Section 7: Continuing a Research Project

7.0 The Continuing Review Procedure
7.1 Greater Than Annual Continuing Review
7.2 Amendments to Protocols
7.3 Identification and Reporting of Unanticipated Problems
7.4 Quality Improvement & Monitoring
7.4.1 Procedures for Quality Improvement & Monitoring
7.5 Policy & Procedures for Data Safety Monitoring Plans (DSMP)

7.0 THE CONTINUING REVIEW PROCEDURE

Any research activity (including exempt, expedited, and full board) involving the use of human subjects that has received initial review and approval by an IRB is subject to continuing review and approval. Time intervals for such reviews shall be made at the discretion of the IRB but shall occur no less than annually (see 7.1).
                Continuing reviews should be submitted on IRBaccess.  Investigators should submit a continuing review when: research is ongoing, the remaining research activities are limited to data collection, the research remains active for long-term follow-up of participants despite the protocol being permanently closed to the enrollment of new participants and all participants having completed all research related interventions, or for the analysis of identifiable data. 
Continuing review may stop only when:

• The research is permanently closed to the enrollment of new participants;
• All participants have completed all research-related interventions; and
• Collection and analysis of private identifiable information has completed.

Full board and expedited studies require the following be submitted for continuing review: a current copy of the consent form, a current copy of the research protocol, and all other additional documents and materials, including questionnaires, payments schedules, recruitment materials, and scripts. Any revisions to the previously approved consent process, the protocol, recruitment, enrollment, or other study related activity are to be submitted as an amendment. The PI must submit via IRBaccess an amendment with updated copies of the revised consent process and form, protocol, recruitment, enrollment, or other study activity or procedure. All changes should be clearly indicated in an obvious font or highlighted. The PI must submit renewal letters from cooperating IRBs as relevant (e.g., site still operational). If the site(s) in question did not have an IRB of record and thus submitted an official letter granting permission for the investigator to conduct the research, then a second letter is not required.

PIs are required to complete the appropriate form (exempt, expedited, or full board) for continuing review applications. IRB staff provides each IRB member with: the continuing review application, the current protocol, consent forms (including newly proposed consent forms), and other submitted documents.  Each member is expected to review these materials in depth.  Each continuing review is assigned to an appropriate primary reviewer (no conflict of interests) by the IRB chair, and the reviewer completes the continuing review checklist (Appendix H). Continuing reviews ensure that current informed consent documents are accurate and complete.  Reviewers are required to ensure that the submitted informed consent documents and protocols are accurate and complete.  Reviewers will compare the continuing review materials with the prior years’ submission materials to verify accuracy and precision.  Then the IRB may vote to “Approve” for continuation, if explicit clarifications are required, “Approved with explicit conditions,” if general clarifications and issues are required, “Table,” or “Disapprove” if the IRB can no longer approve research.  When necessary the IRB may disapprove continuing reviews.  Continuing reviews for expedited studies are reviewed by ORS staff for completeness with respect to the currently approved protocol and then forwarded to the IRB chair or IRB designate, who is a voting member of the IRB, and approved. After thorough and final review, they complete the continuing review form, and grant approval.  ORS staff reviews and approves exempt continuing reviews. No research protocol may continue until final approval for continuation is granted. 

Full board studies are subject to agenda deadlines and will be reviewed accordingly.  Continuing review approval periods are one year from the day of formal re-approval, unless otherwise necessitated (see below). Only continuing reviews received and approved within 30 days prior to the expiration date will be issued a concurrent approval date.  Continuing reviews submitted prior to their expiration date but not formally reviewed and approved by the expiration date are expired and all research and research related activity must cease (see section 2.3.1) until formal IRB re-approval.  HRPP provides PIs a 30-day grace period after the expiration date to submit a continuing review.  However, during this time all research and research related activities must cease (see section 2.3.1).

