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:

Milind Kamkolkar is a seasoned entrepreneur, investor, and C suite executive. Milind currently serves as a Venture Partner at RA Capital Management, committed to building enduring AI Companies. His 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.

Arvind Rajpal is an innovative and results-focused senior executive with broad experience in drug discovery research and early development of novel biotherapuetics. He current serves as the senior executive in Drug Discovery at Xaira Therapuetics, and has prior leadership experience at Genentech, Bristol Myers Squibb, Pfizer, and various other reputable companies. Arvind has 20 years of industry experience in biopharmacuetical and biotech settings. He is an inventor on 20 granted patents and author on 60+ peer-reviewed publications. His teams have generated and transitioned >30 differentiated assets into the clinic for oncology, cardiovascular and metabolic diseases, neuroscience, immunology, anti-infectives, and he has guided biotherapeutics programs in primary and specialty care indications from discovery to proof of concept in the clinic.

Anthony Philippakis is a physician, genomicist, and data scientist. He is a general partner at Google ventures (GV) and an institute scientist at the Broad Institute of MIT and Harvard. As a former cardiologist at Brigham and Women’s Hospital, he invests at the intersection of life sciences and machine learning. Anthony is committed to bringing genome sequencing and data science into the practice of clinical medicine.

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 Acting Deputy Director of the Division of Cardiovascular and Renal Products within the FDA Center for Drug Evaluation and Research.

Aliza Thompson, MD is Acting 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.

Charu Gandotra, MD is the Acting Associate Director of Therapeutic Review in the Division of Cardiology and Nephrology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA). 

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.

Jessica L. Mega, MD, MPH is a leader at the intersection of technology, life science, and health care. She is a Cardiologist at Stanford and serves on the Advisory Board for Stanford's Center for Digital Health. She is a Co-Founder of Alphabet's Verily, and she is on the Board of Directors at Boston Scientific and Danaher Corporation, as well as the Board of Advisors for Research!America and the Duke-Margolis Center for Health Policy. As a faculty member at Harvard Medical School, a Senior Investigator with the TIMI Study Group, and a Cardiologist at Brigham and Women’s Hospital, Dr. Mega led large, international, randomized trials evaluating novel therapies. Dr. Mega is a graduate of Stanford University, Yale University School of Medicine, and Harvard School of Public Health. She completed Internal Medicine Residency at Brigham and Women’s Hospital and Cardiovascular Fellowship at Massachusetts General Hospital.