PHAR 480 Module 1: Drug Discovery & Development PDF

PHAR 480 oiw DRUG DISCOVERY AND DEVELOPMENT MODULE 01 BASIC LANDSCAPE OF THE PHARMACEUTICAL INDUSTRY Please note: This course was designed to be interacted and engaged with using the online modules. This Module Companion Guide is a resource created to complement the online slides. If there is a discrepancy between this guide and the online module, please refer to the module. How can you help protect the integrity and quality of your Queen’s University course? Do not distribute this Module Companion Guide to any students who are not enrolled in PHAR 480 as it is a direct violation of the Academic Integrity Policy of Queen’s University. Students found in violation can face sanctions. For more information, please visit https://www.queensu.ca/academic- calendar/health-sciences/bhsc/ MODULE 01 COMPANION GUIDE PHAR 480 TABLE OF CONTENTS INTRODUCTION..................................................................................................................................................... 6 Introduction....................................................................................................................................................... 6 Video: Introduction to Module 01................................................................................................................... 6 Learning Outcomes........................................................................................................................................... 6 Module Assessments........................................................................................................................................ 6 Assignment: Ensuring a Viable Pharmaceutical Industry......................................................................... 7 Course toolbox.................................................................................................................................................. 7 Module Outline.................................................................................................................................................. 7 SECTION 01: Title................................................................................................................................................... 9 Basis of Drug Discovery and Development.................................................................................................... 9 Introduction to the Drug Discovery and Development Timeline................................................................ 9 Drug Discovery and Development Timeline................................................................................................10 Basic Research and Drug Discovery..........................................................................................................11 Lead Optimization.......................................................................................................................................11 FDA Review...................................................................................................................................................12 Clinical Trials................................................................................................................................................12 FDA Review...................................................................................................................................................13 Post-Approval Research and Monitoring.................................................................................................13 The Cost of Drug Discovery and Development............................................................................................14 The Cost of Drug Development Over Time..................................................................................................15 Section 01: Summary......................................................................................................................................16 SECTION 02: Intellectual Property.....................................................................................................................18 Innovation in the Pharmaceutical Sector.....................................................................................................18 Innovation: Academia vs. Industry................................................................................................................18 Question – Academia vs. Industries..............................................................................................................19 Conflict With Innovation.................................................................................................................................19 Intellectual Property.......................................................................................................................................20 Question – The Purpose of Intellectual Property........................................................................................20 Types of Intellectual Property........................................................................................................................20 Patent...........................................................................................................................................................21 Example: Patents for Humira....................................................................................................................21 Trade Secret.................................................................................................................................................22 DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 2 MODULE 01 COMPANION GUIDE PHAR 480 Trademark....................................................................................................................................................22 Copyright......................................................................................................................................................22 Question – Intellectual Proptery....................................................................................................................23 Question – Patent vs Trade Secret................................................................................................................23 Taking Advantage of Intellectual Property in the Pharmaceutical Industry.............................................23 Question – Solving the Problem of Rising Drug Costs................................................................................24 Increasing Drug Costs.....................................................................................................................................25 The Business of Pharma: Industry Examples..........................................................................................25 Question – Preventing Pharmaceutical Inflation.....................................................................................27 Question – Hiking Drug Costs........................................................................................................................27 Section 02: Summary......................................................................................................................................27 SECTION 03: Introduction to Patents................................................................................................................29 Introduction to Patents..................................................................................................................................29 Video: Things You Probably Didn’t Know About Patents?..........................................................................30 Three Criteria for a Patentable Invention.....................................................................................................30 Question – Patent Criteria..............................................................................................................................31 Timeline of Patent Development...................................................................................................................31 First-to-Invent vs. First-Inventor-to-File........................................................................................................32 Question – First-to-File vs. First-to-Invent.....................................................................................................33 Question – Who is Entitled the Patent?........................................................................................................33 Question – Patent Entitlement......................................................................................................................34 Types of Patents in the Pharmaceutical Industry........................................................................................34 Section 03: Summary......................................................................................................................................35 SECTION 04: patents and the Drug Discovery and Development Timeline.................................................36 Introduction to Patents in Drug Discovery and Development...................................................................36 Patents in the Drug Discovery Stage.............................................................................................................36 Question – Importance of Patenting Structural Variants...........................................................................37 Patents in the Drug Development Stage......................................................................................................37 Pharmacology: Metabolites.......................................................................................................................38 Pharmacology: Active Isomer....................................................................................................................38 Process Methodology.................................................................................................................................39 Late Stage Development Patents..................................................................................................................40 Development of Viagra...............................................................................................................................41 DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 3 MODULE 01 COMPANION GUIDE PHAR 480 Question – New Clinical Indications..........................................................................................................41 After PRoduct-Launch Patents.......................................................................................................................42 Question – Issuing Patents During Drug Development..............................................................................43 FDA Orange