Serious Adverse Events

The IRB-HSR requires the reporting of the following events:

• Internal Serious Unexpected Events
• External Serious Unexpected Events that require change to the protocol or consent.

In addition to IRB-HSR reporting requirements, the study team may have other entities that require the reporting of serious adverse events, for example the sponsor or the DSMB. The study team is responsible for knowing and following the protocol and/or Protocol Application requirements for SAE reporting.

*Remember if IRB-HSR is not the IRB of record, the reporting requirements will be different. If you are using a different IRB, please check with them regarding reporting requirements.

• Useful Definitions
• AE Review Tool for Study Team: Adverse Event Review Algorithm
• IRB Reporting Criteria For Serious Adverse Events
• Reporting Timeline
• How To Submit Serious Adverse Events to the IRB
• External Adverse Events
• Documentation of the IRB’s Receipt of Adverse Events
• When can the Study Team stop sending External Adverse Events to the IRB
• Making corrections to/deleting SAEs submitted using IRB OnLine
• Help and Education regarding Serious Adverse Events

Useful Definitions:

Internal Event
Any adverse event, unanticipated problem, experience, incident or outcome occurring under the jurisdiction of the UVa IRB-HSR will be considered internal. If an event occurs in a subject enrolled in a UVa protocol where a UVA IRB is the IRB of record, then the event is considered Internal. For example, if an event occurs at an outside hospital in a subject enrolled in a UVa protocol then the event will be considered internal.

External Event
Any adverse event, unanticipated problem, experience, incident or outcome occurring outside the jurisdiction of the UVa IRB-HSR will be considered external. For example, if an event occurs in a subject NOT enrolled in a protocol at UVa, or occurs in others associated with a subject who is NOT enrolled in a protocol at UVa, then the event will be considered external.  For example, UVa and other sites may be participating in a multi-site trial. If an AE occurs in a subject enrolled at another site, the event is considered external.   

Adverse Event (AE)
An adverse event will be considered any undesirable sign, symptom or medical or psychological condition even if the event is not considered to be related to the investigational drug/device/intervention. Medical condition/diseases present before starting the investigational drug/device/intervention will be considered adverse events only if they worsen after starting study treatment/intervention.  An adverse event is also any undesirable and unintended effect of research occurring in human subjects as a result of the collection of identifiable private information under the research.  Adverse events also include any problems associated with the use of an investigational device that adversely affects the rights, safety or welfare of subjects.
There are many acceptable definitions for Adverse Events.  The IRB-HSR has adopted the above definition to be used as a default if no other definition is documented in any given protocol. Study teams with a commercial sponsor should always follow the definitions outlined in their sponsor’s protocol. If the protocol is an UVa PI initiated protocol, the definition provided above should be utilized.


Serious Adverse Event (SAE)

A serious adverse event will be considered any undesirable sign, symptom, or medical condition with one or more of the following outcomes:

• is fatal, is life-threatening,
• requires or prolongs inpatient hospitalization,
• results in persistent or significant disability/incapacity,
• constitutes a congenital anomaly or birth defect,
• is medically significant and which the investigator regards as serious based on appropriate medical judgment.
• any serious psychological and emotional distress resulting in study participation (suggesting need for professional counseling or intervention). 

Unexpected Event
Any adverse experience, event, incident, interaction or outcome that is not identified in nature, severity or frequency in the study documentation (protocol, consent, Investigator Brochure, package insert etc) is considered an unexpected adverse event. Any event that is previously not known or anticipated to result from an underlying disease, disorder, or condition of the human subject or the study population may also be considered an unexpected event. For Cancer Center Studies the DSMP tables A, B, or C have additional defining information regarding “unexpected” that is based on AE grade.
Expected Event
Any adverse experience, event, incident, interaction or outcome that is identified in nature, severity or frequency in the study documentation (protocol, consent, Investigator Brochure, package insert etc) is considered an expected adverse event.   Any event that is previously known or anticipated to result from the underlying disease, disorder, or condition of the human subject or the study population may also be considered an expected  event. For Cancer Center Studies the DSMP tables A, B, or C have additional defining information regarding “unexpected” that is based on AE grade.
Unrelated Event
Any adverse experience, event, incident, interaction or outcome for which a causal relationship with the study article, study intervention or study participation is not suspected.
Related/Possibly Related Event
Any adverse experience, event, incident, interaction or outcome for which a causal relationship with the study article, study intervention or study participation is suspected.

