At Advarra, we often get questions about exactly what events should be reported to the IRB. We understand that “reportable events” can be tricky: some “events” are specifically referenced in the regulations, but lack a definition; some are covered in regulatory guidance documents; and some are “industry standard” that are neither an IRB regulation or IRB best practice/guidance. In this blog, we’ll look at what the regulations do and do not say about IRB reporting requirements and how Advarra has addressed some of the undefined “gray areas.”
Pull back the curtain on any IRB, and you’ll find a busy organization that processes, reviews, and exchanges enormous volumes of documents per day, from consent forms to reliance agreements to unanticipated event reports. These “potential” unanticipated event reports, often unintentional protocol violations/deviations, in particular can number in the tens of thousands for a busy IRB, independent and institutional alike. At Advarra, we found that nearly 79% of the reports received in the most recent quarter were either submitted unnecessarily or did not pertain to the aspects of research the IRB oversees.
Why the Excess of Needless Reports?
In 2009, the FDA released guidance clarifying what must be reported to both the IRB and the FDA itself. OHRP also offers guidance on reporting incidents to the IRB and to OHRP (the original 2005 guidance was replaced in 2011). In addition, the FDA published a final rule, effective March 28, 2011, that clarified reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials conducted under an investigational new drug application (IND).
As a result of continued non-adherence to the final rule, in 2015 the Clinical Trials Transformation Initiative (CTTI) initiated a Safety Advancement Project working group, in which members of the Advarra team participated. This is how we learned that after the final rule was published, FDA found the number of submissions to the FDA actually increased! Members of the Advarra team agreed that the 2009 guidance also did very little to decrease the number of safety report submissions to the IRB. Clearly something was driving these submissions—and it wasn’t FDA guidance. In conversations with sponsors and research organizations, a common response for continuing to submit safety reports was “it’s just our SOP.”
Safety reports are only a subset of events that do not require reporting to the IRB. For example, many researchers report every unintentional protocol deviation to the IRB, including events such as participants that miss study visits due to inclement weather. Whether it’s submitting safety reports or unintentional protocol deviations to the IRB, by doing so sponsors and/or researchers are not provided with any regulatory or legal coverage. As far as safety reports, FDA guidance clearly states that unless the event(s) meet the definition of an unanticipated problem (UAP) or unanticipated adverse device effect (UADE), based on the sponsor’s assessment, the agency does not require reporting to the IRB. Most IRBs have adopted an “acknowledgement of receipt” policy for these unnecessary reports, where the IRB provides a letter of acknowledgement that in essence says, “we received your submission, but did not review it.”
What Distinguishes Reportable and Non-Reportable Events?
A key aspect of whether an event should be reported is determining if it pertains directly to the safety of the participants involved in the study. Ask yourself:
- Is the event unexpected (in terms of nature, severity, or frequency) given the information provided in research-related documents and the characteristics of the participant population being studied?
- Is the event related or possibly related to participation in the research?
- Does the event suggest that the research places participants or others at a greater risk of harm than was previously known or recognized, typically requiring updates to the protocol and/or informed consent form (ICF)?
For example, if an anticipated side effect like mild dizziness is occurring with greater severity causing vomiting and temporary vision impairment, that could be an indication that the ICF should be updated to reflect this greater risk or that the procedure must change to ensure the participant has assistance returning home. This is a reportable event once that determination is made.
Consider a participant who, after receiving an injection of the study drug, trips and falls outside the clinic, breaking her ankle. Is it a reportable event? According to that 2009 FDA guidance, it is the study sponsor’s duty to investigate. If a participant falls outside the clinic, are they simply clumsy or unlucky, or is an unanticipated side effect of dizziness emerging? Either way, the sponsor should investigate and determine if the event is related to the person’s participation in the study before reporting to the IRB. The sponsor has the necessary information to make this determination; the IRB does not and cannot fulfill this investigatory role (even a designated single IRB does not have the complete context of a study sponsor).
Another example: Prior to receiving the study drug, participants were required to be weighed so that each person received the correct dosage. However, during an interim analysis study staff discovered that the participants who weighed less than 120 pounds all experienced a precipitous drop in blood pressure shortly after dosing. Is it reportable to the IRB? Let’s measure it against the above list of questions: yes, it was unexpected; yes, it was related to participation in the research; and yes, the event suggests the research placed participants at a greater risk of harm than was previously recognized. This is a reportable event, and measures should be taken to revise the protocol and change the dosing for participants weighing less than 120 pounds.
Further, most events which do not affect participant safety are non-reportable to the IRB. (For information on non-participant safety items that should be reported to the IRB, read our blog on investigator noncompliance.) Protocol deviations or violations, such as a participant neglecting to initial a page of the ICF or failing to return a symptom diary, are not reportable events to the IRB. However, they may be reportable to the sponsor.
How to Know Whether to Report
So, what should research organizations do if they are unsure whether to report an event? Contact your IRB. It’s what the IRB is here for. Rather than wasting resources, call your IRB study contact for guidance in determining whether to report. The FDA has made it clear who is responsible for safety assessments, and it’s not the role of an IRB to manage investigations or draw conclusions. While some sponsors assume IRBs are maintaining awareness of trends, this is not a function of the IRB. Of course, an IRB will identify anything it sees as problematic, but data analysis remains the responsibility of the sponsoring organization.
Need more information on unanticipated problems? Check out our blog Reporting to the IRB: Serious Adverse Events (SAEs) in Drug Studies. Not sure if an event should be reported to Advarra’s IRB? Contact your Study Coordinator for assistance.