Guide to
`Drug Development
`
`A Comprehensive Review and Assessment
`
`

`

`
`
`
`
`Publisher: Charley Mitchell
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`
`Printed in the United States
`
`Spilker, Bert.
`Guide to drug development : a comprehensive review or assessment / Bert Spilker.
`p. ;cm.
`Includes bibliographical references and index.
`ISBN-13: 978-0-7817-7424-6 (alk. paper)
`ISBN-10: 0-7817-7424-1 (alk. paper)
`1. Drug development.
`I. Title.
`[DNLMz 1. Drug Design. 2. Drug Evaluation, Preclinical—methods. 3. Drug lndustry—metods.
`4. Pharmaceutical Preparations. QV 744 5756g 2009]
`RM301.25.S693 2009
`615'.19—dc22
`
`2008000008
`-\
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`accepted practices. However, the authors, editors, and publisher are not responsible for errors or omis-
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`ranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents
`of the publication. Application of this information in a particular situation remains the professional
`responsibility of the practitioner.
`The authors, editors, and publisher have exerted every effort to ensure that drug selection and
`dosage set forth in this text are in accordance with current recommendations and practice at the time
`of publication. However. in view of ongoing research. changes in government regulations, and the
`constant flow of information relating to drug therapy and drug reactions, the reader is urged to check
`the package insert for each drug for any change in indications and dosage and for added warnings
`and precautions. This is particularly important when the recommended agent is a new or infrequently
`employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug Administra-
`tion (FDA) clearance for limited use in restricted research settings. It is the responsibility of health care
`providers to ascertain the FDA status of each drug or device planned for use in their clinical practice.
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`Page 2 of 21
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`

`

`
`
`I3
`
`The Big Picture
`
`The Crucial issue Facing Pharmaceutical
`Companies Today
`
`Functions of Drugs
`
`Poker Game
`Orchestra
`Hurdles Race
`Ocean Liner
`Maze
`
`Overall Perspective of Pharmaceutical
`Companies
`Uniqueness of the Pharmaceutical Industry
`Attributes of Pharmaceutical Companies
`Pharmaceutical Costs and Profits
`
`Competition within the Pharmaceutical Industry
`Perspectives of Different Groups about New Pharmaceuticals
`
`Synopsis of Drug Discovery
`and Development
`Drug Discovery
`Drug Development
`Influence of Regulations on Drug Discovery
`and Development
`
`Connect-the-Dots, Lottery, and
`Other Metaphors
`High Jump
`How Do People View Metaphors?
`
`Interfaces in a Company between
`Major Functions
`
`Resource Allocation
`Allocation of Resources: Pitfalls to Avoid
`
`Major Changes in the Pharmaceutical
`Industry Since 1962
`
`Metaphors of Drug Discovery
`and Development
`Pipeline of Drug Discovery, Development, and Marketing
`Horse Race
`
`Questions to Discuss
`
`References
`
`Additional Readings
`
`To survive and succeed in a hot market, a company must be willing to change everything about itself except its ba-
`sic beliefs. .
`.
`. Give the individual full consideration, spend a lot of time making customers happy, go the last mile
`to do a thing right. Thomas]. Watson, jr., former Chief Executive of IBM. From Fortune (August 31, 1987)
`
`
`
`THE CRUCIAL ISSUE
`FACING PHARMACEUTICAL
`
`COMPANIES TODAY
`
`For research-based pharmaceutical companies, the most critical
`issue today is maintaining a flow of new, innovative drugs that
`ensure the company‘s growth and even survival. Most pharma—
`ceutical companies are fully committed to this challenge because
`the alternative of having a dry period without new products is
`
`
`
`Page 3 of 21
`
`unattractive and its consequences are clear. To meet the chal-
`lenge, companies are adopting strategies of developing their
`drugs on a global basis using state-of—the—art technologies and
`attempting to improve their efficiency of drug discovery and de»
`velopment. Companies primarily obtain their new drugs from
`in-house research discoveries, licensing from other companies
`or groups, orjoint ventures with (or acquisitions of) other com—
`panies, primarily in the biotechnology area. This book describes
`the state-of-the-art standards that exist in many aspects of drug
`discovery and development.
`
`15
`
`

