Adverse Events


A thorough and prompt assessment of adverse events, as well as appropriate reporting of those events, ensures safety of human subjects participating in clinical trials.

It is critical that each study team member know the adverse event reporting requirements to the sponsor and IRB. Those requirements can be located in the protocol, clinical trial agreement, other sponsor correspondence, monitoring reports, and/or the Emory IRB or Western IRB policies.  

Background

The Investigational New Drug (IND) regulations (21 CFR 312) require that, for serious adverse events (SAE):

  • Investigators:  Except for study endpoints, the investigator must immediately report to the sponsor all serious adverse events, regardless of whether the investigator believes that they are drug related or anticipated.
    • Investigator must include an assessment of causality
    • For nonserious adverse events, the FDA requires that the investigator report to the sponsor in accordance with sponsor and protocol requirements, generally on case report forms.
  • Sponsors:  Within 15 days of becoming aware, the sponsor must notify the FDA and all participating investigators via IND safety reports of events that are unexpected, caused by the study drug, and meet the FDA definition of “serious.”

The Investigational Device Exemption (IDE) regulations (21 CFR 812) require that:

  • Investigators report to the sponsor and IRB all reports of unanticipated adverse device effects (UADE) within 10 days of becoming aware.  UADEs are serious, life threatening, or result in death AND unexpected and caused by the device.
  • Sponsors report to the FDA, all participating IRBs, and all participating investigators all UADEs within 10 working days.
    • Sponsors who determine that a UADE presents an unreasonable risk to subjects shall terminate all investigations within 5 days of the sponsor making this determination. 

The human subjects protection regulations (21 CFR 56 and 45 CFR 46) require that the investigator report all unanticipated problems involving risk to participants or others (UP) to the IRB promptly (Emory IRB defines “prompt” as 10 calendar days).  UPs are unexpected, caused by the study intervention, and suggest that there is a risk to subjects or others.

Review UP Guidance 

Adverse Event Scope

The FDA defines an adverse event as any untoward medical occurrence associated with the use of the investigational product in humans, whether or not considered to be related to the investigational product. In order to document assessment of events for SAE, UP, and UADE, as well as document compliance with the regulatory reporting requirements, the investigator must document real-time assessment of all adverse events.

The most common places that AEs exist in source documentation are physician notes, nursing/coordinator notes, lab reports (abnormal lab values could be adverse events), procedure notes, subject diaries (e.g., pill diaries, daily food logs, and symptom diaries), documentation from phone calls or emails with subjects, and adverse event logs.

At the start of a study the subject’s medical history is collected for a baseline assessment. Changes in medical conditions that were noted at baseline must be documented as adverse events. New events/symptoms that occur to the subject during the course of the study are also adverse events.

Best Practice to Comply with the Regulations

To demonstrate proper oversight for the trial and real time adverse event assessment for safety of subjects, the PI should document clinical significance, grade, and attribution of the event to the investigational product. The PI may delegate this activity to other qualified investigators; however, the PI is ultimately responsible and must also fulfill his/her regulatory reporting requirements to the sponsor and IRB.

Organization

It is a best practice for the PI or designee to maintain a system to collect AEs onto a log. This can be accomplished by tasking one person with reviewing all research and medical records relating to the research visit/event and transcribing them to the AE log.  The AE log should be regularly reviewed by the PI, at least weekly, at which time the PI can grade and attribute each AE. While reviewing the AEs, the PI should consider the criteria for SAE, UP, and UADE and report accordingly.   

The AE log should contain fields for description of event, start/stop dates, grade, attribution, and PI signature and date. 

External Adverse Event Reports

Sponsors of multisite studies are required to send all participating investigators reports of certain adverse events, as described above.  Upon receipt of these events to Emory investigators, the PI must review them and document his/her assessment with regards to UP.  If the Emory PI assesses the event as a UP (i.e., Emory subjects are at a risk of harm), that event must be reported to the IRB within 10 calendar days.  The PI should consider taking any of the following measures to protect subjects: halt the study until further information is known, notify subjects, amend the informed consent, and/or obtain reconsent from active subjects.

External AEs will be provided to the PI as described in the protocol, clinical trial agreement, or other sponsor correspondence.  Some drugs may have a large volume of these reports, which can be hard to keep up with.  Ensure that your site has a system of receipt, review, and documentation of the PI’s assessment.  If the sponsor requires that the PI download events from a website, ensure that you set frequent periodic reminders to check the system.

The Emory IRB has a worksheet that can capture the PI’s assessment of external adverse events. Attach the worksheet to the top of each event and have the PI complete the worksheet.  If the PI assesses the event as a UP, it must be reported to the IRB within 10 calendar days of the PI’s assessment.

Tools for External Adverse Events

References

21 CFR 56, 21 CFR 312, 21 CFR 812, 45 CFR 46, FDA Draft Guidance: Safety Reporting Requirements for INDs and BA/BE Studies, FDA Guidance: Guidance for Clinical Investigators, Sponsors, and IRBs; Adverse Event Reporting Requirements to IRBs—Improving Human Subjects Protection, and OHRP Guidance: Guidance on Reviewing and Reporting Unanticipated Problems Involving Risk to Subjects or Others and Adverse Events