BURGER'S MEDICINAL
`CHEMISTRY
`AND DRUG DISCOVERY
`Fifth Edition
`Volume I: Principles and Practice
`
`Edited by
`
`Manfred E. Wolff
`
`lmmunoPharmaceutics , Inc.
`San Diego, California
`
`A WILEY-INTERSCIENCE PUBLICATION
`
`JOHN WILEY & SONS, Inc., New York · Chichester · Brisbane · Toronto · Singapore
`
`Apotex Ex. 1022
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`Apotex v. Auspex
`IPR2021-01507
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`

`

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`Notice Concerning Trademark or Patent Rights .
`The listing or discussion in this book of any drug in
`respect to which patent or trademark rights may exist
`shall not be deemed , and is not intended as
`a grant of, or authority to exercise, or an
`infringement of, any right or privilege protected by
`such patent or trademark.
`
`This text is printed on acid-free paper.
`Copyright © 1995 by John Wiley & Sons , Inc.
`
`All rights reserved. Published simultaneously in Canada .
`
`Reproduction or translation of any part of this work beyond
`that permitted by Section 107 or 108 of the 1976 United
`States Copyright Act without the permission of the copyright
`owner is unlawful. Requests for permission or further
`information should be addressed to the Permissions Department ,
`John Wiley & Sons, 605 Third Avenue, New York, NY
`10158-0012.
`
`Library of Congress Cataloging in Publication Data:
`Burger, Alfred, 1905-
`(Medicinal chemistry)
`Burger's medicinal chemistry and drug discovery. •· 5th ed.
`edited by Manfred E. Wolff.
`p.
`cm .
`"A Wiley-Interscience publication."
`Contents: v. L Principles and practice
`Includes bibliographical references and index .
`ISBN 0-471-57556-9
`L Pharmaceutical chemistry. L Wolff, Manfred E .
`III . Title: Medicinal chemistry and drug discovery .
`RS403.B8 1994
`615'. 19--dc20
`
`IL Title.
`
`94-12687
`
`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
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`CHAPTER NINE
`
`From Discovery to Market:
`The Development of
`Pharmaceuticals
`
`JAN I. DRAYER
`JAMES P. BURNS
`
`G. H. Besselaar Associates
`Princeton, New Jersey, USA
`
`CONTENTS
`
`1 Introduction, 252
`1.1 Evolution of drug development , 253
`1.1.1 Regulatory environment, 253
`1.1.2 Scientific environment, 255
`1.1.3 Commercial environment, 256
`1.2 Costs of drug development, 257
`2 The Drug Development Process , 258
`2.1 Chemistry, 259
`2.1.1 Preformulation, 261
`2.1.2 Product development / formulation, 261
`2.1.3 Phase 2 and phase 3 clinical
`supplies, 261
`2.1.4 Containers, 262
`2.1.5 Closures, 262
`2.2 Preclinical studies, 264
`2.2.1 Acute toxicity , 265
`2.2.2 Subacute toxicity studies, 265
`2.2.3 Chronic toxicity studies, 266
`2.2.4 Carcinogenicity studies, 266
`2.2.5 Mutagenicity studies, 267
`2.2.6 Reproduction studies, 267
`2.2. 7 Special toxicity studies, 267
`2.3 Transition from preclinical to clinical, 268
`2.4 Planning the drug development process , 269
`2.4.1 Assumptions, 269
`2.4.2 Defining the development strategy, 271
`2.4.3 The drug development master plan, 272
`
`251
`
`Burger's Medicinal Chemistry and Drug Discovery,
`Fifth Edition, Volume 1: Principles and Practice,
`Edited by Manfred E. Wolff.
`ISBN 0-471-57556-9 © 1995 John Wiley & Sons, Inc.
