SOCIAL ASPECTS OF DRUG DISCOVERY, DEVELOPMENT AND COMMERCIALIZATION ODILIA OSAKWE, MS, PhD Industrial BioDevelopment Laboratory, UHN-MaRS Centre Toronto Medical Discovery Tower and Ryerson University, Toronto, Canada SYED A A RIZVI, MSc, MBA, MS, PhD (Pharm), PhD (Chem), MRSC Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL, USA Amsterdam • Boston • Heidelberg • London New York • Oxford • Paris • San Diego San Francisco • Singapore • Sydney • Tokyo Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-802220-7 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by Thomson Digital Publisher: Mica Haley Acquisition Editor: Kristine Jones Editorial Project Manager: Molly McLaughlin Production Project Manager: Lucía Pérez Designer:Vicky Pearson To Philomena and Chioma PREFACE A considerable number of textbooks have delivered substantial information on the scientific and technological aspects of drug discovery and development, but very few have touched upon the social aspects The idea of writing this book was stimulated by this necessity along with an emergent notion, which grew out of my experience as a lecturer on this subject, in Ryerson University The Social Aspects of Drug Discovery, Development and Commercialization presents a holistic overview of the entire drug discovery process, as it transitions from inception, to a pill in the hands of the patient It explains the importance for it to be addressed comprehensively, to include all areas that interact with the society This will enable a proper understanding of the workings of the pharmaceutical enterprise, from which springs forth the medical products that are supplied to the wide public This will serve as a knowledge base to streamline ideas and perspectives about how drugs are created and distributed; for a regular citizen, an investor in the pharmaceutical business, or students or professionals who need to be updated on pharmaceutical affairs In other words, this information helps the reader in decision making on the proper approach to healthcare and its products; and provides for the scholar or professional, a strong grounding in this subject area One outstanding characteristic of this textbook is that, it provides definitions and explanations of the relevant background information to serve as a framework for understanding the social aspects, making it a user-friendly resource for a wide range of readers It details the key participants, relationships, and processes involved in the full drug discovery programs that span the pharmaceutical product lifecycle that are necessary for creating the medical solutions delivered to the public, as represented in the pharmaceutical ecosystems Analysis of the paths of pharmaceutical innovation is within the context of the pharmaceutical ecosystem For example, pharmaceutical policy and laws have emanated from extensive debate by a hierarchy of government-appointed groups, agencies, social groups, such as patient representative groups, representatives of charities and consumer associations, pharmaceutical and allied professionals, and other groups from various strata of the healthcare systems who are the voice of command in these decision making activities Pharmaceutical ecosystems embrace the stakeholders, the     xiii xiv Preface processes, and technologies whose cross-interactions strengthen the drug discovery programs What type of knowledge is gained by the readers of this book? The introductory chapter gives a general overview of the whole process, which serves as a foundation for the rest of the 13 chapters Every chapter sequentially builds from the previous and all of which represent a progressive pathway in the discovery of an investigational drug molecule as it morphs into a full drug product that is accessed by the public This book attempts to answer certain exemplary questions Chapter 1: What is the origin, meaning, and relevance of the pharmaceutical laws and regulations? Chapter 2:What is the pharmaceutical productivity landscape? Is pharmaceutical innovation sustainable? What is the technological flow, applicability, and effectiveness? What is the economic landscape for emerging pharmaceutical firms? What are the prospects and trend over the years? Chapter 3: What is responsible for hiatus or demise of the drug discovery pipeline in the initial stages of the drug discovery events? What are the relationships between the emerging and the big pharmaceutical companies? Chapters 4-6: How is the drug discovery pipeline advancing toward providing the needed medical solutions to diseases, especially the deadly ones? What are the hopes of families that have to grapple with life-threatening diseases? What is new in finding disease pathways and new drug molecules? Chapter 7: The animals chosen for testing of drug candidates, does this decision directly correlate with therapy pursued or are animals over utilized? How the different species differ in pharmacological response? Chapters 8 and 9: Are drugs manufactured to precision? What is the reason for drug recalls? Chapter 9: Are clinical trials conducted to reflect specific public interests? What are the patients’ rights as participants in clinical trials? What are the opportunities and setbacks in multinational clinical