IRB Manual: After Approval
All Expedited and Full Board studies must be reviewed at least annually by the IRB. Investigators are also required to close the project out with the IRB when the study ends. Exempt studies are exempt from these requirements, although as noted in a previous chapter, approval is required before modifications are made for all studies, including Exempt projects.
The purpose of continuing review is to determine whether the risk/benefit ratio previously assessed has changed, to ensure that the measures taken to safeguard participants are adequate, that the approved IRB application/protocol is being followed, and that the project reflects any changes that have been made in the regulations for human subjects research since the last approval. In the event of Project Closure, the form provides a final report of how the study progressed and whether or not any problems arose.
Continuing Review of Ongoing Research
Continuing reviews are performed by the IRB Chair or one or more experienced reviewers designated by the IRB chairperson from among the IRB members (45 CFR 46.110(b)). The IRB chairperson or IRB members designated by the chairperson can approve or require modification in (to secure approval of) research, but may not disapprove research using the expedited procedures (45 CFR 46.110(b)). Disapproval of continuing research can only occur after review by the IRB at a convened meeting. All IRB members must be advised of research that has been approved under an expedited review procedure (45 CFR 46.100(c)).
Form and Attachments
The form for requesting continuing review and for closing out a project is the same, posted on the IRB forms page. The Continuing Review/Closure form and any required attachments must be submitted prior to the expiration date designated at last review. A current copy of all assent and consent forms must be attached for all Active studies (except those in data analysis only), even if no changes have been made. For project closure, the form may be submitted at any point prior to expiration. For continuing reviews, the form should not be submitted more than 60 days in advance of the expiration date.
The researcher must check the appropriate box on the form that reflects the current status of the study. Studies cannot be closed if any activity, including data analysis, is still underway or planned. If all data collection is complete, but the researcher is still analyzing data, the box “Active-Post-Enrollment” should be selected. A study may become exempt from future continuing review if all data is de-identified.
Federal regulations require that the IRB conduct ongoing reviews of all non-Exempt protocols at intervals appropriate to the degree of risk, but not less than once per year. The interval is set for each protocol. Most protocols at UNI are approved for one year minus one day, although the approval period may be less if the IRB deems more frequent reviews necessary. Modifications that may have occurred during the year do not change or advance the approval period. The phrase “not less than once per year” means that the research must be reviewed within one year of the date of the Expedited approval date or in the case of Full Board studies, the date of the IRB meeting at which the research was approved (with or without conditions) even though the research activities may not begin until after the IRB has given final approval. Factors to be considered by the IRB in determining the appropriate interval for periodic review include the following:
- involvement of vulnerable populations;
- research conducted internationally;
- the involvement of recombinant DNA or other types of gene transfer protocols;
- any waivers of informed consent procedures;
- research for which participants would be exposed to additional serious risks, such as breach of confidentiality;
- previous suspension of the research due to compliance, record-keeping, or other concerns; and
- studies that pose a very high level of risk to individual participants or some risk to a large number of participants;
In addition, at its discretion the IRB may require review more frequently than annually for studies conducted by investigators that have not been compliance with IRB requirements in the past or studies being conducted by new investigators.
The frequency of continuing review may be changed at any point in the future. Examples of reasons for a change in the length of the approval period may include the following: (a) a large number of participant withdrawals, (b) participant complaints, (c) new information that indicates a change in the participant risk/benefit ratio, (d) unanticipated adverse events/complications that would affect the risk/benefit ratio, (e) a change in primary investigators, and (f) notification of changes in the consent process, research plans, the procedures, or the data collection methods. This list should not be considered exhaustive. However, should a more frequent review be required, the researcher will be provided with a statement of the reasons for the change.
Approval Dates and Communications
The approval and expiration dates for the study will be printed in a formal letter of approval sent to the investigator. Investigators will be informed if a continuing review is required and that s/he is responsible for submitting a Continuing Review form in sufficient time for review to occur prior to the study’s expiration date. For expedited studies, Continuing Review forms should be submitted 2 weeks prior to the expiration date. For full board studies, continuing review requests should be in to the IRB office at least 45-60 days prior to expiration, or otherwise in sufficient time to be distributed prior to the next scheduled Board meeting.
Reminders. Approximately 45-60 days prior to the expiration date for all open non-exempt studies, a Continuing Review/Closure form will be emailed to investigators as a reminder that the study is about to expire. If no email is available for the investigator (typically a student who has left campus), the form is emailed only to the Advisor. If a faculty investigator has left campus, the IRB office attempts to locate a forwarding email or mail address for the faculty member. If there is no response to the initial email and form, a second reminder email is sent to the same individual(s), noting that study expiration is pending and that the study file will be closed upon expiration. If still no response occurs, the file is closed with a notation that the investigator was non-responsive to the IRB renewal/closure requirements. If the study was approved by the full board, a third and final email is sent, notifying the investigator that the study has in fact expired and reminding him or her once again that no further research is permissible without a new review.
