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Accelerating Drugs to Market - Despite Challenges, Adaptive Clinical Trials Reduce Drug Development Costs and Time to Market by GBIResearch

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The report presents various tools and strategies which can accelerate a drug to the market. In this report, GBI Research has studied various hurdles at different stages of drug development that can halt a drug’s development. The report provides detailed information about the need for accelerated drug development. Declining R&D productivity is highlighted as one of the major needs to be addressed. The report outlines misconceptions regarding accelerated drug development; one such major misconception is the cost of development. The cost of an accelerated development program can be effectively managed by implementing a structured and complete program. The report highlights major strategies adopted by pharmaceutical companies to accelerate drug development. The adoption of the latest technologies in lead generation, preclinical stages, and the use of adaptive designs in late phase studies are regarded as tools to accelerate drugs through these stages of development.

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									Accelerating Drugs to Market
Despite Challenges, Adaptive Clinical Trials Reduce Drug Development Costs
and Time to Market
GBI Research Report Guidance




                                              GBI Research Report Guidance
                                              GBI Research’s report “Accelerating Drugs to Market” presents various tools and strategies that can
                                              accelerate a drug to the market. In this report, GBI Research studied various hurdles in the different stages
                                              of drug development that can halt a drug’s progress. The report provides detailed information about the
                                              need to accelerate drug development. The present report highlights major strategies adopted by
                                              pharmaceutical companies to accelerate drug development. Adoption of the latest technologies in lead
                                              generation and the preclinical stages, as well as the use of adaptive designs in late phase studies, are
                                              regarded as tools to accelerate drug development through these stages.
                                              ·     The report includes an executive summary that captures the key takeaways from the report.
                                              ·     Chapter three provides an overview of drug development and highlights various factors, such as the
                                                    need for accelerated drug development, misconceptions regarding accelerated drug development, and
                                                    major causes of delay in the drug development process.
                                              ·     Chapter four provides an overview of the process of lead generation. This chapter also provides
                                                    detailed insights on traditional and emerging strategies of drug development in the lead generation
                                                    stage, along with the advantages and disadvantages of these strategies.
                                              ·     Chapter five gives detailed accounts of accelerating drugs through the preclinical stage of drug
                                                    development. This chapter is supplemented with five case studies.
                                              ·     Chapter six provides in-depth analysis of accelerating drugs through Phase I clinical studies. This
                                                    chapter provides trends in drug transition, and strategies and models adapted to accelerate drug
                                                    transition through this stage of development
                                              ·     Chapter seven provides in-depth analysis of accelerating drugs through Phase II clinical studies. This
                                                    chapter provides trends in drug transition, and strategies and models adapted to accelerate drug
                                                    transition through this stage of development. This chapter highlights the role of selection of endpoints
                                                    and recruitment of patients in accelerating drugs through this stage.
                                              ·     Chapter eight provides in-depth analysis of accelerating drugs through Phase III clinical studies. This
                                                    chapter provides trends in drug transition, and strategies and models adapted to accelerate drug
                                                    transition through this stage of development. This chapter highlights the role of adaptive trials in
                                                    accelerating drugs to the market.




  © GBI Research. This is a licensed product and is not to be photocopied                                                     GBIHC216MR / Published SEP 2012
                                                                                                                                                       Page 2
Executive Summary




