Protecting Human Subjects Guide

6. Continuing Review

Institutional Review Board review is an ongoing process, not a one-time step. Regular reevaluation ensures that research is conducted responsibly. Even in responsibly conducted studies, a one-time review is inadequate, since risks can really be understood only after research has begun, and since the regulations for human subjects research are constantly being refined as the risks and benefits are better understood. Unexpected developments in a project can raise questions about the conduct of the research, and new findings can raise questions about the project.

6.1 Continuing review

"Continuing review" refers to regularly scheduled complete reappraisals of a project. The goals of continuing review are to ensure that the risk/benefit ratio is still acceptable, that the measures taken to safeguard subjects are adequate, that the approved protocol is followed, and that the project reflects any changes that have been made in the regulations for human subjects research since the last approval.

The IRB may require changes in protocol or revisions in the consent form if the study's risks were originally underestimated , but the converse can also occur: the investigators and the IRB may have underestimated the benefit to research subjects.

When continuing review is required

The Department of Health and Human Services (DHHS) Regulations 45 CFR 46, require that "an IRB shall conduct continuing review covered by this policy at intervals appropriate to the degree of risk, but not less than once per year..." This continuing review must be substantive and meaningful.

A notice for renewal and a "continuing review form" are sent to the principal investigator eight to ten weeks before the review date. The form should be completed and returned to the HRPP office by the indicated deadline. The study expiration date is crucial for the continuation of the study. If the study is allowed to expire, all data collection must cease and no funds may be spent. Any lapses in approval for the use of human subjects must be defended to the IRB and to regulatory or funding agencies. A new application and review will be required to reinstate the study if it expires.

If the investigator does not respond to the final notice, the IRB will classify the study as "inactive."

The IRB is required to report all federally funded studies inactivated due to lack of response to requests for continuing review to the Office for Human Research Projects (OHRP). All IRB inactivated studies using investigational drugs or devices will also be reported to the Food and Drug Administration (FDA).

If the study is completed, a researcher must complete a shorter close-out version of the continuing review form as a "final report" on the project.

What to report

Continuing review requires that you complete the Continuing Review Form, attach a current consent form. The Continuing Review Form requires the following information:

the number of subjects enrolled since the last review and the total number of subjects enrolled to date;
breakdowns of the subject population by gender and other demographics;
a summary of the results of the research to date, including:

any unanticipated risks or adverse outcomes, and
any early indication that one of the treatments under study is significantly better or worse than others;

any difficulties recruiting or retaining subjects, an explanation of the difficulties, and the number of subjects who withdrew from the study;
changes in the last year that were approved and the dates they were approved;
if currently recruiting subjects, a copy of the consent form currently in use (as most recently approved by the IRB); and
documentation of FDA approval for investigational drugs, biologics, or devices used in the research that have received FDA approval since the last IRB review.
change in relationship with the study sponsor might require conflict of interest disclosure under the Board of Regents' policy on Conflict of Interest

Incomplete forms will be returned, which may cause a delay in getting the study on the appropriate committee agenda.

Level of review

A project usually merits the same level of review in continuing review as it received originally expedited or full committee review.

6.2 Making changes in research protocols

Once the IRB has approved a project, it must be carried out as planned. Any changes in subject population, recruitment plans, research procedures, study instruments, study sites, or major research personnel must be prospectively approved by the IRB. Enacted changes without prior approval consititute protocol violations.

Researchers planning a change should:

write to the IRB office citing the title and code number of the approved study;
describe the proposed change in lay language;
explain why the change is needed (if the change is proposed by the sponsor or a national group, provide the sponsor's formal notice of a changed or revised protocol);
describe the implications for the subjects; and
provide revised consent documents, if the change will affect the human subjects.

Absent & exiting principal investigators

If a principal investigator is on sabbatical leave from the University, an interim PI must be appointed. The IRB should be informed of this person's qualifications and the new PI should write to the IRB accepting the responsibility for the treatment of subjects. If a researcher leaves the University permanently, the IRB should be notified both of any interim investigators and of the final replacement or the study will be filed as "inactive".

How changes are reviewed

Some minor changes are handled by administrative action. Many changes receive expedited IRB review. Changes that affect the risk/benefit ratio may require full review. Implementation of the change must wait for the IRB's approval.

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6.3 New findings

Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO)

Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure that investigators promptly report “any unanticipated problems involving risk to subjects or others” (UPIRTSO). The IRB defines UPIRTSO as any problem or event which in the opinion of the local investigator was unanticipated, reflects new or increased risk to the subjects and was possibly related to the research procedures. The IRB makes the determination of whether the unanticipated problem meets the criteria as a UPIRTSO.