`

`
`
`16
`
`SECTION 1 I INTRODUCTION AND OVERVIEW OF A COMPANY AND THE INDUSTRY
`
`Another response to the challenge of preventing dry peri-
`ods without new products is to conduct a detailed analysis of
`the entire research and development (R and D) process and seek
`ways of improving current systems, organizational structures,
`and approaches. These internal evaluations used to occur ap-
`proximately once in a five— to ten—year period and often involved
`an outside consulting firm. At the present time. this process tends
`to occur on a more frequent basis or even on a continual basis.
`This book provides specific techniques to help managers judge
`a company’s strengths and weaknesses, and many detailed meth-
`ods used to analyze a pharmaceutical company or its R and D
`activities are presented.
`The world of drug discovery and development is rapidly
`changing, and there is a need for companies to take a broad view
`to develop useful strategies and take advantage of opportunities.
`The information explosion in the published literature provides
`details of technical aspects of drug discovery and development
`on a daily basis. The press, trade associations, and ntttnerotts
`other sources provide information about the pharmaceutical in-
`dustry as a whole (or selected parts) to the public and to health—
`care professionals. There are no sources, however. that provide
`a broad view of the many issues of drug discovery and develop-
`ment from a company‘s perspective. That is the primary inten-
`tion of this book.
`
`FUNCTIONS OF DRUGS
`
`
`When Sir Walter Raleigh was facing the headman‘s ax in his fi-
`nal moments, he reportedly said, “It‘s a sharp drug, but it cures
`all ills." Many people believe that drugs are intended to “cure
`all ills,” but relatively few drugs actually cure a disease. Most
`have other functions, primarily to treat symptoms. These func-
`tions are briefly described because, during the drug discovery
`process, scientists are consciously seeking to find a compound
`with specific properties or functions. During clinical develop-
`ment. one or more of these functions are specifically studied.
`The various uses or functions of drugs can be arbitrarily divided
`into six categories.
`
`1. Prevention. Some drugs are used prophylactically to prevent
`disease. Drugs such as vaccines or fluoride may be given to
`normal individuals to prevent the initial occurrence of a dis-
`ease (e.g., polio, smallpox. or dental carries) or may be given
`to patients at high risk of contracting a certain disease or
`problem to reduce the chance ofits occurrence. Another form
`of disease prevention is sometimes called suppression (see
`category 4).
`2. Cure. The ideal form of treatment occurs when drugs are used
`to cure a disease (e.g., antibiotics are used to cure certain bac-
`terial infections, or anthelmintics are used to cure certain
`worm infections). A cure represents a complete eradication
`of the disease, including the underlying cause (e.g., the pres-
`ence of viruses or bacteria in cells).
`3. "Treatment. Drugs are often used to alleviate symptoms for pa-
`tients who have a chronic disease. These drugs do not cure
`a disease and usually do not affect
`the underlying patho-
`physiology (e.g., antiasthmatics or antianginals), but
`the
`drugs improve the patient’s signs and/or symptoms and lead
`to clinical improvement. Drugs that reduce the risk of dis-
`ease progression illustrate a type of treatment,
`
