PRINCIPLES OF
`
`CLINICAL
`
`PHARMACOLOGY
`
`Second Edition
`
`Arthur J. Atkinson ]r., M.D.
`NIH Clinical Center
`Bethesda, MD 20892-1165
`
`Darrell R. Abemethy, M.D., Ph.D.
`National Institute on Aging
`Geriatric Research Center
`
`Laboratory of Clinical Investigation
`Baltimore, MD 21224
`
`Charles E. Daniels, R.Ph., Ph.D., FASHP
`Skaggs School of Pharmacy and
`Pharmaceutical Sciences
`
`University of California, San Diego
`San Diego, CA 92093-0657
`
`Robert L. Dedrick, Ph.D.
`Office of Research Services, OD, NIH
`Division of Bioengineering and Physical Sciences
`Bethesda, MD 20892
`
`Sanford P. Markey, Ph.D.
`National Institute of Mental Health, NIH
`Laboratory of Neurotoxicology
`Bethesda, MD 20892
`
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`
`CHAPTER
`
`33
`
`Design of Clinical Development
`Programs
`
`CHARLES GRUDZINSKAS
`
`NDA Partners LLC, Annapolis, Mnrylmid, and University of Czzlifornia, San Francisco,
`Center for Drug Development Science, Wtzsliington, D.C.
`
`INTRODUCTION
`
`This chapter provides an overview of the clinical
`drug development process, which includes the clinical
`proof of mechanism (POM), clinical proof of concept
`(POC), the characterization of clinical safety, the char-
`acterization clinical activity, and the generation of evi-
`dence of safety and effectiveness to support regulatory
`review and, ultimately, marketing approval. The clini-
`cal trials that are conducted to generate the safety and
`effectiveness database, to meet the regulatory standard
`of "evidence/’ are referred to as ”confirrning clinical
`trials.” It is this understanding of the clinical effec-
`tiveness and safety of a new drug that provides the
`knowledge for informed decision—making regarding
`the clinical development, approval, marketing, pre-
`scribing, and proper use of a new drug. The clinical
`development process consists of (a) clinical trials for
`scientific development, Cb) clinical trials for scientific
`regulatory purposes, and (c) clinical trials that are
`pharmacoeconomically motivated (1). This chapter
`covers the clinical drug development process with a
`focus on critical decision points and the use of the learn-
`ing and confirming and the label—driven questiowbased
`approaches to designing, developing, and planning
`clinical development strategies.
`This chapter is intended to provide the reader with a
`strategic overview of the manner in which an effective
`and efficient contemporary clinical development
`program is created. It is beyond the scope of a single
`chapter to be able to adequately cover all aspects of
`a clinical development program. More comprehensive
`
`overviews of the operational aspects of clinical plans
`and clinical trial design are provided by texts written
`by Spilker (2) and Friedman (3). For a comprehen-
`sive overview of clinical
`trial design and analysis,
`the reader is referred to Studying a Study and Testing
`£1 Test by Riegelman (4). Information about the new
`drug regulatory review process and how it relates to
`new drug development is presented in Chapter 34
`and at the Center for Drug Evaluation and Research
`(CDER) Handbook web site (5). Another valuable
`resource for the design and conduct of clinical trials
`is a comprehensive glossary of clinical drug develop-
`ment terminology (6). In addition, the US. Food and
`Drug Administration (FDA) announced a Critical Path
`Initiative in 2004 and this provides insight into several
`areas of focus for streamlining the drug development
`process (7).
`
`PHASES, SIZE, AND SCOPE OF CLINICAL
`DEVELOPMENT PROGRAMS
`
`The FDA broadly defines drugs as those compounds
`that are synthesized and biologics as those that are
`produced by living organisms. However, for the pur-
`poses of this chapter, we will use the term ”drug” to
`represent both drugs and biologics.
`
`Global Development
`
`Within the past decade, international guidelines
`and regulations have become more uniform through
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`l’RlNC1l’LhS OF CLINICAL PHARMACOLOGY, SECOND EDITION
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`501
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`Cupyright © 2007 by Academic Press.
`All rights of reproduction in any form reserved.