Book.............................................................................................................................................43 Question – Market Exclusivity of Uloric........................................................................................................43 Case Example: Why are Patents So Valuable?.............................................................................................44 Extending Patent Life: “Pay for Delay”..........................................................................................................45 Question – “Pay for Delay” Tactic...................................................................................................................46 Strategies to Extend Product Life..................................................................................................................47 Vidoe: Why Are Generic Drugs Not Coming To Market Sooner?...............................................................48 Generic Drugs..................................................................................................................................................48 Section 04: Summary......................................................................................................................................49 SECTION 05: Eroom’s Law...................................................................................................................................50 Introduction to Eroom’s Law..........................................................................................................................50 The Origin of Eroom’s Law: Moore’s Law......................................................................................................50 Eroom’s Law: The Increasing Costs of Drug Development and the Decline in Research Efficiency?....51 Eroom’s Law: A Robust Pattern.....................................................................................................................52 Question – Moore’s Law vs. Eroom’s Law.....................................................................................................53 Primary Causes of Eroom’s Law....................................................................................................................53 Secondary Causes of Eroom’s Law................................................................................................................54 The Narrow Clinical Search Problem........................................................................................................54 The Big Clinical Trial Problem....................................................................................................................55 Consequences of Big Clinical Trials...........................................................................................................55 Multiple Clinical Trial Problems.................................................................................................................56 Question – The chief Dead Drug Officer.......................................................................................................56 Seciton 05: Summary......................................................................................................................................57 SECTION 06: Factors Contributing to “Attrition”..............................................................................................58 Attrition in the Pharmceutical Industry........................................................................................................58 Drug Development Attrition..........................................................................................................................58 Success Rates from First-in-Human to Registration in Various Therapeutic Areas................................59 Question – Attrition in Different Therapeutic Areas and Phases..............................................................60 Reasons for Attrition in 1991 vs. 2000..........................................................................................................60 Question – Attrition in the Therapeutic Areas.............................................................................................61 DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 4 MODULE 01 COMPANION GUIDE PHAR 480 How to Reduce Attrition Rates.......................................................................................................................63 Question – Can Success be Increased?.........................................................................................................64 Question – Where Does Attrition Occur?.....................................................................................................64 Question – Importance of Patenting Structural Variants...........................................................................65 Section 06: Summary......................................................................................................................................65 CONCLUSION.......................................................................................................................................................66 Module Conclusion.........................................................................................................................................66 Module Complete!...........................................................................................................................................66 DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 5 MODULE 01 COMPANION GUIDE PHAR 480 INTRODUCTION Please see the online learning module for the full experience of interactions within this document. INTRODUCTION This content was retrieved from Introduction Slide 1 of 6 of the online learning module Welcome to PHAR 480, Drug Discovery and Development. This course will cover the life-cycle of a pharmacologic product, from drug discovery to its development as a marketed therapeutic. You will discuss the social and economic pressures exerted upon the pharmaceutical industry as well as target identification, design and synthesis, in vitro and in vivo efficacy determination, biochemical and biological optimization, preclinical safety assessment, clinical trials, as well as generics and over- the-counter medications. In Module 01, you will be introduced to the Drug Discovery and Development timeline, with an emphasis on intellectual property and patent protection. Disclaimer: The course instructor, Dr. Ozolinš, worked for 12 years in the pharmaceutical industry. Any examples of specific company products are discussed for educational purposes only. He has neither financial ties to any companies or products discussed in the course, nor does he have an axe to grind with any former employers or competitors. VIDEO: INTRODUCTION TO MODULE 01 This content was retrieved from Introduction Slide 2 of 6 of the online learning module Watch the video for an introduction to Module 01 by your instructor, Dr. Terence Ozolinš. (2:23) Page Link: https://player.vimeo.com/video/356408566 LEARNING OUTCOMES This content was retrieved from Introduction Slide 3 of 6 of the online learning module By the end of Module 01, students will be able to: 1. Discuss the role of intellectual property in the pharmaceutical industry 2. Rationalize the major milestones/steps in drug discovery/development 3. Describe Eroom’s law and be able to discuss the factors that contribute to it 4. Describe “Attrition” and discuss the strategies used to influence where attrition occurs in the development pipeline MODULE ASSESSMENTS This content was retrieved from Introduction Slide 4 of 6 of the online learning module These assessments must be completed as part of Module 01. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 6 MODULE 01 COMPANION GUIDE PHAR 480 Ensure a Viable Pharmaceutical Industry – Refer to Page 7 ACTIVITIES THROUGHOUT THE MODULE Note that text responses and interactions will not be graded unless otherwise notified. However, they are recorded within the module and viewable by your instructor. ASSIGNMENT: ENSURING A VIABLE PHARMACEUTICAL INDUSTRY Subpage of Introduction Slide 4 of 6 – Ensure a Viable Pharmaceutical Industry 1/1 In Module 01, you will be introduced to the basic landscape of the pharmaceutical industry and all the different pressures placed on the pharmaceutical industry. In this assignment, students will participate in a discussion with their peers and suggest novel ideas for how to relieve some of these pressures. After the discussion, students will write a brief report discussing one or two of these novel ideas. Students should discuss what changes might prove useful/necessary for the pharmaceutical industry to remain dynamic and viable. It should be noted that many recommendations may have a down- side(s) and these need to be addressed as well. For specific details about this assignment, visit the assignment page in your online learning environment. COURSE TOOLBOX This content was retrieved from Introduction Slide 5 of 6 of the online learning module As you navigate the PHAR 480 modules, you should watch for several course icons. Learn about its role in the course. Pharma Phacts This icon lives in the sidebar of the slide. Clicking it will reveal examples from the pharmaceutical industry that relate to content presented on a given slide. These examples are beyond the scope of this course (non-testable), but are designed to supplement your learning. Notes Tool This icon lives in the sidebar of the slide. Clicking it will reveal the sources for content and/or images on the slide. This icon lives in the sidebar of your module. Clicking it will open the Notes Tool, which enables you to take notes within the module. For more information about using the Notes Tool, visit the Module FAQ. References This icon lives in the sidebar of the slide. Clicking it will reveal the sources for content and/or images on the slide. MODULE OUTLINE DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 7 MODULE 01 COMPANION GUIDE PHAR 480 This content was retrieved from Introduction Slide 6 of 6 of the online learning module Section 01: Overview of the Drug Discovery and Development Process Section 02: Intellectual Property Section 03: Introduction to Patents Section 04: Patents and the Drug Discovery and Development Timelines Section 05: Eroom’s Law Section 06: Factors Contributing to “Attrition” DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 8 MODULE 01 COMPANION GUIDE PHAR 480 SECTION 01: TITLE BASIS OF DRUG DISCOVERY AND DEVELOPMENT This content was retrieved from Section 01 Slide 1 of 6 of the online learning module In the pharmaceutical industry, drug discovery is the process by which a new drug candidate* is discovered, either through the identification of the active ingredient from traditional/natural remedies or by serendipitous discovery. Once the drug candidate has been identified through the process of drug discovery, drug development can occur. Drug development is the process of bringing this new potential pharmaceutical drug to the market. In this section, you will be introduced to the