What to Report

The following events meet the IRB’s definition of UPIRTSO and should be reported within the 10 day time frame:

Any event (including on-site and off-site adverse events, injuries, side effects, deaths or other problems) which in the opinion of the local investigator was unanticipated, involved new or increased risk to subjects or others, and was possibly related to the research procedures
Any accidental or unintentional change to the IRB-approved protocol that increases risk or has the potential to recur
Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research subject
Any publication in the literature, safety monitoring report (including Data and Safety Monitoring Reports), interim result or other finding that indicates an unexpected change to the risk/benefit ratio of the research
Any breach in confidentiality that may involve risk to the subject or others
Any complaint of a subject that cannot be resolved by the research staff
Any other possibly related event which in the opinion of the investigator constitutes an unanticipated risk

Note that issues such as whether the event was on-site or off-site or whether the event involved a death are no longer of primary relevance in determining what should be reported. If the event meets all 3 criteria in the IRB’s definition of UPIRTSO, it should be reported using the reporting form within the 10-day time frame.

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Definitions

Unanticipated (unexpected) problems/events are those that are not already described as potential risks in the consent form, not listed in the Investigator’s Brochure or not part of an underlying disease.

Anticipated (expected) problems are those that are already described as potential risks in the consent form, listed in the Investigator’s Brochure or part of an underlying disease. These do NOT meet the IRB’s definition of UPIRTSO and should be reported in summary form only at the time of IRB continuing review. For example, if death is an expected outcome, this event should be reported only at the time of continuing review.

Problems/events that are unanticipated should be reported to the IRB within 10 working days only if in the opinion of the local investigator they are possibly, probably or definitely related to the research procedures. Unanticipated problems/events that the local investigator deems unlikely or not related do NOT meet the IRB’s definition of UPIRTSO.

Follow-up reports on previous events should be reported as UPIRTSOs if the initial event itself met the IRB’s definition of UPIRTSO AND in the local investigator’s judgment, this follow-up report adds value to the initial report.
Reports of off-site events on studies that are now closed at this site should be reported as UPIRTSOs if the event meets the IRB’s definition of UPIRTSO AND in the local investigator’s judgment, this event may affect risk to subjects who have completed the study.
For reports involving blinded study drug, the assessment of relatedness will often be “at least possibly related” as relatedness cannot always be ruled out. If there are numerous reports on the same blinded drug and these reports all meet the 3 criteria for UPIRTSO, they may be reported on one UPIRTSO form with an accompanying table/spreadsheet. A narrative regarding whether risk is altered or subjects should be notified may be provided for each group of similar events.

Additional Guidance

Reviwing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events dated January 15, 2007 can be found at the Office for Human Research Protections (OHRP) Website.

IRB Review of UPIRTSOs

Once received in the IRB office, completed UPIRTSO reporting forms will be pre-reviewed by IRB staff to determine the level of IRB review required.

Non-UPIRTSO Problems or Events

All problems/events that do NOT meet the IRB’s definition of UPIRTSO should be reported to the IRB in summary form (using a table or spreadsheet) at the time of continuing review. Accompanying documentation (sponsor report forms, etc.) should NOT be included with this summary. If received, such accompanying documentation will be returned to the investigator.

New Risk/Benefit Findings

As a study progresses and the risks and benefits of participating in the study are better understood, researchers sometimes find that the study must be stopped. For example, in some placebo-controlled trials, preliminary findings may give compelling evidence that a new treatment is efficacious. It then becomes unethical to continue giving placebos. (This occurs most frequently in multicenter trials in which a central statistical center receives and processes large volumes of data from several sites.)

In such cases, the investigator should write to the IRB, describe the findings and the need to suspend the placebo portion of the study. If the IRB agrees, the researcher should identify all subjects who received a placebo and invite those subjects to continue in an "open label" study in which all subjects receive the study medication.

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6.4 Keeping Records

Researchers should maintain a file of all documents concerning the use of human subjects in research for 3 years from completion of IRB related work and 6 years for HIPAA, including original paperwork whenever possible, and a copy of everything else. The principal investigator's records should be a mirror image of the IRB's records: where the IRB holds an original, the principal investigator should hold a copy, and vice versa.

The documents that researchers should have on file include:

a copy of the original application submitted to the IRB, including the consent form and the research protocol;
the original of the IRB's response;
a copy of responses to IRB stipulations or requests for additional information;
the original notice of final approval;
a copy of the "Certification of Approval" sent by the IRB to any funding agencies;
copies or originals of all other correspondence with the IRB;
copies of completed "Continuing Review" forms and attachments;
the original notice of renewal of approval and certification, where applicable; and
copies of any inspection or audit reports.

Original signed consent forms should be kept in a secure location separate from correspondence with the IRB but readily available to inspectors. Whenever a subject is a patient of the Fairview Health Services, a copy of the signed form should be placed in the patient's medical chart as a precautionary measure, in case complications with the research protocol occur and emergency medical treatment is required.

IRB records are subject to inspection by federal authorities. Sanctions for incomplete or nonexistent records include suspension of funding, fines, exclusion from future funding, and suspension of laboratory access.

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