                                              Executive Summary
                                              GBI Research’s report “Accelerating Drugs to Market” presents various tools and strategies that can
                                              accelerate a drug to the market. In this report, GBI Research studied various hurdles in the different stages
                                              of drug development that can halt a drug’s progress. The report provides detailed information about what is
                                              needed to accelerate drug development.
                                              R&D productivity is highlighted as one of the major needs. The report outlines misconceptions regarding
                                              accelerated drug development; one such major misconception is the cost of development. The cost in an
                                              accelerated development program can be effectively managed by implementing a structured and complete
                                              program. The report highlights major strategies adopted by pharmaceutical companies to accelerate drug
                                              development. Adoption of the latest technologies in lead generation and the preclinical stages, as well as
                                              the use of adaptive designs in late phase studies, are regarded as tools to accelerate drug development
                                              through these stages.
                                              Drug Development Timelines and Cost of Innovation are the Major Challenges of the Pharmaceutical
                                              Industry
    Drug development timelines
    and cost of innovation are                GBI Research estimates that pharmaceutical R&D expenditure over the years has been increasing compared
    the major challenges for                  to drug approvals. The pharmaceutical industry is research-driven, and is currently facing multiple
    pharmaceutical industry                   challenges, including the patent expiries of blockbuster drugs in multiple therapy areas. Drug development
                                              timelines and the cost of innovation are the major challenges that restrict the growth of the pharmaceutical
                                              industry.
                                              The pharmaceutical industry needs to improve its R&D performance in order to sustain itself and meet the
                                              above-mentioned challenges. In order to decrease the overall time for drugs to reach the market, several
                                              strategies have been implemented by pharmaceutical R&D, including increased use of biomarkers and
                                              surrogate endpoints, improvised clinical trial designs, and better recruitment and retention of subjects in
                                              clinical trials. Collaboration and outsourcing are among the other strategies being implemented by the
                                              pharmaceutical industry to decrease drug development timelines.

                                                Accelerating Drugs to Market, Pharmaceutical and Biotech R&D Expenditure ($bn) versus the Number
                                                of NME/BLA Approvals, the US, 2004-2011

                                                                                         35                                                                                                80


                                                                                                                                                                       67.4        68.3
                                                                                                                                                         65.9                              70
                                                                                         30   31                                                63.7
                                                                                                                                 63.2

                                                                                                                    56.1                                                                   60
                                                                                         25
                                                           Number of NME/BLA Approvals




                                                                                                          51.8
                                                                                                   47.6                                                                             24




                                                                                                                                                                                                R&D Spending ($bn)
                                                                                                                                                                                           50
                                                                                         20                                                      21
                                                                                                                                                          20
                                                                                                                                                                                           40
                                                                                                           18       18
                                                                                         15                                       16
                                                                                                                                                                        15
                                                                                                                                                                                           30

                                                                                         10
                                                                                                                                                                                           20


                                                                                          5
                                                                                                                                                                                           10

                                                                                               5           2         4             2             3         6            6           6
                                                                                          0                                                                                                0
                                                                                              2004        2005     2006          2007           2008     2009          2010        2011

                                                                                                                 NME approvals          BLA approvals   R&D Spending


                                                Source: GBI Research; FDA, 2012; ; PhRMA, 2012




  © GBI Research. This is a licensed product and is not to be photocopied                                                                                                    GBIHC216MR / Published SEP 2012
                                                                                                                                                                                                      Page 3
Executive Summary