processes of Drug Discovery and Development, and the different stages that make up this timeline. You may recall some of this timeline from PHAR 270, Fundamentals of Pharmacology and Therapeutics. The Drug Discovery and Development timeline will be referred to throughout this course and thus, it’s important you have a foundational knowledge of this timeline. Definition*: Drug candidate: The molecule which has been shown to have therapeutic potential and justifies further research and development. INTRODUCTION TO THE DRUG DISCOVERY AND DEVELOPMENT TIMELINE This content was retrieved from Section 01 Slide 2 of 6 of the online learning module Listen to Dr. Ozolinš give a brief overview of the Drug Discovery and Development timeline. (4:57) Start of Audio Transcript: The following figure is one you will see many times throughout the course. It depicts the drug discovery and development timelines. You will undoubtedly see versions of this all over the internet, each with slightly different numbers that can change based on therapeutic areas and the corporations involved. This is just a rough general outline. The first take-home message is that drug discovery and development takes a very long time, generally more than a decade. And if a drug is first in class, it may take much longer because of a variety of new findings that will require investigation along the way. So, as a first step, there may be substantial basic scientific research to understand a disease process or pathway, especially if it is novel. From these studies, a critical pharmacologic target will be identified, and attempts will be made to understand how to manipulate the activity of this target. Upwards of 10,000 chemicals may be screened using robotic high-throughput screening to reveal a few hundred drug candidates that might affect this process. This may take anywhere up to six years. These in turn will undergo a series of optimizations to ultimately lead to a lead candidate. This process is called lead optimization, and generally takes about a year. Included in lead optimization are improvements made to the absorption, distribution, metabolism and excretion characteristics, as well as some simple toxicity screenings such as aims tests and screens to ensure that specific off-target affects are avoided. Each drug or chemical backbone has its own unique profile of off- target affects. Once a lead has been identified, it needs to get approval to be tested on people. This is called first in human, or FIH, or phase one. An investigative new drug application must be submitted and approved DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 9 MODULE 01 COMPANION GUIDE PHAR 480 by the regulator before the drug can be tested in people. The studies conducted to allow for phase one are called FIH, or first in human, enabling studies. And these are comprised primarily of general toxicity and ADME studies that assure the regulator that small amounts of a drug may be given safely to healthy people. The goal here is to identify human metabolites, and to find a maximum tolerated dose. There are, in general, no more than a few dozen people in an FIH study. If FIH is successful, then more non- clinical or laboratory test species toxicity studies of longer duration must be done to ensure that there are sufficient safety margins to warrant testing in people. Phase two is different from phase one in several ways. First, it has hundreds of people in it, and second, test subjects are not healthy, unlike in phase one, they actually have the disease in question. And depending on the indication, the endpoint they may be looking at may just be an improved clinical outcome, or it could in fact be a change in some sort of a biomarker, and we'll talk a little bit more about this later on. Data obtained from phase two will inform the experimental design for phase three, which in general has long-term change in clinical outcome as the endpoint. In other words, was the disease modified? In order to do this, long-term chronic toxicity studies are conducted in test species to assure that long-term ingestion of the drug is safe for people. In phase three, several thousand people may be enrolled, and it may take years to complete depending upon the study outcome. After phase three, all the clinical and non-clinical data are compiled, interpreted and submitted to the regulator agency as a new drug application, or NDA. And it may take two years or more for the data to be reviewed, and not all NDA's are approved. So, drug development is long-term, risky, and very expensive. Recall that between 5,000 and 10,000 chemicals may be in the screen to identify about a further 250 that are then triaged for lead optimization. And of those, of every five to ten chemicals that enter FIH, only one ever gets a letter of approval. The other thing to remember, too, is that just once the drug comes to market, there are other things to be done. The company is obligated to set up a system to record and analyse adverse reactions, as these may only reveal themselves after tens of thousands of people have been exposed to the drug. After about seven to ten years on the market, the patent expires, a generic product picks up the market share, and this is generally the end of a product life cycle. End of Audio Transcript. Reference: Adapted from: PhRMA (2015). Biopharmaceutical Research & Development: The Process Behind New Medicines. Retrieved June 2019 from: http://phrma- docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf DRUG DISCOVERY AND DEVELOPMENT TIMELINE This content was retrieved from Section 01 Slide 3 of 6 of the online learning module Review each of the stages in the Drug Discovery and Development timeline. Basic Research – Refer to Page 11 Lead Optimization – Refer to Page 11 Clinical Trials – Refer to Pages 12 – 13 FDA Review – Refer to Page 13 Post-Approval Research & Monitoring – Refer to Page 13 Reference: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 10 MODULE 01 COMPANION GUIDE PHAR 480 Adapted from: PhRMA (2015). Biopharmaceutical Research & Development: The Process Behind New Medicines. Retrieved June 2019 from: http://phrma- docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf BASIC RESEARCH AND DRUG DISCOVERY Subpage of Section 01 Slide 3 of 6 – Basic Research 1/1 Basic research leads into drug discovery, where target identification and validation, assay development, and lead generation occurs. You will learn more about these aspects of drug discovery in Module 02. Thousands of compounds enter the drug discovery stage without progressing towards clinical studies. References: Matthews, H., Hanison, J., and Nirmalan, N. (2016). “Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives. Proteomes. 4,28. doi: 10.3390/proteomes4030028. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.3390/proteomes4030028 Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- _Facts_And_Figures_2012_LowResSinglePage.pdf LEAD OPTIMIZATION Subpage of Section 01 Slide 3 of 6 – Lead Optimization 1/1 Lead optimization is where the pharmacological activity of a drug is assessed. Various studies are undergone in animal models to determine the absorption, distribution, metabolism, excretion, and toxicity (in vitro and in vivo) profile for a compound of interest. For the 5,000-10,000 compounds discovered during the previous stage, it is estimated only 250 compounds progress towards this stage of development. References: Matthews, H., Hanison, J., and Nirmalan, N. (2016). “Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives. Proteomes. 4,28. doi: 10.3390/proteomes4030028. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.3390/proteomes4030028 Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 11 MODULE 01 COMPANION GUIDE PHAR 480 Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- _Facts_And_Figures_2012_LowResSinglePage.pdf FDA REVIEW Subpage of Section 01 Slide 3 of 6 – FDA Review 1/1 This stage of drug development determines whether a new drug will enter the market. Often, only one drug will be approved for every 5,000-10,000 novel compounds discovered. References: Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- _Facts_And_Figures_2012_LowResSinglePage.pdf CLINICAL TRIALS Subpage of Section 01 Slide 3 of 6 – Clinical Trials 1/1 Clinical trials, composed of three phases, are the first time a new compound is tested in humans. Learn about the role and number of human participants involved in each phase. Phase 1 Phase 1 clinical trials test the new compound in a small group (20-80) of healthy individuals to judge safety and determine dosage. They are sometimes referred to as first-in-human studies. Phase 2 Phase 2 clinical trials are completed with a larger cohort (100-300) and utilizes individuals who have the condition of interest. Phase 3 If the compound being tested is deemed safe and shows utility, phase 3 trials will commence. These are done with large study cohorts (up to 3,000) and will lead to FDA review if the results are positive. Only a small number of novel compounds will make it to this stage of drug development. For example for every 5,000-10,000 compounds that are discovered only five to nine compounds will enter clinical testing. Note: phase 3 trials are sometimes referred to as randomized control trials (RCT). References: What Are Clinical Trials and Studies? (2017). National Institute of Aging. Retrieved June 2019 from: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 12 MODULE 01 COMPANION GUIDE PHAR 480 https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- _Facts_And_Figures_2012_LowResSinglePage.pdf FDA REVIEW Subpage of Section 01 Slide 3 of 6 – Post-Approval Research & Monitoring 1/1 This stage of drug development determines whether a new drug will enter the market. Often, only one drug will be approved for every 5,000-10,000 novel compounds discovered. References: What Are Clinical Trials and Studies? (2017). National Institute of Aging. Retrieved June 2019 from: https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- _Facts_And_Figures_2012_LowResSinglePage.pdf POST-APPROVAL RESEARCH AND MONITORING Subpage of Section 01 Slide 3 of 6 – Post-Approval Research & Monitoring 1/1 Following FDA approval, phase IV clinical trials will often be initiated to assess the effectiveness of the new drug amongst more diverse groups. As well, certain adverse outcomes may only become apparent following long-term use, making it essential that further research is done. Even if further trials are not required by regulators, all drugs undergo post marketing surveillance. This is a programme that is managed by the manufacturers where adverse events are reported and the data collected, and continuously analyzed to look for previously unknown adverse events - if an adverse event is seen it is immediately reported to the Food and Drug Administration (FDA). References: Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3(8), 711. https://doi.org/10.1038/nrd1470. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nrd1470 International Federation of Pharmaceutical Manufacturers and Associations. (2012). The Pharmaceutical Industry and Global Health Facts and Figures 2012. Retrieved July 2019 from: https://www.ifpma.org/wp-content/uploads/2016/01/IFPMA_- DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 13 MODULE 01 COMPANION GUIDE PHAR 480 _Facts_And_Figures_2012_LowResSinglePage.pdf THE COST OF DRUG DISCOVERY AND DEVELOPMENT This content was retrieved from Section 01 Slide 4 of 6 of the online learning module The associated costs of drug advancement increase from discovery into development. As shown in the graph, costs are very low during drug discovery. As you progress into clinical trials (drug development) the greater your investment becomes. If a product failure was to occur during a phase III trial you could potentially lose half a billion dollars from R&D costs*. If attrition occurs fairly early on, you will lose less money. Pharma Phact Torcetrapib In 2006, Pfizer halted a phase III clinical trial on torcetrapib, an experimental drug for the treatment of hypercholesterolemia. The trial had patients taking either a combination of torcetrapib and Lipitor or taking just Lipitor alone. Initial results showed the combination drug to lower low-density lipoprotein (LDL)* cholesterol by 50- 60%, and increase high-density lipoprotein (HDL)* cholesterol by 55-60%. It was later observed the combination drug lead to increased mortality, with 82 deaths in the combination group versus 51 deaths in the Lipitor only group. Safety concerns eliminated usefulness of this drug, causing Pfizer to lose roughly $800 million dollars from investments over the 15 years torcetrapib was in development. Definitions*: R&D costs: Research and development expenses. Low-density lipoprotein (LDL): The form of lipoprotein in which cholesterol is transported in the blood and is associated with coronary artery disease. Also known as “bad” cholesterol. High-density lipoprotein (HDL): A lipoprotein that removes cholesterol from the blood and is associated with a reduced risk of atherosclerosis and heart disease. Also known as “good” cholesterol. Reference: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 14 MODULE 01 COMPANION GUIDE PHAR 480 Daley, L. A., and Vigeland, R. L. (1983). The effects of debt covenants and political costs on the choice of accounting methods. Journal of Accounting and Economics, 5: 195-211. doi: 10.1016/0165- 4101(83)90012-5. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1016/0165-4101(83)90012-5 THE COST OF DRUG DEVELOPMENT OVER TIME This content was retrieved from Section 01 Slide 5 of 6 of the online learning module Large investments are made by drug manufacturers to see their products come to market. Since the 1970s the associated costs of drug development has drastically increased. Review the cost of drug development have increased throughout the years. 1970 - 1980 From 1970-1980, the total costs associated with drug development was $179 million (adjusted for inflation* in 2013). 1980 - 1990 From 1980-1990, the total costs associated with drug development was $413 million (adjusted for inflation in 2013). 1990 - 2000 From 1990-2000, the total costs associated with drug development was $1.044 billion (adjusted for DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 15 MODULE 01 COMPANION GUIDE PHAR 480 inflation in 2013). 2000 - 2010 From 2000- 2010, the total costs associated with drug development was $2.558 billion (adjusted for inflation in 2013). Although, the costs of drug development have increased substantially over the last 40 years, these increases are not proportional to the quantity of drugs developed within the pharmaceutical industry. This is the concept of Eroom’s law, which you will learn about in more detail in Section 05. Drug development associated costs in the 1970s, 1980s, 1990s, and 2000s. Note: These numbers are not universally accepted. Definition*: Inflation: A sustained increase in the price of goods and services over a period of time. Reference: DiMasi, J. A., Hansen, R. W., and Grabowski, H. G. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics: 47: 20-33. https://doi.org/10.1016/j.jhealeco.2016.01.012. Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1016/j.jhealeco.2016.01.012 SECTION 01: SUMMARY DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 16 MODULE 01 COMPANION GUIDE PHAR 480 This content was retrieved from Section 01 Slide 6 of 6 of the online learning module In this section, you were introduced to the Drug Discovery and Development timeline as a whole. You also learned about the associated costs throughout the different stages of the timeline, and how they are increasing over time. Throughout the rest of this module, you will be introduced to the basic landscape of the pharmaceutical industry and the different kinds of pressures placed on this industry. You will learn about each stage of the Drug Discovery and Development timeline in detail throughout the later modules in this course. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 17 MODULE 01 COMPANION GUIDE PHAR 480 SECTION 02: INTELLECTUAL PROPERTY INNOVATION IN THE PHARMACEUTICAL SECTOR This content was retrieved from Section 02 Slide 1 of 14 of the online learning module Innovation is the cornerstone of the pharmaceutical sector. On occasion, drug discovery can happen through chance or luck, although most new pharmaceutical innovations occurs as a result of years of dedicated research and hard work. Within the pharmaceutical sector, research is typically conducted within academia (i.e. universities, colleges) or industry (i.e. pharmaceutical firms, organizations). Despite their common goal of discovering new pharmaceutical innovations to advance human health, their modes of action and visions differ substantially. INNOVATION: ACADEMIA VS. INDUSTRY This content was retrieved from Section 02 Slide 2 of 14 of the online learning module Recall that society relies on two main sectors to provide innovation to the pharmaceutical industry: academic institutions like universities and industries such as pharmaceutical companies. While both of these sectors use research as the impetus for innovation, they differ in their purpose. Learn about innovation in academia and industry settings. Academia Academia generally engages in basic research that is curiosity-driven*. It attempts to understand mechanisms of action pathways and targets. Industry Industry, be it pharmaceutical, biotech, or agriculture/chemical, engages in a more purpose-driven* research. A pharmaceutical company is a corporate entity that has a fiduciary responsibility to be profitable for shareholders. As such, they look for ways to manipulate pathways, often identified and characterised at publicly funded research institutes, to achieve a therapeutic outcome. Thus, much effort is used to identify modulators (inhibitors or activators) and suitable formulations with the goal of developing a product with both therapeutic and monetary potential. Decorative image showing the inside of a pharmaceutical production factory. Pharma Phact In 1989, three researchers at Queen’s University filed a patent for a “Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid”. This shows that, while less common, academia can be useful at designing and developing innovative drugs. Review the patent for this innovation. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 18 MODULE 01 COMPANION GUIDE PHAR 480 Innovation by Queen’s University: Patent Definitions*: Curiosity-driven: Research done for the sake of knowledge, rather than profit. Purpose-driven: Research that is done to achieve a specific goal, usually a mix of creating a drug to help others and creating a drug that will generate a profit. Page Link: https://patentimages.storage.googleapis.com/d1/1c/41/8b49462a7b649b/US5079262.pdf References: Book PNG. (n.d.). Retrieved June 2019 from http://pngimg.com/download/51090 Free Images : dna, doctor, lab, helix, biology, genetic, code, science, Genome, Chromosomes, gene, life, medical, information, report, aid, research, microbiology, medicine, health, illustration, cartoon, font, art, graphic design, animation, smile, fictional character, style 3100x1999 - mohamed hassan - 1585701 - Free stock photos - PxHere. (n.d.). Retrieved June 2019, from: /en/photo/1585701 QUESTION – ACADEMIA VS. INDUSTRIES This content was retrieved from Section 02 Slide 3 of 14 of the online learning module As you have just read, the way academia and industries go about drug discovery differs. Question: Use the drop-down menus to indicate whether the scenario aligns more closely to innovation within academia or industry. Options: Academia, Industry Scenario Innovation Finding a new way to alter pain receptors in the brain. Finding the mechanism by which Crohn’s disease expresses itself in an individual. Feedback: Scenario Innovation Finding a new way to alter pain receptors in the brain. Industry Finding the mechanism by which Crohn’s disease expresses itself in an individual. Academia CONFLICT WITH INNOVATION This content was retrieved from Section 02 Slide 4 of 14 of the online learning module Not surprisingly, the goal of developing a product with therapeutic potential is often viewed as being in conflict with the pressures placed on the pharmaceutical industry to make money. It has often been proposed that publicly funded research institutes should develop therapeutic interventions to avoid this conflict of interest. As such, most research grants in the biomedical sciences must have a translational* component, but developing a drug is risky and is as much art as science. Research scientists do not discover and develop drugs as well as the pharmaceutical industry. Indeed, an emerging trend is for the DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 19 MODULE 01 COMPANION GUIDE PHAR 480 pharmaceutical industry to collaborate with research institutions or smaller start-up companies that have a vast knowledge about a particular area of biology. Definition*: Translational: The application of scientific knowledge to innovations that improve health outcomes References: Attarwala, H. (2010). TGN1412: From Discovery to Disaster. Journal of Young Pharmacists, 2(3), 332-336. Retrieved June 2019 from: https://doi.org/10.4103/0975-1483.66810 INTELLECTUAL PROPERTY This content was retrieved from Section 02 Slide 5 of 14 of the online learning module Given the expensive and uncertain nature associated with innovation during the Drug Discovery and Development timeline, there must be a financial reward to incentivize corporations to take on such risky business. The shareholders who fund these discoveries expect a return on their investment; without profit, innovation is limited. The cornerstone to ensuring there is a financial reward for the corporation is the concept of intellectual property (IP). Intellectual property is any creative work or invention considered to be the property of its creator. Economically, intellectual property is a form of intangible asset. An intangible asset is an asset that lacks physical substance, or is out of warranty (unlike physical assets, such as machinery and buildings). The nature of these assets makes them relatively hard to evaluate. Reference: Intellectual Property for Startups. (n.d.). Retrieved June 2019 from https://www.sparkinnovations.com/intellectual-property-for-startups/ QUESTION – THE PURPOSE OF INTELLECTUAL PROPERTY This content was retrieved from Section 02 Slide 6 of 14 of the online learning module Answer the question about the purpose of intellectual property. Question: Why do you think there are laws to protect intellectual property? Feedback: Intellectual property laws provide exclusive rights to owners, such as publication/copying rights, license to produce/manufacture wares, sell and distribute inventions, or the right to sue when others violated these rights. TYPES OF INTELLECTUAL PROPERTY This content was retrieved from Section 02 Slide 7 of 14 of the online learning module Intellectual property primarily comes in four basic types. