (including at the time of continuing review) indicates a high probability of significant adverse experiences not previously reported; or
  • Projects in which local or outside adverse experience reports create new concerns regarding the need for closer project scrutiny.

In such cases, approvals may be granted for time periods less than one year or, as may be more appropriate, for a limited number of subjects over a period not to exceed one year.

Submission for Continuation Review (Protocol Status Reports)

  • The IRB must conduct continuing review of research at intervals appropriate to the degree of risk, but not less frequently than once per year. The IRB decides the frequency of continuing review for each study protocol necessary to ensure the continued protection of the rights and welfare of research subjects.
  • The continuing review provides an important opportunity to ensure that changes in federal or state policy or IRB practices and expectations are reflected in the protocol and especially the new consent form.
  • The federal regulations do not allow an IRB to approve a study for more than one year. IRBs may approve studies for a period shorter than one year based on the degree of risk. For multi-year research, the principal investigator is responsible for submitting a continuation application prior to the expiration date of the current IRB approval.
  • Approximately eight weeks before the scheduled Meeting Date, the IRB staff will send out the Status Report Forms for those protocols approved via expedited or full board review along with the appropriate email to the Principal Investigator (PI), Study Coordinator (if designated), the Department Contact (if designated) Faculty Advisor (if designated) and the IRB Departmental Coordinator (if designated). If the PI does not have an e-mail address, a hard copy of the status report will be printed out and sent through UVA messenger mail to the PI only. The Status Report will have the due date (approximately one month prior to the meeting date) listed on the form.
  • If the approval expires prior to submission of the continuation application, the investigator is required to suspend subject contact and data collection until the continuation is approved by the IRB. For therapeutic studies where subject safety is a concern, federal regulations allow some flexibility towards the continued treatment for currently enrolled subjects. However, no new subjects may be contacted, recruited, or enrolled in the study until the investigator obtains current IRB approval.
  • If the PI does NOT return the completed Status Form by the Late Due Date the PI will be sent a letter notifying him that the protocol has expired. A copy of this letter will go to the Department Chair, the appropriate grants office and others as indicated. In addition the IRB Chair, vice-chair or designee may refer this PI to the School of Medicine Clinical Trials Office for a Post Approval Monitoring (PAM) review. In addition, the event of "Closed by PI" with a comment of "expired" will be entered in IRB Online.
  • When continuing review of a research protocol does not occur prior to the end of the approval period specified by the IRB, IRB approval expires automatically. Such expiration of IRB approval does not need to be reported to the Office of Human Research Protections (OHRP) as a suspension of IRB approval under HHS regulations.
  • If the PI wishes to reopen the protocol the PI will need to update the protocol and consent (if plan to reopen to enrollment) to the current template. If the protocol does not meet exempt or expedited criteria it will need to go to the full board for approval. In addition, the IRB staff will notify the PAM auditors by email. PAM will initiate audit procedures. The study must receive a "satisfactory" or "exceptional" review before the protocol can be reopened.
  • If a study is more than five years old and still enrolling, the PI will be notified that the protocol and consent form(s) will need to be updated to the current template using IRB online. (IRB-HSR only)
  • Once completed continuing review materials are received, a determination is made whether the continuing review is eligible for expedited review (item 3) or if it should be scheduled for full-board review.
  • Investigators are notified in writing of the decision of the IRB and any changes required. Continued approval is not granted until all required changes have been made and submitted for review and approval. Once approved, the investigator is sent documentation indicating the date of the next study expiration.

Aggregate Review of Research Data

The Data and Safety Monitoring Plan (DSMP) template produced using Protocol Builder when a study presents greater than minimal risk to subjects, asks the Principal Investigator (PI) to determine the appropriate frequency and appropriate content for aggregate reviews.

Responses to these template questions can differ widely depending on the type of risks, and the vulnerability of the study population.  It can be frustrating for the study team to determine what answers best suit the type of risk the study presents to their subjects.  In addition, it is important to note that the responses to these questions must be as accurate as possible since Post Approval Monitors (PAM) will be looking for documentation that aggregate reviews are performed exactly as described in the DSMP.  Therefore the PI will want to be sure to select the appropriate frequency and content in the DSMP.

What is an aggregate review?
Aggregate Review is the cumulative review of specific data that might impact the safety and risk/benefit analysis for a study.

Who is responsible for the aggregate reviews?
If there is not another person or body assessing safety of a study on an ongoing basis (medical monitor, DSMB, etc.) then the responsibility for completing these reviews falls to the PI.  If the study has a Data and Safety Monitoring Board the UVa PI will likely NOT be responsible for aggregate reviews.  In this case it is likely that the DSMP should not have the PI checked as the only person overseeing aggregate safety for the study- because the DSMB is responsible for that function.

Determining the frequency of aggregate review?
For studies that are deemed greater than minimal risk (require full board review), there is a question in the Data and Safety Monitoring Plan template about the aggregate review.  The question reads as follows:

Answer this question ONLY if the PI is the ONLY person responsible for overseeing the safety if the study.

How often will aggregate review occur?

The decision regarding the frequency of PI aggregate review must be based on the amount of risk to which subjects are exposed, the likelihood that previously unknown adverse effects might be discovered, and the vulnerability of the population under study.  Again, if the study  has a Data and Safety Monitoring Board the UVa PI will likely NOT be responsible for aggregate reviews.  In this case it is likely that the DSMP should not have the PI checked as the only person overseeing aggregate safety for the study- because the DSMB is responsible for that function.

