Submissions to the IRB After Initial ApprovalApril 2021 Issue(Note: this article is an update of an article with the same name published in April 2015)Author(s):
IntroductionIIRB oversight is an ongoing process. There are six broad categories of submissions to the IRB that occur after initial approval of the project:
The first category, Continuing Review, is required at Boston Medical Center and BU Medical Campus (BUMC) at least every 3 years for ALL non-exempt Human Subjects research. (Projects determined to be Exempt are not required to have continuing review – see CR TIMES, March 2019). The second category, Amendments, is required prior to ANY change to the non-exempt IRB-approved protocol, consent form, or other study materials. The third category, Reportable Events or New Information, is a broad category that includes Unanticipated Problems, Protocol Deviations, and safety monitor reports with recommended changes. The fourth category, Contact Change Information, is a pathway for only making changes to the contact information in approved consent forms and other subject materials. The fifth category, Recruitment Materials Submission, is a form used to submit new or modified recruitment documents with the approval document from the appropriate Communications Office. The sixth category, Closure Reports, is required when human subjects research activities have been completed and the protocol is ready to be closed. Each of these six will be discussed separately.
Continuing ReviewWhen the Revised Common Rule went into effect, the requirements for continuing review changed. OHRP regulations now require at least annual continuing review for research that requires review by the convened IRB Board. For research eligible for expedited review, or research reviewed in accordance with “limited IRB review” (such as certain exempt categories), no continuing review is required. However, our Human Research Protection Program (HRPP) Policies mandate that researchers submit a “Status Check-In” for all human subjects research studies no later than 3 years after initial approval is granted. FDA regulations, on the other hand, require ongoing review of all non-exempt Human Subjects research. The frequency of this review must be at least annually. The principal purpose of continuing review and status check-in is to reaffirm that the study remains ethical and appropriate; and is done by submitting a “Continuing Review Submission Form” in INSPIR. The initial review application is based upon the investigator’s best assessment about anticipated results, risks, and benefits. The IRB uses its expertise to determine if this assessment is reasonable and supportable. It is only after the research has begun that the real risks can be evaluated and the preliminary results can be used to refine the risk/benefit ratio, and allow the IRB to determine if its original determination was correct. There are factors that the IRB considers when making the determination whether the study should be re-approved: new information either from within the study (e.g., from DSMB reports, deviations, unanticipated problems or subject complaints); or new developments in the particular field provided by a reassessment of the literature. The progress the investigator has made towards recruiting and retaining study subjects is an important part of the assessment done by the IRB at the time of continuing review. This is often an area of concern by the IRB. The purpose of research is the development of new knowledge; and if a study is failing to enroll subjects and is in danger of never achieving this goal, then it may be unethical to continue – particularly if the study involves any significant risk. An investigator whose study is failing to meet recruitment goals is obligated to address this issue at the time of continuing review. The IRB will soon be adding a new question to the Continuing Review form that will proactively ask studies that have not enrolled anyone in the last year to explain why no one has been enrolled, and to provide a plan for increasing enrollment. If this is not adequately addressed in the Continuing Review submission, then the IRB can require this to be provided prior to approval for the study to continue; or alternatively, the IRB can decline to approve the continuation.