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 20 MODULE 01 COMPANION GUIDE PHAR 480 Learn about the four types of intellectual property. Patent – Refer to Pages 19 – 20 Trade Secret – Refer to Page 20 Trademark – Refer to Page 20 Copyright – Refer to Pages 20 – 21 PATENT Subpage of Section 02 Slide 7 of 14 – Patent 1/2 A patent refers to exclusive rights granted by a country to an inventor for a period of time in exchange for public disclosure. The inventor must describe, in detail, the invention and in return, no one else can use the invention unless you have come to an agreement (they have to pay royalties, etc.). A patent typically lasts for 20 years and can cover a number of different things, including the drug, a structural derivative of a drug, a manufacturing process, or a process of administering the drug. A specific inventor will often file multiple patents for each of the different aspects of the invention, so they can hold exclusive rights and no other groups infringe on their idea. The patent is then registered and no other group can submit a patent for the same invention. This process can be time consuming and expensive. You will learn about patents in detail in Sections 03 and 04 of this module. EXAMPLE: PATENTS FOR HUMIRA Subpage of Section 02 Slide 7 of 14 – Patent 2/2 Using the pharmaceutical company AbbVie as an example, they received patents for their drug Humira (adalimumab), an immunosuppressant initially used to treat arthritis, but now used for additional indications (as justified by clinical trials) which increase the breadth of its patents, as well as other patents for production methodology. The abstract of one of the patents covering adalimumab (Humira) is shown in the figure. The abstract of this patent describes the methods of producing adalimumab. If you’re interested, review the full patent for Humira production methodology. Patent: Methods of Producing Adalimumab Abstract: The invention describes improved methods and compositions for producing a recombinant protein, eg an antibody, in mammalian cell culture. In addition, the invention provides improved cell culture media, including improved production media, feed solutions, and combination feeds, which may be used to improve protein productivity in mammalian cell culture. Page Link: https://patentimages.storage.googleapis.com/a7/20/c7/eb32a6c5aa8f22/US9284371.pdf Reference: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 21 MODULE 01 COMPANION GUIDE PHAR 480 AbbVie (2016). United States Patent No. U S 9.284,371 B2. Retrieved June 2019 from: https://patentimages.storage.googleapis.com/a7/20/c7/eb32a6c5aa8f22/US9284371.pdf TRADE SECRET Subpage of Section 02 Slide 7 of 14 – Trade Secret 1/1 A trade secret is exactly that - a secret. It refers to confidential information that is kept secret for economic benefit. A trade secret can be anything, similar to a patent, but you don’t have to register or disclose it to the public. The downside to a trade secret is you run of risk of losing the idea if another group patents it or it becomes public knowledge. One of the most well-known trade secrets is the formula for Coca Cola. TRADEMARK Subpage of Section 02 Slide 7 of 14 – Trademark 1/1 Trademarks are a word, phrase, logo, symbol, design, image, or a combination used by individuals or organizations to represent their products or service and distinguish them from others. A trademark is what distinguishes one organization from another in a marketplace. It is a unique combination of letters, words, sounds, or designs. For example, the name HUMIRA is trademarked by AbbVie. Their logo is also trademarked. Reference: (n.d.). Retrieved June 2019 from: https://www.humirapro.com COPYRIGHT Subpage of Section 02 Slide 7 of 14 – Copyright 1/1 Copyright gives someone the legal right to copy or be given credit to a creation with no need for formal registration. Copyright is usually used to protect any literary work. This can include books, songs, movies, and software. In the pharmaceutical industry, copyright generally applies to the wording and language around the drug, including important safety information for consumers. This can be in the form of advertising or the package insert that comes with the drug. Review the important safety information page on the Humira website. Important Safety Information About Humira (adalimumab) Page Link: https://www.humira.com/important-safety-information DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 22 MODULE 01 COMPANION GUIDE PHAR 480 Reference: Copyright AbbVie. Retrieved June 2019 from: https://www.abbvie.com/ QUESTION – INTELLECTUAL PROPTERY This content was retrieved from Section 02 Slide 8 of 14 of the online learning module Question: Use the drop down menus to match the concept with the type of intellectual property it refers to. Options: Copyright, Patent, Trademark, Trade Secret Concept Intellectual Property Confidential information only shared within the company Important safety information disclosed on the package insert of a drug product. Logo Exclusivity for an invention Feedback: Concept Intellectual Property Confidential information only shared within the company Trade Secret Important safety information disclosed on the package insert of a Copyright drug product. Logo Trademark Exclusivity for an invention Patent QUESTION – PATENT VS TRADE SECRET This content was retrieved from Section 02 Slide 9 of 14 of the online learning module Answer the question about intellectual property. Question: What is the difference between a patent and a trade secret? In what situation would you choose one over the other? Feedback: For a patent, you must go through an extensive and expensive process to receive exclusive rights to an invention. In exchange, you must disclose details regarding the invention the public. For a trade secret, there is no formal process. You can keep the information private within your company, but do not receive the exclusive rights to the invention. In this case, you run the risk of someone else patenting the idea. A company might opt for a trade secret over a patent if they don’t want to go through the entire patenting process (or can’t afford it), or don’t want to disclose the invention to the public. TAKING ADVANTAGE OF INTELLECTUAL PROPERTY IN THE PHARMACEUTICAL INDUSTRY This content was retrieved from Section 02 Slide 10 of 14 of the online learning module DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 23 MODULE 01 COMPANION GUIDE PHAR 480 Because intellectual property gives pharmaceutical companies exclusive rights to their line of products for a set period of time, they essentially have a monopoly and can price the drug at whatever cost, without fear of competition in the form of cheaper, generic versions of the drug. An important issue seen with pharmaceutical companies is the sudden rise in drug costs. Review an article about the rising drug costs in Canada. Drug costs rising fast in Canadian health-care spending, report finds Pharma Phact The Impact of Rising Drug Costs The most widely talked about drug hike was seen when Turing Pharmaceuticals CEO Martin Shkreli bought the rights to Daraprim, a drug used to treat toxoplasmosis*, and raised its price from $13.50 to $750 a pill overnight. The sudden increase sparked outrage. While the company claims the rise in cost would not limit access to the drug and was needed to fund more research in the drug’s indications, others see it as a company limiting access to a lifesaving medicine for the sake of profit. Learn more about the impact of rising drug costs. Drug Goes From $13.50 a Table to $750 Overnight Definition*: Toxoplasmosis: A parasitic disease commonly acquired through consuming undercooked contaminated meat. Page Links: https://www.cbc.ca/news/health/cihi-health-costs-canada-report-prescriptions-pharmacare-1.4390945 https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises- protests.html References: Ireland, N. (2017). Drug costs rising fast in Canadian health-care spending, report finds. CBC News. Retrieved June 2019 from: https://www.cbc.ca/news/health/cihi-health-costs-canada-report- prescriptions-pharmacare-1.4390945 Pollack, A. (2015). Drug Goes From $13.50 a Tablet to $750, Overnight. Retrieved June 2019 from: https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises- protests.html QUESTION – SOLVING THE PROBLEM OF RISING DRUG COSTS This content was retrieved from Section 02 Slide 11 of 14 of the online learning module Answer the question about the impact of pharmaceutical inflation using your knowledge from the CBC article. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 24 MODULE 01 COMPANION GUIDE PHAR 480 In the article “Drug costs rising fast in Canadian health-care spending, report finds”, Steve Morgan (University of British Columbia) suggests that the best solution to lower drug prices is a "national pharmacare program that would determine what treatments are covered and at what price, which would allow for tougher negotiations with global drug companies." Question: In your opinion, how would such a program impact both the health care system and pharmaceutical industry? Feedback: The numerous impacts this may have are major discussion point for health policy decision-makers looking into such a program. You will learn about drug pricing later in the course when we discuss generics and over-the-counters. Page Link: https://www.cbc.ca/news/health/cihi-health-costs-canada-report-prescriptions-pharmacare-1.4390945 Reference: Ireland, N. (2017). Drug costs rising fast in Canadian health-care spending, report finds. C B C News. Retrieved June 2019 from: https://www.cbc.ca/news/health/cihi-health-costs-canada-report- prescriptions-pharmacare-1.4390945 INCREASING DRUG COSTS This content was retrieved from Section 02 Slide 12 of 14 of the online learning module Although much focus is emphasized on discovering, developing, producing, and marketing drugs, commercial enterprises within the pharmaceutical industry use a variety of business strategies to succeed in such a competitive market. One of these strategies is increasing the price of drugs. With hiking drug costs in the pharmaceutical industry, profound financial burden is placed on the general public and health care system. In attempt to control these corporate actions, the United States Senate routinely holds hearings with pharmaceutical