The PI and designated research staff are responsible for identifying, investigating, classifying and reporting adverse events (AE) under U.S. and international regulations, as well as IRB policies and specific study protocols.

To identify potential AEs, designated study personnel have many sources, including medical records, abnormal test results, direct research staff observations and subject-reported events. Sites need to develop and follow a consistent, thorough process for reviewing all records for potential adverse events, Bradley Lieberman, manager of clinical monitoring services at IMARC Research, told attendees at a webinar sponsored by the Association of Clinical Research Professionals last week. The frequency of reviews can depend on several factors, Lieberman said, including the rate of patient enrollment, which tends to be heavier at the start of a trial.

Procedures should ensure that the study team has easy access to all medical records, including outside records, as needed. For example, imaging and lab tests should be reviewed, and automated notifications in the electronic medical reporting system can alert site staff to potential AEs. Reviewing medical records before a subject’s next scheduled follow-up visit also can be a good practice, Lieberman said.

Researchers also need to make sure to get patient confirmation of information that can vary across written medical records, such as medication doses and types.

Sites need to make sure that those assessing AEs are trained, qualified and clearly designated in AE-related procedures. The PI, a co- or sub-investigator or other trained personnel are commonly used, but sponsor and IRB requirements also can play a role in who is delegated to this task. In some cases, the sponsor might have specific instructions, such as that a physician perform the assessment.

The FDA considers AE data a key indicator of patient risk and study data quality, Lieberman noted, and so focuses on this area during study site inspections. Sites need to be prepared for a regulatory inspection with a comprehensive AE plan tailored to each study, he said.

The agency will examine the study’s/site’s process for reviewing and reporting AEs, as well as conducting a review of source materials to determine whether AEs have been reported appropriately. For instance, the agency may ask to:

• Review progress notes and confirm whether an AE report was required;
• Review imaging reports and have the PI explain any findings not reported as AEs;
• Review patient discharge summaries to confirm that all serious AEs were reported;
• Have the PI explain why certain events were deemed part of a pre-existing condition and not reported;
• Have the PI explain the process for determining what is and is not a reportable AE; and
• Receive an explanation as to why certain individual AEs or certain types of events were not reported.

Once AEs have been identified, compliance with AE reporting requirements comes down to two steps, said Michael Marcota, project manager at IMARC: assessment of which events meet the definition of a reportable AE; and timely and accurate reporting of AEs to the device sponsor, the IRB or both, as required under applicable regulations, individual study protocols and IRB policies.

In the assessment stage, the goal is to determine which events qualify as reportable AEs under applicable definitions. Not all events will be AEs. For instance, pre-existing conditions generally don’t qualify, nor do abnormal imaging or lab tests that are not “untoward medical occurrences,” a term often seen in regulatory and other requirements. Generally, the assessment should consider whether an event was:

• Unexpected, a known and foreseeable risk or the natural progression of the patient’s underlying condition;
• Related to the device, study procedures, pre-existing or underlying patient conditions or patient participation in the study; and
• Serious, resulting in hospitalization, disability or incapacity, congenital or birth defect or death, or otherwise threatening the patient’s life and health.

How a site reports AEs depends on regulatory definitions and regulations. FDA regulations in 21 CFR 812.3 define unanticipated adverse events (UAE) that must be reported to the sponsor. The ICH good clinical practices guideline, E6(R2), and ISO standard 14155 likewise define serious AEs. There are some differences among the definitions, so AE review and assessment procedures must account for any that are applicable. In addition, researchers must comply with AE reporting requirements spelled out in the policies of the IRBs responsible for different sites, as well as those in individual study protocols.

This can make it challenging to apply a single AE procedure to different trials that may be subject to different IRBs and protocols, Marcota noted. Even within a single study, if multiple sites are involved, that could mean complying with different IRB policies, since sites may fall under the purview of different IRBs. Timeliness is equally important. Regulations require that UAEs be reported to the device sponsor within 10 days, but specific study protocols or IRB policies may have different requirements.