AmendmentsAny change to a non-exempt study -- including changes to procedures, eligibility criteria, study personnel, funding, and consent forms -- requires approval from the IRB prior to implementing the change, by submitting a “Change Request & Amendments Form” in INSPIR. There is one exception to the requirement for prior IRB approval: when a change to the research has been implemented in order to eliminate an apparent immediate hazard to the subject. Such changes can be implemented immediately, but require reporting to the IRB within 7 days of the event. To do this, you should use a Reportable Event and New Information Form to report this in the same way as a Major Deviation, and indicate that this was done to eliminate an immediate hazard. If the changes proposed to the protocol are extensive, then you should prepare and attach a summary of the changes that are proposed and a rationale for the change, in addition to updating the INSPIR application where needed and attaching the revised sponsor’s protocol when appropriate. If the consent form has been changed as a result of the modification to the protocol, then upload a clean (not redlined) version of the consent form. If the consent form has been changed, you will also be asked to address whether subjects need to be re-consented, and why or why not. If re-consent is required, you will need to explain your process and timeline for re-consenting current subjects. Changes to study personnel are done by submitting an “Internal Study Personnel Changes Form” in INSPIR. Any new BMC/BUMC study personnel must have current human subject research training and have a completed profile within the INSPIR system. If the study meets the definition of a clinical trial, then study personnel must also have current Good Clinical Practice (GCP) training. The approval of personnel changes is done by an administrative process (not a Board action) once the requirements for training and a completed profile are confirmed. Changes to the Principal Investigator are also done by submitting an Internal Study Personnel Change form. The new individual must be eligible to serve as a Principal Investigator, must have the necessary licenses and privileges, and must sign and attach the Responsibilities of the Principal Investigator document. The existing Principal Investigator must submit an Internal Study Personnel Changes form and, if any interactions with subjects are continuing, must also submit a revised consent form listing the new Principal Investigator and any other applicable revised documents seen by subjects. Unlike changes to other study personnel, requests to change the Principal Investigator are reviewed through the expedited procedure. Occasionally, there are situations where you want to allow a one-time change to the approved protocol: for example, to enroll a subject that does not quite fit the approved inclusion/exclusion criteria. You do not wish to modify the protocol for this one subject, but (with the approval of the sponsor) you wish to enroll this subject. The way to correctly do this is to submit a “Protocol Exception Form” to seek prior IRB approval to do this. The IRB staff understands that such a request is often very time-sensitive; and because the form has a different name, the staff is able to quickly identify it and route it to the appropriate IRB chair for review.
Reportable Events or New InformationThere are three major categories of events that require reporting to the IRB: Protocol Deviations, Unanticipated Problems, and Safety Monitor Reports with recommended changes. These are discussed in detail below.
Protocol DeviationsDeviations represent incidents, circumstances or processes that occur during the research that are not part of or are inconsistent with the approved IRB study plan, HRPP policies and procedures, or Federal regulations. Any failure to follow the IRB-approved protocol is a deviation. Deviations are divided into two categories: Major and Minor. Major deviations are deviations that may (1) harm the participant’s rights, safety or well-being, (2) significantly damage the overall reliability of the study data, or (3) represent noncompliance with IRB requirements that may be serious or continuing. Major deviations must be reported to the IRB within 7 days of the investigator or research staff becoming aware of the event using the Reportable Event and New Information (RENI) form. Minor deviations are any unapproved changes in the research study design and/or procedures that do not have a major impact on the participant’s rights, safety or well-being, or on the reliability of the overall study data. Minor deviations must be reported in aggregate to the IRB at the time of continuing review or of status check-in. As part of the continuing review or status check-in, the IRB reviews the summary of minor deviations to assess whether, taken together, they indicate a risk of harm to subjects or others, or if they indicate the possibility of continuing noncompliance.
Unanticipated ProblemsDuring the conduct of a study, unexpected events may occur that have an impact either on the rights and welfare of subjects, or on the integrity of the study data. If such an event occurs and it is related to the subjects’ participation in the research, then the IRB must be promptly informed of this event since it represents information that was not available to the IRB at the time of its most recent review of the research. In order to accomplish its goal of protecting research participants, the IRB must be informed of this new information to reassess the study in light of this new information. An event that is (1) unexpected, (2) is related or possibly related to their participation in the research, AND (3) suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized, almost always requires some change in the study. These events are reported in INSPIR using the RENI form and must be submitted to the IRB within 2 days of the investigator or research staff becoming aware of the event if the Unanticipated Problem is associated with a fatal or life-threatening incident, or within 7 days of submission to the IRB otherwise. Major deviations may represent unanticipated problems; for example, it may have resulted in harm to a subject who had a condition that for safety reasons was an exclusion criterion. However, unlike Unanticipated Problems, this does not require a change to the protocol, but rather a change to the conduct of the study: for example, instituting a checklist of inclusion and exclusion criteria.