executives to question them on their pricing and executive compensation methods. Review some examples of increasing drug costs in the pharmaceutical industry. The Business of Pharma: Industry Examples – Refer to Pages 25 – 27 THE BUSINESS OF PHARMA: INDUSTRY EXAMPLES Subpage of Section 02 Slide 12 of 14 – The Business of Pharma: Industry Examples 1/2 The United States Senate Finance Committee held a hearing on February 29, 2019 with the top pharmaceutical executives to question them on the industry’s pricing practices. Review what the Senate had to say about each of these pharma giants. Abbvie The US State Senate Finance Committee said: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 25 MODULE 01 COMPANION GUIDE PHAR 480 “AbbVie manufactures the top-selling prescription drug in America, the arthritis medication Humira. Over six years, the company doubled the price of a 12-month supply from $19,000 to $38,000. Can patients opt for a less expensive alternative? No they cannot, because AbbVie protects the exclusivity of Humira like Gollum with his ring. Thick cobwebs of patents, legal tricks, and shadowy deals with other drug makers, all to keep the cash flowing.” Disclaimer: The claims made by the politicians in this senate hearing have not been verified. Pfizer The US State Senate Finance Committee said: “Lyrica has increased 163% in price since 2012.” Note: In fact, Lyrica generated $4.5 billion in revenues in 2017. Disclaimer: The claims made by the politicians in this senate hearing have not been verified. Merck The US State Senate Finance Committee said: “[Merck & Co.] cut prices for drugs that provide essentially no revenue to the company. Left untouched were the cash cows, Keytruda and Januvia, which account for more than a quarter of the Merck’s revenue.” Disclaimer: The claims made by the politicians in this senate hearing have not been verified. Johnson & Johnson The US State Senate Finance Committee said: “[Johnson & Johnson] CEO Alex Gorsky said that the pharmaceutical industry needed to self-police on pricing. Sounds good, but it didn’t last long. Three days later, his company hiked the prices of hundreds of its drugs, including drugs that account for billions in Medicare spending.” Disclaimer: The claims made by the politicians in this senate hearing have not been verified. References: Copyright AbbVie. Retrieved June 2019 from: https://www.abbvie.com/ Copyright Pfizer. Retrieved June 2019 from: https://www.pfizer.ca/ Copyright Merck. Retrieved June 2019 from: https://www.merck.com/index.html Copyright Johnson and Johnson. Retrieved June 2019 from: http://www.jnjcanada.com/ Decorative image of the Johnson and Johnson logo. Wyden, Ron. (2019). Wyden Statement at Finance Committee Hearing on Drug Prices with Pharma CEOs. Retrieved from https://www.finance.senate.gov/imo/media/doc/022619%20Wyden%20Statement%20at%20Finance%2 0Committee%20Hearing.pdf DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 26 MODULE 01 COMPANION GUIDE PHAR 480 QUESTION – PREVENTING PHARMACEUTICAL INFLATION Subpage of Section 02 Slide 12 of 14 – The Business of Pharma: Industry Examples 2/2 After reading those quotes from the Senate hearing, answer the question. Question: Based on what you’ve learned so far, what do you think are some of the reasons these pharmaceutical companies increased the price of their drug in the first place. Feedback: There are many reasons why. One reason is the fact that these companies have a fiduciary responsibility to deliver to their shareholders. If the company’s stock isn’t performing well, an easy way to fix this is by increasing their prices, ultimately increasing their total revenue. A second reason could be that a company only has a certain amount of time before their patent expires and generic versions of the drug enter the market. A third reason could be to account for the decrease in sales that will occur once the patent expires, they increase the prices while they still can. In other words, the market has no choice but to bear it. Finally, a fourth reason may be that there have been some recent drug shortages due to problems with the supply chain needed for the manufacturer of some products. With these supply chain problems the cost of the supply increases. QUESTION – HIKING DRUG COSTS This content was retrieved from Section 02 Slide 13 of 14 of the online learning module Answer the question using your knowledge of the relationship between innovation and intellectual property within the pharmaceutical industry. Question: As mentioned previously, a possible way to prevent pharmaceutical inflation is the development of a national pharmacare program. Taking into account the rising cost of lifesaving medication, can you think of ways to circumvent these price hikes without halting innovation? Feedback: As you’ll learn later in this module, limiting the length of intellectual property such as patents encourages the development of generic medication at a lower cost. SECTION 02: SUMMARY This content was retrieved from Section 02 Slide 14 of 14 of the online learning module In this section, you learned about the concept of innovation and how it differs within an academic setting versus an industry. You were introduced to some of the pressures placed on the pharmaceutical industry, including some real-life examples from within Big Pharma, and the downstream effects. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 27 MODULE 01 COMPANION GUIDE PHAR 480 You were also introduced to the idea of intellectual property and the four different types of IP that exist - patents, trademarks, trade secrets, and copyright. While all four types are important within the pharmaceutical industry, you will focus on patents and how they fit into the Drug Discovery and Development timelines in Sections 03 and 04 of this module, respectively. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 28 MODULE 01 COMPANION GUIDE PHAR 480 SECTION 03: INTRODUCTION TO PATENTS INTRODUCTION TO PATENTS This content was retrieved from Section 03 Slide 1 of 13 of the online learning module As you learned in Section 02, there are four different types of intellectual property - patents, trade secrets, trademarks, and copyright. Patents are of particular importance - they drive the pharmaceutical industry, as they can guarantee profit and ensure all the time and cost put into drug discovery/development is worthwhile. Thus, patents will be the focus of this section. In this section, you will examine the patenting process in greater detail. You will learn about the criteria required to receive a patent and how to determine who actually deserves the patent, as well as a few different types of patents that can be issued. Patent law is complicated and the consequences of how patent law is interpreted can have significant financial repercussions - in the billions of dollars! Listen to Dr. Ozolins elaborate on the patents that Pfizer holds. (2:29) Start of Audio Transcript: Viagra's patent, originally scheduled to expire in late March of 2012, has been extended until April 2020. There was a lot of informed speculation in recent years about what would happen when Viagra finally did become available in generic form. Several drug companies were poised to take advantage of the opportunities presented by the expired patent, most notably Teva Pharmaceuticals. Teva gained tentative approval from the Food and Drug Administration, or FDA, to market a generic version of Viagra. So what happened? Well, in March of 2010, however, Pfizer sued Teva for patent infringement and this was based on a second Pfizer patent which runs until 2019. The second patent is sometimes referred to as a "method of treatment patent," and in that method of treatment patent, Pfizer argued that even though sildenafil was to come up for grabs in 2012, Pfizer should retain exclusive rights to market it as an erectile dysfunction treatment until 2019. Ultimately, Pfizer prevailed against Teva in a 12-day bench trial held in the summer of 2011 and it was declared that the company's Viagra patent would stand solid through until 2019. Early in 2012, Pfizer was granted an additional six months of U.S. patent protection for Viagra because the company was studying the effect of another one of its products containing Viagra's active ingredient sildenafil in children with pulmonary hypertension. With this latest development, Pfizer's patent for Viagra stands through April of 2020. Sildenafil is used for persistent pulmonary hypertension and is marketed under the name of Revatio. So as a result of all this, there is no legal generic Viagra that's available in the United States despite what some online advertisers claim, nor is there an over-the-counter version of this drug yet. This example shows how important patents are and how bitterly they will be fought over as this decision allowed Pfizer to retain billions of dollars of revenues for many more years. As a side point, some of my prior students who study drug discovery and development here at Queen's have gone on to become patent lawyers. End of Audio Transcript. Reference: U.S. Food and Drug Administration. (2019). Patent and Exclusivity for: N020895. Retrieved 18 July 2019 from: https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=020895& DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 29 MODULE 01 COMPANION GUIDE PHAR 480 Appl_type=N VIDEO: THINGS YOU PROBABLY DIDN’T KNOW ABOUT PATENTS? This content was retrieved from Section 03 Slide 2 of 13 of the online learning module Before going in depth on the timeline of patent development, and where patents can be issued during drug development, it is important to have a general understanding of this process, and how patents work. Watch the video for a brief overview on the patent process. As you watch, focus on the importance of patents to pharmaceutical companies. (1:43) Page Link: https://www.youtube.com/watch?v=MZdt8nms9ms THREE CRITERIA FOR A PATENTABLE INVENTION This content was retrieved from Section 03 Slide 3 of 13 of the online learning module In order for an invention to be patentable, it must be able to satisfy three criteria under patent laws. Learn about the three criteria required for a patentable invention. Novelty The claimed invention cannot be previously known or available to the public in a single reference. I.e., there exists no “prior art” (any information or disclosure that is available to the public before the filing of a patent application). Non-Obviousness The patentable invention must not be obvious to a person of ordinary skill in the art at the time the invention is made. Utility A patent is obtained for an invention if it is “useful” (the utility aspect). An invention must have an industrial application to meet the utility requirement of a patent. This means that the invention must be able to be used in any kind of industry. Pharma Phact Countries vary in their interpretation of utility, and in Canada this has affected the ability of pharmaceutical companies to protect their products with patents. Many pharmaceutical products have had their patents stripped for “lack of utility” even though they are used to treat patients