Assessing and reporting adverse events (AEs) in clinical trials is critical to ensuring the study is as safe as possible and the participants have the most up to date information so they can decide whether to continue their participation in the research study. These responsibilities and reporting requirements are outlined in U.S. regulations. However, it’s not always clear to research professionals what should be reported, who should do the reporting, and which oversight entity(ies) should review the report.
In 2009, the Food and Drug Administration (FDA) released a guidance document on AE reporting to IRBs. The guidance seeks to “assist the research community in interpreting requirements for submitting reports of unanticipated problems, including certain adverse events reports” to the IRB.
What Does FDA Guidance Say About SAE Reporting?
For research conducted under an investigational new drug (IND) application, the agency’s guidance states (bold and italics added for emphasis):
- Investigators are required to report promptly “to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug.”
- “If the adverse effect is alarming, the investigator shall report the adverse effect immediately.” (21 CFR 312.64(b))
- Sponsors specifically are required to notify all participating investigators (and FDA) 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” (21 CFR 312.32(c)(1)(i)(A),(B))
- More generally, sponsors are also 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” (21 CFR 312.55(b)).
- Investigators are required to report promptly “to the IRB… all unanticipated problems involving risks to human subjects or others,” including adverse events that should be considered unanticipated problems. (21 CFR 56.108(b)(1), 21 CFR 312.53(c)(1)(vii), and 21 CFR 312.66)
So what does this mean in practice?
- Investigators report to the sponsor: Any adverse event (AE) determined to be caused by (or probably caused by) the drug
- Sponsors report to investigators and FDA: Any AEs associated with the study drug that are both serious and unexpected, as well as any finding from animal research suggesting a significant risk to human subjects
- Sponsors should also inform investigators of any new observations regarding the drug, especially AEs and safe use concerns
- Investigators and sponsors report to the IRB: All unanticipated problems (UAPs) involving risks to human subjects or others
- The challenge: Determining which AEs should be considered UAPs warranting IRB reporting
Apart from a few serious, uncommon AEs, usually considered to be strongly related to drug exposure (e.g., Stevens Johnson syndrome, hepatic injury, anaphylaxis), single/isolated AE reports typically do not meet the criteria of a UAP.
Who Should Assess AEs in Clinical Trials?
According to FDA guidance, the sponsor should assess AEs in clinical trials. The agency states in its guidance, “FDA believes that the sponsor is better positioned than the individual investigator to assess the overall safety of the investigational drug because the sponsor has access to serious adverse event reports from multiple study sites and multiple studies and is able to aggregate and analyze these reports.
“Moreover, the sponsor is more familiar with the drug’s mechanism of action, class effects, and other information. For these reasons, investigators must immediately report any serious adverse event to the sponsor, whether or not the investigator considers the event to be drug related (21 CFR 312.64(b)).”
What is an Unanticipated Problem Involving Risk to Human Subjects or Others?
OHRP and FDA guidance defines UAPs as:
- Unexpected (in terms of nature, severity, or frequency) given the information provided in research-related documents and the characteristics of the subject population
- Related or possibly related to participation in the research
- Suggests the research places subjects or others at a greater risk of harm than previously known or recognized
This means an SAE deemed as expected, as identified in the study documentation, but is occurring at greater frequency or severity (as determined by the sponsor’s assessment) should be reported to the IRB as a UAP.
Which AEs Should Not Be Submitted to the IRB?
However, serious adverse events (SAEs) determined to be unrelated to the study, or are directly related to the subject population’s disease, should not be submitted to the IRB.
For SAEs where relatedness has not yet been determined, and further analysis is required, IRB submission should only happen after the investigator and the sponsor have determined the SAE was related to the test article. The IRB will likely request the sponsor’s assessment before reviewing.
Per FDA, “It is important to note that some events that would not meet the criteria for reporting in an IND safety report would be considered unanticipated problems involving risk to human subjects (e.g., informed consent or privacy issues, certain adverse events that could not be caused by the investigational drug, such as events that occur prior to test article administration as a result of a washout period or due to a screening procedure).”
SAEs occurring at other sites and provided to each investigator (e.g., IND safety reports or suspected unexpected serious adverse reactions [SUSARs]) should only be submitted to the IRB following the sponsor’s assessment that the event(s) do in fact meet the UAP criteria. For multisite studies, the sponsor will typically report a UAP on behalf of all sites.
It is important to note UAPs will often have implications for study conduct, such as:
- A protocol update (e.g., additional safety monitoring, updates to inclusion/exclusion criteria, etc.)
- Changes to the informed consent form (ICF) and/or investigator’s brochure
- Changes to the enrollment status (e.g., enrollment/screening and/or dosing hold)
The IRB must be notified of a UAP promptly, but no later than two weeks or 10 business days from the time of identification.
For example, at Advarra, when the IRB receives SAEs or safety reports that do not meet the UAP criteria (as defined by the above FDA guidance), the submitting party will receive acknowledgement of receipt only. The item will not receive IRB review. When these items are submitted by a sponsor or contract research organization (CRO), Advarra’s default process is to generate an acknowledgement of receipt to all open sites, though sponsors/CROs may opt-out of this process.
IRB reporting policies vary, so consult your IRB of record to ensure you understand their requirements.
Note: This article was originally published on December 14, 2018, and has been updated to include new and clarifying information.