Guidance for Research Involving Human Subjects

Transcription

1 DATA AND SAFETY MONITORING Purpose: This is not meant to be a governing document and, as with all research involving human subjects (hereafter referred to as HSR), the Indiana University Institutional Review Board (IRB) has independent authority to approve or disapprove HSR. For questions regarding specific protocols, please contact IU Human Subjects Research Office in Indianapolis at (317) or in Bloomington at (812) CONTENTS I. Definitions II. Background and Summary III. DSMP A. What is in a Data and Safety Monitoring Plan? IV. Who monitors data and safety? A. Internal to Study Team B. External to Study Team V. What is a Data and Safety Monitoring Board? A. When is a DSMB necessary? B. When is a DSMB unnecessary? VI. Investigator Responsibilities A. New Study Submissions 1. Expedited Studies 2. Full Board Studies B. Renewals VII. IRB Responsibilities A. Review of Plan is Required B. Is the Plan Adequate? C. Renewal VIII. Addendum: Risk Matrix IX. Resources I. DEFINITIONS Data and Safety Monitoring: safety review. The IRB is tasked with ensuring that risks to subjects in research are minimized. One way the IRB accomplishes this task is to review a study team s proposed procedures for reviewing study data and monitoring subject safety. This review is called Data and Safety Monitoring (DSM), and it can vary from study to study. Monitoring is needed to ensure and enhance the safety of study subjects. Monitoring also assures the scientific validity of the study, i.e., to protect the data and preserve its integrity. Data and Safety Monitoring Plan (DSMP): the proposed procedure for reviewing study data and monitoring subject safety within a study. A DSMP is submitted by the study team and is unique to each study. Depending on the risks a subject population may be exposed to, a DSMP may 1

2 consist of anything from an annual review of enrollment data to a monthly review of complete study data by an independent board. Not all DSMPs will appoint a DSMB. Data and Safety Monitoring Board (DSMB) or Data and Safety Monitoring Committee (DSMC): an independent monitoring entity that is tasked with completing review at specified intervals. The DSMB should be composed of members whose expertise and experience provide them the ability to note problems that should be addressed and make recommendations to ensure subject safety. Additionally, these reviewers should not possess a conflict of interest with the research, including a financial interest in the outcome of the research. Note: The IU Simon Cancer Center does not use the terms DSMB and DMC interchangeably. It identifies DSMBs as study-specific boards and the DMC at the IUSCC as a committee that reviews all trials that are not externally monitored, such as investigator-initiated studies. II. BACKGROUND AND SUMMARY In order for the IRB to approve research involving human subjects, the IRB must determine that risks to subjects are minimized. When appropriate, the research must make adequate provisions for monitoring the data collected to ensure the safety of subjects. III. DSMP A. What is in a Data and Safety Monitoring Plan? A DSMP, depending on the risks, size, and complexity of the research, may account for: Types of data and events, for example: o Data Quality o Subject recruitment, accrual, and retention o Adverse events o Procedures for the protection of subject privacy o Information from outside sources that may impact subject safety (related studies, scientific reports, therapeutic development) Roles and responsibilities for gathering, evaluating, and monitoring data Frequency of review of data and events (no less than annually) Reporting of adverse events and unanticipated problems Actions taken upon specific events o Statistical analyses (interim analysis) o Pre-planned stopping rules Because the risks inherent to research vary greatly from study to study, data and safety monitoring is reviewed within the context of the study. A study team will be prompted to answer questions about a DSMP when the study exposes subjects to greater than minimal risk. A DSMP should take into account the risks within the study and provide an adequate plan to review study data in order to minimize those risks. Additionally, monitoring may at times need to account for stopping rules should an overwhelmingly positive response be noted. Resources are available to investigators to construct a data and safety monitoring plan (CTSI Bioethics and Subject Advocacy Program). 2