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`252
`
`From Discovery to Market: The Development of Pharmaceuticals
`
`2.4.4 Critical components of the clinical part
`of the drug development master
`plan, 275
`2.5 Clinical research; the conduct of clinical
`trials, 279
`2.5. 1 Phase 1 clinical research, 280
`2.5.2 Phase 2 and phase 3 clinical
`research, 282
`2.5.3 Periapproval clinical trial
`programs, 286
`2.5 .4 Development of the fin al protocol and
`case report fo rms, 286
`2.5.5
`Investiga tor selection, 288
`2.5.6 Monitorin g of studies, 290
`2.5.7 Evaluation of adverse events in clinical
`trials, 291
`2.5.8 E thical considerations in clinical
`research, 292
`2.5.9 Clinical trial reports, 295
`2.5 .10 When to stop the development of a
`drug, 295
`2.5. 11 Regulatory review during the conduct
`of clinical trials, 296
`2.5. 11.1 End of phase 2 and phase 3
`conferences, 297
`2.5. 11.2 FDA interactions under
`subpart E, 297
`2. 5.11.3 Regulatory approval
`process, 298
`2.5.11.4 Approval and launch, 299
`
`1 INTRODUCTION
`
`Through the early years of this century ,
`most drugs or medicines that were sold to
`the public were little more than home
`remedies or extracts of various natural
`products including barks and flowers , that
`owed their activity more to the alcoholic
`content of the elixir than to the actual
`activity of the product. With the advent of
`modern drug discovery technology and the
`ability to synthesize chemicals with specific
`pharmacologic activities, drug development
`has evolved considerably from that point.
`This chapter addresses the process of
`modern drug development from the point
`where a candidate drug has emerged from
`the drug discovery process, up through
`regulatory approval, and beyond into peri(cid:173)
`approval and post-marketing activities. Al(cid:173)
`though the development of drugs is becom-
`
`ing an increasingly global endeavor, the
`focus of this discussion is the U.S. Food
`and Drug Administration (FDA) and the
`associated
`steps
`in drug development
`necessary to satisfy the FDA , the regula(cid:173)
`tory body that holds the power of approval
`or disapproval for drugs on the U .S. mar(cid:173)
`ket. The FDA also has statutory authority
`for approval of other therapeutic / diagnos(cid:173)
`tic modalities such as biologics and devices;
`however, this chapter will focus exclusively
`on drug development even though there
`are many concepts of drug development
`that are applicable to both biologics and
`devices.
`During drug development , not only does
`the FDA evaluate the scientific merit of the
`data presented in support of approval of a
`drug, but also the labeling or package
`insert which contains the directions for use
`of the approved drug. The labeling in-
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`1 Introduction
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`structs physicians about the mechanism of
`action of the drug: the specific indication(s)
`approved for the drug; any special precau(cid:173)
`tions that patients should be advised to
`take when using the drug; any safety issues
`that have arisen in animal or human testing
`with the drug that physicians and patients
`should be aware of; potential adverse ef(cid:173)
`fects and their incidence that have been
`known to occur in clinical studies and could
`therefore occur in clinical use; any poten(cid:173)
`tial for abuse or addiction; and dosing
`recommendations (see Table 9.1). The con(cid:173)
`tent of this labeling determines how the
`approved drug can be marketed and pro(cid:173)
`moted. As such, labeling becomes a crucial
`document that can ultimately define the
`commercial success of the drug and the
`blueprint upon which drug development
`should be planned and executed. The evo(cid:173)
`lution of that drug development process is
`the starting point of this chapter.
`
`1.1 Evolution of Drug Development
`
`Three factors have played a major role in
`shaping the evolution of drug development.
`They are: Regulatory Environment, Sci(cid:173)
`entific Environment, and Industrial/Com(cid:173)
`mercial Environment. Each of these en-
`
`Table 9.1 Standard Sections of a Package
`Insert
`
`• Description
`• Clinical Pharmacology
`• Indications and Usage
`• Contraindications
`• Warnings
`• Precautions
`• Adverse Reactions
`• Drug Abuse and Dependence
`• Overdosage
`• Dosage and Administration
`• How Supplied
`
`vironments has had an impact, but not
`necessarily at the same time or to the same
`degree. They have evolved at their own
`pace.
`
`1.1.1 REGULATORY ENVIRONMENT. During
`drug discovery, only general federal laws,
`regulations, or guidelines regarding en(cid:173)
`vironmental protection, animal care and
`scientific misconduct govern the basic re(cid:173)
`search process. However, once a chemical
`becomes a candidate for development to
`ultimate commercialization, the company
`developing this product must be aware of
`the specific laws, regulations, and guide(cid:173)
`lines that are appropriate to the develop(cid:173)
`ment of such products so that the results of
`the investigations conducted will be accept(cid:173)
`able to the Food and Drug Administration
`(FDA) and health regulatory authorities in
`other countries as necessary.