                                              The US Food and Drug Administration (FDA) approved 24 New Molecular Entities (NMEs) and six Biologic
    The USFDA approved about                  License Applications (BLAs) in 2011, and the R&D expenditure reported by Pharmaceutical Research and
    24 NME and 6 BLA’s in 2011                Manufacturers of America (PhRMA) members was roughly $68.3 billion (PhRMA, 2012). There was negative
                                              growth seen in the number of NMEs approved between 2004 and 2011, while R&D expenditure grew at a
                                              Compound Annual Growth Rate (CAGR) of 5.3% during the same period. In 2010, R&D expenditure was
                                              highest among the study period, while there was decline in R&D expenditure during 2011. R&D expenditure
                                              is continuously increasing as compared to the number of molecules being approved. The launch of a new
                                              drug in 1999 cost around $842m, which significantly rose to $1.3 billion in 2011 (Tufts Center for the Study
                                              of Drug Development, 2011). In addition to this, pricing pressure and the patent expiries of major
                                              blockbuster drugs have added to the challenges faced by the pharmaceutical industry. Pharmaceutical
                                              companies are keen to develop and improve returns on their R&D investments.
                                              Patient Recruitment and Retention is One of the Major Reasons for Delay in Drug Development
    Patient recruitment and
    retention is a major cause                Patient recruitment and retention are essential for conducting a successful clinical trial, and are considered
    for delay in timely                       to be the major cause for delay in their completion (The Center for Information and Study on Clinical
    completion of clinical trials             Research Participation, 2011). Difficulty in recruiting patients for clinical trials remains the top reason for
                                              delay in drug development; approximately 86% of trials are deferred due to a delay in patient recruitment,
                                              and about 20% of principal investigators fail to enroll a single patient (Sullivan, 2004).
                                              Pharmaceutical companies are undertaking various strategies to counter the problem of patient
                                              recruitment; these include amendments in protocol design, use of endpoints, and appropriate site selection
                                              procedures. In order to evaluate patient data, an adequate number of patients are required. It is hard to
                                              derive conclusions from a trial where there is insufficient patient data due to low retention. Clinical trial
                                              objectives may fail because of inadequate patient recruitment, as final patient data is highly dependent on
                                              the number of patients. Pharmaceutical companies are applying efforts to recruit appropriate numbers of
                                              qualified study participants in a cost-effective manner.
                                              In addition to recruiting a substantial number of study participants, another minor issue related to
                                              recruitment is consent forms; generally, patients are biased about participating in research, and getting
                                              consent from study participants adds to the existing issues. However, it is an essential part of clinical
                                              research. Trial participants are mostly provided with health and life insurance from the sponsor, which acts
                                              as an incentive for recruitment, apart from any study fees.
                                              Improvised Protocol Designs to Accelerate Clinical Trials
                                              Clinical trials can be accelerated by using improvised protocols. Pharmaceutical companies can benchmark
                                              their protocols with other study protocols in a similar therapy area or indication. This can help
                                              pharmaceutical companies in prioritizing their design elements and balancing the overall protocol. Protocol
                                              amendments can lead to delays in drug development, mainly due to patients’ unwillingness to follow up
                                              with the amended protocol. Due to the nature of novel therapies, the number of elements and procedures
                                              per protocol are often increased, leading to overburdened protocols that can halt the pace of drug
                                              development (The Tufts Center for the Study of Drug Development, 2011).
                                              Study protocols must be thoroughly validated for their scientific value and feasibility. Protocols must be
                                              designed to meet regulatory obligations, and any unnecessary procedures should be avoided. They should
                                              provide adequate consideration for the patients participating in the clinical trials. Protocols designed during
                                              the last decade required more time for patient enrollment due to a stricter eligibility criteria, which led to
                                              an overall delay in drug development. A typical protocol consists of about 50 eligibility criteria; due to this,
                                              many patients do not qualify to participate in a clinical trial, and patient enrollment takes longer. The
                                              average frequency of procedures performed on a subject is increasing, burdening study participants and
                                              decreasing their retention.




  © GBI Research. This is a licensed product and is not to be photocopied                                                      GBIHC216MR / Published SEP 2012
                                                                                                                                                        Page 4
Executive Summary




                                              Seamless Trials can Help the Transition from Phase II to Phase III
                                              Seamless clinical trial design is a type of design that combines the objectives of separate phases/trials of
                                              clinical drug development into a single trial. This type of design is also referred to as an operationally
                                              seamless clinical trial design. This type of design reduces the time lapse between the separate phases of
                                              drug development, and can be helpful in reducing the number of patients required per trial.
                                              An operationally seamless Phase II/III design will utilize continuous enrollment of patients and an
                                              instantaneous transition of the drug from Phase II to Phase III. The results of such trials are analyzed
                                              independently. In seamless trials, combining two trials or using a nonstop design must be evaluated prior to
                                              the start of the trial. In addition to these points, endpoints must be appropriately selected.
                                              Issues arising from seamless designs can be categorized into design issues, analytical issues, monitoring
                                              issues and logistical issues. Design issues can be further divided into feasibility issues, issues related to trial
                                              modifications, and issues arising from implementation of the design into the trial. Analytical issues can be
                                              classified as issues specific to validity and to analysis of combined information. Issues related to patient
                                              safety, elimination of study arms, development costs and financial planning can be classified as monitoring
                                              issues.




