Judy Li, Amit Bhattacharyya, and William (Bill) Wang, ASA Biopharmaceutical Section Safety Working Group

Safety assessment, monitoring, and safety surveillance—also referred to as pharmacovigilance—is a key component of the pharmaceutical product development life cycle. Pharmacovigilance is defined as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any drug-related problem, according to the World Health Organization’s 2002 report titled The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products.

In the past, most pharmacovigilance departments at biopharmaceutical companies focused on the handling of individual adverse event reports. However, there has been a shift from individual cases to aggregate analysis to identify potential adverse drug reactions in recent years. While individual adverse event case handling remains relevant for understanding specifics of each case, the expectations for marketing authorization holders and clinical trial sponsors have increased in aggregate safety evaluation in drug development, life cycle management, and post-marketing surveillance.

Statistical methodology for safety assessment for monitoring and reporting will need to be further developed to match that for efficacy. In addition to evolving improved methodologies to support safety evaluation, our new complex world will require a multidisciplinary approach. No longer will the “safety doc” be alone in determining and explaining safety issues with the simple analysis used in years past. That said, statisticians also need to enhance their knowledge of the clinical aspects and safety background so they can interpret the safety concerns in drug development. What’s needed is a true medical-statistical joint venture to develop the models in the 21st century for safety evaluation.

The industry has been slowly preparing itself for such a collaborative approach over the last few years. In 2014, the ASA’s Biopharmaceutical Section started a safety working group (ASA BIOP-SWG) that included members from both regulatory agencies and industry. The working group initially focused on design and analysis of cardiovascular safety outcome trials for type II diabetes drugs. Later, it expanded into a systematic review of multisource safety data and corresponding analysis strategies.

In parallel, another dedicated working group was formed in 2015 to further empower the biostatistics community in quantitative safety monitoring. One initiative of this safety monitoring working group was to focus on a systematic review of statistical methodologies on safety monitoring, which include Bayesian and frequentist methods, blinded versus unblinded safety monitoring, individual case analysis versus aggregate meta-analyses, pre-marketing versus post-marketing evaluation, static versus dynamic safety reviews, and methods of safety data visualization.

Another initiative was to perform a thought-leader interview and industry survey on the current practices and future direction of statistical safety statistics practice, tools, and methods. In addition, a systematic review of safety regulations at both global and regional levels (e.g., US, EU, Japan, China) was conducted and published.

To cultivate interdisciplinary collaboration, the aforementioned two efforts were integrated and expanded into one joint interdisciplinary working group between the ASA Biopharmaceutical Section and the DIA scientific communities in 2019. The collaboration between the ASA and DIA—a global, member-driven organization mobilizing life sciences and health care professionals—offers an opportunity for cross-functional global innovations. In service of this cause, the team has assembled industry, regulatory, and academic experts in drug safety and statistics to develop a series of contributions. These include, but are not limited to, the following:

• Develop interdisciplinary frameworks for aggregate safety assessment planning and visual tools to enable/enhance cross-disciplinary collaboration (workstream 1/WS1)
• Deep dive into various safety assessment and monitoring methodologies, including safety-enabled benefit-risk evaluation and machine learning methods (WS2)
• Investigate design/analysis approaches for the integration and bridging of randomized controlled trials and real-world evidence for safety decision-making (WS3)

The working group has been productive in the pursuit of strategic and methodological advances in bringing clinical safety assessment, monitoring, and reporting to patient safety in clinical trials. Using 2018 as an example, the working group has done the following:

• Expanded WS1 into a fully operational and highly productive ASA-DIA working group in safety evaluation
• Started an interactive safety graphics (ISG) interdisciplinary task force to develop a fit-for-purpose visualization tool
• Established the safety-enabling benefit-risk task force and contributed to the DIA get-the-question-right series
• Established a new WS3, “Integrating RCT/RWE for Safety Decision-Making”
• Grown into a sizable multidisciplinary working group with ~ 40 statisticians and ~10 physicians across industry, regulatory, and academic researchers
• Presented at more than six scientific conferences, delivered more than 12 presentations and three short courses, and published more than three manuscripts 
• Established a leadership council to enhance our procedure/guidelines for enrolling membership, working together, and publishing together

The working group had a great start in 2019, with the following new activities:

• A benefit-risk assessment planning task force was formed, building on our aggregate safety assessment planning task that started in 2018
• An interactive visualization tool was developed to evaluate drug-induced serious hepatotoxicity by our ISG task force
• A new safety paper series with the DIA Therapeutic Innovation & Regulatory Science journal was started. In the near term, the paper series will include a summary of our industry survey on safety monitoring, a review of the global safety regulatory landscape on aggregate safety assessment, and a framework for aggregate safety assessment planning
• A book project, Quantitative Methodologies and Interdisciplinary Practice for Safety Monitoring and Benefit-Risk Evaluation (running title) has been initiated
• At least six scientific sessions and three short courses will be offered at various scientific conferences by our working group. These include the following:

• Two short courses, a presentation, and a “content hub” at the 2019 DIA annual meeting in San Diego, focusing on topics of safety evaluation and interactive graphics
• Two topic-contributed sessions at the 2019 Joint Statistical Meetings in Denver
• An invited session on the visualization of clinical trial data at the 2019 Midwest Biopharmaceutical Statistics Workshop
• One short course and two invited sessions at the 2019 ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop

Through these various multidisciplinary efforts, the ASA BIOP-SWG is changing how drug safety and benefit-risk are incorporated into clinical development programs, which includes assessment, monitoring, and reporting as part of the regulatory submission and review. This will bring to fruition a coherent drug safety lifecycle based on sound clinical judgment and statistical rigor.