`The involvement of the Federal govern(cid:173)
`ment in the regulation of drugs and the
`close relationship of this regulation of drugs
`with foods, dates back more than 100
`years. At that time, the practice of medi(cid:173)
`cine in the United States was generally
`limited to providing advice on the con(cid:173)
`sumption of various herbs, spices, and
`other food substances that were taken to
`achieve the desired result; for instance,
`maintenance of good health or improved
`health. Because of this differentiation, the
`U.S. Department of Agriculture has been
`the federal agency that was initially respon(cid:173)
`sible for monitoring the potential adverse
`health effects resulting from adulterated
`food products. Specifically,
`this respon(cid:173)
`sibility fell to the Division of Chemistry
`within the Department of Agriculture and
`this department has been the entity which
`is the direct forerunner of the present Food
`and Drug Administration.
`The regulation of drugs in the United
`States has largely been shaped by three
`major events. First, in the early 1900s,
`there were widespread abuses in the food
`industry, especially the meat packing indus-
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`From Discovery to Market: The Development of Pharmaceuticals
`
`try. As a result of focus on meat packing by
`a number of " muckraking" journalists and
`the publication of a book in 1906 by Upton
`Sinclair entitled The Jungle (1), there was
`substantial outcry on the part of the public
`to reform the food industry . Coincidental
`with public outcry , the Division of Chemis(cid:173)
`try had performed a number of food prod(cid:173)
`uct investigations and determined that a
`wide variety of harmful substances could be
`found in the food products. As a result, the
`Federal Government passed the Pure Food
`and Drugs Act of 1906. This law prohibited
`the mislabeling and adulteration of food
`and drugs sold in interstate commerce. Be
`aware that, at this time, little advertising of
`drugs had been aimed directly at physicians
`since any non-narcotic drug could be pur(cid:173)
`chased without a physician's prescription.
`The next major event that helped shape
`the regulatory environment was the "Elixir
`of Sulfanilamide Tragedy" of 1937. Up to
`this time, drugs were not required to be
`tested for safety or efficacy before being
`introduced into the market. The only re(cid:173)
`quirement was that the drug not be adulter(cid:173)
`ated and the required information instruct(cid:173)
`ing the physician or consumer about its use
`be contained on the label. Sulfanilamide
`had been one of the first miracle drugs to
`emerge from drug discovery during this
`century, showing great promise as an all(cid:173)
`round antiinfective agent. The manufac(cid:173)
`turer of sulfanilamide, thinking that this
`drug in liquid form would make a good
`medicine for sore throat , proceeded to
`prepare an " elixir" of the drug in di(cid:173)
`ethylene glycol, a highly toxic, common
`ingredient in automobile antifreeze. How(cid:173)
`ever, this toxicity was not recognized at the
`time. Because there was no required safety
`testing, this elixir was introduced onto the
`market with no safety tests having been
`conducted. Subsequently, 107 children
`were killed who had consumed the product.
`As a result, there was a nation-wide outcry
`for new and stricter legislation regulating
`the marketing of drugs.
`Responding to this public outcry, the
`
`U.S . Congress passed the Food, Drug, and
`Cosmetic Act of 1938 (FD&C Act). This
`act and its many subsequent amendments,
`has been the controlling legislation for all
`foods and drugs. For the first time , the
`safety of drugs was now required to be
`tested prior to their introduction into the
`market. Under the FD&C Act of 1938,
`now all drug manufacturers had to submit a
`New Drug Application (NDA) to the FDA
`before introducing the drug in interstate
`commerce. This application required that a
`manufacturer list the drug's intended uses
`and provide the FDA with adequate sci(cid:173)
`entific evidence that the new drug was safe
`for the intended uses. An NDA became
`effective 60 days after filing provided the
`FDA proposed no objections. If the gov(cid:173)
`ernment did not raise objections,
`the
`manufacturer was free
`to proceed with
`product introduction .
`For the next 24 years , all drugs were
`approved essentially on safety with no
`statutory requirement to demonstrate ef(cid:173)
`ficacy. The regulatory environment of this
`period was much different than from today .
`The cost of regulatory compliance was
`relatively minor and the average regulatory
`review time was approximately 7 months .
`Interestingly, the main drug-related con(cid:173)
`cern of the U.S. Congress during this
`period was the profits of companies, not
`the products of these companies.
`The third defining event that prompted
`new drug regulations for the regulatory
`environment , was again a tragedy. In the
`early 1960s, a new drug, Thalidomide , was
`approved and used in Europe for nausea
`associated with pregnancy. By 1962, there
`was mounting evidence
`that pregnant
`women receiving Thalidomide were giving
`birth to children with severe deformities.
