Continuous safety monitoring is a fundamental part of the drug development and life cycle management. Regulatory guidance, such as ICH E2C, ICH M4E(R2), FDA IND safety reporting guidance (2012, 2015) and the upcoming ICH E19 (under development) highlight the importance of valid statistical methodology for signal detection, analysis and reporting. In particular, safety monitoring requires an holistic, accumulative and dynamic approach of integrating medical judgment with quantitative evidence. From statistical perspectives, the likelihood approach provides a robust way to integrate the quantitative evidence, either in the Frequentist framework or in the Bayesian framework of incorporating data-driven objectivity and experience-driven subjectivity.
This tutorial session will examine the application of likelihood principles in safety monitoring. This includes (1) A primer on the likelihood principles under Frequentist/Bayesian frameworks; (2) Likelihood approach for blinded safety monitoring; (3) Sequential Probability Ratio Test and its generalizations ; and(4) Likelihood Ratio Test (LRT) based methods for safety monitoring. In particular, Dr Ram Tiwari, Dr Lan Huang and Dr Zhihao “Howard” Yao of the US FDA will join force to discuss the LRT methods and applications in the FDA adverse event monitoring. They will also demonstrate the dynamic visual analytical implementation using R*Shinny.
Dr. William (Bill) Wang is an executive director, clinical safety statistics, in the department of Biostatistics and Research Decision Sciences (BARDS), Merck Research Laboratories. He has over 20 years of experience in the pharmaceutical industry, with expertise and research publications in statistical design, analysis, clinical data management and their technology enablement. During his 15-year tenure at Merck, he supported regulatory filings in multiple therapeutic areas and established the BARDS Asia Pacific operation. Since 2010, he has served on the DIA China Regional Advisory Board and the DIA’s Global Community Leadership Council (CLC), including the chairmanship of the DIA China Statistics Community. He was a recipient of the DIA global inspire award award in 2012. He is currently chairing an ASA safety monitoring working group, and a deputy topics-leader in the ICH E17 working group on multi-regional clinical trials.
Krishan Singh has been working in the pharmaceutical industry for 29 years, starting at Smith Kline & French which subsequently became GlaxoSmithKline following mergers/acquisitions. In his 29 years in the industry as a statistician, he has supported the clinical development of drugs across a number of therapeutic areas leading to successful regulatory submissions and market authorization of six new drugs in cardiovascular, inflammation and tissue repair, anti-infectives, respiratory and rare diseases. He is currently a member of the ASA Safety Monitoring Working group. Krishan brings extensive experience in the application of statistical methodologies for the evaluation of safety and efficacy of investigational drugs.
Dr Ram C. Tiwari is the Director for Division of Biostatistics, CDRH, effective June 27, 2016. He joined FDA in April 2008 as Associate Director for Statistical Science and Policy in the Immediate Office, Office of Biostatistics, Office of Translational Sciences, CDER. Prior to joining FDA, he served as Program Director at National Cancer Institute, NIH, and as Professor and Chair, Department of Mathematics, University of North Carolina at Charlotte.
Dr. Tiwari received his MS and PhD degrees from Florida State University in Mathematical Statistics; he is a Fellow of the American Statistical Association, and an Elected Member of the International Statistical Institute. He is a past President of the International Indian Statistical Association. He has published 200+ research papers on a wide range of statistical topics. His current research interests include developing frequentist and Bayesian methods in clinical trials and pre-and-post market drug/device safety evaluation.