The IRB has the authority to observe or appoint a third-party to observe research conduct, including consent procedures.  It may also consider whether a study requires independent verification from sources other than the PI to ensure that no material changes have occurred since the last IRB approval.  The IRB will require verification of the information provided for continuing review when:

1. continuing review materials appear inconsistent or inaccurate compared to prior applications or records and discrepancies cannot be resolved via communication with the PI, or
2. the IRB determines that such actions are useful as part of a corrective action plan for any unanticipated problem or event.

If the findings of such investigations during the continuing review process warrant corrective actions, the IRB may suspend or terminate a research project to ensure the quality of research. Continuing review materials (reviewer checklists, research determinations, and specific protocol findings) are stored in the IRB files.

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7.1 GREATER THAN ANNUAL CONTINUING REVIEW

The IRB may require certain protocols be reviewed more than annually. Any study requiring more than annual review will have a limited set approval time period. The frequency of continuing review is to be determined by the IRB appropriate to the protocol under review. The IRB will require more than annual review because of any of the following:

1. Noncompliance history
2. Marginal Risk / Benefit Ratio
3. As necessitated by protocol
4. QA&I recommendation
   

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7.2 AMENDMENTS TO PROTOCOLS

All amendments, modifications, or changes (exempt, expedited, and full board) to protocols or consent forms must be requested online using IRBaccess – the Application to Amend a Research Protocol (Appendix I) and at https://utdirect.utexas.edu/
vr/IRBAmendment.WBX and reviewed and approved, as appropriate, by the ORS/IRB under the same procedure as for initial review, prior to making any changes in study procedures. Requests must describe what modifications are desired, why the changes are required, and if the changes pose any additional risks to the subjects. PIs are required to submit complete and updated research materials and indicate all changes in a different font or highlight.

When amendments, modifications, or changes are reviewed by the convened IRB, all IRB members will be provided with a copy of all documents submitted by the investigator. Minor changes to the protocol or consent forms may be administratively approved according to 45 CFR 46.110(b)(2). The UT IRB uses the expedited review procedure to review minor changes in previously approved research. Minor changes are defined as changes that involve minimal risk procedures and/or do not increase the risk or decrease the potential benefit to subjects, do not involve one or more of the regulatory criteria, and may include Categories 1-7 (according to 45 CFR 46.110(a)). Typical changes include changes in key personnel, non-significant changes in sample size, an addition of a questionnaire that does not include sensitive or controversial questions, a change in the compensation schedule, an addition of a site, etc.

Minor amendments submitted to ORS will be forwarded to the IRB chair or Chair’s designee for review and approval. All expedited and full board amendments are reviewed using the “Amendment Reviewer Checklist” (Appendix I).  At the Chair’s discretion the amendment may be reviewed by the full convened IRB. Changes considered to be more than minor must be reviewed at a convened IRB meeting.

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7.3 IDENTIFICATION AND REPORTING OF UNANTICIPATED PROBLEMS

The IRB requires PIs to promptly report a summary of each unanticipated problem to the IRB using the IRB Unanticipated Problem Form (Appendix J) and at https://utdirect.utexas.edu/vr/IRBAdverse.WBX.

DEFINITIONS: The University defines an “unanticipated problem involving risks to participants or others” as an event that was (1) unforeseen, (2 more likely than not related to the research, (3) either caused harm to participants or others, or placed them at increased risk of harm.

An unanticipated problem may be any of the following:

1. An actual unforeseen harmful or unfavorable occurrence to participants or others that relates to the research protocol (injuries, side effects, deaths);
2. An unforeseen development that potentially increases the likelihood of harm to participants or others in the future;
3. A problem involving data collection, data storage, privacy, or confidentiality;
4. A participant complaint about IRB approved research procedures;
5. New information about a research study (e.g., a publication in the literature, interim findings, safety information released by the sponsor or regulatory agency, or safety monitoring report) that indicates a possible increase in the risks of the research;
6. Changes in approved research initiated without IRB review and approval to eliminate apparent immediate hazards to the participant;
7. Incarceration of a subject.

The process for reporting an unanticipated problem is as follows:

A. Reporting responsibilities of PI:

1. Within 5 days of knowledge of the unanticipated problem, the PI is asked to submit the Unanticipated Problem Form to the IRB office.
2. Expected adverse events (adverse events described in the risks section of the consent form) are to be reported in the annual continuing review application.

