Adverse Events

• Introduction
• Useful Definitions
• How to Submit an Adverse Event

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

External, Serious, Unexpected Adverse Events also must be reported 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 Data and Safety Monitoring Plan outlined in 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 Data and Safety Monitoring Plan outlined in the protocol do not need to be submitted to the IRB unless the sponsor requires submission. 

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.  For example, if an event occurs in a subject enrolled in a protocol at UVa, or occurs in others associated with a subject who is enrolled in a protocol at UVa, 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 which 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. An important medical event is any AE that may not result in death, be life-threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions of SAEs.

OR

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 adverse event.

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 adverse event. 

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 Adverse 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.

How To Submit Adverse Events

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

Submitting AEs Using IRB Online:

(This is the required process for submitting Internal, Serious, Unexpected AEs and for External events where, due to this event, the risk section in the consent and/or the risk section of the protocol documented in the Data and Safety Monitoring Plan requires modification.)
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."
• when entry is complete follow the on-screen directions.

If the AE is internal, unexpected and serious, OR external, and due to this event, the risk section in the consent and/or the risk section of the protocol documented in the Data and Safety Monitoring Plan requires modification, the investigator will print out the AE form after entering it online, obtain required signatures and submit the original to the IRB-HSR office with backup documentation such as medical narratives, revised consents, etc.  Verify that none of the backup documentation includes subject identifiers such as name, medical record #, initials, or date of birth. 

If the AE is external and does not result in modification ofthe risk section in the consent and/or the risk section of the protocol documented in the Data and Safety Monitoring Plan and/or does not meet the IRB-HSR reporting criteria, the AE will automatically be downloaded into IRB online as an expedited AE event when the event is submitted

IRB Online

Submitting External AEs that do not affect risk or result in modification to the risk section of the consent and/or the risk section of the protocol documented in the Data and Safety Monitoring Plan.

THE IRB-HSR DOES NOT REQUIRE THAT THESE DOCUMENTS BE SUBMITTED.  IF YOUR SPONSOR REQUIRES THAT YOU SUBMIT THESE DOCUMENTS PLEASE FOLLOW THE INFORMATION BELOW:

There are 3 acceptable methods for reporting to the IRB-HSR any Serious, Unexpected External Adverse Events that DO NOT affect risk or result in modification to the risk section of the protocol or consent::  

1. IRB Online submission.  This method is required for external AEs resulting in modification to the risk section of the consent and/or the risk section of the protocol as documented in the Data and Safety Monitoring Plan. Instructions for submission are previously outline
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 as documented in the Data and Safety Monitoring Plan 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 attach a Routing Form to the hard copy of the AE report and either drop this by the drop box located on Barringer 4, place in Messenger Mail, Box 800483, or bring to the IRB-HSR office.
3. Non-UVa/ Batch AE Submission Form (Appendix A.)  This method is acceptable if no modification to the risk section of the consent and/or the risk section of the protocol as documented in the Data and Safety Monitoring Plan is required due to this event AND is the preferred method when the study team received large numbers of external events (>5 AEs to report).   The Non-UVa/Batch AE Submission Form must be completed and the PI must sign 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 drop box located on Davis 5, 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 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.

If the event is entered using IRB Online…
If the AE is entered on IRB Online, is internal,  unexpected and serious OR, is external, serious unexpected and results in modification to the protocol or consent, the study team will print out the AE form after entering it online, obtain required signatures and submit the original to the IRB-HSR office with backup   documentation such as medical narratives, revised consents, etc.  Please make sure none of the backup documentation includes subject identifiers such as name, medical record #, initials, date of birth.  Upon receipt the IRB-HSR Staff will enter the tracking # as received.  The report will then be reviewed by the IRB-HSR Director or designee and the IRB-HSR Chair or IRB-HSR Vice-Chair or designee.

Once the event is reviewed by the IRB-HSR Director and Chair or their designees it will be noted as reviewed in the database.  The person submitting the AE will receive an email verifying receipt and review.  The AE will also be listed on the next IRB-HSR meeting agenda under AE Notification. 
The study team should print out all emails/forms and file them in the protocol regulatory file.

IF the event is submitted by sending in a hard copy of the report provided by the sponsor…
If the AE is external, unexpected and serious and does not result in modification to the protocol or consent, the study team may submit the hard copy of the AE from the sponsor (as long as there are not too many.  If you receive more than 5, use of the Batch AE Submission Form is recommended.)   The study team should write the IRB-HSR number on the hard copy, attach a Routing Slip, and either drop the submission at the Barringer 4 Drop Box or send via Messenger Mail to Box 800483.   Upon receipt the IRB-HSR Staff will enter the receipt of the AE report into the database, stamp the form with the Acknowledgement of Receipt stamp.   A copy of the stamped form will be forwarded to the study team.  The original report will be placed in the IRB-HSR files.  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…
If the AE is external, unexpected and serious and does not result in modification to the protocol or consent, the study team may submit the AE using the Non-UVa Batch AE Submission Form. The study team will print out the Batch AE form and complete the requested information. The PI signature and date fields should be present on each page submitted.   Obtain required signatures and submit the original to the IRB-HSR office.   Upon receipt the IRB-HSR Staff will enter the receipt of the AE report into the database, stamp the form with the Acknowledgement of Receipt stamp.   A copy of the stamped form will be forwarded to the study team.  The original report will be placed in the IRB-HSR files.  Non-UVa Batch AE Submission Forms are not reviewed. 

If a study is closed to enrollment, in data analysis or has been closed with the IRB-HSR and the PI receives an adverse event report from another site, the report does not need to be submitted to the IRB-HSR UNLESS you feel the adverse event reported may affect subjects previously enrolled at UVa.  In this case a modification will be required to add an addendum to the consent in order to communicate the new risk information to the participants.

Revised 10/27/09