trials? Chapter 10:Why are certain drugs more compatible with certain individuals and the experienced adverse events in only certain individuals? What is the applicability of individualized or precision medicine? Chapter 11: How does patents alter drug accessibility? What are the legal factors that affect patents and emergence of generics? How fast could generics be reached? Chapter 12: How does drug marketing benefit the end user? Chapter 13: What is the flow of drug pricing around the globe? This book could serve as a training tool or reference guide for students and professionals in most of health science and allied disciplines; pharmacy, pharmaceutical sciences, pharmacology, clinical and translational research, medicine, nursing, and more This also applies to those in pharmaceutical Preface xv law and policy, health policy and management, and pharmacoeconomics It can also be a useful information base for students and professionals in regulatory affairs, who are expected to be thorough in the knowledge of drug discovery The text is delivered in a concise, direct, and soft language to stimulate interest and enliven your readership I would like to extend my personal gratitude to Dr Syed A.A Rizvi for his valued contribution to this work Most and foremost, my hearty thanks goes to He who is the pillar of my life and who supplied the knowledge, courage, and strength that carried me throughout this process Introduction 1  TRENDS IN DRUG DISCOVERY The pharmaceutical industry is of tremendous value to society, mainly because of the active discovery and development of pharmaceuticals, which have increased quality of life through both ameliorating pain and suffering, and the treatment of diseases Major landmarks in drug discovery that preceded the thalidomide tragedy in the 1950s have led to a total overhaul of regulatory systems Extensive federal governance has been deemed necessary to address the unsatisfactory efficacy and safety standards that characterized earlier drug manufacturing systems, which underlie the high standards imposed on companies that manufacture and distribute drugs to the public Since then, increasingly innovative breakthroughs have contributed immensely to the changing pharmaceutical landscape The first major historical accomplishment was the innovation boon of the 1990s, a period marked by a rise in the production of blockbuster drugs that has contributed to more than one-third of the total pharmaceutical revenues, totaling US$149 billion [1] Market growth rate skyrocketed due to expansion of the number of high selling drugs, which lifted the position of the pharmaceutical industry in the global economy [2] Products from the leading five pharmaceutical companies – Pfizer, Roche, AstraZeneca, Merck & Co., and Novartis – topped the list of the best-selling drugs, such as Prozac, an antidepressant drug; Lipitor® (atorvastatin), which is used to treat blood cholesterol; and Plavix® (clopidogrel), which inhibits the formation of blood clots following myocardial infarction Many of these drugs attract interest, particularly because they target chronic diseases Large financial returns generated from just a handful of these drugs sustain the research and development (R&D) for emerging drugs However, this business model is no longer very promising because patents are expiring Diversification to niche market drugs is increasingly being expected so as to shift focus from the blockbuster drugs market to those drugs that target other diseases in demand of medical therapy Thus, today’s R&D is largely driven by new medical discoveries associated with a high probability of economic     xvii xviii Introduction and technical risk These types of diseases require discovery of difficult targets that limit innovation speed and cash flow with a high price of unpredictability For example, the emergence of HIV/AIDS points to the need to expect a therapy that has hitherto been a distant reality Incremental shifts in the configuration of the industry over time culminated in the technological breakthroughs of the early twentieth century when interpretation and understanding of molecular biology changed drastically Groundbreaking biological techniques like proteomics and genomics emerged along with more sophisticated techniques that utilize advanced statistical and mathematical platforms coupled with computerbased strategies in biology and chemistry Most of these are molecular modeling, simulations, combinatorial chemistry, high-throughput technology, and high-performance computing Dynamic models created a framework to integrate the knowledge base within the functional areas and, most importantly, the high technology applications further facilitated a better handling of the rapidly growing volume of “big data” to scale down the complicated R&D processes for a better workflow and output The “omics” revolution represents an advancement in molecular science that improved understanding of the molecular linkage of cause and function of diseases to enable the finding of the networks of pathways and, ultimately, the disease targets [3–5] A model mechanism of drug action enables the drug discovery and development team to understand how drugs act in whole body systems, organs, and at