B. Reviewing and reporting responsibilities of the IRB and ORS:

1. Unanticipated problems not meeting the definition above involving risks to participants or others (foreseen, not related to the research procedures, and did not cause harm to participants or others, or place them at increased risk of harm):  The IRB Chair, ORS Director, and Program Coordinator(s) will confer to determine if the reported unanticipated problem meets the criteria of the definition: an event that was (1) unforeseen, (2) more likely than not related to the research, (3) caused harm to participants or other, or placed them at an increased risk of harm. For those unanticipated problems failing to meet the criteria, ORS will work with the PI and work towards a satisfactory and reasonable resolution for all parties. If the event is determined to be an unanticipated problem, it will be referred to the full IRB for review.  ORS will formally report back to the PI all submitted unanticipated problem reports determined to be not unanticipated problems.
2. Unanticipated problems found to meet the definition above are placed on the agenda for the next IRB review.
   1. The unanticipated problem form is distributed to all IRB members in advance of the meeting.  All IRB members will be provided with a copy of the report.  The primary reviewer will be provided with a copy of the report, the protocol with all approved modifications, and currently approved consent documents.
   2. If after reviewing the information the IRB determines that the event was not an unanticipated problem, the issue will be returned to the ORS to be handled administratively.
   3. The IRB votes to take one of the following actions:
      1. Accept the actions taken by the PI to report and resolve the incident;
      2. Notifying current participants when information about the unanticipated problem might affect their willingness to continue to take part in the research;
      3. Alter the continuing review schedule
      4. Peer review monitoring
      5. Approve with explicit changes:
      6. Notification of previous subjects;
      7. Modification of consent and/or protocol;
      8. Suspension of some or all research activities
      9. Approve the study for a shorter period of time (e.g. 6 months versus 12 months);
      10. Terminate the study for cause.
3. The IRB follows the Reporting Policy found in Section 2.0.6 for procedures taken when reporting unanticipated problems that involve risk to participants or others.
4. Deliberations and determinations of the IRB will be fully documented in the minutes.

Additional Reporting Requirements:

1. If a sponsor funds or supports the study, then the PI is responsible for notifying the sponsor.  For any studies under FDA jurisdiction, it is the PI and / or sponsor’s responsibility to notify the FDA within 24 hours.
2. Similarly, if the study is a multi-site project, and the unanticipated problem occurs at a site other than The University, then the sponsor is required to inform investigators of unanticipated problems or reactions that occur at other sites. When PIs are informed of unanticipated problem(s) in sponsor safety memos or other correspondence, then the PI must notify the IRB using the IRB Unanticipated Problem Form (Appendix F or http://www.utexas.edu/research/rsc/
   humansubjects/forms.html). Reports to the IRB should be submitted as promptly as possible after receipt of the report from the sponsor.
3. Note that notifying the IRB does not relieve the PI from his/her responsibility to notify the sponsor and / or FDA (as applicable).

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7.4 QUALITY IMPROVEMENT/MONITORING (PEER REVIEW COMMITTEE)

The purpose of the IRB Quality Improvement/Monitoring Program is twofold:

1. Quality Assurance. We are committed to the process of quality assurance. This process includes (a) the initial and ongoing review of research protocols by the IRB, (b) the organized dialogue between researchers and the IRB for the purposes of education of both parties, and (c) the peer review, or monitoring, of ongoing research (Title 45 Code of Federal Regulations Part 46, Protection of Human Subjects).
   
   

   The circumstances that lead to peer review are detailed below and include such criteria as:

   1. The pursuit of additional information to expand the content knowledge of the IRB collectively
   2. research that is subject to high levels of university exposure 
   3. research involving high-risk populations or procedures
   4. unanticipated events that pose risk to study participants
   5. significant non-compliance
2. Quality Improvement through Education. We are committed to efforts to improve all processes surrounding the implementation of research involving human subjects, and the review of such research.  By this plan, the goal is to enhance the quality of the dialogue between Researchers and research oversight committees and relevant offices (e.g., Institutional Review Board (IRB) and the Office of Research Support (ORS)). This is an education plan whereby Researchers, IRB members, and ORS representatives are invited to participate in a discussion of a program of research, research methodology, and administrative processes involved in the submission, review, and approval of research studies.