AE Review Tool for Study Team: Adverse Event Review Algorithm

Does the event meet the definition of an AE?

No 

Record per DSMP

Yes 

Does the event meet the criteria for serious?

No 

Record per DSMP

Yes 

Was the event Unexpected?

No 

Record per DSMP

Yes 

Record AE using data collection tool specified in DSMP (Data Safety and Monitoring Plan in the IRB Protocol or Application.

Report to IRB-HSR using IRB Online if event is internal. If external, you may use IRB Online, submit hardcopy or submit via the Non-UVA Batch AE Submission Form. Also report to any other entity (Sponsor, DSMB) per the DSMP.

IRB Reporting Criteria For Serious Adverse Events:

Internal events:
The IRB-HSR requires that all Internal, Serious, Unexpected adverse events be reported to the IRB-HSR using the IRB Online program within 7 days of the time the study team 
receives knowledge of the event.

External events
External, Serious, Unexpected Adverse Events must be reported to the IRB-HSR using the IRB Online program ONLY if the event results in a change to the risk section of the consent and/or modification to the protocol.
External, Serious, Unexpected Adverse Events that DO NOT result in change to the risk section of the consent and/or modification to the protocol do not need to be submitted to the IRB unless the sponsor requires submission.

Reporting Timeline

Internal, unexpected SAEs and External SAEs resulting in modification to the protocol/consent must be submitted to the IRB-HSR within 7 days from the time the study team received knowledge of the event. This includes the electronic submission and the AE reporting form.  If the internal SAE resulted in harm or death to the subject that was definitely caused by study participation the SAE should be reported to IRB-HSR within 24-hours. In addition, the appropriate Dean and Office of Risk Management should be notified within 24-hours.

The IRB-HSR will make a Late Reporting notation to all internal, serious, unexpected adverse events reported greater than 7 days from the time the study team received knowledge of the event. Repeated incidences of late AE reporting may constitute continuing noncompliance

How To Submit Serious Adverse Events to the IRB

The IRB may not be the only entity to which your adverse event must be reported. Your protocol or IRB application DSMP will outline all entities requiring an adverse event report.

Submitting AEs with the Original Application:
Sponsors may have individual AE reports that need to be submitted to the IRB along with the original protocol application. The study team should attach any adverse events provided by the sponsor to the Investigator’s Brochure and submit them with the original protocol application to the IRB.

Submitting AEs Using IRB Online:
IRB Online is a tool that may be used to record all adverse events.
However it is the REQUIRED submission  process for:

• Internal, Unexpected and Serious, AEs
• External events when, due to this event, the risk section in the consent and/or the protocol requires modification.

To enter or submit the events described above, an IRB-HSR Adverse Event Reporting Form will be completed online.

• Go to IRB Online
• Log in
• Click on Adverse Events
• If you have never submitted an AE via IRB Online, select "How to Submit Adverse Events On Line." Otherwise select "Enter a New AE."
• Use the on-screen directions to complete the report
• SAVE the information. When the AE is SAVED, it will appear in SAVED AES until you are ready to submit. DO NOT PRINT SAVED AES FOR SIGNATURE. SAVED AES should be considered NOT FINAL.
• Once the information is finalized, you are ready to submit. Select the SUBMIT button to submit the SAE to the IRB.
  • AEs/SAEs that do NOT meet reporting criteria are automatically downloaded into IRB OnLine database once you hit SUBMIT. You will be able to see this event from the REPORTS view of IRB Online’
  • SAES that meet the reporting criteria are not automatically downloaded when you hit SUBMIT. Instead these SAEs are routed to a temporary INBOX in IRB OnLine. You will not be able to view the SAE any longer and the IRB can only see the IRB Number, the AE number and the name of the SAE.
• If the SAE meets reporting criteria, you will get an email with the Adverse Event Reporting Form attached. Complete the form and obtain signatures from the PI/ designee.
• Submit the report to the IRB within 7 days from the time you had knowledge of the event.
  • If additional backup documentation is submitted such as medical narratives, OR records, etc., verify that none of the backup documentation includes subject identifiers such as name, medical record #, initials, or date of birth. 
• Once the IRB receives the report of the SAE, it will be logged in as received and shortly thereafter it will be reviewed and assigned to an IRB Meeting. Once this happens you will:
  • receive another email telling you when the SAE will be reviewed. Save this email with your regulatory files for this SAE.

