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Reporting Unanticipated Problems and Adverse Events to the IRB

In response to confusion regarding Adverse Events (AEs) and Unanticipated Problems (UPs) and the types of events or information that must be reported to an IRB, the Office of Human Research Protections (OHRP) and the Food and Drug Administration (FDA) issued guidance in 2007 to clarify their positions regarding reporting requirements related to AEs and UPs. More recently, the FDA published final guidance regarding the topic. The objective of this article is to provide a review of the regulatory requirements and guidance regarding the reporting of AEs and UPs to an IRB.

Regulatory Overview

The regulatory guidance published by OHRP and FDA in 2007¹ emphasize that principal investigators must report to the IRB those events that represent "any unanticipated problem involving risks to subjects or others."² This message was reiterated in the 2009 FDA guidance.³ The guidance also underscores that the review and reporting of AEs and UPs must occur in a timely manner, and that when the information is submitted to the IRB, the sponsor/investigator reporting the AE and/or UP should provide some sort of analysis regarding the significance and relatedness of the event to the clinical trial rather than merely reporting large volumes of information with out any context. By including such information, OHRP and FDA believe that the IRB can better fulfill its responsibility for protecting human subjects.

Unanticipated Problems Defined

Investigators confront a variety of events at their site that may be potential UPs. These include: serious adverse events; protocol deviations; prospective protocol waiver requests; investigator felony; study staff fraud; participant pregnancy; adverse audit or enforcement action; investigator felony; unresolved research participant complaint; and FDA Form 483 warning letters. Investigators also receive reports and communications from study sponsors that may include Unanticipated Problems. These reports include: IND safety reports; investigator brochures; DSMB summary reports; reports, publications, or interim results or findings; sponsor audits; notice of early study termination; and revised labeling.

So what exactly is an unanticipated problem involving risks to participants or others? According to OHRP and FDA, in order for an event (outcome, experience, or incident) to be classified as a potential UP that must be promptly reported to the IRB, all three of the following criteria must be satisfied:

• be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
• be related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
• suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

An "unanticipated" event is one that is not identified in nature, severity, or frequency in the relevant safety documents(s) for the study product or is not identified as a possible risk in the study protocol or the informed consent form for the study. A reportable event can occur in either a clinical setting (such as a serious and unanticipated reaction to the study drug) or a non-clinical setting (such as the loss of a laptop with study data).

It is ultimately the decision of the Board whether a reportable event constitutes an UP. If the Board determines that an event is an UP, it must report the UP to the FDA and/or OHRP and also notify the sponsor and institutional officials.

Sponsor vs. IRB: What are an Investigator’s Reporting Requirements?

The types of events that must be reported by a principal investigator to a sponsor and IRB differ. Regulations require a sponsor to monitor all AEs experienced by a study’s participants (e.g., Sponsors (1) monitor all AEs, protocol deviations, and other events; (2) perform data analysis and trending for the study; (3) can delegate data monitoring to a separate entity, such as a data safety monitoring board ("DSMB"); and (4) must report their findings at least annually to the FDA). Regulations, however, only require an IRB to develop procedures to ensure prompt reporting of "unanticipated problems involving risk to human subjects or others." Consistent with these requirements, investigators must therefore report all adverse events and protocol deviations to the sponsor and all unanticipated problems involving risk to human subjects or others to the IRB. This is where the confusion lies. How exactly does one determine which adverse events are unanticipated problems and which ones are not?

Adverse Events in Relationship to Unanticipated Problems

Adverse events are defined as "any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research,"⁴ and include psychological and physical harm. Adverse can be serious or non-serious. The OHRP guidance includes the following Venn diagram, which summarizes the general relationship between adverse events and unanticipated problems:

In light of the three criteria that must be satisfied in order for an event to be an unanticipated problem involving risks to participants or others (unexpected; related or possibly related; and places subjects or others at a greater risk of harm), the diagram illustrates three important points:

• The vast majority of adverse events occurring in human subjects are not unanticipated problems (Area A).
• A small proportion of adverse events are unanticipated problems (Area B).
• Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (Area C).

Quorum Review IRBs Reporting Requirements related to AEs and UPs

Quorum requires Principal Investigators to promptly report all serious adverse events as wells as all events that may constitute unanticipated problems involving risk to research participants or others. New or updated safety information relating to study or study product must also be reported. The following table summarizes the events or information that must be reported to Quorum within 10 business days of their occurrence.

For a complete summary of Quorum’s reporting requirements, please refer to the Safety Information and Unanticipated Problems Reporting Guidelines located on our website at www.quorumreview.com. An excerpt version of Quorum’s reporting guidelines (reportable events that occur at the PI’s research site or are associated with the PI and events that occur external to the PI’s research site and are reported to the PI) is below.

Please contact our Customer Relations Department at (206) 448-4082 or customerrelations@quorumreview.com, for more information regarding Quorum’s reporting requirements.

¹OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events" (January 15, 2007); FDA [Draft] "Guidance for Clinical Investigators, Sponsors and IRBs, Adverse Event Reporting-Improving Human Subjects Protection" (April 2007).

²45 CFR 46.103(b)(5); 21 CFR 56.108(b)(1); 21 CFR 312.53(c)(1)(vii); 21 CFR 312.66.

³FDA "Guidance for Clinical Investigators, Sponsors and IRBs, Adverse Event Reporting to IRBs-Improving Human Subjects Protection" (January 2009).

⁴The OHRP definition is similar to the International Conference on Harmonization, E-6 Guideline for Good Clinical Practice.