   This process may be initiated by either the Researcher or the IRB.  The process may focus on a specific research protocol, or a series of research projects characteristic of the Researcher's laboratory or office.  These organized field observations and interactions are instigated by invitation and are not to be interpreted as an investigation of a "for-cause" action (discussed below).

   It is a Federal mandate that Institutional Review Boards be composed of members who possess expertise with regard to the protocols under review.  Adjunct members may be appointed to the IRB when such expertise does not exist on the Board. It is a useful process, however, that proficiency be developed among current board members and relevant ORS staff members. Likewise, it is commensurate with the IRB's mission to ensure the wellbeing of human participants that individual investigators be aware of the federal policies for research involving human subjects. To serve these purposes, selected departments, investigators, and research laboratories may be invited to participate in a process of discussion and review.

   Following this review, recommendations may be made to improve the integrity of human subjects protection in research.

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7.4.1 Procedures for Quality Improvement / Monitoring

Investigator initiated Peer Review:

Investigators interested in participating in Peer Review should contact the Office for Research Support and Compliance and indicate an interest in having a Peer Review Committee schedule a visit. Investigators are invited to engage in the educational process in the event that their research offers a unique opportunity for the IRB to become proficient in an area of research (e.g., unusual populations or special techniques). 

IRB initiated Peer Review:

As needed, a protocol, research group, or department may be selected based on the IRB’s determination that additional information or quality verification is required regarding human participant rights and safety. The identification of such protocols, research groups, or departments may be based on protocols with unique populations/procedures, protocols identified by a history of recurrent unanticipated events, or non-compliance.  The goal of the peer review in these cases is to ensure full IRB understanding of the research protocols and full understanding by the Researcher, research group, or department regarding IRB policies and procedures. University of Texas at Austin is committed to conducting high-quality research that is reliable, reproducible, and generalizable. Educational efforts towards that end are regularly provided to researchers and their staff members.

Procedural steps and necessary information:

Following the determination that a Peer Review is to be conducted with regard to a protocol, research group, or department, a review committee composed of two IRB members and one staff person from the Office of Research Support is appointed to begin the peer review process. The investigator will be notified in writing that his/her research has been selected for Peer Review. Relevant department personnel, as well as the indicated chair of the departmental review committee will also be notified.

The Peer Review Committee will contact the PI and coordinate the fulfillment of steps that the Committee, the Researcher, research group, and/or department will follow to ensure research integrity.

• The review process may be conducted on-site, may necessitate access to relevant protocol files, and may require the Researcher or research coordinator to be present to handle questions as they arise.
• The materials reviewed by the Peer Review Committee may include, but are not limited to reviewing all regulatory documents related to the study, requesting additional materials for review (e.g., consent forms, summary of procedures, specific subject records, exclusion/exclusion criteria, unanticipated problem reports, intervention records, follow-up procedures, etc.), DRC collaboration (Departmental Review Committee), Lab/Field review (e.g., observation of study procedures or consent process, review of data management), and attendance at an IRB meeting.
• The Peer Review Committee may also contact and interview random participants to ensure that the study procedures were conducted in accordance with the approved protocol and that participants were adequately informed what to expect when they initially enrolled in the study.

Finally, a report is generated that evaluates the quality of human subjects protection as demonstrated in the reviewed protocol, research program, or department.  The report may contain affirmation of features of the protocol(s) that demonstrate high regard for the protection of human subject participation in research.  The report may also contain explicit recommendations for improving the protection of human participant rights and well-being. This letter is copied to the investigator(s), relevant departmental personnel, DRC, and is filed with the Office of Research Support. Points of dialogue and minor concerns will be addressed with the Researcher and research staff – and if there is educational merit – with the DRC.  More serious problems may necessitate a report being forwarded to the Vice President for Research

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7.5 POLICY & PROCEDURES FOR DATA AND SAFETY MONITORING PLANS¹⁸ (DSMP)

Concerns within Congress and Federal agencies responsible for assuring the safety and welfare of subjects participating in clinical research studies have prompted the issuance of new guidance and policies on oversight of clinical trials. More specifically, many investigators are now required by either the Federal government or private sponsors to establish plans for ongoing, real time data and safety monitoring in studies involving human subjects.  Specific responsibility for and methods of data and safety monitoring depend in part on the sponsor of the study (e.g., industry sponsored-FDA regulated, NIH supported, or investigator initiated).