IRB Online

External Adverse Events:
The IRB-HSR does NOT REQUIRE that external adverse events be submitted unless they are serious unexpected and result in modification to the risk section of the protocol and/or consent.  
If the event meets IRB-HSR reporting criteria, see the section above for reporting instructions.

If the event does not meet IRB-HSR reporting criteria, but your sponsor requires IRB reporting, then there are 3 acceptable methods for reporting to the IRB-HSR:   

1. IRB Online submission. Instructions for submission are outlined above under “Submitting AEs Using IRB Online”.

2. Submit the hard copy of the AE report to the IRB. This method is acceptable if no modification to the risk section of the consent and/or the risk section of the protocol is required due to this event AND when the study team receives only occasional external AE reports (<5 to report). The study team is asked to add the IRB-HSR Number/UVA Study Tracking Number on each report and submit via email to the IRB-HSR office.
3. Non-UVa/ Batch AE Submission Form . This method is acceptable if no modification to the risk section of the consent and/or the risk section of the protocol AND is the preferred method when the study team receives large numbers of external events (>5 AEs to report). The Non-UVa/Batch AE Submission Form must be completed and the PI must sign and date each form submitted. The study team is asked to attach a Routing Form to the hard copy of the Non UVa/Batch AE Submission Form and either drop this by the IRB-HSR Drop Box located on Davis 5 in the SOM Grants &Contracts office, or place in Messenger Mail- Box 800483, or bring to the IRB-HSR office.
4. A Summary of Adverse Events provided by the sponsor will be accepted and actually preferred by the IRB as long as there is a statement from the sponsor indicating that none of the events reported affect the safety profile of the study or will result in any modification to the current risk section of the protocol and consent

Documentation of the IRB’s Receipt of Adverse Events

If the event is submitted using IRB Online:
An automatic email will be sent to the study team to acknowledge receipt of the AE. The study team should save all emails/forms and file them in the study regulatory file.

If the event is submitted by submitting a report outside of IRB Online:
(Only allowed for AEs that do not meet reporting criteria)
Upon receipt the IRB-HSR Staff will enter the receipt of the AE report into the database, upload the document into IRB Pro and notify the study team via email that the report is in IRB Pro.  External AEs that do not affect the safety of the study will not be reviewed by the IRB.  

If the event is submitted using the Batch Submission Form:
(Only allowed for AEs that do not meet reporting criteria)
Upon receipt the IRB-HSR Staff will enter the receipt of the AE report into IRB Online, upload the document into IRB Pro and notify the study team via email that the report is in IRB Pro. Non-UVa Batch AE Submission Forms are not reviewed.

When can the Study Team stop sending External Adverse Event to the IRB-HSR?

The IRB-HSR does not require the submission of External Adverse Event Reports unless the event represents a newly identified risk that will result in modification to the protocol and/or consent.

If the sponsor requires the study team to submit external AEs, the study team may stop sending these reports:

• if a study is closed to enrollment and in data analysis 
• if the study has been closed with the IRB-HSR 

Making Corrections To /Deleting SAEs submitted using IRB OnLine

There are times when SAEs Reports will need to be corrected or deleted after they have been submitted. There are different actions that can be taken at various stages of SAE submission.  Please find the scenario that best describes the status of the AE in question and follow the directions for that scenario. 

The IRB-HSR staff will not correct events. They will return events for correction/deletion or delete events that were erroneously entered under the wrong protocol. 

The study team must make this request via e-mail that includes the IRB-HSR protocol number and the IRB-HSR AE Tracking Number.

Help and Education Regarding Serious Adverse Events

1. Refer to your study documents (protocol/IRB application) to better understand any protocol-specific reporting requirements.
2. Feel free to contact the IRB-HSR for assistance anytime. Please refer to the Staff Directory on the website under General Information and call the person responsible for Adverse Events. 
3. View the Learning Shot on Adverse Events on the IRB-HSR website. Under IRB-HSR RESOURCES select Education and then select IRB Learning Shots - IRB Online Education. Scroll down to the Learning Shot entitled:Safety Reporting Part 1: Serious Adverse Events
4. Consider attending an IRB 101 educational session.