Reporting to the CPHS: Unanticipated Problems & Serious Adverse Events Team This Topic is near and dear to my heart Lorri Wettemann Senior Human Research Analyst and Education Specialist April 3, 2018

Why report adverse events and unanticipated problems? Overview and Background Forms and Memo Questions and Answers

Identify problems Identify trends Changes in risks Changes in benefits = New Information Safety and Science Take Action? Rationale for submitting UPRS to CPHS is to ensure that the research team and CPHS/Dartmouth fulfill their obligations to protect research subjects/participants. Reporting is an important component of ongoing protections for participants once a study is up and running. Reassess risk/benefit, and if the risk profile still meets the criteria for approval of the research. Safety! Alert us to unanticipated risks to subjects or problems in the research 21 CFR 50 & 56; 312, 812 and OTHERS (21 Food and Drugs) 45 CFR 46 (Public Welfare)

All data needs to be reviewed, as appropriate, based on the nature of the study. §46.111 Criteria for IRB approval of research: (6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. That is why the CPHS application Form includes: It is the role of the CPHS to ensure appropriate data and safety monitoring is in place for research projects.  The data and safety monitoring plan is dependent on the nature of the study and can range from an independent DSMB to PI oversight.  When there is a DSMB/DMC the Membership Charter should be uploaded as a supporting document in Rapport.  Appropriate plans vary. Assure your DSM plan is working properly. Send DSM reports as received and at time of continuing review. Know your plan, If no report, why?

FDA guidance: Draft April, 2007 Procedural Jan., 2009 OHRP guidance Jan. 2007 Released new reporting guidance addressing what had become the norm in the modern era of multi-site, international research, often involving a single agent studied for various diseases and disorders- large trials producing a tremendous amount of data. Two excerpts from the guidance follow “…increasingly large volumes of individual adverse event reports- often lacking in context and detail- are inhibiting rather than enhancing IRB’s ability to adequately protect human subjects.” April 2007 DRAFT Guidance lines 22- 23 “In particular, the practice of local investigators reporting individual unanalyzed events to IRBs, including events from all centers in a multi-center study, often with limited information and without any explanation of how the event represents an ‘unanticipated problem,’ has led to the submission of large numbers of reports to IRBs that they cannot adequately assess.” April 2007 DRAFT Guidance line 78- 82.

Reporting goal: Balance between under-reporting (miss effects) and over-reporting (dilution or noise) When it comes to reporting to IRBs- the goal is to June 12, 2007

Data and Safety Monitoring (DSMB) Data Monitoring Committee (DMC) Big picture- frequency and context Denominator information Assignment information or unblinding Filling a necessary and important role is the IRB, and investigators not appropriately situated to assess the significance of individual external adverse events. DSMB best-situated, to review the information and assess it within the frame of the study – and the overall agent. Variables!

Adverse Events CPHS Regulatory Reporting Responsibility: UPIRTSO Unanticipated Problems that are not a medical event Certain Adverse Events Adverse Events Report to CPHS Breach of confidentiality Programming error leading to inconsistent dosing or assignments Problem with manufacturing of drug/device leading to safety concern Adverse Event: Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in research, whether or not considered related to the subject’s participation in the research

Sponsor DSM FDA PI CPHS OHRP We have the same goal, the same purpose Protect research participants while advancing science and knowledge

Forms and Memo Questions and Answers Thank you!