Pathways to Efficient Drug Development - Advances in Modeling and Simulation Outcomes to Fuel Pipeline Productivity

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					Pathways to Efficient Drug Development
Advances in Modeling and Simulation Outcomes to Fuel Pipeline Productivity
GBI Research Report Guidance




                                              GBI Research Report Guidance
                                              ·     Pharmaceutical R&D will always be a long and risky process. However, the pharmaceutical industry has
                                                    a huge opportunity to exploit new technologies, experiment with new business models and work
                                                    together with partners in new ways to improve the drug discovery and development processes.
                                              ·     Chapter three of this report looks in more detail at precompetitive research and evaluates how the
                                                    industry is pulling together to research solutions to problems that are common to all companies.
                                              ·     Chapter four investigates innovation in the clinical drug development arena, documenting modeling
                                                    and simulation based approaches to improving efficiency, as well as novel clinical trial designs.
                                              ·     Chapter five examines innovation in business models within the industry that aim to help the industry
                                                    to achieve its mantra of ‘doing more with less’, which will be critical for its future success.




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                                                                                                                                                    Page 2
Executive Summary




                                              Executive Summary
                                              Over the past 15 years the number of applications for new drugs and biologic licenses that have been
                                              approved by the US Food and Drug Administration (FDA) has fallen steadily, despite rising R&D expenditure.
                                              The industry has been forced to consider its business strategies in the light of this changing environment.
      Rising drug development                 Companies are concerned by the fact that they rely ever more on revenue from a few products, many of
      costs, increasing attrition             which are now losing patent protection, and by investors’ lack of confidence in future product pipelines,
      rates and regulatory hurdles,           which is adversely affecting their market capitalization. These facts, in combination with other industry
      have caused the industry                statistics including rising drug development costs, increasing attrition rates and higher perceived regulatory
      and regulators to work                  hurdles, have caused the industry and regulators to work together in recent years to explore improved
      together to explore                     pathways for drug discovery and development. This report provides an overview of the current state of the
      improved pathways for drug              industry, key initiatives in this area, and their progress towards improving the efficiency of drug
      discovery and development               development.
                                              Collaborations Aim to Tackle Major Scientific Challenges
                                              Collaboration and open innovation through public-private partnerships enable research that would not be
                                              possible for companies to undertake individually. Many examples of collaborative projects exist and these
                                              are funded in large part by the FDA’s Critical Path Initiative and the European Innovative Medicines
                                              Initiative. The areas of research tackled by these consortia are those viewed as critical to more efficient
                                              drug development and are generally termed precompetitive. In other words, they are fields of activity in
                                              which large companies agree to collaborate and invest jointly (despite the fact that they compete in the
                                              drug market) because the activities do not provide an immediate commercial advantage to any particular
                                              participant. Key areas of research include qualification of biomarkers of efficacy or safety, knowledge
                                              management strategies to exploit large datasets, data standards and models of disease processes.

                                                Pathways to Efficient Drug Development, Key Areas of Precompetitive Research


                                                                                 Knowledge management
                                                                                      strategies to
                                                                                                                     Data standards
                                                                                      exploit large
                                                                                        datasets




                                                           Identification and
                                                               qualification                                                                Models of disease
                                                            of biomakers of                                                                    processes
                                                            efficacy or safety
                                                                                                     Key areas of
                                                                                                    precompetitive
                                                                                                       research




                                                Source: GBI Research

                                              Experiences gained by early consortia have helped facilitate the logistical challenges of setting up new
                                              collaborations. The viable collaborative models that have emerged over the past few years still represent
                                              different and experimental approaches to public-private partnerships. Over the next few years those in the
                                              field will continue to learn from these early experiences and build on those projects found to be most
                                              successful. The field will not stand still as newer models, such as the Arch2POCM project which does not
                                              involve intellectual property sharing or generation, push the boundaries of precompetitive research and
                                              open innovation. Whether or not they succeed, these partnerships could represent a major change to the
                                              way in which pharmaceuticals are researched and value created, setting the stage for future collaborations.




