375. Monitoring Data for Participant Safety

Updated July 1, 2021

Among the Department of Health and Human Services (DHHS) criteria for IRB approval of research at 45 CFR 46.111 is the requirement that when appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants (§ CFR 46.111(1)(6)). The University interprets “when appropriate” to apply to all research posing greater than minimal risk. By routinely and periodically examining accruing data for indications of harms (including physical, psychological, economic and social harms, or changes to benefits), Principal Investigators (PIs), sponsors, independent monitors, or monitoring boards or committees may:

• identify new risks or anticipated risks that appear in greater severity or frequency than originally expected; and
• make data-based decisions about whether a study may progress as planned, requires amendments to better protect participants, or should be closed to enrollment or terminated.

Assessment of Level of Risk

Monitoring should be commensurate with risks and with the size and complexity of the trials. Investigators are required to develop a Data and Safety Monitoring Plan (DSMP) appropriate in scope to the anticipated risks of the research. The monitoring might be conducted by the researcher, the sponsor (e.g., medical monitor, safety monitoring committee), or by an independent monitoring board.

Monitoring Plan for Minimal Risk

Minimal risk research does not require an independent Data and Safety Monitoring Board (DSMB). Monitoring is the responsibility of the investigator.

All protocols presenting the potential of risk to participants, even minimal risk, should address how the investigator will monitor risk and report adverse events. A minimal risk study is defined as one where the probability and magnitude of harm and/or discomfort in the proposed research are not more than ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Minimal risk studies may include non-therapeutic studies such as survey research, questionnaires, blood samples (venipuncture or intravenous catheter insertion), observational studies, DEXA scans, routine MRI scans, special diets, exercise testing, EKGs, and anthropomorphic evaluations. However, survey research and questionnaires may present more than minimal risk to participants if they address highly sensitive information. inclusion of special populations (children, prisoners, pregnant women mentally disabled persons, or economically and/or educationally disadvantaged persons) who may be more sensitive or vulnerable to the risks posed by the research, regardless of the study, may increase the level of risk to moderate or high.

Monitoring Plan for Moderate Risk

The monitoring plan for Moderate Risk research will, in most cases, require independent safety monitoring.

Moderate risk studies exceed the minimal risk but constitute less risk to the participant than studies with the potential for serious risks to participants. Moderate risk studies may include phase I, II or phase III multi-institutional trials, studies using drugs for their indicated use, studies that use invasive hemodynamic monitoring with arterial lines, and studies in which blood and tissue specimens are stored. Studies in which blood is drawn for genetic studies, either real time and/or stored for later use are also deemed to present risk to participants. For some strictly genetic studies, in targeted populations, the investigator may serve as the monitor. For small, moderate risk studies, monitoring might be performed by an independent investigator who is an expert in the agent being studied and the patient population.

Monitoring Plan for High Risk

The monitoring plan for high risk research may require a DSMB. For some high risk studies, monitoring might be performed by a single, independent investigator who is an expert in the agent being studied and the patient population.

Protocols presenting the potential for serious risks and adverse events may include clinical trials using investigational agents, gene transfer studies, studies using FDA-approved agents for non-approved indications; Phase I clinical trials; studies requiring investigator-initiated IND's (investigational new drug) or IDEs (investigational devices); and some Phase II clinical trials. This category may include studies involving procedures in which there is a high risk for adverse events such as conscious sedation or interventional radiology. Studies in which some or all participants are at risk of death or severe morbidity because of existing illness or disease are also considered high risk.

Minimum Requirements for Plans to Monitor Data for Participant Safety

When designing the Data Safety Monitoring Plan (DSMP) (see Policy Manual Definitions), University and affiliate investigators are advised to consider the following questions and examples:

Who will monitor the data for safety concerns?

• Principal investigator or designated co-investigator
• Named designee unassociated with the project (i.e., independent monitor)
• Independent Data Safety Monitoring Board or Committee (DSMB/C) (see Policy Manual Definitions), convened by the principal investigator or sponsor

When the study sponsor is responsible for data and safety monitoring, how will the Principal Investigator's local monitoring activities be integrated into the sponsor's plan?

• Requirements for reporting local adverse events/effects
• Requirements for routine reporting of predetermined outcomes or specified safety information
• Requirements that the contract or funding agreement should include arrangements so that data and safety monitoring plans are provided to the organization or provided to the researcher who provides them to the IRB.

What data or safety information will be reviewed?

• Type, seriousness, number, or frequency of adverse events/effects that occur locally or are pooled across all sites for multisite research
• Unanticipated problems involving participants or others that occur locally or are pooled across all sites for multisite research
• Participant outcomes, including morbidity and mortality, and drop-out rates and profiles
• Interim findings, including vital signs, and anthropometric and laboratory values
• Incidental or secondary findings that affect research risk or the reasonableness of risks with consideration for research benefits
• Reports from independent monitor or DSMB/C
• Findings other studies involving the same or similar investigational drug or device, or experimental intervention

How will the data/safety information be collected?