  © GBI Research. This is a licensed product and is not to be photocopied                                                        GBIHC216MR / Published SEP 2012
                                                                                                                                                          Page 5
Table of Contents




                                              1         Table of Contents
                                              1   Table of Contents ........................................................................................................................................ 6
                                                  1.1      List of Tables .................................................................................................................................... 8
                                                  1.2      List of Figures................................................................................................................................... 8
                                              2   Introduction ................................................................................................................................................ 9
                                              3   Accelerating Drugs to Market - Overview ................................................................................................. 10
                                                  3.1      Drug Development Process ........................................................................................................... 12
                                                      3.1.1      Early Stage Drug Discovery.................................................................................................... 12
                                                      3.1.2      Clinical Development Time and Protocol Amendments ......................................................... 13
                                                      3.1.3      Phase I ................................................................................................................................... 14
                                                      3.1.4      Phase II .................................................................................................................................. 14
                                                      3.1.5      Phase III ................................................................................................................................. 14
                                                      3.1.6      Registration ........................................................................................................................... 14
                                                      3.1.7      Phase IV ................................................................................................................................. 14
                                                  3.2      Need to Accelerate the Drug Development Process ..................................................................... 15
                                                      3.2.1      Strict Regime in Regulations of Drug Approvals .................................................................... 15
                                                      3.2.2      Declining Returns on R&D Investment................................................................................... 16
                                                      3.2.3      Low R&D Productivity ............................................................................................................ 17
                                                  3.3      Misconceptions of Accelerated Drug Development ...................................................................... 17
                                                      3.3.1      Completeness of the Drug Development Process .................................................................. 17
                                                      3.3.2      Cost of Accelerated Drug Development................................................................................. 17
                                                      3.3.3      Quality of Study in Accelerated Drug Development .............................................................. 17
                                                  3.4      Causes of Delay in Drug Development .......................................................................................... 18
                                                      3.4.1      Delay during the Nonclinical Stage of Drug Development..................................................... 18
                                                      3.4.2      Delay During the Clinical Stage of Drug Development .......................................................... 18
                                              4   Accelerating Drugs Through the Lead Generation Phase .......................................................................... 20
                                                  4.1      Process of Lead Generation ........................................................................................................... 20
                                                      4.1.1      Pre-Discovery......................................................................................................................... 20
                                                      4.1.2      Target Identification .............................................................................................................. 21
                                                      4.1.3      Target Validation................................................................................................................... 21
                                                      4.1.4      Lead Identification ................................................................................................................. 22
                                                      4.1.5      Early Safety Tests .................................................................................................................. 22
                                                      4.1.6      Lead Optimization ................................................................................................................. 23
                                                  4.2      Traditional Strategies of Lead Generation ..................................................................................... 24
                                                      4.2.1      High Throughput Screening ................................................................................................... 24
                                                      4.2.2      In Vitro Studies of Drug Absorption ....................................................................................... 25
                                                      4.2.3      In Vitro Studies of Protein Binding......................................................................................... 25
                                                      4.2.4      Fragment-Based Lead Discovery ........................................................................................... 26
                                                      4.2.5      Antisense Technology ............................................................................................................ 27
                                                      4.2.6      Iterative Focused Screening................................................................................................... 28
                                                  4.3      Emerging Strategies of Lead Generation ....................................................................................... 28
                                                      4.3.1      Improving High Throughput Screening.................................................................................. 28
                                                      4.3.2      Improving In Vitro Assays for HTS ......................................................................................... 29
                                                      4.3.3      Whole Animal Imaging and Microscopy................................................................................ 29
                                                      4.3.4      Computerized Combinatorial Chemistry and 3D Molecular Modeling .................................. 30
                                                      4.3.5      Molecular Bioimaging ........................................................................................................... 32
                                                      4.3.6      Omics-Technology and Bioinformatics .................................................................................. 33
                                                      4.3.7      Outsourcing of Lead Generation ........................................................................................... 36
                                              5   Accelerating Drugs Through the Preclinical Stage ..................................................................................... 38
                                                  5.1      Preclinical Studies - An Overview .................................................................................................. 38
                                                  5.2      Preclinical Study Design and Planning ........................................................................................... 38


