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Any incident, experience or outcome that is: Adverse events (AE):Any untoward or unfavorable medical occurrence in a human subject; including any abnormal sign, symptom or disease that is temporally related to the research, whether or not it is related to the subject's participation in the research. Examples of AEs include:
If the event is untoward and it happens during the study, its an AE. The IRB obviously doesn't want to know about every cold a child catches or every minor injury. It is interested in serious problems that are unexpected and therefore might affect the IRB's prior risk - benefit assessment. What else besides an AE could be an unanticipated problem?Examples: Unanticipated Problems
The common feature of the events listed in the box on the right is that all potentially place subjects at risk of serious harm. Even when no actual harm occurs, if the event meets the definition of an unanticipated problem, it must be reported to the IRB. When the event goes beyond simply potential harm to where actual harm befalls a subject, then the event would be considered an adverse event. Adverse events make up the most frequently reported unanticipated problem reported to the IRB. Which Problems Require Prompt Reporting?Prompt reporting is required for all unanticipated problems which means those that are serious, unexpected and related to the research activity. This requirement for reporting unanticipated problems includes both CHOP-enrolled subjects and subjects enrolled at external sites. SAE Reports from External SitesSponsors and cooperative study groups frequently forward all SAE reports that take place during a multi-center trial, to all site investigators regardless of whether or not the event constitutes an unanticipated problem. Many of the reports relate to subjects who are not like those participating in the trial underway at the local site. The reports often come from trials for different disease indications or from subjects of different age groups with different pre-existing medical conditions. It is often impossible for an IRB to draw any conclusions from these reports as far as how they relate to the subjects in the trial that is going on at the local site. To help clarify which reports need to be forwarded to the IRB, the FDA has issued an extremely useful guidance document for investigators and IRBs entitled Adverse Event Reporting to IRBs — Improving Human Subject Protection . This guidance should be read by all those conducting FDA-regulated research and who receive SAE reports from sponsors. The guidance makes clear that only those reports that meet the definition of an unanticipated problem should be shared with the IRB; the investigator should store the rest in the study file. Minimizing the number of reports submitted to the IRB reduces wasted effort for both the investigators and the IRB and without increasing risk to participants. Which external SAE reports need to be reported promptly to the IRB?Sponsor's letters often state that the report should be filed with the IRB if required by local policy. The CHOP IRB prefers to review only those reports that meet (or at least might meet) all of the criteria for being an unanticipated problem. Investigators and study teams should store all other external reports in their study binders but need not forward these to the IRB. In the event the sponsor requires submission of the report to the IRB, this can be noted in the eIRB submission form and an acknowledgement will be sent automatically. Reports that suggest that subjects or others are placed at a greater risk of harm then initially anticipated should be accompanied by an Action Plan that outlines the steps that will be taken to mitigate the newly identified risk(s). If the sponsor of a multicenter study does not propose any changes, it is suggestive that the event does not meet all of the criteria for an unanticipated problem. The Action Plan should include one or more of the following:
The IRB has issued a Memo outlining Procedures for Reporting External SAE Reports that provides a more detailed explanation. Unanticipated Problems Decision TreeThe decision tree branches and considers separately the reporting requirements for serious adverse events (SAE) from other unanticipated problems. An SAE is defined as an adverse event that:
The Unanticipated Problems Decision Tree on the right is available as a pdf for viewing or download. Timelines for Prompt Reporting of Unanticipated ProblemsEvents that satisfy all of the criteria for an unanticipated problem must be reported promptly to the IRB in addition to the reporting obligations to the sponsor or regulatory authorities. The reports should be sent to the CHOP IRB in accordance with the following timelines:
What is an unanticipated problem according to OHRP?Unanticipated Problem:
related to a subject's participation in the research; and. suggests that the research places subjects or others at greater risk of harm - physical, psychological, economic or social harms - than was previously known or recognized.
What needs to be reported to the IRB?Investigators are required to report promptly “to the IRB… all unanticipated problems involving risks to human subjects or others,” including adverse events that should be considered unanticipated problems (21 CFR 56.108(b)(1), 21 CFR 312.53(c)(1)(vii), and 21 CFR 312.66).
What is an unanticipated problem in research?An unanticipated problem is by definition unexpected, whereas an adverse event may be either expected or unexpected. Unanticipated problems may or may not be adverse events. Adverse events relate to harm to participants; unanticipated problems may involve an increased risk of harm even if no actual harm occurred.
Which of the following is something an IRB should do with respect to review of GSD research?Which of the following is something an IRB should do with respect to review of GSD research? Seek consultants with expertise in specific segments of GSD communities to provide information on research in those communities.
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