Reporting Unanticipated Problems and Adverse Events to the IRB: What, When and How
June 2015 Issue
By John F. Ennever, MD, PhD, CIP,
The April 2015 Feature Article in the CR TIMES broadly described the types of submissions to the IRB that occur after the initial approval. The May 2015 Feature Article described the revised policy on the reporting of protocol deviations (also known as “protocol violations”). The purpose of this article is to clarify what, when and how Unanticipated Problems and Adverse Events are reported to the IRB during the course of an approved research project. This is an update to the CR TIMES article published in 2007 which described the then-new policy on reporting only Unanticipated Problems to the IRB.
The protection of the rights and welfare of human research subjects is a responsibility shared among the investigator, the research staff, the sponsor, and the institution’s human subject protection program. When the IRB approves a new protocol, it must make a determination that, among other things, the risks to the subjects presented by the research are reasonable in anticipation of the potential benefits.
When a study is proposed, the investigator/sponsor provides their best assessment of what the risks are and proposes ways to minimize these risks. They also make an assessment of the potential benefits. The IRB evaluates the balance between the risks and benefits enumerated by the investigator. Working together to facilitate the consent process, the investigator and the IRB also create a consent document that includes information about risks and benefits that the potential subject needs in order to make an informed decision.
Once a study is initiated, there is information about the occurrence of actual adverse events and unexpected problems – they are no longer just theoretical risks of harm. The logic behind the reporting requirements of these actual occurrences is that the IRB must reassess a study when the information indicates that changes may be needed to the protocol to redress the balance between risks and benefits.
Although the PI has the ultimate responsibility for keeping track of events in the study, many large studies have an external safety monitoring body, which can be called the Data Safety Monitoring Board, the Data Monitoring Committee, the Data Coordinating Center, the Adverse Event Monitor, etc. These safety monitoring bodies receive information from all sites, and periodically provide reports to each PI.The remainder of this article will address reporting requirements for information that the IRB needs to reassess the risk/benefit balance in two circumstances: a single significant event (called an Unanticipated Problem), or the accumulated evidence from the overall pattern of less-serious or expected events.
An Unanticipated Problem (UP) is an event that by itself indicates an increased or new risk. Such individual events must be reported to the IRB within 2 business days of the PI becoming aware of the problem (including receiving a report of an Unanticipated Problem from a sponsor or safety monitor for another site).
The complete term for UPs is, “unanticipated problems involving risks to subjects or others.” The PI should determine whether an incident, experience, or outcome qualifies as an unanticipated problem by evaluating whether it meets all three of the following criteria:
When a PI determines that an event constitutes an Unanticipated Problem, he/she submits a report using the UPSER form in INSPIR. The submission must include an explanation from the investigator or sponsor as to why the event is considered an unanticipated problem, as well as a description of the proposed protocol changes or other corrective actions to be taken. Problems that are unexpected, related, or possibly related and which represent a greater risk to subjects will almost always require modification to the protocol and/or the consent form. These proposed changes should be submitted separately in a protocol Change Request and Amendment Form as soon as possible.The IRB will notify institutional officials, sponsors, and if applicable, OHRP and FDA of all unanticipated problems. The IRB provides copies of these reports to the PI.
The PI of a study has the responsibility to periodically evaluate all adverse events. If the pattern of harms is different than what was originally anticipated, then this must be reported as an Unanticipated Problem. For example, a known side effect that is occurring more frequently, or is more severe, than was originally expected would need to be reported as an Unanticipated Problem as soon as this pattern was revealed by this analysis.
To assure that such an analysis is periodically performed, it is a requirement for continuing review. The purpose of continuing review is for the IRB to reassess whether the research continues to meet the criteria for approval, based on the reported progress of the study as well as any new information that may affect the balance between risks and benefits. The PI is required to submit a Progress Report at least 30 days prior to the expiration of approval using the Continuing Review Submission Form.
The Progress Report must include a summary report that lists all adverse events and unanticipated problems occurring at the BU/BMC site (internal) and study-wide (external – this should be by reference to the latest safety monitor’s report, if available). The PI must also provide an analysis of whether the pattern of the events, in total, suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm), based on their nature or frequency of occurrence, compared to what was known at the time of the last IRB continuing review.The Continuing Review Submission form has a section for the summary of adverse events and unanticipated problems; or, the PI can create and attach a separate document. The format of the summary reports may vary. Some may list each occurrence individually, while others may summarize adverse events according to categories (i.e., 5 headaches, 3 episodes of nausea, 2 leg pain, etc.). However, all must include an analysis of whether the information indicates a change in the risks of the research.
Reporting to the IRB:
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