  © GBI Research. This is a licensed product and is not to be photocopied                                                                                           GBIHC216MR / Published SEP 2012
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Table of Contents




                                                      5.2.1      Preclinical Study - Strategic Planning .................................................................................... 38
                                                      5.2.2      Key Considerations During Preclinical Study Design .............................................................. 38
                                                  5.3      Strategies and Models to Accelerate the Transition from Preclinical Phase to Clinical Phase I .... 39
                                                      5.3.1      In Vitro ADMET Screening Models......................................................................................... 40
                                                      5.3.2      In Vivo ADMET Screening Models.......................................................................................... 40
                                                      5.3.3      In Silico ADMET Screening Models ........................................................................................ 41
                                                      5.3.4      Accelerating Drugs to Market through Effective Documentation in the Preclinical Phase .... 41
                                                  5.4      Recent Technology Developments ................................................................................................ 42
                                                      5.4.1      Biomarkers ............................................................................................................................ 42
                                                      5.4.2      Nanotechnology .................................................................................................................... 42
                                                      5.4.3      In Vivo Imaging ..................................................................................................................... 43
                                                  5.5      Accelerating Drugs to Market - Preclinical Models: Case Studies ................................................. 43
                                                      5.5.1      Apredica’s Customized In Vitro ADMET Screening Assays ..................................................... 43
                                                      5.5.2      AVEO Pharmaceuticals’ Breakthrough with Transgenic Mouse Model for Human Breast
                                                                 Cancer ................................................................................................................................... 44
                                                      5.5.3      Preclinical Models of Hepatocellular Carcinoma and Biomarker Strategy by Pfizer.............. 44
                                                      5.5.4      Simulation Modeling to Treat Spinal Cord Injuries by Novartis ............................................. 45
                                              6   Accelerating Drug Transition in Phase I Studies ........................................................................................ 46
                                                  6.1      Phase I Clinical Studies - An overview ........................................................................................... 46
                                                  6.2      Phase I Study Design and Planning ................................................................................................ 46
                                                      6.2.1      Standard Design .................................................................................................................... 46
                                                  6.3      Strategies and Models to Accelerate Transition from Phase I to Phase II ..................................... 46
                                                      6.3.1      Site Selection and Management............................................................................................ 46
                                                      6.3.2      Strategies to Minimize Site Initiation Delays ......................................................................... 48
                                                      6.3.3      Role of the Site Management Organization in Decreasing Timelines.................................... 49
                                                      6.3.4      Optimizing Clinical Trial Supply through a Clinical Trial Management System ..................... 50
                                                      6.3.5      Patient Recruitment Strategies ............................................................................................. 51
                                              7   Accelerating Drug Transition in Phase II Studies ....................................................................................... 53
                                                  7.1      Phase II Clinical Studies - An Overview .......................................................................................... 53
                                                  7.2      Phase II Study Design and Planning ............................................................................................... 53
                                                  7.3      Strategies and Models to Accelerate Transition from Phase II to Phase III ................................... 53
                                                      7.3.1      Selection of Primary Endpoint ............................................................................................... 53
                                                      7.3.2      Randomization of Phase II Trials ........................................................................................... 53
                                                      7.3.3      Use of Biomarkers ................................................................................................................. 54
                                                      7.3.4      Statistical Designs in Phase II Trials ....................................................................................... 54
                                                      7.3.5      Increasing Patient Recruitment through the Use of Social Media ......................................... 54
                                                      7.3.6      Seamless Phase II/III Designs................................................................................................. 55
                                              8   Accelerating Drug Transition in Phase III Studies ...................................................................................... 56
                                                  8.1      Trends in Drug Transition from Phase III to NDA Filing ................................................................. 56
                                                  8.2      Issues and Challenges in Drug Transition ...................................................................................... 56
                                                  8.3      Strategies and Models to Accelerate Transition from Phase III to NDA Filing ............................... 56
                                                      8.3.1      Adaptive Trial Designs ........................................................................................................... 56
                                                      8.3.2      Recruitment and Retention of Patients in Phase III Clinical Trials ......................................... 57
                                              9   Accelerating Drugs to Market - Appendix ................................................................................................. 58
                                                  9.1      Market Definitions......................................................................................................................... 58
                                                  9.2      Abbreviations ................................................................................................................................ 58
                                                  9.3      Bibliography .................................................................................................................................. 59
                                                  9.4      Research Methodology ................................................................................................................. 62
                                                      9.4.1      Coverage ............................................................................................................................... 62
                                                      9.4.2      Secondary Research .............................................................................................................. 62
                                                      9.4.3      Primary Research .................................................................................................................. 62
                                                      9.4.4      Expert Panel Validation ......................................................................................................... 63