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`Ex. 1058-0003
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`
`the International Conference on
`the efforts of
`Harmonization (ICH)
`(8). The efforts of the ICH,
`which included participation of regulatory agencies,
`industry, and academia from the United States,
`Europe, and Japan, have resulted in a series of com-
`prehensive ICH Guidances. These guidances address
`effectiveness (E), safety (5), and manufacturing (M),
`and develop a Common Technical Document.
`
`Clinical Drug Development Phases
`
`files a New Drug Application (NDA) or Biologics
`License Application (BLA) with the Food and Drug
`Administration. FDA approval of these applications is
`required before the product can be marketed in the
`United States. Similar procedures are in place in other
`countries (i.e., a Marketing Authorization Application
`in Europe and/ or the equivalent regulatory submis-
`sion in Japan and other parts of Asia); here the focus
`is primarily on U.S. regulatory review processes and
`requirements.
`
`Traditionally, the clinical development process has
`been divided into four phases.
`
`Phase IV
`
`Phase I
`
`As described in Chapter 31, Phase I includes first-
`in-human (FIH) trials to provide information about
`the safety (tolerability) and pharmacokinetics of a new
`drug. These trials are usually conducted in healthy
`volunteers unless the trials involve certain cytotoxic
`drugs such those used in cancer and HIV treatments.
`It should be noted that Phase I-type clinical pharma-
`cology trials, such as those to study pharmacokinetics
`in special populations, can and do occur throughout
`the clinical drug development process (see Chapter 1,
`Figure 1.1).
`
`Phase II
`
`trials in individuals
`Phase 11 consists of small
`with the illness to be treated (usually trials of 24
`to 300 persons). The goals of Phase II trials are to
`provide either a proof of mechanism or a proof of the
`hypothesized therapeutic concept, identify the patient
`population(s) in which the new drug appears to work,
`and determine an appropriate dose regimen for sub-
`sequent large-scale trials. Dose regimen includes the
`loading dose, maintenance dose, dose frequency, dose
`duration, and dose adjustments for special popula-
`tions and for coadministration with other drugs.
`
`Phase III
`
`Phase III trials are trials conducted to confirm the
`effectiveness of a new drug in a broad patient popu-
`lation in order to establish clinical settings in which
`the drug works or does not work. These trials also
`are designed to provide an evaluation of the fre-
`quency and intensity of adverse drug events that are
`likely to be encountered in subsequent clinical use.
`These trials are large (250 to >lOOO patients) so as to
`provide information that can reasonably be extrapo-
`lated to the general population. After successful com-
`pletion of Phase III trials that meet U.S. requirements,
`the sponsor of the development program generally
`
`Phase IV trials are conducted as postmarketing
`efforts to further evaluate the characteristics of the new
`drug with regard to safety, efficacy, new indications
`for additional patient populations, and new formu-
`lations. Phase IV is generally used to characterize
`all post-NDA/BLA clinical development programs.
`However, some organizations use Phase IV to describe
`only FDA-requested clinical trials and use Phase V to
`describe internally motivated market expansion trials
`(e.g., new indications, new formulations, updated
`safety databases).
`It is noteworthy that in an attempt to better char-
`acterize the types of information and knowledge that
`are developed during each phase, terms such as early-
`Phase II or late-Phase III (or Phase Ha and Phase Hlb,
`respectively) have crept into the clinical development
`lexicon. Although the traditional four phases are help-
`ful in broadly defining a clinical drug development
`program, the use of these phases in a strict chrono-
`logical sense or as milestones would be misleading.
`A strict chronological interpretation would infer that
`pharmacokinetic determinations are very limited and
`only occur in the early (Phase 1) part of the clinical
`drug development process, and that Phase IV market
`expansion trials are started only after the new drug
`has been approved. Therefore, instead of thinking of
`drug development as a series of consecutive phases, it
`is preferable to think of the drug development process
`as a series of interactive knowledge-building efforts,
`like the expanding layers of an onion, that allow us to
`make cogent scientific drug development decisions.
`
`Drug Development Time and Cost — A
`Changing Picture
`
`Clinical drug development is a complex, expensive,
`and lengthy process that can be thought of as having
`several main objectives in support of the ultimate
`goal — marketing approval with the desired indica-
`tions and claims. The average cost of bringing one
`new medicine to market cited by the Pharmaceutical
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`Research and Manufacturers of America (PhRMA)
`(9, 10) is $799 million, and a report by Bain & Company
`(11) estimates the cost for a new drug at $1.7 billion.
`These cost estimates take the following factors into
`consideration:
`
`I The actual cost of the successful drug discovery
`and development programs.
`I The cost of money [the financial return that would
`be realized if the money spent on research and
`development (R&D) were invested in long-term
`notes].
`0 The cost of unsuccessful discovery and
`development projects ("dry holes”).
`
`The actual ”out-of-pocket” expense for a single new
`drug varies, depending on the number of indications,
`formulations, and study participants needed to obtain
`regulatory approval, but is probably in the neigh-
`borhood of $200 million to more than $300 million.
`It is noteworthy that if one divides the total R&D
`spent for the year 2004, ~$38.8 billion (12), by 34, the
`number of new molecular entities (NMEs) that were
`approved by the FDA during 2004 (13), one arrives at
`an estimate of ~$1.14 billion per NME. It also should
`be noted that since large pharmaceutical companies
`expend approximately one-half of their R&D funds
`on line extensions, the average cost per new drug
`approved for marketing may indeed approach an aver-
`age cost of approximately $500—700 million, which, of
`course, includes funding for the 11 out of the 12 drugs
`that enter clinical trials but never achieve marketing
`approval (14).
`Estimates for the cost per participant in a clinical
`trial range from less than $2,000/ person for a short
`treatment, to as much as $15,000/ person for lengthy or
`complex treatments. In addition to the clinical grants
`to investigators, the full clinical costs include develop-
`ment of the protocol and of the clinical investigators’
`brochure, clinical investigator meetings, monitoring
`and site visits, clinical data collection, data quality
`resolution, data management and analysis, and report
`preparation. If the clinical database needed to achieve
`approval requires 4,000 to 8,000 study participants, one
`can see how the cost of the clinical portion of drug
`development can quickly approach $150 million.
`Clinical drug development requires the integra-
`tion of many disciplines, including discovery research,
`nonclinical and clinical development, pharrnacomet-
`rics, statistics and bioinformatics, regulatory science,
`and marketing to identify, evaluate, develop, and
`achieve regulatory approval for the successful market-
`ing of new drugs.
`In the recent past, the overall time from the initiation
`of a drug discovery program to regulatory approval
`
`was 10 to 15 years, but this has been reduced so that
`development timelines now range from 4 to 6 years.
`Much of the time and expense of drug development
`is related to the large numbers of individuals who
`need to be studied in clinical trials. Clinical develop-
`ment programs with large numbers of individuals are
`needed for therapies such as broad-spectrum antibi-
`otics, which usually are developed for many indica-
`tions. Similarly, large clinical programs are needed
`for a vaccine or flu treatment. In these cases the
`incidence of the disease is small and many individu-
`als are needed to demonstrate a clinically significant
`difference in disease incidence between test-drug-
`treated and placebo—treated study participants. As a
`result, contemporary clinical development plans usu-
`ally include a minimum of 1,500 participants, the ICH
`default minimum, and often exceed 6,000 participants.
`The drivers that determine the size of a clinical
`
`development program include what is referred to as
`the "treatment effect size” and the intended level of
`differentiation that is being sought by the developer.
`The treatment effect is determined by the underly-
`ing population event rate and the expected event rate
`in the treated population (3). The level of differentia-
`tion impacts the trial size in that if developers want
`to provide evidence that their drug is as safe as an
`already marketed drug that has an adverse event rate
`in the range of 4%, it has been estimated that an
`80,000-patient trial would be need to provide convinc-
`ing evidence that the new drug is ”equivalent" with
`regard to the incidence of the adverse event being
`studied. Likewise, there have been recent occurrences
`in which the incidence of certain adverse events for
`an already marketed drug was in the range of 30-40%
`and the developer of a new drug wanted to demon-
`strate that the new drug had an adverse event rate of
`one-half that of the already marketed drug. Although
`convincing evidence of a clinically significant decrease
`in the adverse event rate might be generated with
`250-500 patients, it may require much larger trials to
`demonstrate that the new drug has the same level
`of effectiveness as the existing drug (”noninferiority”
`of the new drug). Otherwise, the argument could be
`made that the new drug may be safer, but may also
`be less effective (eg, 50% safer, but also 50% less
`effective).
