In order to better characterize the safety profile of investigational new drugs during clinical development and to identify safety issues and data gaps earlier in the development process, more interest and attention have been paid to ongoing aggregate safety evaluation. The FDA guidance on Safety Reporting Requirements for INDs recommends a systematic approach of safety surveillance that includes a process for reviewing, evaluating and managing accumulating safety data. In addition, the FDA IND safety reporting final rule requires a safety report whenever aggregate analysis indicates that events occur more frequently in the drug treatment group than in a concurrent or historic control group. Early planning for assessment of emerging safety signals and review of aggregated safety data throughout the development program are driven by multi-disciplinary safety management teams (SMTs). Ongoing aggregate safety evaluations are designed to help SMTs judge the strength of evidence, to stimulate their discussion and to improve their assessment of the accumulating safety data.
Safety monitoring during clinical development requires a partnership between clinical and statistical scientists. A systematic, coordinated approach to identify, assess and characterize safety topics of interest enables investigators to develop clinical as well as quantitative understanding of the safety profile. A special challenge in ongoing aggregate evaluation of safety data is the application of appropriate statistical techniques with a safety mindset, as opposed to strict statistical inference, with the emphasis shifted from testing and confirming to exploration, for learning, medical judgement and decision-making within a quantitative framework. A cumulative meta-analytic review is recommended as a routine part of the safety monitoring process so that adverse drug reactions can be detected and characterized as readily as possible. As the database matures, aggregate analysis becomes more important for detection and evaluation of signals. As CIOMS VI states, “causality judgments based on analysis of multiple cases/aggregate data are almost always more meaningful and typically have a greater impact” (than the traditional case-based medical review).
Our goal is to empower the broader cross-disciplinary, cross-regional community to discover and promote practical quantitative solutions for safety monitoring during clinical development. Audience participation will be highly encouraged. This tutorial session will present the work that has been done by the ASA Biopharm / DIA Interdisciplinary Safety Evaluation scientific working group, with the following components: