Adverse Events

A thorough and prompt assessment of adverse events, as well as appropriate reporting of those events, ensures safety of human participants participating in clinical trials. Each study team member must be knowledgeable of 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 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 participants shall terminate all investigations within 5 days of the sponsor making this determination.

The human participants 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 IRBs promptly (Emory IRB defines “prompt” as 10 business days). UPs are unexpected, caused by the study intervention, and suggest that there is a risk to participants or others. The Emory IRB website has guidance (link to https://www.irb.emory.edu/guidance/reportable.html) on making UP determinations.

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. This is a broad scope. To document assessment of events for SAE, UP, and UADE, and 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 considered adverse events), procedure notes, participant diaries (e.g., pill diaries, daily food logs, and symptom diaries), documentation from phone calls or emails with participants, and adverse event logs.

Document the participant’s medical history at the start of the study. Changes in medical conditions that were noted at baseline must be documented as adverse events, e.g., worsening of an existing condition. New events/symptoms that occur to the participant during 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 participants, 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.

AE Log

The PI or designee should maintain a system to record AEs on a log. If multiple AEs are expected to occur in each participant because the study either involves a higher risk intervention or an ailing population, generate one AE log for each participant. If few AEs are expected for the study, maintain one AE log in the regulatory binder that will cover all participants. Start with the Emory AE log template (link to https://www.ctac.emory.edu/_includes/documents/sections/tools/ae_log.docx) and revise it to match the sponsor or protocol terminology (e.g., “Grade 1” vs “mild”).

Since AEs exist in multiple source documents but should be recorded to one AE log, the study team must take proactive and prompt measures to obtain the PI’s assessment and record onto the AE 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. Another strategy for documenting PI assessment of AEs is for the PI to document assessment (clinical significance, grade, and attribution) in the electronic medical record and later a research coordinator transcribes the PI’s assessment to the AE log. The AE log should contain fields for description of event, start/stop dates, grade, attribution, and PI signature and date.

Throughout the study AEs may recur or change in severity. Each time an AE recurs or changes in severity, close out the initial AE with a stop date and start a new AE with the grade change. For example, if a participant’s headache were to change from a grade II to a grade IV record a stop date for the initial grade II headache and record a new AE with a new start date for the grade IV headache. Recording AEs in this manner will provide a more reliable case history versus recording “intermittent headache” or “headache” with no stop date. AE logs may become long in some studies but will keep a more reliable record.

While reviewing the AEs, the PI should consider the criteria for SAE, UP, and UADE and report accordingly.

External Adverse Event Reports

Sponsors of multi-site studies are required to send all participating investigators reports of certain adverse events. Upon receipt of these events to Emory investigators, the PI must review and document his/her assessment with regards to UP. If the Emory PI assesses the event as a UP (i.e., Emory participants or others are at a greater risk of harm than previously known), that event must be reported to the IRB within 10 business days. Working with the IRB, the PI should consider taking any of the following measures to protect participants: halt the study until further information is known, notify participants, modify the informed consent, and/or obtain reconsent from active participants.

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 PI can document his/her assessment of external adverse events by completing Emory IRB’s Assessment Form for Events (link to https://www.irb.emory.edu/_includes/documents/sections/reportable_event_assessment_form.docx). 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 business days of the PI’s assessment.

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 Participants Protection, and OHRP Guidance: Guidance on Reviewing and Reporting Unanticipated Problems Involving Risk to Participants or Others and Adverse Events