`
`Although the cost of drug development is likely
`to remain high, contemporary drug development
`technologies, the availability of high-quality contract
`research organizations (CROs) for the outsourcing
`of key efforts, and the emergence of online clini-
`cal trial data collection and management (”e-R&D”)
`have reduced the average time from drug discov-
`ery to NDA/BLA submission to a new benchmark of
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`4 to 6 years. In addition, regulatory review procedures
`have been streamlined, further shortening the time
`required to bring new drugs to market. For instance,
`the FDA is increasingly requesting that INDS be sub-
`mitted in electronic format using the ICH Common
`Technical Document format (15).
`
`Impact of Regulation on Clinical
`Development Programs
`
`As described in Chapter 34, the Kefauver~Harris
`Drug Amendments (16) were passed by Congress in
`1962 to ensure drug efficacy and greater drug safety.
`For the first time, drug manufacturers were required
`to prove to FDA the clinical effectiveness of their
`products before marketing them. This legislation led
`to the corresponding development at the FDA of a
`formalized process of regulatory review. This pro-
`cess is needed to determine whether there is adequate
`knowledge to be able to make an informed evalua-
`tion about the benefit-to-risk profile of the new drug,
`and to then decide whether the proposed product
`should be approved for use by certain segments of
`the nation's population. The regulatory review pro-
`cess requires the integration of many of the same
`disciplines required for drug development, includ-
`ing basic pharmacology, pharmacometrics, toxicology,
`chemistry, clinical medicine, statistics, and regula-
`tory science. As will be emphasized subsequently,
`the ultimate "product” of the drug development and
`drug review process is the package insert (P1) or label
`that contains the information regarding the approved
`indication(s) and the expressed and implied basis that
`a prescriber uses to decide what drug to prescribe for
`which patients, and in what dose, dose interval, and
`duration.
`
`The statement that the proof of effectiveness would
`be derived from ”well—controlled investigations” has
`been the cornerstone of the FDA’s position for the
`requirement of
`two positive adequate and well-
`controlled clinical trials, both of which must demon-
`strate effectiveness at the P < 0.05 level (16). However,
`in practice, most clinical development plans include
`more than just two studies to document efficacy and
`evaluate safety. in a pilot study reported by Peck (1)
`of a cohort of 12 of the 51 NDAS that were approved
`by the FDA in 1994—1995, the total number of clini-
`cal trials in each submission ranged from 23 to 150.
`In those trials that were designed to establish efficacy
`and evaluate safety, the number of study participants
`ranged from 1,000 to 13,000. Peck has pointed out that
`these NDAs probably reflect clinical plans that were
`designed in the mid-1980s.
`
`A retrospective review of five recent NDAs and
`BLAs was conducted by research fellows at the Center
`for Drug Development Science (CDDS) using infor-
`mation found on the CDER and Center for Biologics
`Evaluation and Research (CBER) web sites (17). This
`review is summarized in Table 33.1 and indicates
`that the size of the clinical development plans for
`these five diverse products ranged from a total of 10
`to 68 clinical trials and included between 1,069 and
`8,528 participants. The large number of participants in
`some clinical development programs may reflect the
`intensity with which sponsors focus on demonstrat-
`ing a clinically significant differentiation. For example,
`the sildenafil NDA for treating erectile dysfunction
`included population subgroups to demonstrate effi-
`cacy regardless of baseline severity, race, and eti-
`ology. Patient etiology subgroups included specific
`trials in patients whose erectile dysfunction was psy-
`chogenic, due to spinal cord injury, or a result of
`diabetes (18). The rofecoxib NDA supported both an
`indication for osteoarthritis and an indication for pain
`management, requiring demonstration of effectiveness
`in three distinct pain models as well as the demon-
`stration of differentiation in improved gastrointestinal
`safety when compared with multiple traditional non-
`steroidal anti-inflammatory drugs (NSAIDS). Similar
`retrospective analyses can be made for both NDAS (19)
`and BLAS (20) by downloading the reviews prepared
`by the FDA medical officers, chemists, pharmacol-
`ogists, and clinical pharmacologists. These reviews
`provide an excellent starting place for understanding
`the design of a clinical drug development program.
`In several of the clinical development programs
`analyzed in Table 33.1, there is a substantial reduc-
`tion in the number of clinical trials from that reported
`in the pilot study of 1994-1995 NDA approvals. This
`reduction is seen as a positive move in shortening
`the time and expense of drug development. Even
`more impressive speed records are being set for drug
`development that uses structure—based drug discovery
`approaches and effective and efficient clinical develop-
`ment programs based on critical label—driven question-
`based decision-ma king. The development of a protease
`inhibitor may hold the speed record with the following
`metrics (21):
`
`0 The first—in-human dose was 18 weeks after the
`start of the nonclinical safety program.
`I Phase II started 9.5 months after the start of the
`nonclinical safety program.
`0 The NDA was submitted 3.5 years after the
`discovery of the drug.
`
`In the 1999 annual report from Monsanto, it was
`stated that the development and NDA submission
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`Clinical Development Programs
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`505
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`TABLE 33.1 Retrospective Reviews of Recently Approved NDAs and BLAS“
`
`' Drug
`
`Indication
`
`FIH” to
`
`NDA filing
`(years)
`
`Phase I
`Trials‘ Participants Trials Participants Trials Participants Trials“
`
`Phase II
`
`Phase III
`
`Total
`
`Participants”
`
`Trastuzumabh Breast
`(l-Ierceptinfl )
`cancer
`Etanercept
`Rheumatoid
`(Enbrel®)
`arthritis
`Zanamivir
`Treatment of
`(Relenzafi)
`influenza
`
`Sildenafil A
`(Viagra‘~‘-‘kl
`Rofecoxib
`(Vioxx"@\)
`
`Erectile
`dysfunction
`Osteoarthritis,
`pain
`
`6-1 0
`
`6-7
`
`4-5
`
`5
`
`4~5
`
`3
`
`8
`
`I8
`
`42
`
`31
`
`48
`
`163
`
`446
`
`905
`
`940
`
`5
`
`3
`
`7
`
`13
`
`2
`
`532
`
`503
`
`3,275
`
`493
`
`1,855
`
`1
`
`23
`
`3
`
`13
`
`13
`
`459
`
`1,331
`
`1,588
`
`4,679
`
`5,733
`
`10
`
`34
`
`28
`
`68
`
`46
`
`1,069
`
`2,045
`
`5,309
`
`6,082
`
`8,528
`
`"The assignment of trials and study participants was not always straightforward based on the source documents and should be used as
`only semiquantitative estimates of the size of each phase. For instance, in the etanercept BLA there were 3 efficacy and 23 safety studies. We
`have categorized the efficacy studies as Phase II and the safety studies as Phase III.
`l’Timc of FIH trial for the approved indication was derived from sources in addition to those on the FDA web sites and in several cases
`represents an educated estimate.
`‘Phase I includes all of the clinical pharmacology studies that in many cases were conducted within 12 months of the NDA\BLA submission.
`‘fThe total number of trials indicated is the number of trials included in the NDA\BLA and might not include certain trials ongoing at the
`time of the NDA\BLA submission.
`“The total number of study participants indicated is the number of participants in the NDA/BLA and might not include participants in
`certain trials ongoing at the time of the NDA\BLA submission.
`
`of the COX-2 inhibitor celecoxib was completed in
`39 months from the FIH dose. This is even more
`remarkable when one takes into account
`that
`the
`
`celecoxib NDA contained data from over 9,000 patients
`with osteoarthritis, rheumatoid arthritis, and surgical
`pain. These data were used by the FDA to approve
`celecoxib for
`the indications of osteoarthritis and
`rheumatoid arthritis.