`Although this drug had not yet been ap(cid:173)
`proved in the U .S., the publicity surround(cid:173)
`ing the events in Europe and the possibility
`that this drug or a similar drug could be
`approved in the U.S ., prompted the U.S.
`Congress to further strengthen the regula(cid:173)
`tion of drugs. Thus, in 1962 the Kefauver-
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`Harris Amendments to the FD&C Act of
`1938 were approved by the U.S. Congress.
`With
`these amendments , manufacturers
`now had to demonstrate proof of effective(cid:173)
`ness of their products as well as proof of
`safety before marketing any new drug. The
`amendments also mandated that the FDA
`had to approve , rather than just review, an
`NDA before a drug could be marketed. A
`new regulatory document appeared on the
`scene at this time , the Investigational Ex(cid:173)
`emption to a New Drug Application or
`IND. In order to meet the requirements of
`establishing
`the effectiveness of drugs,
`manufacturers were now required to con(cid:173)
`duct clinical studies of their drugs. This
`requirement necessitated the shipment of
`" investigational" drugs in interstate com(cid:173)
`merce which would be in violation of the
`FD&C Act. Thus, an exemption to this
`Act, an IND , was established to allow for
`the shipment of investigational drugs for
`the purpose of conducting clinical trials.
`In addition to these three pivotal defin(cid:173)
`ing events of the regulatory environment,
`additional legislation and regulations have
`further defined the regulatory environment.
`These initiatives have included the passage
`of the Orphan Drug Act of 1983, which
`provided financial and commercial incen(cid:173)
`tives to manufacturers of "Orphan Drugs"
`to bring these drugs to market for the
`limited population for which they were
`intended. These drugs are designed to treat
`diseases or conditions affecting less than
`200,000 people in the United States.
`The next major legislation was the Drug
`Price Competition and Patent Term Resto(cid:173)
`ration Act of 1984. Under the provisions of
`this Act, pharmaceutical manufacturers
`could file what were termed abbreviated
`NDAs (ANDAs) to market generic ver(cid:173)
`sions of already approved drugs whose
`patent life had expired and which had been
`on the market for a sufficient period of
`time so that their marketing exclusivity
`(usually 5 years) had expired.
`On its own initiative the FDA has also
`been attempting to improve and streamline
`
`the drug development and approval pro(cid:173)
`cess. Thus, new regulations have been
`promulgated on February 22, 1985 affecting
`NDAs, and on March 19, 1987 affecting
`INDs. Additional regulations promulgated
`by the FDA and designed to get drugs on
`the market more quickly, have included:
`the Treatment IND regulations of 1987
`(intended to provide promising investiga(cid:173)
`tional new drugs to desperately ill patients
`before general marketing begins); regula(cid:173)
`tions of 1988 for Drugs intended to Treat
`Life-threatening and Severely Debilitating
`Illnesses (intended to facilitate the develop(cid:173)
`ment, evaluation and marketing of such
`products especially where no satisfactory
`alternative therapy exists) ; and the Acceler(cid:173)
`ated Approval Regulations of 1992 (intend(cid:173)
`ed to provide expedited marketing approv(cid:173)
`al of drugs for patients suffering from life(cid:173)
`threatening illnesses when the drugs pro(cid:173)
`vide meaningful therapeutic benefit com(cid:173)
`pared to existing treatment).
`Even though the FDA is both a scientific
`and a political agency, charged with
`protecting the public against unsafe and
`ineffective drugs, it also has a public health
`mission to promote the availability of drugs
`to meet perceived public health needs.
`Those needs are framed against three con(cid:173)
`stituencies: the public, Congress , and the
`Executive Branch , of which the FDA is a
`part. Each of these constituencies can and
`will exert pressure on the FDA to satisfy
`various agendas. Decisions taken by the
`FDA try to balance the various competing
`needs of each constituency.