`4. Suppression. Drugs are often used to suppress the signs and/or
`symptoms of a disease and prevent them from occurring or
`to prevent the disease process from progressing. Suppression
`is often a continuation of therapy after the acute episode or
`problem has improved and is referred to as maintenance ther-
`apy. Suppression is a type of prevention but is used in pa-
`tients who have a disease as opposed to normal persons who
`want to prevent getting a disease. Examples are antiepileptic
`or antimigraine drugs given after an acute episode to prevent
`recurrences.
`
`5. Diagnosis. Some drugs are used to help physicians establish
`the diagnosis of a patient’s disease or problem (cg, radio-
`contrast dyes). it would be desirable if there Were many drugs
`available for this purpose, but relatively few such drugs ex-
`ist. Drugs are sometimes used for a short time as a thera-
`peutic trial to help prove a diagnosis. It is assumed that if a
`patient improves after a therapeutic trial with a drug, then
`the diagnosis is proven. If the patient does not improve, then
`the conclusion is reached that the diagnosis is incorrect. This
`practice is considered to be an undesirable way of using drugs
`in many situations (e.g., to use antibiotics without obtaining
`cultures that demonstrate the presence of a bacteria) because
`physicians should assiduously attempt to diagnose medical
`problems before initiating treatment.
`6. Enhancement ofhealth People desire the best state of health pos-
`sible. Many try and achieve this state through drugs (e.g., vita-
`mins and minerals) as well as through other means (e.g.. diet
`and exercise). These drugs cannot be said to be replacing a de-
`ficiency, and some may only offer a psychological sense of well»
`being. Dietary supplements are another example of this category.
`
`Many drugs fit into two or more of these categories. Such
`drugs may be used for either one or two functions at the same
`time. One example of this latter situation is illustrated with the
`Fab antibody fragment of digoxin. This drug (Digibind) simul-
`taneously diagnoses and treats life-threatening digoxin toxicity
`by binding molecules of digoxin in the blood, making them un-
`available for binding at their site of action on cells in the body.
`If the patient has toxicity resulting from a digoxin overdose, then
`he or she will usually be helped by the drug. If the patient does
`not have a digoxin-induced toxicity, then the drug will be inef-
`fective. Some drugs that usually fit in one category may also be
`used for other purposes. One example is when antibiotics are
`used prophylactically in high-risk patients to prevent develop-
`ment of a bacterial infection (e.g., during dental procedures in
`patients who have had rheumatic heart disease) as well as ther—
`apeutically in others to cure many specific infections.
`
`OVERALL PERSPECTIVE
`OF PHARMACEUTICAL COMPANIES
`
`
`Uniqueness of the Pharmaceutical Industry
`It is critically important for senior executives to have a detailed
`understanding of their industry. This helps them reach more in-
`formed and sometimes better decisions about many important is-
`sues, policies, and questions that frequently arise. Yet, one often
`reads speeches of a pharmaceutical company’s chief executive or
`senior company officers who may be top lawyers, financiers, or
`marketing experts but who do not understand the basic concepts
`and processes of how drugs are discovered and developed. The
`
`Page 4 of 21
`
`
`
`