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                                                                                                                                                               Page 3
Executive Summary




                                              Scientific and Business Innovations Collide to Change Drug Development
                                              Industry has a challenging goal in bringing safer and more efficacious drugs to the market more efficiently.
                                              Innovations including adaptive clinical trials, exploratory clinical trials and the increased use of modeling
                                              and simulation throughout the drug development process have all been studied for some years, suggesting
                                              that innovation is hard, but important. These methods are now permeating drug development at different
                                              speeds in different companies and as experience with each grows their real value will become more
                                              apparent. Ongoing efforts to validate and qualify the different approaches will be important for building
                                              regulators’ confidence in their use in decision making processes. Key groups of stakeholders will play pivotal
                                              roles in driving the future of the industry to achieve more efficient drug development.
                                              Innovation is also occurring in the business models applied within individual companies to enable them to
                                              achieve “more with less”. The efforts of the largest pharmaceutical companies to redesign their drug
                                              development process and spend more time looking externally for new products should provide more
                                              opportunities for entrepreneurial scientists – either those in start-up companies or academia – to pursue
                                              new molecules or targets. To a large extent, these efforts reflect the same trend towards greater openness
                                              and collaboration that is seen in the precompetitive space. One significant feature of many of the
                                              collaborations is the extent to which companies are making internally developed and proprietary
                                              compounds available to academic groups for screening against new drug targets. Companies are developing
                                              networks of providers for new products and services, but it remains to be seen to what extent these will
                                              really contribute to improved efficiency in the drug development process.
                                              Through adoption of these new scientific approaches and business models, companies are hoping not only
                                              to refuel their pipelines but to regain the confidence of both investors and the public in their ability to
                                              deliver meaningful treatments for patients while at the same time generating profits.




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                                                                                                                                                      Page 4
Table of Contents




                                              1         Table of Contents
                                              1   Table of Contents ........................................................................................................................................ 5
                                                  1.1      List of Tables .................................................................................................................................... 7
                                                  1.2      List of Figures................................................................................................................................... 8
                                              2   State of the Industry ................................................................................................................................... 9
                                                  2.1      Introduction..................................................................................................................................... 9
                                                      2.1.1      The Rising Costs of Drug Development .................................................................................. 10
                                                      2.1.2      Drug Attrition ........................................................................................................................ 12
                                                      2.1.3      Patent Expiries....................................................................................................................... 14
                                                      2.1.4      Regulatory Hurdles ................................................................................................................ 15
                                                      2.1.5      The Fourth Hurdle: Reimbursement ...................................................................................... 16
                                                  2.2      Innovation in the Drug Development Paradigm ............................................................................ 16
                                                      2.2.1      The Critical Path Initiative ..................................................................................................... 16
                                                      2.2.2      The Innovative Medicines Initiative ....................................................................................... 18
                                                  2.3      Improving Drug Development ....................................................................................................... 19
                                                  2.4      2012 and Beyond ........................................................................................................................... 20
                                              3   Collaboration in the Precompetitive Space ............................................................................................... 21
                                                  3.1      Defining Precompetitive Research ................................................................................................ 21
                                                  3.2      Building Successful Consortia ........................................................................................................ 23
                                                      3.2.1      Choosing the Research Topic ................................................................................................. 23
                                                      3.2.2      The Set-Up Phase .................................................................................................................. 23
                                                      3.2.3      Project Management............................................................................................................. 24
                                                      3.2.4      Measuring Success ................................................................................................................ 25
                                                      3.2.5      Case Study of a Successful Private Public Partnership: The Alzheimer’s Disease
                                                                 Neuroimaging Initiative......................................................................................................... 26
                                                  3.3      Qualification of Biomarkers of Efficacy or Safety .......................................................................... 26
                                                      3.3.1      Case Study: Biomarkers of Kidney Injury ............................................................................... 29
                                                      3.3.2      Case Study: The Biomarkers Consortium ............................................................................... 31
                                                  3.4      Open Innovation Platforms ........................................................................................................... 32
                                                      3.4.1      Case Study: OpenPHACTS ...................................................................................................... 33
                                                      3.4.2      Case Study: Sage Bionetworks............................................................................................... 34
                                                  3.5      Data Standards .............................................................................................................................. 35
                                                      3.5.1      BioSharing: Standard Cooperating Procedures ..................................................................... 35
                                                      3.5.2      Clinical Data Standards ......................................................................................................... 36
                                                      3.5.3      Data Standards and the FDA ................................................................................................. 36
                                                  3.6      Conclusions.................................................................................................................................... 37
                                              4   Improving Drug Development Efficiency................................................................................................... 38
                                                  4.1      Modeling and Simulation .............................................................................................................. 38
                                                      4.1.1      Modeling and Simulation: A View from the Regulators ........................................................ 39
                                                      4.1.2      Model Qualification ............................................................................................................... 40
                                                      4.1.3      Modeling and Simulation Expertise and Consultancy............................................................ 40
                                                  4.2      Innovative Approaches to Clinical Trials ........................................................................................ 41
                                                      4.2.1      Adaptive Clinical Trials .......................................................................................................... 42
                                                      4.2.2      Case Study: The I-SPY 2 Trial ................................................................................................. 44
                                                      4.2.3      Exploratory Clinical Trials ...................................................................................................... 45
                                                  4.3      Engaging Stakeholders .................................................................................................................. 46
                                                      4.3.1      Patients ................................................................................................................................. 46
                                                      4.3.2      Regulators ............................................................................................................................. 47
                                                      4.3.3      Payers .................................................................................................................................... 47
                                                  4.4      Conclusions.................................................................................................................................... 47
                                              5   Business Models ........................................................................................................................................ 48