`
`1.1.2 SCIENTIFIC ENVIRONMENT. From ex(cid:173)
`ploratory science to receptor-specific and
`molecule-specific research ,
`the scientific
`environment surrounding the development
`of drugs has rapidly evolved over the last
`30-40 years. Interestingly, over 90% of all
`the drugs in use in 1964 were unknown
`prior to 1938. By comparison , Reis-Arndt
`reported that about 490 new chemical en(cid:173)
`tities were marketed in the seven major
`markets of the world or by the seven major
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`From Discovery to Market: The Development of Pharmaceuticals
`
`drug producing companies in the world
`between 1976 and 1985 (2). These seven
`major drug producing countries are the
`United States,
`the United Kingdom,
`France, Italy, Germany , Switzerland, and
`Japan. Commenting on this information ,
`Drews noted than an internal panel at
`Hoffmann-La Roche and some outside
`pharmacologists, looked at these drugs and
`tried to characterize them in the same way
`the FDA had done (3). The 3 categories
`used were: (a) drugs that really allowed or
`enabled novel treatment that had not been
`available previously; for example , drugs for
`diseases that probably had not been treat(cid:173)
`able up to that time; (b) drugs that repre(cid:173)
`sented some distinct advantage over exist(cid:173)
`ing therapy without really allowing for
`novel therapy; and (c) drugs that have
`provided modest increments of quality or
`therapeutic versatility compared to drugs
`that have already existed . This panel classi(cid:173)
`fied only 8 (1.5 % ) of these compounds as
`truly representing novel therapy , whereas
`406 (83.5 % ) were classified as providing no
`significant novelty or improvement. These
`results, which show a tremendous degree of
`redundancy in drug research and develop(cid:173)
`ment, should not be construed as a criti(cid:173)
`cism of that effort. Redundant develop(cid:173)
`ment of similar therapeutic entities has led
`to
`the approval of products that have
`provided therapeutic relief for that sub(cid:173)
`group of patients for which a similar prod(cid:173)
`uct did not provide the degree of relief
`necessary.
`As the end of this century nears , sci(cid:173)
`entific research has evolved to the point
`where research can now be focused at the
`molecular, cellular, and receptor level. This
`focus will allow for targeted research to
`improve the potential for causing a positive
`therapeutic effect while diminishing or
`eliminating the potential for unwanted ef(cid:173)
`fects. In addition,
`the ability to study
`disease mechanisms will be significantly
`improved so that drugs can go beyond
`providing symptomatic relief of serious
`
`diseases to actually preventing or stabilizing
`a disease condition. Also , research in the
`biotechnology area has much promise for
`attacking diseases of genetic defects. Thus ,
`it appears that the pharmaceutical industry
`is poised for another golden era of pharma(cid:173)
`ceutical development toward the relief and
`elimination of diseases .
`
`1.1.3 COMMERCIAL
`ENVIRONM ENT. The
`U .S. pharmaceutical industry has evolved
`to the point where it is a major player in
`the U.S. and world economies . Not only is
`the pharmaceutical industry a leader in
`innovative development of pharmaceuticals
`but it also has a positive balance of trade
`with the rest of the world in terms of
`exporting their products . As the world
`shrinks as a trading market , it is only
`natural that more formal links be consti(cid:173)
`tuted among international partners in the
`development of products or among the far
`flung
`international entities of a single
`corporation. Thus, the day of independent
`development of drugs for Europe, for the
`U.S. and for other markets is gradually
`disappearing. Presently , the development
`of drugs is more on a global level so that
`one clinical development program will suf(cid:173)
`fice for registration of a product in all
`appropriate markets worldwide. This uni(cid:173)
`versality demands strong project manage(cid:173)
`ment and information links with the various
`elements of the developmental team world(cid:173)
`wide , as well as extensive knowledge of the
`world regulatory environment to ensure
`compliance with all appropriate regula(cid:173)
`tions. Lastly , universality requires special
`attention to marketing issues so as to suc(cid:173)
`cessfully commercialize the product in its
`various markets. The increasing govern(cid:173)
`mental demand to restrain cost on pharma(cid:173)
`ceuticals is requiring pharmaceutical com(cid:173)
`panies to look very closely at their de(cid:173)
`velopmental costs in relation to the pro(cid:173)
`grams that they want to develop. The need
`for strict project and budget management
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`has never been more apparent than in the
`pharmaceutical industry at this time.
`As the industry moves towards the end
`of this century, more than likely there will
`be continued consolidation of the industry
`into several large companies with the small(cid:173)
`er companies joining in these ventures or
`falling by the wayside. The emergence of
`the biotechnology industry is still evolving
`and will play a role in the evolution of
`mainstream pharmaceutical industries who
`are also developing their own biotechnol(cid:173)
`ogy capabilities as well. Whether the bio(cid:173)
`technology industry will live up to its full
`potential remains to be seen .