• Case report forms
• During study visits
• Via telephone calls with participants

How often will routine safety monitoring occur and how often will cumulative data be reviewed to identify patterns?

• Specified number of weeks or months from the onset of the research, and specified intervals thereafter
• Other parameters such as after enrollment of a specified number of participants or following a predetermined number of adverse reactions

How will adverse reactions be assessed to determine intensity, severity, frequency, and relatedness to the research?

• Use of existing standards or definitions to code/categorize adverse reactions
• Use of existing standards to code/grade adverse events
• Use of standardized incidence ranges to codify frequency
• Use of standardized or predetermined scales or categories for relatedness
• Application of knowledge related to the drug pharmacology; known or typical events associated with use of a drug/device, class of drugs/devices, or procedure or intervention; or typical progression of the disease or condition under study

What specific findings would trigger an immediate suspension of the research?

When and how often will data monitoring findings or reports be submitted to the IRB?

• As specified in the University policy for reporting problems to the IRB

How will participants be referred to medical or psychological services that may be required because of participation in the research?

How will the individual participant be notified of findings that may affect her/his/their health or welfare?

• Informed consent using a revised and updated informed consent document
• Informed consent using an addendum to the existing consent document
• Investigator or sponsor letter or other correspondence
• Orally, at participant's next research or clinical appointment

Plan for Monitoring Safety/Confidentiality

The DSMP should at a minimum address the following issues:

• A description of the plan to ensure the integrity of the data, including: (a) A description of the systems for storing and backing up the data; (b) A listing of who will monitor and review the data, and a description of the monitor’s qualifications (Note: it may be appropriate for the PI to serve as the monitor); (c) The frequency of review (e.g., specific points in time, or after a specific number of participants have enrolled); (d) A description of the data to be monitored; (e) Procedures for analysis and interpretation of the data; (f) Actions to be taken upon specific events or endpoints.
• Procedures for communication from the data monitor to the IRB and other sites;
• Protection of the rights and welfare of participants during the recruitment, consenting process and study participation;
• Protection of participant privacy and confidentiality;
• A description of the mechanisms for detecting, reviewing and reporting unanticipated problems involving risks to participants or others by the investigative team at a frequency and intensity sufficient to ensure the safety of participants.
• Assurance that research responsibilities delegated by the principal investigator to investigative team members are carried out in accordance with the protocol, federal regulations, federal, state and local laws and institutional policies and procedures.

Plan for Data Management

Investigators are required to:

• Indicate who is responsible for collection and storage of data.
• Describe how data will be organized, managed, and stored. Security measures used to protect study data from loss or inappropriate use (password protection, restricted access to database, database backup etc.).
• Include a description of how often interim data will be reviewed and by whom.
• Indicate who will perform aggregate analysis of data and adverse events, if applicable.

Other Considerations for Data Safety Monitoring

For multicenter trials when the University is the coordinating site, the local PI is responsible for reviewing and assessing safety reports forwarded by sponsors, research monitors, DSMB/C or cooperative groups.

The University IRB considers the data and safety monitoring needs of studies that do not have or are not required to have a DSMB/C; and studies that are blinded, have multiple sites, enroll vulnerable populations, or employ high-risk interventions.

When a DSMB/C is not required, the IRB may determine that statistical tests are warranted for the PI to analyze interim or safety data to determine whether harm is occurring.

IRB Review

As part of its review process, the convened IRB will review the information contained in the protocol to ensure that plans for data and safety monitoring have been developed in accordance with the guidelines above and are adequate for the protocol under review. The IRB’s decision regarding the adequacy of the plan will be recorded in the IRB meeting minutes.

The IRB will consider provisions such as:

• What safety information will be collected, including serious adverse events.
• How the safety information will be collected (e.g., with case report forms, at study visits, by telephone calls with participants).
• The frequency of data collection, including when safety data collection starts.
• The frequency or periodicity of review of cumulative safety data.
• Whether the plan includes establishing a data monitoring committee and a plan for reporting data monitoring committee findings to the IRB and the sponsor.
• For studies that do not have or are not required to have a data monitoring committee and are blinded, have multiple sites, enter vulnerable populations, or employ high-risk interventions, the IRB will carefully review the data and safety monitoring plan and determine whether a data monitoring committee is needed.
• If not using a data monitoring committee, and if applicable, statistical tests for analyzing the safety data to determine whether harm is occurring.
• Provisions for the oversight of safety data (e.g., by a data monitoring committee).
• Conditions that trigger an immediate suspension of the research, if applicable.