It is the investigator’s responsibility to ensure that his or her research is submitted for review in time for continuing approval. If the continuing review form is not received by the IRB office at least by the study expiration date, the study approval automatically expires and new application for review will be required in order to continue the study.
In the event that the study is not approved either through continuing review or via a new review process by the study’s expiration date, all research activities must stop at that point until approval is again obtained. The only exception to this is if stopping the research would cause harm to participants (e.g., by removing them from a clinical trial), in which case the IRB needs to be notified of this immediately.
Review Process for Active Projects
For most projects that need ongoing approval, the reviewer will receive a copy of the past protocol and modifications from the study file, as well as the current Continuing Review/Closure form and materials. (For active projects in which no participants have been enrolled, or participant enrollment has been completed, reviewers may simply choose to review the Continuing form and materials without examining the overall file.) During the review, the reviewer may email any questions or concerns to the investigator. If it is an expedited study, the reviewer may simply approve the study for continuation by sending an email to the investigator, which will be followed by a more formal letter of approval from the IRB office. If the study required full board review, one member of the IRB will receive all past materials and all IRB members will receive all current materials plus a summary of the protocol provided by the member facilitating the review. The investigator(s) (and advisors if applicable) are invited but not required to attend the meeting as well. Full board continuing reviews are in other ways similar to initial reviews, in that materials are reviewed, any concerns raised, and a vote taken on the protocol.
Continuing Approval Category
Most studies will be approved at the continuing review point in the same regulatory category under which they were originally approved. However, there are exceptions to this when the circumstances, including risks/benefits for participants, have changed. For example, a study originally approved as Expedited may be reviewed by the full board at the continuing review point if new components have been added such that Expedited review is no longer allowed, or simply because the lead reviewer wishes to consult with the other members of the Board.
As another example, studies that were originally reviewed by the full board may be subsequently reviewed under Expedited procedures (i.e., by one reviewer) under the following conditions: a) no participants have yet been enrolled; b) the study is inactive; c) the study is completed; or d) participant enrollment is closed and the study is in data analysis only. The results of expedited reviews for original full board studies are reported to the committee members on the IRB monthly status sheets.
Studies that are in the Active-Post-Enrollment phase may be approved as Exempt at the continuing review point if the study now meets the criteria for Exempt studies, including that all identifiers and/or links to identifiers have been removed from the dataset.
Submitting the Continuing Review/Closure form prior to the expiration date is not optional. As noted above, investigators are required to return the form even if the study is completed and renewal is not needed. The form serves both purposes.
Investigators may return the Continuing Review/Closure form at whatever point the project is complete, rather than waiting until the end of the approval period to close the study. Student researchers and all others completing projects in the middle of the approval period are encouraged to do this to avoid having to subsequently receive reminder materials after the end of the study. Students are often difficult to contact at the expiration point since they may have left campus by that time, in which case Advisors are expected to complete materials on their behalf and will receive multiple requests to do so. Upon receipt by the IRB, the form will be forwarded to an IRB committee member for review, who will either share any questions or concerns s/he may have about the study with the investigator, or will approve closure of the study and the file will be closed by the IRB office without further communication with the investigator.
Policy Regarding Study Modifications
When changes are needed in a previously approved protocol, the investigator is responsible for requesting and receiving IRB approval for the changes before the changes are implemented. However, when changes are made to eliminate an immediate hazard or serious potential risk to participants, review of those changes may be requested after it occurs, provided the request is made within 10 days of occurrence. If non-emergency changes are introduced without advance approval, the investigator will be considered to be out of compliance with IRB regulations. This policy applies to all projects, regardless of funding source, and including those originally determined to be Exempt from ongoing review.
Which Modifications Need Review
Changes or additions that require review and approval by the IRB are those that may affect the assessment of risks and benefits for participants from the research, including the potential legal, social, economic, health, and privacy risks.
Examples of modifications that need review include:
- any revisions to consent materials beyond minor editorial or grammatical changes;
- adding a new measure or instrument, or changing current measures or instruments
- adding or changing the sample(s) of participants;
- adding or changing the review of academic or medical records;
- involvement with participants again for follow-up research that was not originally included in the protocol;
- adding a site for recruitment or data collection;
- changing key personnel on the study (individuals involved in decision-making, recruitment, or data collection);
- changing the procedures for how participants are invited/recruited into the study;
- changing the data collection procedures.