`
`1.2 Costs of Drug Development
`
`The development of pharmaceuticals is
`complex , lengthy , and expensive . The pro(cid:173)
`cess includes many steps from the synthesis
`and scale-up of the product through animal
`testing to the testing of the compound in
`the target population of patients. Of each
`5,000 chemical entities synthesized , it has
`been estimated that only 250 will reach
`animal testing , 5 will reach the level of
`clinical
`testing in healthy volunteers or
`patients and only one will ultimately reach
`the market place (4). Others have esti(cid:173)
`mated that of all drugs that reach the first
`phase of clinical
`testing , approximately
`10% will reach the market in one way or
`form. Unfortunately , which of the drugs in
`development will be successful cannot be
`predicted.
`Data from DiMasi et al. have provided
`some insight into the areas where the
`pharmaceutical industry has spent research
`money (5). Between 1976 and 1990, 269
`new chemical entities were approved by the
`Food and Drug Administration
`in
`the
`United States. Of these entities, 131 (49% )
`were defined as having little or no gain over
`existing products , 94 (35 % ) were classified
`as having a modest gain over existing
`therapies and 41 (15 % ) significantly im-
`
`treatments with only 3
`proved ex1stmg
`drugs (1 % ) fulfilling the greatest therapeu(cid:173)
`tic need: the treatment of AIDS . DiMasi
`has calculated that , on average , the clinical
`development of these drugs took from 2. 7
`to 6.4 years for the various therapeutic gain
`classifications, the shortest for drugs in the
`area of the greatest therapeutic need. The
`regulatory review for drugs in the four
`different categories ranged from 1.2 to 3.1
`years.
`Obviously, drug development carries a
`significant financial burden. It has been
`estimated that global research and develop(cid:173)
`ment expenditures for pharmaceutical com(cid:173)
`panies have reached 24 billion dollars (1990
`dollars) with 30% of this amount spent on
`discovery and clinical evaluation of new
`drugs (6). According to DiMasi (5), the
`overall development of a new chemical
`entity costs approximately 114 million dol(cid:173)
`lars (1987 dollars). In a recent report, the
`Office of Technology Assessment estimate
`that the average after tax cash requirement
`for drugs that reached the market in the
`1980s, was 65 million dollars (1990 dollars)
`(4) . These costs are out-of-pocket costs
`only and do not include capitalization or
`opportunity costs.
`Undoubtedly , for a variety of reasons,
`the cost of the development of new chemi(cid:173)
`cal entities will increase. In view of the
`recent pressure on cost reductions in medi(cid:173)
`cal health-care worldwide , leading to sig(cid:173)
`nificant reductions in the revenues from the
`sales of pharmaceuticals, the industry has
`no option but to focus its discovery and
`development activities on drugs that can be
`marketed globally; new entities that prom(cid:173)
`ise at least a modest gain over existing
`therapeutics, and on new treatment for
`diseases for which drugs are not available
`in the marketplace . Recently , various phar(cid:173)
`maceutical executives have commented that
`the development of a pharmaceutical that
`will be the fifth drug in its class in the
`market place can not be tolerated in the
`future. Such comments seem appropriate in
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`258
`
`From Discovery to Market: The Development of Pharmaceuticals
`
`view of revenues listed for the numerous
`angiotensin-converting enzyme (ACE) in(cid:173)
`hibitors now available in the marketplace ,
`for the treatment of hypertension. Re(cid:173)
`venues drop significantly with the order in
`which the drug reaches the market. A
`similar picture has been provided for the
`many calcium channel blockers that have
`reached the market to treat a variety of
`cardiovascular diseases including angina ,
`cardiac arrhythmias and hypertension.
`An urge to speed up the discovery,
`development and review processes for new
`drugs has been created with the purpose of
`extending the patent life of these drugs in
`the marketplace and hence, to gain the
`highest market share possible .
`Unfortunately , the time from discovery
`to market of new pharmaceuticals is not
`expected to be reduced significantly , de(cid:173)
`spite new technologies and computerization
`innovations in the entire process . Any time
`gained through modernization of the drug
`development process will be offset by more
`rigorous scientific demands on the evalua(cid:173)
`tion of the product and increasing regula(cid:173)
`tory requirements . These constraints will
`result in more complex clinical trials and
`greater numbers of patients being exposed
`to assess the benefit / risk ratio of the new
`pharmaceutical.
