In pharmaceutical R&D, 

nothing is too small when it comes to safety. 

Pooled safety information is crucial 

during clinical trials of drugs. 

How should CRO companies deal with it?

Recently, an online interpretation meeting for the "Pooled Analysis of Safety Information from Clinical Trial Projects - Consensus" was hosted by CMAC. Juping Xu, the Senior Pharmacovigilance (PV) Director of Taimei Technology, chaired the meeting. Bangxi Wan, Vice President of Taimei Technology, and Jun Li, the PV Medical Director of Elixir Clinical Research attended the meeting. Based on their practical experience in pooled analysis and explorations in the field of digital PV, they discussed the details of the consensus with several industry experts, which provided clearer directions and methods for CROs to effectively carry out pooled analysis of safety information.

Seven questions and answers provide a more comprehensive understanding of the main topics discussed at the meeting, delving deeper into pooled analysis of safety information from clinical trial projects.

Q1. Under what background was this consensus document written and published?

On March 17, 2023, the Center for Drug Evaluation of the National Medical Products Administration issued the "Guidance for Pooled Analysis and Reporting of Safety Information during Drug Clinical Trials (Trial)", which aimed to direct sponsors to use scientific methods to assess individual safety reports during clinical trials and to develop a plan for pooled analysis of safety information. However, since the release of the Guidance, there has been a lack of consensus in the industry regarding the data scope and methods of pooled analysis. In this context, the Pharmacovigilance Frontier Research Center of CMAC convened industry experts to set up a working group and draft the "Pooled Analysis of Safety Information from Clinical Trial Projects - Consensus", which serves as a reference for peers in the industry.

The Consensus focuses on three aspects: data aggregation, including PV and Electronic Data Capture (EDC) data; analysis methods, including analytical indicators, frequency, and methodology; and data visualization, including the presentation of visualized data and visual analysis reports.

Q2. Should scientific literature data be included in the pooled data after generating individual reports?

In the view of Bangxi Wan, the pooled analysis method does not strictly define the scope of safety data, and the core is to determine whether the data scope is consistent with the goal of the pooled analysis. If the objective is to perform an evaluation analysis to compare inter-group incidence rate, literature data is evidently not an appropriate data source. However, if at the same time of quantitative analysis, references and spontaneous reports are also needed for qualitative analysis, scientific literature data will become an important data source.

Q3. What are the common criteria for assessing which EDC system data can be used for pooled analysis?

Bangxi Wan believes that the common criteria include data comparability and interpretability. According to the Guidance, the data that can be used for pooled analysis should at least comprise those from completed and ongoing trials under the same active ingredient's IND (Investigational New Drug) application. Generally, phase I trials involving healthy participants are not typically included in the pooled analysis. Additionally, when considering which EDC data to aggregate, it's important to ensure the comparability of data across relevant domains (such as demographics, laboratory tests, medical history, adverse events, and end times) and that the data can be reasonably interpreted.

Q4. How can data from different PV systems be aggregated into a single PV system? What are the common methods?

The first method is to follow the stipulations of ICH E2B (R3) to submit IND safety reports. This method can process data efficiently, which requires less follow-up work, facilitates information transfer, and allows for the immediate access of safety data for further processing and analysis.

The second method involves manual data entry or SIM import and other auxiliary methods. It is suitable for cases with fewer reports, but the number of fields that can be imported is limited, and important information may be missing, necessitating manual supplementation. When choosing a method for data aggregation, factors such as volume of reports, preparation difficulty, and data integrity should be comprehensively considered.

Q5. For reports unblinded due to the reporting of SUSARs (Suspected Unexpected Serious Adverse Reactions), 

why is it recommended to include report information without blinding codes in the pooled analysis?

In response to this question, Jun Li shared his insights. He believes that the primary reason is to maintain the integrity of the trial, ensure the accuracy and reliability of the trial data, and guarantee that the collection and analysis of all relevant data during the trial adhere to consistent standard operating procedures. During drug clinical trials, sponsors should establish detailed standard operating procedures for maintaining blinding and ensure that all relevant personnel (whether blinded or unblinded) are well-informed and strictly adhere to these procedures. Additionally, to prevent potential bias or interference, sponsors should take stringent measures to create a "firewall" between blinded and unblinded personnel. Those involved in regulatory reviews or in compiling reports on pooled analysis of safety information should not participate in the trial implementation or the analysis of its results. The task of reporting SUSARs which lead to unblinding falls under the category of the implementation and result analysis of trial projects. Therefore, for personnel involved in relatively independent pooled analysis, blind management should be applied. Hence, when SUSAR reports are included in the pooled analysis, they should be devoid of any blinding codes.

Q6. What are some common presupposed safety events of interest?

Events related to the underlying diseases or technical status of the study population, such as disease progression and death in cancer patients, pneumonia in chronic obstructive pulmonary disease (COPD) patients, and ketoacidosis in diabetic patients; events related to the demographic information of the participants, such as cardiovascular diseases and hip fractures in elderly patients; and events related to the background regimen of the clinical trial and concomitant use of study drugs, such as bone marrow suppression with chemotherapy drugs, and lymphocyte depletion in CAR T-cell therapy.

"These events have certain incidence rate, so they require special attention in clinical trials with preset monitoring and management measures, " said Jun Li, who has extensive experience in signal and risk management throughout the whole lifecycle of numerous drugs.

Q7. Can data from single-arm trials also be included in pooled analysis?

It depends on the specific context and the significance of the data analysis. In certain cases, incorporating data from single-arm trials into the pooled analysis can be meaningful, particularly when these data can offer supplementary information or contribute to refining the overall trends and results. However, in single-arm trials, causality judgement may be more critical due to the lack of a control group for comparison. It necessitates a more cautious evaluation of the data's relevance and reliability. Therefore, when deciding whether to include data from single-arm trials in pooled analysis, a comprehensive consideration is required, which includes the purpose of the data analysis, the reliability and integrity of the data, and the judgement of individual causality relationships.

The pooled analysis of safety information during drug clinical trials is a vital supplement to the evaluation of individual safety events, which contributes to the timely identification and recognition of significant risk signals. The Pharmacovigilance Medical Team of Elixir Clinical Research (ECR Global) has long been dedicated to PV medical work throughout the entire lifecycle of different drugs and accumulated extensive experience in pooled analysis of safety information, with which it is able to offer professional and comprehensive safety evaluations and risk management services to sponsors, holders, and the entire industry, and ensure the safety and efficacy of drug usage.

For more details, please contact 

info@ecr-global.com