`

`
`
`CHAPTER 3 I THE BIG PICTURE I7
`
`various factors that influence drug discovery and development
`may also not be well understood. Although most companies may
`be operated and managed as if they make “widgets,“ a pharma-
`ceutical company must not.
`Major factors that differentiate pharmaceutical companies
`from other companies are listed below. Some of these factors are
`only a matter of degree, including: (a) the long period of time re-
`quired to develop and market a newly discovered drug; (b) the
`high degree of financial risk and uncertainty ofa drug's future, even
`after it is launched; (c) the large number of highly restrictive reg-
`ulations that govern all aspects of a drug's development, produc-
`tion, and marketing; (d) the inability to predict when the next
`important drug discovery will occur; and (e) the large number of
`variables and factors that are involved in biological experiments,
`technical development, and especially clinical trials. This last point
`means that a large number of interpretations of information is pos—
`sible in many situations. Each of these critical aspects means that
`it is essential to have as full an understanding of the drug discov-
`ery and development process as possible. It is also important to
`understand the factors that relate to creating and maintaining an
`appropriate environment in which drug discovery will flourish.
`The pharmaceutical industry shares some characteristics
`with many other industries, including other high-technology in-
`dustries, as follows:
`
`1. A rapidly changing environment in which products are sold.
`Many of these changes are highly unpredictable, both in the
`nature and rate of change.
`2. Competition in all areas of importance (e.g., product discov-
`ery, development, and marketing)
`
`Many aspects of the corporate environment in which these
`activities take place are nuances of the corporate culture. Cor-
`porate culture shapes the strategies used by a company to
`develop drugs and is discussed in several other chapters of
`this book. This culture-strategy interaction is also discussed by
`Shrivastava and Guth (1985).
`
`Attributes of Pharmaceutical Companies
`Many individuals, especially those who have limited time to de-
`vote to an issue or question, want to understand “the big pic-
`ture.” In some circles, this cliche is as common as “the bottom
`line“ (i.e., the overall impression or amount). The big picture
`obtained after looking at a pharmaceutical company includes
`consideration of its (a) core and other businesses, (b) overall
`size, (c) current and planned activities, ((1) profitability, (e) ap-
`proaches to drug discovery and development. and (0 current
`portfolio of marketed and investigational drugs.
`
`Core and Other Businesses
`
`18 the company strictly a pharmaceutical company, a healthcare
`company, or a company engaged in a wide variety of businesses?
`If the latter, how does the drug business fit into the company’s
`overall mission? Some large companies seem to go through cycles
`of divesting nonpharmaceutical businesses and acquiring them.
`
`Overall Size
`
`This aspect may be described in terms of sales per year, num-
`bers of workers, assets. or other factors. Size does not necessar-
`ily correlate with profit or number of drugs marketed. This topic
`is described more in Chapter 19.
`
`Page 5 of 21
`
`Current and Planned Activities
`
`This aspect primarily relates to whether the company is research
`based, licenses its drugs and develops them, and/or is a generic
`company. Another aspect is whether the company works with
`biologics or possibly devices or combinations of these types of
`products. This topic is described throughout this hook.
`
`Profitability
`The relative profitability of a pharmaceutical company may be based
`on a comparison with other pharmaceutical companies or on a
`between-industry comparison with other companies of the same size.
`A few mums of illustrating a company’s profitability are illustrated
`in Chapter ‘32, and establishing prices is discussed in Chapter 98.
`
`Approaches to Drug Discovery and Development
`Companies vary from those that utilize highly formal approaches
`to drug development to those that emphasize flexibility This as-
`pect is described throughout this book. Organizational structures
`are primarily described in Chapters 19 and 41.
`
`Current Portfolio of Marketed and
`
`lnvestigational Drugs
`The portfolio of marketed drugs may include multisource (i.e.,
`drugs susceptible to generic competition), patent-protected, or
`otherwise protected (e.g., with exclusivity under the Orphan
`Drug Act or under Hatch-Waxman provisions of the law) drugs.
`Drugs under development (i.e., investigational drugs) are as-
`sessed by the medical and commercial value of the company’s
`portfolio of potential new products (see Chapter 52).
`
`Pharmaceutical Costs and Profits
`
`A significant part of the “big picture" relates to profits. The Food
`and Drug Administration (FDA) regulations and guidelines since
`1962 have required many more premarketing studies to be con-
`ducted than previously. Good laboratory Practices and Good Man-
`ufacturing Practices regulations have also increased the costs of
`bringing a new drug to market. Regulations, however, are only one
`of many factors that have resulted in the higher prices charged for
`drugs. Other factors include the steadily mounting costs for labo-
`ratory equipment, clinical trials, staff salaries, and other compo-
`nents of drug discovery and development. As a result of increased
`healthcare expenditures during the 19605 and 19705, the govern-
`ment reacted. It has taken various steps (e.g., encouraging generic
`competition, passing maximum allowable cost regulations, and
`providing bonuses to pharmacists who dispense generic drugs) to
`force drug prices down. Food and clothing prices. however, have
`been kept artificially high by government price support programs
`for agriculture and tariffs and import quotas on foreign textiles.
`The major reason why pharmaceutical companies are will-
`ing to invest hundreds of millions in high-risk research is that
`the rates of return for the few commercially successful drugs are
`also high. if the rates of return are markedly diminished, as is al-
`ready occurring in some countries, pharmaceutical companies
`will be much less willing in the future to invest their money in
`research. Economic analyses clearly show that, if regulations di-
`minish profits for pharmaceutical companies on their few suc-
`cessful drugs below a certain minimum,
`the companies will
`reduce the investments they are willing to make in research. With-
`out sufficient research, drug discovery will be slowed, and this
`will decrease the rate at which new drugs will reach the market.
`
`
`
`