  © GBI Research. This is a licensed product and is not to be photocopied                                                                                         GBIHC216MR / Published SEP 2012
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                                                  9.5      Contact Us ..................................................................................................................................... 63
                                                  9.6      Disclaimer ...................................................................................................................................... 63


                                              1.1       List of Tables
                                              Table 1:     Accelerating Drugs to Market, NME Approvals By The FDA, 2004-2011 ...................................... 15
                                              Table 2:     Accelerating Drugs to Market, Pharmaceutical and Biotech R&D Expenditure ($bn) versus
                                                           Number of NME/BLA Approvals, the US, 2004-2011 ................................................................... 16
                                              Table 3:     Accelerating Drugs to Market, Comparison of Microdialysis with Ultrafilteration....................... 25
                                              Table 4:     Accelerating Drugs to Market, Factors for Minimizing Time Delays in Site Initiation, 2010......... 48


                                              1.2       List of Figures
                                              Figure 1:    Accelerating Drugs to Market, Development Timeline for New Drugs ........................................ 10
                                              Figure 2:    Accelerating Drugs to Market, Stages of Drug Development ....................................................... 12
                                              Figure 3:    Accelerating Drugs to Market, Amendments per Protocol and Changes per Amendment .......... 13
                                              Figure 4:     Accelerating Drugs to Market, NME Approvals By The FDA, 2004-2011 ..................................... 15
                                              Figure 5:    Accelerating Drugs to Market, Pharmaceutical and Biotech R&D Expenditure ($bn) versus
                                                           Number of NME/BLA Approvals, the US, 2004-2011 ................................................................... 16
                                              Figure 6:    Lead Generation Strategies and Technologies in Drug Discovery, Drug Discovery Process ......... 21
                                              Figure 7:    Lead Generation Strategies and Technologies in Drug Discovery, Applications of Lead Generation
                                                           Process ......................................................................................................................................... 22
                                              Figure 8:    Accelerating Drugs to Market, Pathways For Optimizing Lead Through Screening...................... 23
                                              Figure 9:    Lead Generation Strategies and Technologies in Drug Discovery, HTS Absorption, Distribution,
                                                           Metabolism and Excretion Assay .............................................
								
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