`Finally, the drug development process
`will likely be prolonged because of increas(cid:173)
`ingly complex
`interactions between de(cid:173)
`velopment partners , through mergers, joint
`ventures, co-development agreements , or
`outlicensing among pharmaceutical com(cid:173)
`panies worldwide .
`From the data presented , there is an
`increasing need within the pharmaceutical
`industry to focus its drug discovery and
`development on those drugs that meet the
`needs of the market (customers) . Changing
`these processes can make them more time
`and cost efficient so that pharmaceutical
`products can be developed on a global
`basis. In fact, many companies already are
`changing the way they are structured and
`
`have implemented many of the Total Qual(cid:173)
`ity Management principles that have helped
`other companies
`to become more cost
`efficient (7).
`Anticipating that, once a new drug de(cid:173)
`velopment candidate has surfaced, the reg(cid:173)
`ulatory requirements for the development
`of such a product have been determined,
`and the potential future market share has
`been assessed , the development plan for
`such a drug would be relatively straight(cid:173)
`forward and comparable between pharma(cid:173)
`ceutical companies worldwide. Unfortuna(cid:173)
`tely , this scenario is not the case . Drug
`development plans differ significantly with
`the culture, size and experience / expertise
`of each pharmaceutical company . The pro(cid:173)
`cess is quite different for a large, well(cid:173)
`established,
`centralized
`pharmaceutical
`company, with several new drug candidates
`under development and an established mar(cid:173)
`ket in a selected number of therapeutic
`areas, than for a small start-up biotechnol(cid:173)
`ogy company with
`limited financial re(cid:173)
`sources and virtually no expertise in the
`development of new drugs (with many
`variants in between these extremes).
`In this chapter, guidance will be pro(cid:173)
`vided on the drug development process in a
`structured manner, from late pre-clinical
`studies
`through market approval and
`beyond. The approach presented is based
`on the understanding of regulatory require(cid:173)
`ments and targeted on the needs of the
`consumer. The expectation is that the ap(cid:173)
`proach can be implemented by any com(cid:173)
`pany (large or small) , on a local or world(cid:173)
`wide scale and in its entirety or as separate,
`deliberate steps.
`
`2 THE DRUG DEVELOPMENT
`PROCESS
`
`The drug development process can arbit(cid:173)
`rarily be subdivided into 2 phases , early
`and late. The early phase of drug develop(cid:173)
`ment includes parts of preclinical toxicolo-
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`2 The Drug Development Process
`
`259
`
`gy, IND preparation and the implementa(cid:173)
`tion of a relatively small number of Phase 1
`and early Phase 2 clinical studies. At the
`end of this process, if a drug survives these
`early hurdles with no significant deficien(cid:173)
`cies , (e .g., preclinical toxicity , lack of ef(cid:173)
`ficacy, unacceptable
`tolerance) a drug
`should have more than a 50% chance of
`surviving a full fledged clinical development
`in the target patient population and of
`reaching marketing approval. This phase
`of drug development requires input from
`people with good knowledge of the com(cid:173)
`pany's vision and mission , the regulatory
`environment, and the scientific input from
`consultants , with
`limited
`input
`from
`marketing analysts.
`The late phase of the drug development
`process includes long-term preclinical and
`clinical studies after which the data on the
`drug will be submitted to regulatory au(cid:173)
`thorities for marketing approval. In the late
`phase, personnel involved are project man(cid:173)
`agers and people with broad experience in
`clinical research, regulatory affairs and in
`marketing. These individuals are different
`from those involved with early drug de(cid:173)
`velopment.
`
`2.1 Chemistry
`
`The various act1V1ties ongoing in the
`areas of chemistry, pre-clinical research ,
`
`clinical research, and regulatory review
`during the early and
`late development
`phases are presented in Table 9.2.
`Activities in each of these phases should
`be implemented following a specific plan
`with a predetermined budget , defined inter(cid:173)
`mediate and final goals, and rewards. Com(cid:173)
`monly , most activities included in the early
`development phase will be performed by
`the pharmaceutical company , while late
`phase development activities are done
`more frequently by utilizing outside re(cid:173)
`sources.
`Table 9.3 lists the various disciplines and
`activities within these disciplines as they
`relate to the drug development process.
`These
`act1v1t1es are performed under
`specific regulations and guidelines: Good
`Manufacturing Practices
`(GMP) , Good
`Laboratory P