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Post-Approval Monitoring Understanding the Investigator’s Role Part Two

Who Conducts Monitoring Activities? The IRB does not conduct monitoring activities It is responsible for ensuring that an appropriate monitoring plan is in place and for reviewing monitoring reports. The investigator is responsible for ensuring that monitoring requirements are met including maintaining appropriate study records, providing all relevant information to internal and external monitors or monitoring boards, and retaining monitoring reports. In industry-sponsored studies, the sponsor often sends monitors to visit clinical sites. Independent monitoring boards may rely on information submitted regularly by investigators. For selected studies conducted at U-M, the Office of Research Compliance Review (ORCR) may conduct proactive not-for-cause reviews of study plans, conduct, and record- keeping as well as for-cause reviews as requested by the IRB or UMOR.

What is a DSMP? A data safety monitoring plan (DSMP) is the portion of the protocol that describes: Steps the research team will take to identify, address, and report any physical, social, or psychological events that may result from participation in a study How data integrity will be maintained throughout the duration of the research project The DSMP describes the: frequency of monitoring activities; roles of internal and/or external monitors; and procedures for treatment or resolution of any issues identified during monitoring, including a description of circumstances that will result in halting or terminating research.

What Is a DSMB? A formally appointed independent Data and Safety Monitoring Board (DSMB) advises the study team regarding subject safety, study conduct, and efficacy. AKA Data Monitoring Committee (DMC) AKA Data and Safety Monitoring Committee (DSMC) DSMB performs regular interim analyses of the accumulating data. A DSMB is particularly important in situations in which subject safety concerns may be unusually significant, including where the study may ethically require early termination based on a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis; involves use of a drug that may induce an unacceptable toxicity; compares rates of mortality or major morbidity; or is being performed in a fragile population, such as children, pregnant women or the very elderly.

What Is a DSMB? A DSMB may be also be required by a federal sponsor or by institutional policy. For instance, interventional cancer clinical trials initiated by U-M investigators, use the UMCCC Data and Safety Monitoring Committee (DSMC) unless an independent trial-specific DSMB is established. FDA guidance: “All clinical trials require safety monitoring, but not all trials require monitoring by a formal committee that may be external to the trial organizers, sponsors, and investigators. ... [DSMBs] are generally not needed, for example, for trials at early stages of product development. They are also generally not needed for trials addressing lesser outcomes, such as relief of symptoms, unless the trial population is at elevated risk of more severe outcomes.”

How Do U-M IRBs Evaluate Monitoring Plans? “When appropriate,” a study must “make adequate provision for monitoring the data collected to ensure the safety of subjects" as a requirement for IRB approval. U-M IRBs generally require a DSMP as part of any study in which research-related adverse events are expected especially research-related serious adverse events Researchers present their DSMP in sections 32, 32-1, and 32-2 of the eResearch application; the information in these sections may also refer to the study-specific protocol.

How Do U-M IRBs Evaluate Monitoring Plans? Some ORIO reports submitted to the IRB may indicate the integrity or validity of study data has been compromised. Protocol deviation Accident/incident Report(s) to or from oversight entity IRB should consider whether the approved data monitoring provisions are sufficient whether the investigator is implementing them as approved The IRB can require a study be amended to improve monitoring provisions.

Additional Resources FDA Guidance on Oversight of Clinical Investigations https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf FDA Guidance on Investigator Responsibilities https://www.fda.gov/downloads/Drugs/.../Guidances/UCM187772.pdf UM HRPP Operations Manual – Part 6 http://research-compliance.umich.edu/operations-manual-roles-and- responsibilities-investigators-and-research-staff#roles NIH Policy for Data and Safety Monitoring https://grants.nih.gov/grants/guide/notice-files/not98-084.html

Thank you. Avery Avrakotos Kate Sasamoto Sana Khoury-Shakour The Office of Research Compliance Review Lark Speyer Judy Birk IRBMED