Heather Kopetskie, MS, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical planning, analysis, and reporting for Phase 1, 2 and 3 clinical trials and observational studies. Her research experience includes over 8 years focusing on solid organ and cell transplantation through work on the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT) project.  In addition, Heather serves as Rho’s biostatistics operational service leader, an internal expert sharing biostatistical industry trends, best practices, processes and training.

Hyunsook Chin, MPH, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical design, analysis, and reporting for clinical trials and observational studies. Her therapeutic area experience includes: autoimmune diseases, oncology, nephrology, cardiovascular diseases, and ophthalmology. Specifically, her research experience has focused on solid organ transplantation for over 8 years on the CTOT projects. She also has several publications from research in nephrology and solid organ transplantation projects. She is currently working on several publications.

An Adverse Event (AE) is any unfavorable or unintended sign, symptom, or disease temporally associated with a study procedure or use of a drug, and does not imply any judgment about causality. An AE is considered Serious if in the view of either the investigator or sponsor, the outcome is any of the following:

• Death
• Life-threatening event
• Hospitalization (initial or prolonged)
• Disability or permanent damage
• Congenital anomaly/birth defect
• Required intervention to prevent impairment or damage
• Other important medical event

When a serious adverse event (SAE) occurs the site investigator immediately reports the event to the sponsor. Both the site investigator and the sponsor assess causality for every SAE. Causality is whether there is a reasonable possibility that the drug caused the event. The FDA believes the sponsor can better assess causality as they have access to SAE reports from multiple sites and studies along with a familiarity with the drug’s mechanism of action. When expedited SAE reports are delivered to the FDA the sponsor causality is reported instead of the site investigator’s.

Causality assessments may differ between the site investigator and sponsor. It is important to understand the difference in assessments to ensure proper reporting and conduct through a trial. For example, if stopping rules rely on causality should the sponsor’s or site investigator’s causality assessment be used? Which causality assessment should be used for DSMB and CSR reports? To better understand how to handle these situations it’s important to understand the differences.

We reviewed over 1400 SAEs from 76 studies over the last 6 years. Each SAE had causality assessed against an average of 3.8 study interventions (e.g. study medication 1, study procedure 1, etc.) for a total of over 5300 causality assessments. Related causality included definitely, possibly, and probably related while Not Related included unlikely related and unrelated. At the SAE level an SAE was considered related if at least one study intervention was determined related.

Table 1: Causality Comparisons

Sponsors deemed more SAEs to be related to study interventions than site investigators. This relationship is maintained when looking at the breakdown of SAEs by severity with the sponsor determining a larger percentage of SAEs related to the study intervention. This also held for the majority of system organ classes reviewed.

What actions can we take with this information when designing a trial?

1. If any study stopping rules rely on causality the study team may want to consider using the sponsor causality to ensure all possible cases are captured. The biggest hurdle with this transition would be acquiring the sponsor causality in real time as it is not captured in the clinical database.
2. For DSMB reports, if only the site investigator causality is reported the relationship to SAEs may be under reported versus the information the FDA receives. Given the sponsor more often assesses SAEs as related this is important information that should be provided to the DSMB members when evaluating the safety of the study.
3. For clinical study reports, both SAE and non-serious adverse events are reported. The study team should determine what information they want to include. The sponsor safety assessments are not included in the clinical database but it is what the FDA receives during the conduct of the trial. Additionally, if the sponsor more often assesses SAEs as related the report may under report related SAEs if only the site investigator assessment is used in the report.

Note that these findings are based on studies Rho has supported and may not be consistent with findings from other trials/sponsors.  Additionally, in some studies the site investigator may have changed the relationship of the SAE based on discussions with the sponsor and we do not have any information to quantify how often this occurs.