• IRB Member Considerations When Evaluating Reported Events as Possible Unanticipated Problems (Narrated PowerPoint)
• Policy 801 Reporting Research Events and Guidance for Reporting Research Events and Noncompliance

IND Safety Reports are communications from a Sponsor that relay information about adverse events possibly related to an Investigational New Drug (IND) and do not necessarily reflect an event that occurred at an NIH site or as part of an NIH protocol. These reports are usually sent by email or through a web-based portal and may lack full context of the event. 

The event may have occurred on a different protocol that is using the same investigational product. This may mean that the participants on your trial may also be at risk of experiencing the same adverse event.  The FDA requires Sponsors to notify all participating investigators in a written IND Safety Report of “any adverse experience associated with the use of the drug that is both serious and unexpected” and “any finding from tests in laboratory animals that suggests a significant risk for human subjects.”¹  Sponsors are required to “keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use.”²  Additional helpful information can be found in Section II of the 2009 FDA Guidance titled “Adverse Event Reporting to IRBs — Improving Human Subject Protection: Guidance for Clinical Investigators, Sponsors, and IRBs.”

¹ 21 CFR 312.32(c)(1)(i)(A),(B)

² § 312.55(b

• In some cases, NIH PIs will receive an IND Safety Report from a study that is not under oversight by the NIH IRB but that is using the same investigational product being used in the NIH study. The event may have occurred on an unrelated study or on the same multisite protocol being conducted at a non-NIH site that is being overseen by a non-NIH IRB.  The NIH PI must evaluate the Safety Report and determine if the event is a possible unanticipated problem (UP) or new information that might affect the willingness of subjects on the NIH study to enroll or remain in the study. If so, the event should be reported in PROTECT for the NIH study via a Reportable New Information (RNI) submission. The PI should also consider if a protocol modification and an updated consent need to be submitted to the IRB for the NIH study based on the circumstances of the event being reported.  Note that the IRB will not provide a UP determination for an event that occurred on a protocol for which they are not the IRB of record.  However, they will review the submission and determine whether your proposed corrective actions regarding the event are sufficient.  For the full definition of an Unanticipated Problem, please refer to OHSRP Policy 801 Reporting Research Events Section 4.10 “Unanticipated Problem Involving Risks to Subjects or Others.” (Refer to Question 5 for details on reporting in PROTECT.) 
• If the event in the IND Safety Report occurred on a protocol for which the NIH IRB has oversight, and it meets the definition of a UP or represents new information that might affect the willingness of a subject to enroll or remain in the study, the event should have been previously reported to the NIH IRB within 7 calendar days of an investigator becoming aware of the event. Only if there is new information from the Sponsor contained in the subsequent Safety Report that would change the PI’s determination of the event or if it has not previously been reported, should the IND Safety report be submitted to the NIH IRB via a follow-up RNI submission.  At the time of the original RNI submission, the PI should consider if a protocol modification and an updated consent should also be submitted to the IRB based on the circumstances of the event being reported.  In most cases, when the NIH IRB is the IRB of Record, the modification will be reviewed concomitantly with the RNI submission at the same IRB meeting. (Refer to Question 5 for details on reporting in PROTECT.)

• For the full definition of an Unanticipated Problem, please refer to the OHSRP Policy 801 Section 4.10: “Unanticipated Problem Involving Risks to Subjects or Others.”
• If the sponsor is requiring a protocol modification or changes to the consent form as a result of the event, it is likely that the event meets the definition of an Unanticipated Problem or New Information.
• The FDA Guidance referenced in question 2 above specifically addresses the burden of the increasing number of IND Safety Reports and contains examples of when events meet the definition of a UP and when they should be reported to the local IRB.
• Section IIIA of the FDA Guidance provides information regarding whether an adverse event is an Unanticipated Problem and is titled, “How to Determine If an AE is an Unanticipated Problem that Needs to Be Reported.” This section includes full guidance and examples of events that would be considered Unanticipated Problems.

• If the event occurred at a site under the oversight of the NIH IRB and is a possible UP or new information that might affect the willingness of subjects to enroll or remain in the study, the event should have been reported in PROTECT within seven calendar days of the event per OHSRP Policy 801 and before the Sponsor would have issued an IND Safety report.  The subsequent IND Safety report would only need to be submitted to the NIH IRB if the information provided by the Sponsor in the report changes the PI’s previous determination of the event or if the event had not been previously reported to the IRB.
• If the event occurred on a protocol under the oversight of a non-NIH IRB, “New Information” should be selected in in the identify the categories section of the RNI Smart Form even if the PI determined that the event is a UP (See Question 4).You should not select "Unanticipated Problem" since the NIH IRB cannot make a UP determination for a study overseen by a non-NIH IRB. In these cases, submission of the RNI to the NIH IRB serves to provide the Board with the new relevant information in order to determine if the new information (e.g. a new risk was discovered with the investigational product being used on a different protocol) should be added to the NIH consent form and protocol that uses the same investigational product. The NIH IRBB will review the submission and determine whether your proposed corrective actions regarding the event are sufficient.  

• If the event occurred on a study overseen by a non-NIH IRB, only submit the IND Safety Report to the NIH IRB if the event meets the definition of a UP or represents new information that might affect the willingness of a subject to enroll or remain in the study. In that case, the event should be reported to the NIH IRB as New Information. Note that the IRB will not provide an UP determination for an event that occurred on a non-NIH IRB study. (See question 5 for details on how to submit a RNI in PROTECT.)
• If the event occurred on a protocol overseen by the NIH IRB, the event should have already been submitted to the IRB within 7 calendar days if it is a possible UP or relevant new information. The subsequent IND Safety report would only need to be submitted to the NIH IRB if the information provided by the Sponsor in the report changes the PI’s previous determination of the event or if the event had not been previously reported to the IRB.
• In either case, OHSRP Policy 801 can be provided to the Sponsor if they have questions, and you may also reference the FDA Guidance. The Sponsor may request that investigators keep a log of the PI’s review and subsequent written assessment of IND Safety Reports provided by the Sponsor.