By Karen Outten, executive director of clinical trial safety reporting, Merck
One of the most time consuming, but necessary, operational tasks that sites must manage is the reporting of serious adverse events (SAEs) during a clinical trial. The FDA reports that it receives over 1 million adverse event reports each year and each report is required to be manually reviewed in a timely manner. Combine that with the SAEs that are reported for all other health authorities around the globe, and the total number of reports to be reviewed is staggering.
Patient safety and continuation of clinical trials are dependent on this process. But what counts as an SAE? The FDA considers the following to be a serious adverse event:
- A threat to the patient’s life
- In-patient hospitalization or prolongation of an existing hospitalization
- A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly, birth defect, or important medical events that may not result in death
- Requires hospitalization when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition
While sponsors are required to follow the same health authority reporting regulations, there is a lack of standardization across the data fields collected on SAE case report forms and SAE paper reporting forms. The resulting variation can create ambiguity for investigators working with multiple sponsors to conduct clinical trials, leading to delay and uncertainty in the process of collecting a patient safety data set that provides a complete clinical picture of the SAE.
Developing and adopting an industry standard around SAE data collection is expected to add inherent value across patients, sites, sponsors, and health authorities. An industry standard is expected to optimize clinical trial safety data collection and provide efficiencies in the SAE data collection and reporting processes, including the potential to reduce the number of SAE case versions required to obtain a comprehensive SAE report. Earlier availability of high-quality comprehensive SAE reports will protect patients from unnecessary risks and support detection of important safety signals and the development of a robust safety profile.
In 2019, TransCelerate BioPharma realized that there was a need to have a list of common serious adverse event data fields that the biopharma R&D industry could follow to increase the quality and comprehensiveness of SAE reports. The organization created the Common Serious Adverse Events Fields Initiative, which gathered contributors from the clinical and pharmacovigilance operations at our 20 member companies to compile this list.
Through their work, the team named four key benefits:
- Supply health authorities and an industry standard-setting organization with a proposed common core list of SAE fields to help create an SAE data collection industry standard
- Supports the complete clinical presentation of an SAE
- Allows for independent clinical assessments
- Positively impacts patient safety, investigators, health authorities, and sponsors
The TransCelerate Common SAE team completed their assessment and transitioned it to Clinical Data Interchange Standards Consortium (CDISC). To kick off the project, the Common SAE team conducted a comprehensive landscape assessment to understand the applicable current industry regulations. Following the regulatory landscape assessment, each team member provided a third-party consultant with a copy of the SAE reporting form currently in use by their company. The consultant collected, blinded, and aggregated all data fields into a master list of 1,238 data fields. Simply put, across the participating member companies, despite ostensibly collecting the same data to report to the same regulators, 1,238 differently named fields were used, which shows the scale of the challenge. This not only highlighted the lack of consistency across trial sponsors but also the challenges facing investigators working with multiple clinical trial sponsors.
The team performed an SAE fields commonality assessment across the 1,238 data fields included in the master list. Once like data fields were grouped together, the team divided the data fields into nine categories containing 833 unique fields. Data fields were assessed for commonality and relevance. For example, all data points related to collection of concomitant medications were grouped together.
At the end of this multi-phase approach, the master list became a list of 133 unique data fields to comprise the list of common SAE fields that would provide a complete clinical picture of a serious adverse event. This final list was cross-referenced and compared to the industry guidance and regulations reviewed during the initial regulatory landscape assessment to ensure compliance with regulatory safety reporting requirements without sacrificing data quality or comprehensive data collection.
TransCelerate’s final result is the “Common SAE Fields Project Overview & Outputs” slide deck and methodology. Once completed, TransCelerate transitioned this deliverable to CDISC’s CDASH SAE Standard team in late 2019. Five team members from the TransCelerate SAE Common Fields team also transitioned to the CDISC team as volunteers to serve as subject matter experts.
CDISC has worked for the past 18 months to develop this new industry standard surrounding SAE data collection. In early April 2021, CDISC published its CDASH SAE V2.0 Supplement, which captures how to structure serious adverse events concepts for regulated clinical trials and align with E2B (R3) Electronic Transmission of Individual Case Safety Reports Implementation Guide—Data Elements and Message Specification.
The CDASH SAE Supplement v2.0 expands AE and other domains from the CDASH Model v1.1 and its Implementation Guide, CDASHIG v2.1, as well as Controlled Terminology to include additional data elements that capture information in an SAE form, facilitating sponsor generation of an E2B message for reporting of an individual case study report (ICSR) to regulatory authorities.
All sponsors are required to follow the same health authority reporting regulations. By using a Common SAE fields list, sponsors can reduce ambiguity for investigators. Additional sponsor benefits may include improved efficiencies in SAE reporting operations, an advancement in the quality of data collected, and improved initial report submissions, thereby reducing repetitive case versions. Altogether, this will allow for earlier knowledge of a drug’s benefit and/or risk.
These efforts underscore the importance of collaboration. The ability of pharmaceutical companies, investigators, and health authorities to work in partnership to bring new medicines to market for the benefit of patients and human health is a critical mission we can all stand behind. Development of a standard robust process for SAE reporting to support patient safety is one significant way to help achieve this goal.
About The Author:
Karen Outten is executive director of clinical trial safety reporting within Global Clinical Safety and Pharmacovigilance (GCS&PV) at Merck Research Laboratories (MRL). She has more than 20 years of experience in the pharmaceutical industry, including preclinical research, clinical research, and drug safety and pharmacovigilance. Today, Outten leads a global team of clinical safety scientists supporting clinical trial safety reporting across the Merck early- and late-stage clinical development portfolio. Outten was the team lead of the TransCelerate Common SAE Fields Initiative and has transitioned to the CDISC Clinical Data Acquisition Standards Harmonization (CDASH) SAE Standard team as a subject matter expert to support the development of an industry standard for SAE data collection.