Examples of modifications that do NOT require review are:
- dropping a measure or instrument (unless it is used to screen or monitor the welfare of study participants);
- making minor editorial or grammatical revisions to approved documents that are unrelated to the sensitivity of the questions or the privacy of the participants;
- removing a research site from the study;
- changing the strategy or procedures for data analysis.
If in doubt whether or not a proposed change requires review, the investigator should simply send in an email describing the change to the IRB Administrator.
- Modifications are typically reviewed fairly quickly without the use of a special form. The investigator should simply send an email to the IRB Administrator describing the proposed changes and attach any consent forms or other participant materials that must be changed as well. The communication should include a reference to the original IRB protocol number. The request will be forwarded to an IRB Chair or other reviewer for expedited review, unless the study is being monitored by the full board, in which case the request will be reviewed at the next regularly scheduled meeting of the IRB. In either case, the investigator will receive an email from the primary reviewer noting questions or concerns about the modification, or approving the changes as requested and allowing the study to continue with the modification. A formal letter of approval is not issued for modifications. Documentation of all modifications is entered into the IRB database and the study file.
- Certain modifications may be authorized immediately by the IRB office staff, without being reviewed by a designated IRB member. These include: a) adding a site, when the study was approved to include multiple sites; and b) adding or changing key personnel. If multiple sites for a study are planned, at least one site must provide a letter of cooperation before the study can be approved by the IRB. Subsequent letters of cooperation should be forwarded to the IRB Administrator, preferably with the protocol number and/or investigator name noted on the letter. (See Chapter 8 regarding requirements for letters or emails documenting cooperation.) When each letter is received, the IRB Administrator will send an email confirming receipt of the letter and authorizing recruitment and data collection to commence at that site. If the study was originally approved for only one site, and the investigator now proposes to add or change sites, the request will be forwarded for formal review by a designated IRB member.
- If the study was originally reviewed by the full board, modifications may also require full board review. If the changes proposed are minor (e.g. changes to student personnel, minor revisions to participant materials, addition of study sties), regulations allow these to be approved under an expedited process.
Requirements for Reporting
All problems or adverse events that occur during the course of an approved research project must be reported to the IRB. According to federal regulations, problems or potential adverse reactions that were anticipated by the researcher at the time of approval must be reported at periodic review or closure. Problems or adverse events related to the research that were not anticipated must be reported promptly after being discovered by the investigator, either within 7 or 14 days, depending on the seriousness of the event, as outlined below. Unfortunately, these regulations are somewhat complex, so a good rule of thumb is if anything unexpected occurs during your project, such as data being lost or stolen, a participant becoming upset, or a research procedure not being carried out as approved, simply send an email to the IRB Administrator and report it.
Anticipated (expected) problems are those that involve potential risks previously described to the IRB, and to participants in the consent form and other participant materials. Anticipated problems should be reported in summary form at the time of IRB continuing review or project closure, whichever comes first. For example, emotional distress is a possible outcome of the research anticipated at the outset, this event should be reported at the time of the next review.
Unanticipated problems are those that have not previously been noted as potential risks of the research to the IRB and the participants, and which suggest that the research places participants or others at a greater risk of harm (physical, psychological, social, or economic) than was previously known or recognized. When unanticipated problems occur, the investigator should assess whether or not the incident, experience, or outcome is related to the research. If not, the problem should be reported in summary form at the time of continuing review. If, in the opinion of the investigator, the problem or event is possibly, probably or definitely related to the research procedures, it must be reported to the IRB within 14 days of when the investigator learns of it.
Adverse Events are defined as any untoward or unfavorable medical occurrences in one or more human participants, including any abnormal sign, symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research. Adverse events include both physical and psychological harm, but not social, economic, or other kinds of harm. Instances of serious harm (death, disability, or hospitalization) that are unexpected are referred to as Serious Adverse Events.
In summary, Unanticipated Problems are unexpected, related to the research, and involve risk. Those that involve physical and psychological harm are called Adverse Events. (Only Adverse Events that were unexpected are considered Unanticipated Problems.) Thus, the following guidelines must be followed for reporting Unanticipated Problems and/or Adverse Events:
- Adverse Events (involving psychological or physical harm) that were not expected must be reported to the IRB within 7 days of the investigator learning of it, whether or not they are related to the research.
- Other Unanticipated Problems (involving social, economic or other harm) that were not expected must be reported to the IRB within 14 days of the investigator learning of it, if they are related to the research. If they are not related, these can wait until the continuing review or closure point.
- Serious Adverse Events, which involve death, hospitalization, and disability, that were not expected must be reported within 7 days to the IRB, whether related to the research or not.
- Any problems or events that were anticipated should be reported at continuing review or closure.