`

`
`
`18 SECTION~1 I INTRODUCTION AND OVERVIEW OF A COMPANY AND THE INDUSTRY
`
`Competition within the
`Pharmaceutical Industry
`An additional piece of the “big picture" is the risk from competi-
`tion. Competition within the pharmaceutical industry exists on
`several levels. These include (a) being first to enter new thera-
`peutic markets, (b) price and other types of competition (e.g.,
`perceived benefits) on similar products within a single therapeu-
`tic market, and (c) manufacturing generic versions of the same
`drug. The evidence that supports the view that there is significant
`competition in the pharmaceutical industry includes (a) price flex-
`ibility on specific products; (b) instability of market share over a
`period of a few years; (c) high rate of corporate mergers, buyouts,
`and bankruptcies; and (d) licensing arrangements.
`
`Perspectives of Different Groups
`about New Pharmaceuticals
`
`When drug discovery and development issues are being presented
`and discussed, numerous perspectives could be used. These include
`those of various groups both within and outside the pharmaceuti-
`cal industry. Representative groups within the indusrry would in-
`clude people in marketing, production, science, medical, and
`technical development functions. Representative groups outside the
`industry include patients. physicians. and regulatory agencies. Most
`of this book presents the perspectives of those within the industry.
`Nonetheless, it is useful to review briefly the overall perspective of
`some groups from both within and outside the industry.
`
`Perspectives about New Drugs by Groups
`within the Pharmaceutical Industry
`
`The perspectives of pharmaceutical company employees about
`new drugs are somewhat influenced by their background and
`discipline within their company. Informed and knowledgeable
`people view drugs in terms of a combination of medical, scien—
`tific, and commercial parameters. Others focus more on one of
`these (or other) aspects of a new drug.
`in-
`Many groups within and outside the pharmaceutical
`dustry often ascribe logic to a drug’s discovery or its develop-
`ment that is actually a convenient teleological explanation (i.e.,
`they work backward to derive an explanation that fits the ob-
`served events). Events usually seem clearer in hindsight when
`numerous activities are rearranged in people's minds, rough
`edges are smoothed out, and loose threads (e.g., false leads and
`approaches) are conveniently forgotten or ignored. As a result,
`the story of many drugs‘ discovery and development appears log-
`ical and orderly, whereas many false turns, accidents, and mis-
`takes, as well as luck were involved. Lucky errors may have
`directed the drug along the right path to its success. Many drug
`discoveries have occurred and paths of development were cor-
`rectly followed despite some people’s attempts to proceed in a
`different direction. There are a few noteworthy exceptions to this
`somewhat cynical view that truly illustrate a logical and step-
`wise approach to drug discovery and development.
`People in each company often talk about new upcoming
`drugs much as company stocks are described. The perceived value
`of a drug to a company often has precipitous changes based on
`casual or formal comments from the FDA, investigators, or com—
`pany scientists. These changes are often more related to emotional
`reactions to the drug‘s characteristics, uninformed judgments, or
`other reactions that do not reflect the drug‘s true value. The per-
`ceived value of a drug to stockbrokers and to stockholders in terms
`
`of eventual profit also rises and falls precipitously based on news,
`which may or may not be accurate or relevant to the drug's true
`value. These changes in perceived value are illustrated in Fig. 3.1.
`
`Perspectives about New Drugs by Groups outside '
`the Pharmaceutical Industry
`
`The perspective about new drugs under development in groups
`outside the pharmaceutical industry varies widely depending on
`the specific drug and the specific audience. A number of gener—
`alizations, however, can be made because different groups have
`differing frames of reference for looking at new drugs.
`
`1. Patients. Patients view new drugs in terms of hopes for im-
`provement of symptoms, underlying disease, or risk factors.
`Cost of new therapy may also be a major consideration. More
`sophisticated patients will have at
`least some awareness
`of risks and the benefit-to-risk ratio present with the new
`therapy.
`2. Regulatory authorities. Regulatory authorities view new drugs
`from the nation’s health perspective in terms of potential health
`problems resulting from adverse events as well as potential
`benefits. Regulatory agencies often focus on worst-case
`scenarios.
`
`3. Competitors. Competitors within the pharmaceutical indus-
`try view a new drug as a minor to major threat to their own
`marketed drugs and/or new investigational drugs. In some
`cases, a company‘s own development strategy will be markedly
`influenced by competitors‘ progress, and in other cases, the
`potential competitors will be ignored.
`
`trade associa-
`Some perspectives of consumer advocates,
`tions, physicians, academicians, legislators, reporters, and other
`groups are discussed in Section 4 of this book.
`
`SYNOPSIS OF DRUG DISCOVERY
`
`AND DEVELOPMENT
`
`Drug Discovery
`When asked for a definition of Hinduism, one religious scholar
`said, “it‘s simple; anyone who says he is a Hindu is one." The
`reason for this statement is that Hinduism has not rejected or
`cast out beliefs of the past but has continued to build on them
`and to add new beliefs. Likewise, the processes of drug discov-
`ery are multifaceted, and new ways of finding drugs are contin-
`ually being added without discarding methods of the past. Thus,
`some people view drug discovery primarily in terms of the
`new methods of biotechnology or high throughput screening,
`whereas others emphasize the importance of computer-assisted
`methods of drug discovery. Neither of these relatively new ap-
`proaches is the major means of discovering novel drugs, nor are
`the oldest methods of random screening or haphazard trial and
`error that have been used for over 100 years.
`The major methods of discovering new drugs today are
`those used during the past 50 years. The most important method
`is the trial-and-error empirical approach. Novel compounds
`called analogues are made that are similar to marketed or known
`drugs. Other compounds are also made that are distantly related
`or may be totally unrelated to marketed or known drugs. These
`compounds are hypothesized to have biological activity and are
`
`Page 6 of 21
`
`