Safety Monitor Reports with Recommended ChangesResearchers must notify the IRB through the RENI form when they receive a report from a safety monitoring body, such as an independent Data and Safety Monitoring Board, that contains recommended changes in the protocol, consent form, or other aspect of the research. Reporting as a RENI is required in addition to the submission of the amendment that will request the corresponding changes so that the IRB can review the recommended changes in a timely manner, in case any immediate action is needed to minimize hazards to subjects. This report is due no later than 7 days after the investigator or research staff member receives the report from the safety monitoring body.
Contact Change InformationRequests to change the contact information in one or more approved consent forms or other approved subject materials are made using the “Contact Information Change Request Form”, unless the change is required because of a change in the Principal Investigator (as the change in Principal Investigator request is made using an Internal Study Personnel Change form, described above in the Amendment section). This form was implemented as a simpler way for investigators to change contact information in approved consent forms and other subject materials, without needing to include as part of an amendment that involves many other types of more complex modification requests. The request is made with a separate form, and goes through an administrative review process, rather than approval by the IRB, with the intent of saving time and effort for researchers and the IRB. The submission information must include the revised documents in an editable format, a description of the proposed changes, and an indication of the choice for notifying already-enrolled subjects of the new contact information (in addition to general plans such as call forwarding or providing the new phone number in a voicemail message for the old phone number):
In general, the IRB does not think it is necessary to notify subjects who are not expected to have any further study visits, phone calls, or mailings, because such subjects will usually not have a reason to contact the study team. Occasionally, a subject may want to try to get information long after their active participation has ceased. The main IRB number, 617-358-5372, which is on every consent form will always be kept active so that such subjects will be able to contact the IRB even if the study team numbers on their consent forms are no longer correct.
Recruitment Material SubmissionSimilar to the Contact Change Information form, the IRB implemented a new type of form in INSPIR called the “Recruitment Materials Submission Form”. This form is used solely to submit these type of materials so that they can be reviewed more quickly without the need to review other changes made as part of an amendment. Importantly, in order for the IRB to approve the recruitment materials using this form, the recruitment *method* must already be approved by the IRB as part of the existing study protocol or application. For example, the IRB cannot approve a new study flyer as part of this form if you have never detailed your plans to use study flyers. If you need to request approval for a new recruitment method, you will need to submit an Amendment as detailed above. The submission information for this form must include the materials that have been approved by the Boston University School of Medicine Communications, the Goldman School of Dental Medicine Communications Office, Boston University School of Public Health Communications, or the Boston Medical Center Communications and Marketing Department; and the approval document from the communications office that reviewed and approved these materials. The process for obtaining approval from the appropriate Communications group is detailed here.
Final ReportYou are required by our policy to file a Final Report once you have completed all activities that constitute “human subjects research” as discussed in the CR TIMES, June 2014. There is some confusion as to when you can close a study. Briefly, once you are no longer collecting data on subjects and have completed any analysis that requires use of personally-identifiable data, then you can close your study by submitting a “Final/Closure Report Form” in INSPIR. For more details on study closures, see the CR TIMES, September 2014. Final Reports are required for non-exempt research, exempt research, and studies that have been ceded to an external IRB. The submission information for closure of non-exempt research must include: enrollment; demographics; auditing or monitoring results; adverse events, deviations, and subject complaints; closure processes (including plans for destroying or anonymizing study data and whether data or specimens will be moved into a repository); study status (never started or closed); and new risks. The submission information for closure of exempt or ceded research must simply include that research activities are no longer occurring.
SummaryAs you can see, IRB oversight of active human subjects research is an ongoing process. The IRB is committed to working with you on making sure that research conducted once IRB approval is obtained is done so in an ethical and compliant way. |