MED227 - Fall Quarter
Drug Development: Key Issues in Regulation, Benefit vs. Risk, and Commercialization

This session will provide an interactive overview of drug development spanning from initial target validation, preclinical efficacy and safety assessments, toxicology, the Investigational New Drug (IND) Application, the three Phases of clinical human drug testing, key regulatory interactions, the NDA process, market considerations, and early funding. The regulatory process will be emphasized.

In this session, we will review the history of the early rofecoxib (Vioxx) development program, the hypothesis regarding the theoretical cardiovascular/thrombotic risk associated with COX-2 inhibition, the subsequent clinical evaluation of that risk, and the company’s decision to withdraw Vioxx from the market.

This session will begin with an overview of several types of study designs used in support of medical product development, including actual case examples such as renal denervation for treatment resistant hypertension. We’ll discuss how these designs fit into the evidence pyramid, and consider what conditions make the designs more or less suited to various settings. After an introduction to different statistical methods used to examine diverse types of endpoints, we’ll turn to some situations where initial analytical approaches may be misleading. These examples will serve to elucidate how important it is to frame a question correctly in order to draw meaningful scientific conclusions.

Despite the recognized relationship between Type 2 Diabetes and macrovascular complications like heart attack and stroke, evidence that antidiabetic medical therapies can reduce the risk of coronary heart disease, cerebral vascular disease or peripheral arterial disease has historically been sorely lacking. In the face of evidence that newer therapies developed in the 1990’s and beyond did no better than older drugs and may have presented some new safety issues, the FDA, prompted by a controversial publication of meta-analyses of completed trials, took the extraordinary step of requiring large CV outcomes trials either at the time of registration or as post-approval commitments, with mixed results. Perhaps as a bonus, some newer classes of antidiabetic medications have more recently, as a product of this requirement, demonstrated net cardiovascular benefits that might otherwise have gone unstudied. Aspects related to the regulatory environment, strength of evidence and association, and statistical issues that have evolved in parallel, will be presented and discussed.

Cardiovascular effects of drugs in a major reason for new chemical entities to be discontinued from development, or to have issues identified during clinical trials. Thus assessment for possible cardiovascular safety signals is critical. This seminar will explore the preclinical and clinical approaches to evaluating drugs for potential cardiac adverse effects.

What is the role of AI-powered technology and advanced analytics in discovering and developing new drugs? With several invited experts we will discuss what has been achieved so far and what they expect to see in the short and long term. The panelists are leaders in the field who will share their direct experience and insights in starting companies that utilize AI, machine learning and other technologies in discovering new targets, optimizing drug candidates, and making development more efficient with the goal to bring better therapies to patients faster.

Panelists:

Nabiha Saklayen is CEO & co-founder of Cellino, a personalized regenerative medicine company developing an AI-guided laser editing platform for autologous cell-based therapies. Cellino’s proprietary technology makes personalized stem cell-derived therapies scalable for the first time. Nabiha has published several peer-reviewed articles in the field of pulsed-laser delivery to cells. Nabiha was selected as a Pioneer in MIT Tech Review's 35 Innovators under 35 list for her patented inventions in cellular laser editing and is on the 2019 Forbes 30 under 30 List for Healthcare. She received her Ph.D. in Physics from Harvard University as a Howard Hughes Medical Institute (HHMI) International Fellow. She is also the inaugural Tory Burch Foundation Fellow in Genomics at the Innovative Genomics Institute led by Nobel Laureate Dr. Jennifer Doudna.

Kristen Fortney - Kristen is founder and CEO of BIOAGE, a company with a mission to develop a broad pipeline of therapies that target aging in order to increase healthspan and address chronic diseases. The company’s proprietary human aging cohorts have blood samples collected up to 45 years ago, with participant -omics data that is tied to extensive medical follow-up records including detailed future healthspan, lifespan, and disease outcomes. BIOAGE built a systems biology and AI platform that leverages these rich datasets to identify the molecular drivers of age-related pathology. Kristen received her PhD in Medical Biophysics from the University of Toronto, followed by postdoctoral training at Stanford University where she was a fellow of the Ellison Medical Foundation / American Federation for Aging Research. She has over 10 years of experience developing novel bioinformatics approaches for data-driven investigation into the mechanisms of aging and age-related disease, with 18 published papers spanning computational drug discovery, biomarkers of aging, and the genetics of exceptional human longevity.