`

`
`
`CHAPTER 3 I THE BIG PICTURE 19
`
`
`
`Exoeulve
`Peoslmism
`Phase
`
`gals:
`
`- Reaction to
`Newer Data
`
`o Balanced
`View
`
`_
`Perception
`of Medical
`
`value
`
`High
`
`Moderate
`
`Low
`
`Low
`
`Very
`
`Figure 3.1 How the perception of a medical innovation changes over time from
`an exaggerated phase to an overly pessimistic phase and then to a balanced view.
`This latter phase may lead to rejection or enthusiastic acceptance as well as the
`in-between conclusion shown.
`
`then tested by empirical methods using relevant animal mod-
`els. Some animal models are related to human disease. If the
`
`compound is found to have biological activity of interest, it is
`called a chemical lead or a lead compound. If the lead is highly
`active, it will stimulate chemists to make many new compounds
`that are chemically related to the lead compound. Eventually, a
`compound is hopefully found that has a sufficient number of
`positive qualities and few negative qualities compared to exist-
`ing therapy so that it justifies additional animal studies. It is
`usually hoped that this compound will become a drug (one pos-
`sible exception is when a company develops a “research tool”
`to assist its search for active compounds but realizes that this
`compound cannot become a marketed drug). This marks the end
`0] the drug discovery period and the start of drug development. The
`compound is now considered as a candidate compound for drug
`development.
`The processes of drug discovery are not straightforward. There
`is a certain amount of disorder in the system. Too much order and
`control are usually considered detrimental, although there should
`be a sound rationale underlying the activities conducted.
`Many factors must be considered by scientists when choos-
`ing specific compounds to make and test. These issues as well
`
`as other methods of discovering drugs are discussed in Chapter 8.
`The one final method of drug discovery that must be mentioned
`is serendipity or accident. Mark Twain once aptly said that the
`greatest inventor of all was accident. Serendipity occurs both in
`preclinical laboratories as well as in clinical trials and in clini-
`cal practice. Observant scientists or physicians have made many
`such discoveries that have led to new drug uses.
`
`Drug Development
`Drug development is a highly complex process involving thou-
`sands oi different activities. For the most part, these activities
`are not described in this book but may be found in references
`(see references and additional readings at the end of chapters).
`Figures 124.1 and 124.2 in the book Guide to Clinical Trials
`(Spilker 1991) illustrate how many of these activities are inter—
`connected. As opposed to drug discovery. where a certain degree
`and type of disorder is encouraged, drug development has order,
`organization, and discipline as goals. Too much disorder can be
`highly detrimental to the process of bringing a drug to market.
`After a candidate compound to be studied further as a po-
`tential drug is identified, we enter the world of drug development.
`
`Page 7 of 21
`
`
`
`