3 IV. WHO MONITORS DATA AND SAFETY? The party performing data and safety monitoring should vary depending on the potential risks, complexity, and nature of the study. In many situations, various groups or individuals may share responsibility for different aspects of study monitoring and oversight. If a study is multi-site, a central reporting entity should be used to communicate between sites and IRBs. A. Internal to Study Team 1. Principal investigator/study team a. Generally appropriate for studies that involve a small number of subjects at a single site and the interventions are minimal risk or when there is a low risk: benefit assessment. Close, continuous monitoring is expected. 2. Sponsor a. The sponsor often completes the monitoring when it is a multi-site trial with a low risk: benefit assessment. 3. Internal monitoring is often suitable for Phase I and early Phase II trials. Early studies are frequently not randomized or controlled so accumulating results are known to the investigators and sponsor. Internal monitors often review the data during frequent conferences due to study design. Issues regarding statistical interpretation or confidentiality of interim data are therefore generally less relevant in this setting. B. External to Study Team 1. Institutional/departmental monitor: independent affiliation from the research/researchers but possesses relevant expertise a. May be suitable when research is occurring at a single site and contains a low risk: benefit assessment. Appropriate to include additional expertise or objectivity from the investigators involved in the research. 2. Safety/Medical monitor: Often affiliated with a contract research organization (CRO) a. Monitors may act alone in monitoring or may act as a supplemental monitor to other individuals or entities 3. DSMB/DMC: a group of individuals with relevant expertise that reviews accumulating study data on a regular basis a. Required by FDA for emergency research where informed consent is waived (21 CFR 50.24(a)(7)(iv)) b. Required by NIH for multi-site clinical trials involving interventions that entail potential risk to the subjects (NIH policy) c. Generally established for large, randomized multi-site studies that evaluate treatments intended to prolong life or reduce risk of a major adverse health outcome d. Commonly recommended for late Phase 2 and Phase 3 clinical trials 3

4 V. DATA AND SAFETY MONITORING BOARDS A. When is a DSMB necessary? 1. The following types of studies are required to have a DSMB appointed: a. NIH sponsored Phase III clinical trials (as well as some Phase I and II) b. FDA sponsored planned emergency research c. Other studies when required by the IRB 2. Studies that fall under the following categories are most likely to have a DSMB: a. Large, multisite randomized studies evaluating treatments intended to prolong life or reduce risk of a major adverse health outcome b. Controlled trials comparing rates of mortality or major morbidity 3. The FDA recommends the use of a DSMB where a sponsored study includes: a. A study endpoint which might ethically require termination of the study at interim analysis, where a highly favorable or unfavorable finding is made b. A particular safety concern, such as administration of treatment by an invasive method (done only for research purposes) c. A subject group that includes a fragile population such as children, pregnant women, the elderly, or the terminally ill or those with diminished capacity d. A subject group at elevated risk of death or other serious consequences, even with a study objective that addresses a lesser endpoint B. When is a DSMB unnecessary? The FDA cautions that DSMBs add administrative complexity and require additional resources, so they are not recommended for all clinical trials. (FDA Guidance) 1. DSMBs are generally not needed for: a. Trials at early stages of product development; or b. Trials addressing lesser outcomes, such as relief of symptoms, unless the trial population is at elevated risk of more severe outcomes. c. Multisite studies or late phase studies using an approved drug for a new indication may not require an independent monitor such as a DSMB. The IRB may request justification for not using an independent monitor, such as when there is a low risk to benefit assessment. 2. DSMBs are not needed for: a. Social/Behavioral Studies b. Phase I: Generally, a DSMB is not required in Phase I studies because they are designed to include frequent internal monitoring. These trials typically advance faster than later-phase trials, so the monitoring plan must be commensurate with that frequency of monitoring. VI. INVESTIGATOR RESPONSIBILITIES A. New Study Submissions In KC IRB, data and safety monitoring information will be entered into the Questionnaire F Data Safety Monitoring. 4