Alex Zhavoronkov is the CEO of Insilico Medicine, a Rockville-based leader in the next-generation artificial intelligence technologies for drug discovery, biomarker development, and aging research. At Insilico he pioneered the applications of generative adversarial networks and reinforcement learning techniques for generating the novel molecular structures with the desired properties. He was the first to develop the deep-learned multi-modal predictors of age for drug and biomarker development. Prior to founding Insilico Medicine, he worked in senior roles at ATI Technologies (acquired by AMD in 2006), NeuroG Neuroinformatics, the Biogerontology Research Foundation and YLabs.AI and established AgeNet.net competitions and Diversity.AI initiative. Since 2012 he published over 120 peer-reviewed research papers and books including “The Ageless Generation: How Biomedical Advances Will Transform the Global Economy” (Palgrave Macmillan, 2013). Dr. Zhavoronkov holds two bachelor degrees from Queen’s University, a master’s in Biotechnology from Johns Hopkins University, and a PhD in Physics and Mathematics from Moscow State University. He is the adjunct professor of artificial intelligence at the Buck Institute for Research on Aging.

Milind Kamkolkar is a seasoned entrepreneur, investor, and C suite executive. Milind’s career has spanned big pharma (Novartis & Sanofi) & biotech (Cellarity), management consulting and numerous technology and software startup companies focused at the intersection of health, technology and data. Milind is a featured speaker (TedX), Top 100 Leaders in AI,Business Transformation Top 150 Leader and thought leader in Digital Health, AI & Big Data.  Milind has served as a Board Advisor & mentor to numerous startups, founders and VC firms focused on entering the life science space through digital, data or AI. He has also served as an Honorary Lecturer for physician entrepreneurship at BartsX, Faculty at Exponential Medicine and a Former Special Advisor to the UN Global Sustainable Development Goals program. Milind holds a B.Sc. from the University of Sydney and M.S. from Thomas Jefferson University.

Phase 3 studies are the most expensive part of drug development, usually costing tens or hundreds of millions. In this session we will examine the main issues leading to failures in phase 3, such as misinterpreting early evidence based on biomarkers, errors in selecting the target patient population, primary endpoint, or dose. We may review illustrative case studies. Our guest discussants will be Dr. Aliza Thompson and Dr. Norman Stockbridge who lead the cardiovascular and metabolic division of the FDA.

Norman Stockbridge, MD, PhD, received his MD in 1978 and PhD in Physiology in 1981 from Duke University. He received post-doctoral training at Duke and New York Medical College. Dr. Stockbridge was a Staff Fellow at the NIH National Eye Institute. In 1985 he joined the faculty of the Department of Surgery at University of Alberta doing basic cellular electrophysiology research. Dr. Stockbridge joined FDA's Division of Cardio-Renal Drug Products in 1991, serving as a medical officer, medical team leader, and deputy division director, prior to becoming the division director. He is currently the Director of the Division of Cardiovascular and Renal Products within the FDA Center for Drug Evaluation and Research.

Dr. Aliza Thompson is Deputy Director at the Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research (CDER), at the U.S. Food and Drug Administration (FDA). Dr. Thompson joined the FDA in 2007; her team focuses on products being developed to treat renal-related indications. She received her medical degree from Johns Hopkins Medical School and completed her Internal Medicine and Nephrology training at Columbia University/New York-Presbyterian Hospital. She holds a Master of Science in Biostatistics/Patient Oriented Research Track from the Columbia University Mailman School of Public Health.

This session will provide an interactive overview of drug development spanning from initial target validation, preclinical efficacy and safety assessments, toxicology, the Investigational New Drug (IND) Application, the three Phases of clinical human drug testing, key regulatory interactions, the NDA process, market considerations, and early funding.

One can have a terrific idea for a drug, but it is critical early in order to get initial funding, and throughout a drug’s development cycle to rigorously define the commercial case- in which patients will it be used, what is the value proposition, what are the competitor drugs, how strong is the intellectual property, etc. A guest expert will discuss these important points, the tools that are helpful, and engage in active discussion.

The presentation of clinical trial results plays a critical role in the dissemination of important new information for patients and health care providers. Sometimes, these presentations can be filled with biases and skewed representations of the results. In this session, we’ll review presentations from major cardiology meetings and dissect them with a critical eye, aiming to identify discrepancies and biases.