`
`that may help
`Another important development
`reduce the time and cost of drug development is
`found in the May 1998 FDA "Guidance for Industry:
`Providing Clinical Evidence of Effectiveness
`for
`Human Drug and Biological Products” (22). This
`guidance points out that in section ll5(a) of the FDA
`Modernization Act
`(FDAMA), Congress amended
`section 505(d) of the Food Drug and Cosmetic Act
`to indicate that the FDA may consider "data from
`one adequate and wel1—controlled clinical investigation
`and confirmatory evidence” to constitute substantial
`evidence if FDA determines that such data and evi-
`dence are sufficient
`to establish effectiveness (22).
`In making this clarification, Congress raised the possi-
`bility that fewer clinical trials may be needed than in
`the past. This appears to reflect the fact that contem-
`porary multicenter clinical trials typically enroll more
`patients than do single-center trials that were con-
`ducted in the past, as well as the substantial progress in
`
`drug development science that has resulted in higher
`quality clinical trial data.
`
`GOAL AND OBJECTIVES OF CLINICAL
`DRUG DEVELOPMENT
`
`The ultimate goal of the clinical drug develop-
`ment process is to achieve approval to market a new
`drug for the desired indications, based on an effective
`and efficient clinical plan that fully characterizes the
`differentiating features of the new drug. Target prod-
`uct profiles (TPPS) and target package inserts (TPIS),
`described in Chapter 27, are valuable design and plan-
`ning tools for the design of effective and efficient
`clinical development plans and are consonant with
`the presentation in this chapter (23, 24). An impor-
`tant development that was intended to promote the
`use of these tools is that the CDER Division of Cardio-
`
`Renal Drug Products in l999 launched a pilot program
`for working with sponsors to develop a label-driven
`approach to drug development. As anticipated, this
`program has been extended to other FDA divisions.
`Two key resources for input into the design of
`a successful clinical development program are the
`corresponding therapeutic FDA Guidance (25, 26) and
`the publicly available reviews by FDA reviewers for
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`previously approved drugs (27). Additional input may
`be gained by interactions with the Study Endpoint
`and Label Development (SEALD) division within the
`Office of New Drugs/CDER.
`The goal of an effective and efficient clinical
`drug development process is met by achieving seven
`objectives that generate an understanding of
`the
`intrinsic and extrinsic characteristics of the new drug
`being developed.
`
`Objective 3 —-—- Activity
`
`Objective 3 is to characterize as early as possible
`the dose regimen (e.g., dose, dose frequency, dose
`duration) and patient populations in which the new
`drug is active, in order to be able to select the dose
`regimen to be used in subsequent large confirming
`trials.
`
`Objective 4 — Effectiveness
`
`Objective 1 —- Clinical Pharmacology
`and Pharmacometrics
`‘
`
`Objective 4 is to confirm drug effectiveness in large-
`scale clinical
`trials. The results of these trials are
`
`Objective 1 of clinical development focuses on
`understanding the factors that influence the absorption,
`distribution, metabolism, and elimination (ADME) of
`a new drug, as well as the relationship between
`drug concentrations in various body fluids or organs
`and the observed pharmacological effects. This under-
`standing includes how different and special patient
`populations handle the drug, the potential for drug-
`drug interactions, as well as how patients might
`handle the drug differently in short-term treat-
`ments vs long-term treatments. ”Pharmacometrics”
`can be thought of as a quantitative description of
`pharmacology that includes the design and analysis
`of protocols and studies related to drug therapy ques-
`tions and that provides insights into the processes
`controlling the time course of drug concentrations
`and therapeutic and toxic responses (28). Thus, clin-
`ical pharmacology and pharmacometrics underlie the
`entire clinical drug development process, but deserve
`particularly heavy emphasis at the beginning and at
`the end of the clinical drug development program.
`
`Objective 2 ——- Safety
`
`Objective 2 entails the assessment of a new drug
`to determine what types of clinical side effects can be
`expected and in which patient populations, at what
`doses and dose durations, and whether the side effects
`are reversible and, if so, after how long. This knowl-
`edge is summarized in the Integrated Summary of
`Safety (ISS) portion of the NDA/ BLA submission and
`is used by regulatory authorities to decide what should
`be included in the precautions or warnings sections of
`the drug label.