5 1. Expedited Studies For studies that involve no more than minimal risks to subjects, the submission must describe how the data will be monitored in order to ensure the safety and well being of the subjects. a. Provisions for monitoring data may be as simple as the study team reviewing the data on an ongoing or interim basis to ensure that the study is proceeding as planned and no additional risks have been identified. 2. Full Board Studies For studies that involve greater than minimal risk to subjects, the submission must provide a plan addressing several key elements: a. The plan should clearly explain who is responsible for the monitoring of the data, their role in the study (if applicable), and if the individual or committee is independent from the sponsor and/or the PI of the study. b. The IRB will likely require that the following elements be monitored: Data Quality, Subject Recruitment, Accrual, Retention, Outcome and adverse event data, Assessment of scientific reports or therapeutic development, Results of related studies that may impact subject safety, and procedures designed to protect the privacy of subjects. c. There may be other elements to be monitored, and those should also be included as a part of the initial submission. d. The submission must also describe how often the individuals or committee responsible for the DSMP will monitor the study. i. Keep in mind that this information will be reviewed at the time of study renewal. The Board will want to see that the individuals/committee actually met at the intervals that were indicated in the DSMP in the initial study submission. e. Any planned statistical analysis, pre-planned stopping rules, and/or endpoints in the study should be explained. This section should describe whether the protocol has any planned recruitment stops or statistical analyses to allow safety monitoring to occur at certain points during the study. B. Renewals At the time of renewal, the Renewal Questionnaire in KC IRB must be completed. The section discussing Data and Safety Monitoring Plans can be found in Section 3, Protocol Event Summary. 1. If the study includes a DSMP, Section 3 should describe the findings since the beginning of the study (or last renewal). Many times, sponsors or study teams will provide meeting minutes or notes from the scheduled data reviews, which should be attached with the renewal submission on the Notes & Attachments tab. If applicable, this section should explain why there have been no findings since the last review. 2. If the study has a Data and Safety Monitoring Board, submit the following on the Notes & Attachments tab: a. DSMB report at each renewal. If no report is available or the DSMB has not met since the last review, the Renewal Questionnaire should explain why. The DSMB report should include: i. Confirmation that the monitoring entity reviewed adverse events, subject withdrawal, complaints, and any interim findings; 5

6 ii. The date of the review; and iii. The monitoring entity s assessment of the information that was reviewed. If the monitoring entity has not identified any issues and recommends continuation of the study, this recommendation should be included in the report as well. b. Local adverse event data. VII. IRB RESPONSIBILITIES Review of plan is required A criterion for approval by the IRB is that, when appropriate, the research plan makes adequate provisions for monitoring the data to ensure the safety of subjects (45 CFR (a)(6)). AAHRPP also charges the IRB with the responsibility to evaluate whether research submitted for review satisfies this criterion. Is the plan adequate? For minimal risk studies, which can include biomedical and social/behavioral research, the IRB will evaluate whether the provisions for monitoring data are adequate. For non-interventional studies, the IRB expects that the PI will review data regularly to ensure that the study is proceeding as planned. For interventional studies, the IRB expects that the PI will review and monitor recruitment, adverse events, procedures for maintaining privacy and confidentiality, and safety, outcomes, or endpoints. For studies that are greater than minimal risk or are FDA-regulated, the IRB likely will expect that all of the elements listed above (see What is in a Data and Safety Monitoring Plan?) are being monitored as part of the data and safety monitoring plan. In addition, the IRB will evaluate who is responsible for the data and safety monitoring and whether the frequency/timing of the monitoring is appropriate. Finally, the IRB will review any planned statistical analyses, preplanned stopping rules, actions to be taken upon specific events, and/or endpoints. Renewal The IRB has the responsibility to ensure that results from data and safety monitoring justify the continuation of IRB approval of the research study. If the plan outlined in the Summary Safeguard Statement or Data Safety Monitoring Questionnaire indicates that a DSMB will meet regularly, the IRB requires the renewal submission to include all reports for DSMB meetings that occurred since the last renewal. At the time of renewal, the IRB has within its authority to request changes to the monitoring plan. VIII. ADDENDUM: RISK MATRIX The chart on the following page is intended as a supplement to this guidance. It contains factors to be considered when developing a DSMP, ways to enhance monitoring, and examples of research for illustration. These examples are not exhaustive, and should not be relied on for determining the exact data and safety monitoring procedures a study should use. 6