`

`20
`
`SECTION I I INTRODUCTION AND OVERVIEW OF A COMPANY AND THE INDUSTRY
`
`STAGE
`
`PRIMARY
`EVENT THAT TRIGGERS
`ACTIVITIES
`THE NEXT STAGE
`‘—
`
`aE
`
`- Targets Sought
`- Models Sought
`
`0 Discovery Team Formed
`- New Compounds Made to
`Be Screened
`- Older Compounds from
`Catalogue Screened
`
`Scientific
`
`Breakthrough
`and Success
`
`Biologically
`Interesting Activity
`Identified
`
`(Lead Compound)
`
`threatening disease without adequate treatment or drug for a rare
`
`Late
`Discovery
`
`- Lead Compound's Structure
`Explored to Improve Activity
`and Decrease Taxicity
`
`Decision Made to
`Study a Specific
`Compound in Humans
`
`Early
`Development
`
`- Secondary Testing of
`Candidate Compound
`
`Establishment of a
`Project
`
`Preclinical
`Development
`
`Clinical
`Development
`
`- Project Team Formed
`- Chemical Sceleup and
`Formulation
`
`- Preparation for Human Testing
`
`Initial Clinical Trial
`
`0 Drug Evaluated in Humans
`
`Regulatory Approval
`
`Marketing
`
`- introduction and Sale of Drug
`
`Figure 3.2 Major stages of drug discovery. development, and marketing indicating some of
`the primary activities conducted during each period and the event that triggers or initiates
`the next stage.
`
`Figure 3.2 illustrates the different stages of drug discovery (i.e.,
`Stages A to C), development (i.e., Stages D and E), and market-
`ing (Lei, Stage F). Early activities of drug development involve an
`iii-depth analysis of the candidate compounds profile in additional
`animal studies. This period usually lasts from six to 18 months.
`If both the positive and negative attributes are acceptable, it means
`that the compound has a benefit-to-risk ratio adequate to pursue
`development. At that point, the candidate compound is elevated
`to become a project compound, which means that it will be tested
`in humans if it can pass other preclinical requirements Project
`compounds are managed during their development by a project
`team whose members represent different departments within the
`
`company. In very small companies. a project team of independent
`consultants with at least one company representative is often as—
`sembled. This is sometimes referred to as a virtual project team.
`The project compound prograses through technical develop-
`ment, toxicology, metabolism, and other animal studies until it re—
`ceives a green light from the company, the regulatory agency, and
`the Institutional Review Board/Ethics Committee to be tested in hu-
`
`mans. At the time of initial testing in humans, a project compound
`becomes a project drug. There are three phases of clinical trials that
`a drug passes through before it receives regulatory approval and may
`be sold as a marketed drug. In a few situations (e.g., drug for a life-
`
`Page 8 of 21
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`

`

`CHAPTER 3 I THE BIG PICTURE
`21
`
`
`
`
`
`
`Industry Discovers,
`Develops, and Markets
`New Medical
`Products
`
`
`
`
`
`Govemments.
`Academicians. and
`Healthcare Professionals
`Improve Healthcare
`and Systems
`
`
`
`New Products, Services, and
`Innovations Introduced
`
`
`
`
`
`Medical Standards, Guidelines.
`and Practices Improved
`
`
`
`Patient Healthcare
`
`Is Improved
`
`
`
`
`
`
`
`
`
`
`
`Benefits Attained for
`
`Patients, Families, and Society
`
`Figure 3.3 Ideal synergy between industry, government, aca-
`demia, and healthcare professionals in bringing new medical
`treatments to patients for their benefit and that of society.
`
`disease), Phase 3 may be omitted. The clinical testing of a known
`drug for a new use usually begins with Phase 2 tests because the
`Phase 1 tats for initial safety data have already been completed.
`The attrition rate from stage to stage is usually high. It is es-
`timated that as many as 10,000 compounds are synthesized for
`every ten that reach the stage of human testing. Of these ten com-
`pounds, only one eventually reaches the market. The success rate
`of new compounds and projects is discussed further in Chapter 56.
`The terms used to describe the various stages a drug passes
`through (lead compound, candidate compound, project compound,
`project drug, an