`Although safety is identified as the second objective,
`the highest priority needs to be given to gathering rel-
`evant safety information throughout the drug devel-
`opment process. In light of the withdrawal of Vioxx in
`September 2004 (29, 30) and the subsequent congres-
`sional hearings, the FDA is reorganizing to strengthen
`its preapproval safety reviews (31).
`
`summarized in the Integrated Summary of Efficacy
`(ISE) portion of the NDA/ BLA submission and play an
`important role in determining appropriate therapeutic
`indications, dose regimens, and benefit/ risk ratios for
`various patient populations.
`
`Objective 5 — Differentiation
`
`Objective 5 is to provide evidence that the new
`drug will provide enhanced Value to patients over
`other available drugs with regard to effectiveness and
`patient safety and adherence (compliance).
`
`Objective 6 —- Preparation of a Successful
`NDA/BLA Submission
`
`Objective 6 centers on the preparation of a reviewer-
`friendly submission that regulatory authorities will
`use to determine whether to permit marketing of the
`new drug for the indications and close regimens being
`sought.
`
`Objective 7 — Market Expansion and
`Postmarketing Surveillance
`
`Objective 7 underscores the fact that clinical devel-
`opment efforts do not stop with the regulatory
`approval of an NDA or BLA but continue throughout
`the life cycle of the product. Market expansion is
`accomplished by demonstrating effectiveness, safety,
`and value of the drug in new patient populations,
`by demonstrating its use in combination with another
`product, or by introducing new formulations to
`improve patient adherence or simply to increase mar-
`ket share. Planning for this expansion process begins
`far in advance of the submission of the drug dossier
`to a regulatory agency for a review. Likewise, it is
`increasingly common for sponsors to initiate a post-
`marketing surveillance program to track the emer-
`gence and severity of any adverse events that were .
`or were not observed during the pre-NDA clinical
`development program.
`
`Ex. 1058-0008
`
`Ex. 1058-0008
`
`

`
`Clinical Development Programs
`
`507
`
`CRITICAL DRUG DEVELOPMENT
`PARADIGMS
`
`Six critical paradigms that have evolved within the
`last decade are valuable tools in ensuring the rapid
`and successful clinical development of new drugs.
`
`Label-Driven Question-Based Clinical
`Development Plan Paradigm
`It is appropriate that we begin with the label-driven
`question-based focus, since the ultimate product that
`is ”produced” from a clinical drug development pro-
`gram is the descriptive drug label that is approved
`by a regulatory agency (32). The label—driven question-
`based paradigm is one in which the entire drug
`development program is designed with a focus on
`generating the knowledge about the new drug that is
`needed to be able to address the elements that make
`up the drug label or package insert (PI). The objective
`of a well-written PI is to provide prescribers with the
`information that is needed to make informed decisions
`regarding the clinical use of the drug.
`A PI
`includes the following information: Who
`should receive the new drug? How much drug should
`be given? How frequently should the drug be given?
`For how long does the drug need to be given to be
`effective? And, of course, the PI must include much
`additional important prescribing information regard-
`ing drug—drug interactions, the effect of the patient’s
`age on the drug's activity, how to administer the drug,
`potential adverse effects of which the prescriber and
`patient need to be aware, and the contraindications,
`precautions, and warnings. One way to remember
`the "label—driven question~based" drug development
`concept is to think: "We sell only the package insert,
`we give away the product!”
`An appropriate analogy is the purchase of a com-
`puter program on a compact disk (CD). The CD itself
`probably costs pennies to manufacture. What we pur-
`chase is the value of the knowledge that is on the CD
`and the effort that went into producing that knowl-
`edge. The costs of medicines are very much the same
`as the costs associated with these software products.
`We are, of course, paying for the research and develop-
`ment costs associated with bringing the new product
`to market, plus the manufacturing, advertising, and
`distribution costs of the medicine, but a majority of
`the costs are associated with the value of the product
`to our health.
`
`Differentiation Paradigm
`
`Differentiat