For example, the following events are considered Unanticipated Problems which must be reported within the 7 day time frame, using the Problem-Event Reporting form:
- Any event, which in the opinion of the local investigator, was unanticipated, involved risk to participants or others, and may have been related to the research procedures;
- Any accidental or unintentional change to the IRB-approved protocol that involves 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, 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 indicates an unanticipated risk or that cannot be resolved by the research staff; or
- Any other possibly related event which in the opinion of the investigator constitutes an unanticipated risk of physical or psychological harm.
When an investigator has an Unanticipated Problem or Adverse Event to report, he or she must complete the Problem-Event Reporting Form, sign it, and mail or drop it off at the IRB office. The IRB Administrator will review it and forward it to the IRB Chairperson. If the Chair determines it warrants full board consideration, it will be presented to the committee at its next regularly scheduled meeting, unless an immediate meeting is called for. The Chair and/or the Board will determine what, if any, action should be taken in response to the problem or event.
Examples of corrective actions or substantive changes that might need to be considered in response to an unanticipated problem or adverse event include:
- review/approval of changes to the research protocol that were initiated by the investigator prior to obtaining IRB approval to eliminate apparent immediate hazards to participants;
- modification of inclusion or exclusion criteria to mitigate the newly identified risks;
- implementation of additional procedures for monitoring participants;
- suspension of enrollment of new participants;
- suspension of research procedures in currently enrolled participants;
- modification of informed consent documents to include a description of newly recognized risks; and
- provision of additional information about newly recognized risks to previously enrolled participants.
The IRB is required by Federal Regulations to report incidents to the Office of Human Research Protections (OHRP) when one of the following occurs: a) Unanticipated Problem (unexpected, related to research, and involving risk); b) Serious or continuing noncompliance by an investigator; or c) Suspension or termination of a protocol. Unanticipated Problems must be reported “promptly”, which is to be defined by the institution according to the nature and severity of the problem, but reports to OHRP are encouraged within 4 weeks of the IRB receiving the information. All UNI projects are covered by these requirements, regardless of funding source. Upon receipt, the OHRP will assess the adequacy and timeliness of the institution’s response to the problem. When a report is sent to the OHRP, a copy will also be sent to the investigator, and possibly his/her department head, the dean of the college, and the Provost.
Example of an Unanticipated Problem that is not an Adverse Event. Investigator must report promptly and IRB must report it to the OHRP.
An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students. The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work. This is an unanticipated problem that must be reported because the incident was (a) unexpected (i.e., the investigators did not anticipate the theft); (b) related to participation in the research; and (c) placed the participants at a greater risk of psychological and social harm from the breach in confidentiality of the study data than was previously known or recognized.
An investigator is conducting a psychology study evaluating the factors that affect reaction times in response to auditory stimuli. In order to perform the reaction time measurements, participants are placed in a small, windowless soundproof booth and asked to wear headphones. The IRB-approved protocol and informed consent document describe claustrophobic reactions as one of the risks of the research. The 20th subject enrolled in the research experiences significant claustrophobia, resulting in the participant withdrawing from the research. This example is not an unanticipated problem because the occurrence of the claustrophobic reactions in terms of nature, severity, and frequency was expected.
An investigator performs prospective medical chart reviews to collect medical data on premature infants in a neonatal intensive care unit (NICU) for a research registry. An infant, about whom the investigator is collecting medical data for the registry, dies as the result of an infection that commonly occurs in the NICU setting. This example is not an unanticipated problem because the death of the subject is not related to participation in the research, but is most likely related to the infant’s underlying medical condition.
Example of Adverse Event that is an Unanticipated Problem. Investigator must report it promptly to the IRB and the IRB must report it to OHRP.
A behavioral researcher conducts a study in college students that involves completion of a detailed survey asking questions about early childhood experiences. The research was judged to involve no more than minimal risk and was approved by the IRB chairperson under an expedited review procedure. During the completion of the survey, one participant has a transient psychological reaction manifested by intense sadness and depressed mood that resolved without intervention after a few hours. The protocol and informed consent document for the research did not describe any risk of such negative psychological reactions. Upon further evaluation, the investigator determines that the participant’s negative psychological reaction resulted from certain survey questions that triggered memories of physical abuse as a child. The investigator had not expected that such reactions would be triggered by the survey questions. This is an example of an unanticipated problem that must be reported in the context of social and behavioral research because, although not serious, the adverse event was (a) unexpected; (b) related to participation in the research; and (c) suggested that the research places participants at a greater risk of psychological harm than was previously known or recognized.
Office of Human Research Protections (OHRP), Department of Health and Human Services. “Guidance on Reviewing and Reporting Unanticipated Problems involving Risks to Subjects or Others and Adverse Events.” January 15, 2007.