a subcellular level There is a growing technical competence in targeting smaller patient populations to narrower therapeutic areas for personalized medicine – a greater selectivity offered by genomics The Orphan Drug Act was intended to advance treatments for rare disease This is increasingly leading to new drugs that are effective on smaller defined patient populations that fall into the “orphans” category, with a foreknowledge furnished by an increased understanding of the causes of the diseases.This presents an opportunity for companies to specialize in particular aspects of the drug development process, which is a more promising pathway to innovation success These revolutionary scientific and technological discoveries have brought changes that underscore a dynamic society undergoing major transformation – a change encompassing all the varied levels of the complex processes This dynamic society requires an integrated framework to bring together all the processes within and across all aspects of the pre- and postdrug launch of candidate drugs A robust pharmaceutical innovation system Introduction xix that would promote effective cooperation and communication among the stakeholders is highly desirable 2  THE PHARMACEUTICAL ECOSYSTEM The pharmaceutical ecosystem refers to the interdependent relationships among levels of interacting stakeholder networks in connection with processes, tools, and infrastructures that are controlled by policies, laws, and opinions The stakeholder groups are the discovery and development team, academia, physicians, healthcare providers, payers, patients, advocacy groups, consumers groups, and the public or civic society All these players have unique perspectives about the pharmaceutical industry in connection with the needs, values, and preferences of the area of the public they represent The infrastructure is the technological platform and core facilities used to drive the drug product from concept to access The strategic issues – regulatory structures and reform, local and national cultures, politics, federal laws, economic and reimbursement policies, intellectual property and patent policies, product factors, and marketing dynamics – are also the tools for streamlining the utility of medicines during the pre- and postmarketing stages This is the pivot upon which the pharmaceutical industry rotates That is to say, all the R&D operations that are the core aspect of drug discovery and development are extensively affected and controlled by these social values The definition mentioned earlier implies that all aspects of the ecosystem contribute toward most or all of that which translates into a new medical product A functional ecosystem is characterized by uniform interdependent relationships, which is critical for the continuation of the system Thus, a pharmaceutical industry that exhibits a functional ecosystem will be more efficient in satisfying its anticipated intended purpose Figure shows the relatedness of all the players in the pharmaceutical value chain leading to a functional pharmaceutical ecosystem with inference to the drug product The pharmaceutical value chain is the totality of functions that are performed within big pharmaceutical companies until product phase-out There are networks of multichannel interactions at various levels around the development of a pharmaceutical product This explains the enormous complexity of pharmaceutical innovation Meaningful cooperation among all the elements offers the promise of high-performance collaboration, processes, and utility of tools and infrastructure [6] xx Introduction Figure 1  Cross-Functional Interactions in the Pharmaceutical Ecosystem The pharmaceutical ecosystem could be defined as the convergence of networks of cross-interacting subsystems across the drug product pipeline, which has a stake in the efficiency of the drug development and access to the marketed drug 3  ASPECTS OF THE PHARMACEUTICAL SYSTEMS AND THE STAKEHOLDERS 3.1  Government and Policies The government provides revolutionary policies that improve the entire pharmaceutical environment, such as federal laws, economic/reimbursement policies, intellectual property and patent policies, and health policies The major national regulatory authorities are the Food and Drug Administration (FDA) for United States, the European Medicines Authority (EMA) for Europe, and the Pharmaceuticals and Medical Devices Agency (PMDA, KIKO) for Japan 3.2  Drug Discovery Research and Development Target identification through the optimization stage involves biochemists, pharmacologists, systems biologists, cell biologists, immunologists, and ... The Social Aspects of Drug Discovery, Development and Commercialization presents a holistic overview of the entire drug discovery process, as it transitions from inception, to a pill in the hands... Therefore, social aspects of drug discovery and development are the public tools or aspects of public life within the pharmaceutical ecosystem that have a mutual impact on drug discovery and development. .. convergence of networks of cross-interacting subsystems across the drug product pipeline, which has a stake in the efficiency of the drug development and access to the marketed drug 3  ASPECTS OF THE