with diseases. Learn about patent utility and the problem Canadian pharmaceutical companies face. Intellectual Property Page Link: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 30 MODULE 01 COMPANION GUIDE PHAR 480 http://innovativemedicines.ca/innovation/intellectual-property/ QUESTION – PATENT CRITERIA This content was retrieved from Section 03 Slides 4-5 of 13 of the online learning module Answer the question about your new potential patent. Question: You are a curious graduate student and for various reasons you have reason to believe that Humira might actually treat Alzheimer’s disease. You perform the experiment to test your hypothesis in an appropriate laboratory animal species and to your delight the disease does not progress! Would you be able to profit from this discovery? Feedback: Continue to compare your response to the one provided by your instructor. Your Response Dr. Ozolin’s Answer Yes, you might be able to profit for several reasons: The current patents only relate to the diseases described by “Conditions Humira treats.” Alzheimer's is not listed as one of the conditions. The idea is novel unless you described your results publicly at a scientific conference or in a peer- reviewed manuscript. The idea was not obvious and indeed it seemed a bit crazy to even try. There is utility in this invention – Alzheimer’s is an unmet medical need with no effective treatments to date. TIMELINE OF PATENT DEVELOPMENT This content was retrieved from Section 03 Slide 6 of 13 of the online learning module The lifecycle of a patent typically lasts 20 years from development into expiration. However, the effective patent term is only part of this time frame due to the period required to develop a product after the patent is filed. The effective patent term is the time that the drug is on the on the market generating revenues. Listen to Dr. Ozolins elaborate on the timeline of patent development. (2:10) Start Audio Transcript: What you see in front of you is a figure depicting an effective patent life cycle with the actual patent. And what do I mean by that? Well, using the example illustrated here, we have company ABC, which files a patent application during its pre-clinical research, and that begins the patent clock ticking. So, they have 20 years now of patent exclusivity and that is in, let us say, for example, 2004. So, at that point, you've lost 0 years of patent protection. However, we know drug development and research takes time. So, what's happened is by the time A BC is ready to begin clinical testing and files its IND, a few years have already passed. In this instance, two years. So, in effect, you now only have 18 years of patent protection left. And, of course, things don't always go quickly and smoothly. And what ends up happening here is that after about 10 years of clinical testing, company ABC finally files its NDA, or New Drug Application. And so, what has happened here DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 31 MODULE 01 COMPANION GUIDE PHAR 480 now is you've lost a further 10 years and when you combine that with some of the other losses that you've had prior, you now only have eight years of effective patent life cycle left. So, that was the scenario if everything goes well. So, what if, for example, the review process didn't go well? Let's say, for example, the FDA had questions about some of your observations, or they wanted you to do further experiments to clarify some toxicity that was observed. In that case, you would not be allowed to enter the market for a further potentially year or more, which means that you further lose more of your effective patent term. In which case, you may only have seven or six years within which to sell your drug on the open market and get a return on your investment. End of Audio Transcript. 20 Company ABC files a patent application during preclinical research, starting the 20-year patent clock. 18 Company ABC is ready to begin clinical testing and files an Investigational New Drug (IND), starting the FDA approval process. 17 The Canadian Intellectual Property Office issues Company ABC’s patent. 8 After 10 years of clinical testing, Company ABC files an New Drug Application (NDA). 7-6 A longer than anticipated FDA approval process of your NDA reduces your effective patent term. FIRST-TO-INVENT VS. FIRST-INVENTOR-TO-FILE This content was retrieved from Section 03 Slide 7 of 13 of the online learning module Historically, there have been two different systems for granting patents. The first was called the “first- to-invent” (FTI) system and, as you can imagine, granted the patent to the inventor who first thought of the idea. On September 16, 2011, Barack Obama signed the America Invents Act, switching the US from the "first-to-invent" system to a "first-inventor-to-file" (FTF) system for patent applications filed on or after March 16, 2013. Canada changed from FTI to FTF in 1989. One study by researchers at McGill University found that contrary to expectations: "The switch failed to stimulate Canadian Research & Development (R&D) efforts. Nor did it have any effects on overall patenting. However, the reforms had a small adverse effect on domestic-oriented industries and skewed the ownership structure of patented inventions towards large corporations, away from independent inventors and small businesses." References: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 32 MODULE 01 COMPANION GUIDE PHAR 480 United States. (2011). Leahy-Smith America Invents Act. Washington, D.C.: U.S. G.P.O. Retrieved June 2019. Lo, S., & Sutthiphisal, D. (2009). Does it Matter Who Has the Right to Patent: First-to-invent or First-to- file? Lessons From Canada. Retrieved June 2019 from: doi:10.3386/w14926 (2016). America Invents Act of 2011 is enacted into law by President Obama. Retrieved June 2019 from: https://www.ifia.com/official/activity-report/activity-report-2011/world-wide-priority/ QUESTION – FIRST-TO-FILE VS. FIRST-TO-INVENT This content was retrieved from Section 03 Slide 8 of 13 of the online learning module Timeline: Question: Based on the timeline, check the box that indicates who has patent rights. Options: Inventor X, Inventor Y System Patent Rights Under the First-to-Invent System Under the First-Inventor-to-File System Feedback: System Patent Rights Under the First-to-Invent System Inventor X Under the First-Inventor-to-File System Inventor Y Definition*: Reduce to practice: The step after conception of an idea that involves the formation of an idea. QUESTION – WHO IS ENTITLED THE PATENT? This content was retrieved from Section 03 Slide 9 of 13 of the online learning module Read the scenario and answer the question about patent entitlement. Assume Tom conceives of a new mousetrap on January 1, 2006. Tom works diligently from January 1, 2006, to February 1, 2006, to prepare a patent application, and Tom files his patent application on February 1, 2006. Thus, Tom constructively reduced his invention to practice on February 1, 2006. Assume Jerry conceives of the same mousetrap on January 10, 2006, and diligently files a patent application on the new mousetrap on January 20, 2006. Question: Who is entitled to the patent on the mousetrap? Explain your answer. Feedback: DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 33 MODULE 01 COMPANION GUIDE PHAR 480 Under the first-to-invent system, Tom is entitled to the patent on the mousetrap, because he conceived the mousetrap before Jerry and still worked diligently to reduce it to practice by filing. QUESTION – PATENT ENTITLEMENT This content was retrieved from Section 03 Slide 10 of 13 of the online learning module Read the scenario and answer the question about patents. As a further extension of the example, assume Tweety conceived of the same mousetrap on December 31, 1990. Tweety never told anyone about the mousetrap and did not work on reducing the mousetrap to practice for many years due to financial reasons. Tweety finally actually reduced the mousetrap to practice on February 15, 2006. Question 1 of 2: Who is entitled to the patent on the mousetrap? Feedback: Continue to compare your response to the one provided by your instructor. Dr. Ozolins Answer Because Tweety did not diligently work to reduce the invention to practice in the period before others' conception of the same invention, he is not entitled to a patent over Tom or Jerry. However, if Tweety has published her idea in the public domain before 2006, then this publication can be a basis to reject or invalidate Tom or Jerry's patent. TYPES OF PATENTS IN THE PHARMACEUTICAL INDUSTRY This content was retrieved from Section 03 Slide 12 of 13 of the online learning module In the pharmaceutical industry, a patent can be placed on a variety of different aspects of a drug. Review examples of the types of patents. Molecules Pharmacological compound or active metabolite Protein fragments or nucleic acid fragments Processes Manufacturing process Purification method Diagnostic processes New Composition/Formulation New compositions of two or more ingredients New formulations (e.g. extended release, gel, patch) Specific Forms Enantiomers/Isomers DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 34 MODULE 01 COMPANION GUIDE PHAR 480 Polymorphs Salts, Esters Prodrugs New Indications Compounds for use to treat disease Methods of treatments New patient subgroups Dosage regimen Others Diagnostic tests R&D-technology Targets/biomarkers Devices such as inhalers SECTION 03: SUMMARY This content was retrieved from Section 03 Slide 13 of 13 of the online learning module In this section, you learned about a type of intellectual property called patents. A patent refers to exclusive rights granted by a country to an inventor for a period of time in exchange for public disclosure. In order for something to be patentable, it must be novel, non-obvious, and have utility. Patents used to be filed under a “first-to-invent” system - whoever could prove they were the first to invent the idea received the patent. As of 1989, Canada switched to a “first-inventor-to-file” system. There are many different types of patents, including molecular patents, process patents, and new composition patents, to name a few. In the next section, you will learn about how patents fit into the Drug Discovery and Development timeline. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 35 MODULE 01 COMPANION GUIDE PHAR 480 SECTION 04: PATENTS AND THE DRUG DISCOVERY AND DEVELOPMENT TIMELINE INTRODUCTION TO PATENTS IN DRUG DISCOVERY AND DEVELOPMENT This content was retrieved from Section 04 Slide 1 of 17 of the online learning module Recall the Drug Discovery and Development timeline from Section 01. A patent can be issued at each stage of this timeline. In this section, you will be introduced to four areas where patents fit into the Drug Discovery and Development timeline: Additionally, you will learn about the tactics used by pharmaceutical companies to extend product-life, and the cost of the patenting process. Review the areas of the Drug Discovery and Development timeline. Reference: Adapted from: PhRMA (2015). Biopharmaceutical Research & Development: The Process Behind New Medicines. Retrieved June 2019 from: http://phrma- docs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf PATENTS IN THE DRUG DISCOVERY STAGE This content was retrieved from Section 04 Slide 2 of 17 of the online learning module You will begin learning about the kinds of patents given out at each stage of the Drug Discovery and Development timeline at the beginning: with drug discovery. The first step towards drug discovery is hit identification. Hits are small molecules that have been identified to bind to a target of interest, and alter its function. There are often two kinds of molecular patents that are issued at this stage. Learn about these two kinds of patents. Structure of Interest Following hit identification, chemists are able to conduct thorough structure activity relationship (SAR) studies on these “hit” molecules. From these S A R studies, a pharmacophore* will be identified that has significant activity. This pharmacophore is then patented. You will learn about SAR studies in Module 02. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 36 MODULE 01 COMPANION GUIDE PHAR 480 Structural Variants A variety of subtle structural variants of the pharmacacore exist that can also have the desired chemical activity. These variants will be identified and protected with patents, since one of these may become the actual marketed product. Pharma Phact Google has a plug-in called Google Patents, which allows you to search patent codes. For your interest, use the plug-in to find the patents for both the structure of interest covering atorvastatin and atorvastatin itself. Patent codes: Structure of Interest – US 4 6 8 1 8 9 3 A Atorvastatin – US 5 2 7 3 9 9 5 A Google Patents Definition*: Pharmacophore: A part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes. Page Link: https://patents.google.com Reference: Hughes, J. P., Rees, S., Kalindjian, S. B., and Philpott, K. L. (2011). Principles of early drug discovery. British journal of pharmacology, 162(6), 1239-1249. doi:10.1111/j.1476-5381.2010.01127. Retrieved June 10 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1111/j.1476-5381.2010.01127.x QUESTION – IMPORTANCE OF PATENTING STRUCTURAL VARIANTS This content was retrieved from Section 04 Slide 3 of 17 of the online learning module Answer the question about applying patents to structural variants. Question: From the viewpoint of a pharmaceutical company, why do you think it would be necessary to patent structural variants? Feedback: If the entire chemical space were not protected, a competitor could, with very little effort, make a very close chemical variant and develop a direct competitor to the original product. PATENTS IN THE DRUG DEVELOPMENT STAGE This content was retrieved from Section 04 Slide 4 of 17 of the online learning module Once a lead chemical is identified during drug discovery, a comprehensive drug development DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 37 MODULE 01 COMPANION GUIDE PHAR 480 campaign is launched where new characteristics of the chemical can be identified and protected through patents. Three areas for novel discovery include: pharmacology, pharmaceutical development, and process methodology. Learn about patents in each novel area of discovery. Metabolites and Isomers – Refer to Pages 38 – 39 Process Methodology – Refer to Pages 39-40 PHARMACOLOGY: METABOLITES Subpage of Section 04 Slide 4 of 17 – Metabolites and Isomers 1/2 During drug development, novel metabolites can be identified, often showing to have greater potency or lower toxicity than the original chemical of interest. A new patent can then be issued on the original chemical outlining the optimal dosage regimen necessary to produce these metabolites. Review an example from the pharmaceutical industry. Example: Busiprone Drug manufacturers Bristol-Myers Squibb (BMS) introduced the utility of this method to extend the patent-life on their drug buspirone (BuSpar). Just 11 hours prior to the expiration of the original patent, BMS had a patent approved which outlined the optimal use of buspirone for the production of 6- hydroxybuspirone, the metabolite of interest. Introduction of this new patent inhibited generic versions of buspirone to enter the market, causing revenue loss for generic drug manufacturers planning to introduce generics later that same year. Reference: Borchardt, J. (29 Nov 2000). Drug Metabolites Can Now Be Patented. The Scientist. Retrieved on June 2019 from: https://www.the-scientist.com/news-analysis/drug-metabolites-can-now-be-patented-55299 PHARMACOLOGY: ACTIVE ISOMER Subpage of Section 04 Slide 4 of 17 – Metabolites and Isomers 2/2 Isomerization may also occur in which one isomer may be active or even toxic. In this instance a new patent can be issued to one isomeric form because the racemic mixture* may have undesirable effects associated with it. Alternatively, the racemic mixture may produce the desired effects but one isomer simply shows greater efficacy, leading to the application of a new patent on the isomer of interest. Review an example from the pharmaceutical industry. Example: Omeprazole Omeprazole, was the first drug to successfully treat acid reflux. It was later observed that the S- isomer* was more effective, leading to an additional patent being placed on S-omeprazole specifically. Switch between the S- and R-isomers* of omeprazole. DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 38 MODULE 01 COMPANION GUIDE PHAR 480 S-Isomer R-Isomer Definitions*: Racemic Mixture: A racemic mixture is a solution containing equal parts of the S- and R- isomers of a compound. S-isomer: Highest priority groups at a chiral center (an atom with four different groups) are aligned counterclockwise in order of priority. R-isomer: Highest priority groups at a chiral center (an atom with four different groups) are aligned clockwise in order of priority. References: Kendall, J. M. (2003). Review article: esomeprazole - the first proton pump inhibitor to be developed as an isomer. Alimentary Pharmacology and Therapeutics, 17: 1-4. doi: 10.1046/j.1365-2036.17.s1.1 Retrieved June 2019 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1046/j.1365- 2036.17.s1.1.x PubChem. (2015). Esomperazole. Retrieved June 2019, from: https://commons.wikimedia.org/wiki/File:Esomeprazole.svg PubChem. (2007). Omeprazole. Retrieved June 2019, from: https://commons.wikimedia.org/wiki/File:Esomeprazole.svg#/media/File:Omeprazole.svg PROCESS METHODOLOGY Subpage of Section 04 Slide 4 of 17 – Process Methodology 1/1 As you just learned, although patents can be applied to different chemical compositions of a drug, there is also the ability to apply patents to the process methodology. Process methodology refers to the chemical or biological preparations utilized to produce these compounds. This allows drug manufacturers to cover both the use of the methods and the actual product itself, by filing unique patent claims. For instance, in 1988 McNeil AB Inc. applied for a patent to protect the methodology behind the creation of a sustained release tablet. Patent application by McNeil AB Inc. Pharmaceutical Sustained Release Matrix and Process Pharma Phact Humira’s Patent Estate DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 39 MODULE 01 COMPANION GUIDE PHAR 480 AbbVie holds about 136 patents for their major immunosuppressant drug Humira. This makes it extremely difficult for another company to replicate the drug without using processes and techniques to which the pharma giant continues to hold rights. In comparison, typical drugs usually have no more than a dozen patents. Of these patents, 22 are for various diseases or methods of treatment, 14 on drug formulation, 24 on manufacturing practices, and 15 other patents. With the latest expiration date as 2034, Humira has been able to double its typical protection span! Page Link: https://patentimages.storage.googleapis.com/6b/9c/fb/e282e2c706cfa9/AU603675B2.pdf Reference: Koons, C. (2017, September 7). This Shield of Patents Protects the World’s Best-Selling Drug. Retrieved June 2019 from https://www.bloomberg.com/news/articles/2017-09-07/this-shield-of-patents-protects- the-world-s-best-selling-drug LATE STAGE DEVELOPMENT PATENTS This content was retrieved from Section 04 Slide 5 of 17 of the online learning module Clinical development can lead to the creation of new intellectual properties, including novel clinical indications, dosage regimens, and combination drugs. Patents can then be issued during the later stages of drug development based on these novel findings, allowing drug manufacturers to prolong the shelf-life of a product. Learn about patent protection during the later stages of drug development. New Clinical Indications Often during development it becomes apparent that the drug of interest may be able to treat conditions that were not originally intended. For instance, Viagra, a medication used for erectile dysfunction, was originally developed as an antihypertensive medication. Learn about the development of Viagra. Development of Viagra – Refer to Pages 40 - 42 New Dosage Regimens Formulation design is difficult and often lags behind other aspects of drug development. Therefore, it is often in the final pivotal clinical trial that the dosage form of the drug is finally determined. The six-day dosage regimen for methylprednisolone, a corticosteroid hormone used to suppress the immune system, is presented in the figure. Some conditions may worsen when this drug is suddenly stopped, thus, the dose needs to be gradually decreased (reduced by 4 mg/day). This new dosing regimen can be patented, and is designed to incorporate the dosing taper. Combination Drugs Occasionally, during the later stages of clinical trials it may become apparent that there are advantages DRUG DISCOVERY AND DEVELOPMENT | PHAR 480 MODULE 01 PAGE 40 MODULE 01 COMPANION GUIDE PHAR 480 to giving two drugs simultaneously. A common example of drug combination is taking lisinopril (treats high blood pressure) and atorvastatin (treats abnormal lipid levels) to treat heart disease. This new drug combination could receive a new patent. Reference: (2009). Methylprednisolone. Retrieved June 2019 from: https://commons.wikimedia.org/wiki/File:Sandoz.Methylprednisolone.4mg.jpg DEVELOPMENT OF VIAGRA Subpage of Section 04 Slide 5 of 17 – Development of Viagra 1/3 Viagra was initially developed as an antihypertensive medication, but the clinical trial was halted because it failed to meet its clinical endpoints. Many of the clinical trial participants did not want to return the unused medications, and eventually clinicians determined why the male participants were reluctant to comply. As a result a new patent was issued for erectile dysfunction and an entire multibillion dollar franchise and new therapeutic area was born. Following the initial product launch, new clinical indications of the active ingredient, Sildenafil, were observed. This lead to the issuing of new patents for two types of pulmonary arterial hypertension (1) altitude sickness, and; (2) persistent pulmonary hypertension in infants. Reference:

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