The methods and amount of monitoring required are somewhat dictated by the degree of risk involved to the individual subjects and the complexity of the research. Some research activities may require the establishment of a Data and Safety Monitoring Plan (DSMP) to review interim analyses of data and cumulative unanticipated problem data to determine if the research activities should continue as originally designed, be changed, or be terminated.

Much of the research conducted at The University pertains to social and behavioral sciences, is generally considered to be not greater than minimal risk. Thus, many research studies may not be required nor need to establish a DSMP.  The IRB requires the establishment of a DSMP in cases in which the risk level is more than minimal.

1. Federal Regulations.  Both OHRP (http://www.hhs.gov/ohrp/
   humansubjects/guidance/contrev0107.htm) and NIH (http://grants.
   nih.gov/grants/guide/notice-files/not98-084.html) have written statements on the definition of a DSMP, the types of information that it may review, and when it should be reported to and used by an IRB in its continuing review process.
2. Information requested of researchers.  At time of submission of a new protocol, researchers are asked to complete an application form for their research (Appendix B).  Item #24 of this application, asks “whether a person (other than the PI) or a group will be responsible for reviewing unanticipated problems and other issues related to the safety of the study”.  If the researcher provides an affirmative response, then s/he is asked to provide further clarification of what exact procedures they have planned for review of such events and the type of DSMP that has been developed.  In addition to the application, a researcher is asked to submit a research protocol.  Section VII (Risks section) of this protocol also asks the researcher to describe a process for review of unanticipated problems, along with a DSMP.
3. The continuing renewal form.   In order to receive an annual renewal of a research study, the researcher must complete a Continuing Review Form (Appendix D).  Item #10 of this form requests information on whether a DSMP has been created, along with a copy of any findings determined by them at this time.  This information may include a current statement from the DSMP or sponsor indicating that it has reviewed study-wide unanticipated problems, interim findings, and any recent literature that may be relevant to the research.
4. Circumstances in which an IRB considers a DSMP to be appropriate.  In studies that are greater than minimal risk, the IRB requires the inclusion of a data safety monitoring plan (DSMP).
5. Issues the IRB considers in evaluating the adequacy of a DSMP.  The following elements of the DSMP will be reviewed by the IRB to determine whether the DSMP has adequate potential for qualified, timely review of useful information regarding participant information:
   1. Reporting mechanisms
   2. Frequency of monitoring and reporting; such as subject accrual number, or length of time after study has begun
   3. Qualifications and number of people serving on the DSMP and whether they have any perceived conflict of interest with the investigator or sponsor.
   4. A specific list of the data to be reviewed.
   5. Procedures for reviewing, analyzing and interpreting the participant data.
   6. If specific end-points are anticipated in a study under scrutiny of a DSMP, a list of the actions the DSMP might take when such end-points are reached.
   7. Methods of communication between
      1. the DSMP and the IRB, and if the study is a multi-site study
      2. methods of communication between the sites, DSMP and the IRB
    
6. DSMP Responsibilities
   1. Become familiar with the research protocol and the procedures for data safety and monitoring.
   2. Review interim analyses of outcome data and unanticipated problem reports to determine if the study can continue as originally designed or if the study should be changed or terminated.
   3. Review and approve major proposed modifications to the study prior to submission of the proposed modifications to the IRB.
   4. Provide the “study leadership” and University of Texas at Austin IRB with written information relating to the trial, e.g., a summary of unanticipated problems reported (from all sites), and recommendations with regards to continuance of the study at the completion of each meeting.

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