7 Factors to Consider when Drafting a DSMP When creating a plan for monitoring, it is important to consider the nature, complexity, and risks of the study. When deciding whether to enhance the monitoring plan (see below for ways to do that), one should consider the factors listed below. The more of these factors that are present, and the more these factors increase risks to subject safety, the IRB is more likely to request heightened review procedures. Research is greater than minimal risk Large subject population Lengthy duration of research Multi-center study Use of investigational drug or device Randomization to research intervention Inclusion of a control group Endpoints that include mortality or major morbidity Enhancing your DSMP There are several ways to account for increased risks posed by research, in the development of a DSMP. Below are examples of ways to enhance your DSMP to account for the presence of the factors listed above. These are simply guidelines, and your DSMP may not adhere strictly to them. Frequency of Review Annually Quarterly Weekly Reviewers P.I. only P.I. along with independent reviewer P.I. reviews local data, while DSMB reviews all study data across all sites Planned Statistical Analyses and Actions None Interim analysis planned after reaching half of enrollment goal Multiple pre-planned stopping rules included, related to subject safety and efficacy of intervention Lower Risk Higher Risk A DSMP should take into account all factors of the research to adequately plan for monitoring of subject safety. At right are three examples of studies, with facts about the research and potential requests from an IRB to account for them. A study surveys 15 healthy adult subjects about their preferred toothpaste. The IRB asks that the PI monitor the study by reviewing enrollment data at the time of renewal, and report any protocol deviations at the appropriate time. A study collects blood twice from 50 child subjects. The IRB asks that the PI monitor the study, along with a Higher Risk colleague in the same Dept. who is not on the study team. The IRB also asks the study team to report findings after the first 10 children have completed study procedures. A multi-site study uses an investigational drug to treat diabetes in patients who have had serious reactions to conventional treatments. The IRB asks that the study team enlist the services of a DSMB to review study data every quarter, and provide reports to the IRB at the time of renewal.

8 IX. RESOURCES A. OHRP CFR (a)(6): When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. 2. Guidance on Continuing Review of Research B. AAHRPP 1. Evaluation Instrument for Accreditation a. Element I.8.B: In studies were Sponsors conduct research site monitoring visits or conduct monitoring activities remotely, the Organization has a written agreement with the Sponsor that the Sponsor promptly reports to the Organization findings that could affect the safety of participants or influence the conduct of the study. b. Element I.8.C: When the Sponsor has the responsibility to conduct data and safety monitoring, the Organization has a written agreement with the Sponsor that addresses provisions for monitoring the data to ensure the safety of participants and for providing data and safety monitoring report to the Organization. c. Element II.3.B: The IRB has and follows written policies and procedures for reviewing the plans for data and safety monitoring, when applicable, and determines that the data and safety monitoring plan provides adequate protection for participants. d. Element III.1.C: Researchers employ sound study design in accordance with the standards of the discipline. Researchers design studies in a manner that minimizes risks to participants. 2. Tip Sheets a. Tip Sheet 1: Criteria for Approval of Research b. Tip Sheet 6: Evaluating Provisions for Monitoring Data and Safety in Proposed Research c. Tip Sheet 20: Sufficient Information to Determine Whether the Criteria for Approval are Met C. FDA CFR (a)(6) 2. Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees D. NIH 1. NIH Policy for Data and Safety Monitoring 2. Further Guidance on a Data and Safety Monitoring for Phase 1 and Phase 2 Trials 3. Guidance on Reporting Adverse Events to Institutional Review Boards for NIH- Supported Multicenter Clinical Trials E. VA CFR (a)(6) 2. VHA Handbook F. DOD CFR (a)(6) 2. DOD Directive G. IU SOP for HSO 1. Safety Monitoring H. Indiana CTSI Bioethics and Subject Advocacy Program 1. Resources to construct a data and safety monitoring plan 7

9 I. KC IRB Crosswalk: 1. F Data Safety Monitoring a. Minimal risk 1. Describe the provisions for monitoring the data to ensure the safety of subjects b. Greater than minimal risk 1. Explain who will be responsible for the data and safety monitoring, including their role in the study, if any, and whether the individual or committee is independent from the sponsor and/or PI. 2. Choose all of the following which will be monitored as part of the DSMP: i. Data quality ii. Subject recruitment iii. Accrual iv. Retention v. Outcome and adverse event data vi. Assessment of scientific reports or therapeutic development vii. Results of related studies that may impact subject safety viii. Procedures designed to protect the privacy of subjects ix. Other: describe 3. Describe how often individuals or committee responsible for the DSMP will monitor the study: 4. Describe any planned statistical analyses and any pre-planned stopping rules, actions to be taken upon specific events, and/or endpoints. a. Some protocols include planned recruitment stops or statistical analyses to allow for data and safety monitoring to occur at certain points during the study. If your study includes such a plan, or if specific stopping rules have already been denoted, describe them here. If not, simply N/A or nothing planned at this time is sufficient. 8