Recommendations for Annual Aggregate Review:

For studies that are deemed just slightly greater than minimal risk, an annual review is fine.  These studies require full board, but present only slightly greater than minimal risk to the subjects.  Examples of these kinds of studies include:

  • Well-described, short term treatments to relieve common symptoms with known safety data at a single site,
  • Trials with procedures such as indwelling catheters, endoscopy, lumbar puncture, bone marrow biopsy, oral glucose tolerance, induced sputum, skin biopsy, and routine imaging studies.  These studies are commonly done in clinical practice.  The risk profile for these procedures is well understood.  Annual review would be sufficient even if these tests are being done solely for research.
  • Collection of sensitive information via questionnaire or survey where a privacy plan is in place.
  • Therapeutic trials of an agent or device that are already approved for use in the study population to be studied, for the indication under study, at the dose, and frequency which is already approved and the study is taking place at a single site (UVa Only)
  • Blood draw studies where the volume and/or frequency exceeds that which is allowed under expedited criteria.

Recommendations for Monthly Aggregate Review:
For studies that pose significant risk to the subject, a monthly aggregate review would be appropriate. 

Some examples of these kinds of studies include:
  • Clinical trials of diseases where the endpoints are major morbidity or mortality
  • Study involves the assessment of serious toxicity,
  • Studies requiring the implantation of any device solely for research
  • Studies on new chemicals, drugs, or biologics for which there is limited or no available safety data in humans
  • Gene transfer studies
  • Multisite studies involving risk to subjects
  • Studies involving high-risk clinical procedures performed solely for research purposes

Recommendations for Aggregate Review performed at Frequencies other than Annual or Monthly:
For studies that do not fall neatly into “slightly greater than minimal risk” or “significant risk”, an alternate timing for aggregate review (every other month, quarterly, every 6 months, etc) may be appropriate.  These kinds of studies may present moderate risk to subjects and include the following:

  • Interventions performed for research that present low or minimal risk to subjects and subjects represent a vulnerable population (children, prisoners, etc.)
  • Subjects with diseases are exposed to placebo,
  • Therapeutic interventions involving procedures such as insulin clamps or organ biopsies
  • Studies that involve subjects with illness being treated with procedures that may result in moderate to severe adverse events
  • Studies involving combinations of previously approved therapies for a particular condition (approved for the population under study and the approved dose, for the approved indication at the approved frequency, using the approved route.)

Determining the appropriate content for aggregate review:

The DSMP template asks the PI to check what items will be reviewed at the time of aggregate review

  • If the study team is not collecting the data,  do not indicate that data will be examined in the aggregate review!  For example if there are no dose escalation rules, de-escalation rule, study stopping rules, etc., then do not indicate that these data  will be reviewed during aggregate review.  This may seem obvious, but it is one of the most frequent errors found during DSMP review.
  • It is impossible to review for safety if adverse events and unanticipated problems are not reviewed.  It is almost always safe to assess these criteria during aggregate review.
  • Check the only criteria for which the study team has access.
  • Check only the criteria that make sense for the study.  For example, if the study involves a one-time questionnaire, then assessing early withdrawal data will likely not be helpful and does not make sense for a study of this nature.
  • Be clear in the DSMP what criteria the study team will review and at what frequency.  Perhaps the study team  plans to do a monthly review of AEs but only wish to review Early Withdrawal data on an annual basis.  Make sure it is clearly documented in the DSMP what criteria the study team plan to review and how often it is intended to be reviewed.

How do you do an aggregate review?

  1. At the frequency noted in the DSMP for the protocol, the PI will pull the cumulative information collected thus far for the data points indicated per the DSMP (e.g. AEs, Unanticipated problems etc.). The data may be found in individual case files, in a spreadsheet or in a database from which reports can be generated.   How this data is stored and pulled together or generated for aggregate review must be determined by the study team early in the study.
  2. The PI will review all of the data asking the following questions:
    1. Are there any trends noted?(safety, enrollment, early withdrawal, etc)?
    2. Does the risk/benefit profile remain as previously described in the protocol?
    3. Are there any modifications to the protocol and consent that would diminish additional risks, promote enrollment, encourage subjects to complete the study etc. 
  3. The PI needs to make the following decisions based on the aggregate review: 
    1. Is it safe for this study to continue as is; or is a modification required OR must the study be closed?

How do you document the aggregate review?

If only annual aggregate reviews are required, a provision is made to document annual aggregate reviews in the Protocol Status Form which is e-mailed out to study teams prior to Continuation review.  If this section of the Protocol Status Form is completed, then no further documentation of an annual review is required.

If the aggregate review must take place at a frequency other than annually, then documentation for the aggregate review should include the following:

  • IRB-HSR Number
  • Protocol title
  • Date of the review
  • Content of the review (AEs, etc.)
  • Determination of continuation status (study to continue with no modification required due to this review, study to continue with the following modifications: insert, or study to be stopped due to (insert).
The Aggregate Review Form is available to assist in documenting the aggregate review.  This form or something similar to this form may be used for documentation purposes.

What documentation must be sent to the IRB-HSR?
There is a question in the DSMP that asks how often documentation of aggregate review will be submitted to the IRB.  If you have determined that an annual submission is sufficient, then you need only complete the Protocol Status Form that is sent to you for the continuation review.  No additional documentation needs to be submitted.

If some other frequency has been checked, submit documentation of aggregate reviews to the IRB at the frequency indicated in the DSMP.  The Aggregate Review Form may be used for this purpose.

What must be maintained in the Study Records/Regulatory Files?
Make sure the documentation of your aggregate reviews is safety stored.  This documentation will be reviewed during Post-Approval Monitoring.  

 

*Taken from UVa IRB-HSR Research Guidance