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                                                                                                                                                                                            Page 5
Table of Contents




                                                  5.1    Introduction................................................................................................................................... 48
                                                  5.2    R&D Reorganization ...................................................................................................................... 48
                                                    5.2.1     Mimicking the Biotech Environment ..................................................................................... 48
                                                    5.2.2     The Fully Integrated Pharmaceutical Network Model ........................................................... 49
                                                5.3      Open Innovation ............................................................................................................................ 50
                                                    5.3.1     Case Study: An Open Innovation Incubator ........................................................................... 51
                                                    5.3.2     Case Study: Open Innovation Drug Discovery at Eli Lilly........................................................ 52
                                                5.4      Funding for External Innovation .................................................................................................... 53
                                                    5.4.1     Collaborative Commercialization .......................................................................................... 54
                                                5.5      Academic Partnerships and Translational Medicine ..................................................................... 55
                                                    5.5.1     Translational Science in the US.............................................................................................. 57
                                                    5.5.2     Case study: Medical Research Council/AstraZeneca ............................................................. 58
                                                5.6      Conclusions.................................................................................................................................... 59
                                              6 Appendix ................................................................................................................................................... 60
                                                6.1      Abbreviations ................................................................................................................................ 60
                                                6.2      Methodology ................................................................................................................................. 61
                                                    6.2.1     Primary Research .................................................................................................................. 61
                                                    6.2.2     Secondary Research .............................................................................................................. 62
                                                6.3      References ..................................................................................................................................... 62
                                                6.4      Contact Us ..................................................................................................................................... 66
                                                6.5      Disclaimer ...................................................................................................................................... 66




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                                                                                                                                                                                           Page 6
Table of Contents




                                              1.1      List of Tables
                                              Table 1:     Pathways to Efficient Drug Development, Clinical and FDA Approval Times across Therapeutic
                                                           Classes (2005-2009) ...................................................................................................................... 11
                                              Table 2:     Pathways to Efficient Drug Development, Transition Probability at Each Stage of Clinical Drug
                                                           Development ................................................................................................................................ 12
                                              Table 3:     Pathways to Efficient Drug Development, Overall FDA Approval Success Rate for New Chemical
                                                           Entities by Therapeutic Area ........................................................................................................ 12
                                              Table 4:     Pathways to Efficient Drug Development, Loss of US Sales Revenues Due to Patent Expiries ($m;
                                                           2010–2013) .................................................................................................................................. 14
                                              Table 5:     Pathways to Efficient Drug Development, Drugs Withdrawn from the Market in the US (1992–
                                                           2010) ............................................................................................................................................ 15
                                              Table 6:     Pathways to Efficient Drug Development, Ongoing Projects of the Critical Path Institute .......... 17
                                              Table 7:     Pathways to Efficient Drug Development, Proposed Network for Evaluating PPPs in the
                                                           Pharmaceutical Sciences .............................................................................................................. 25
                                              Table 8:     Pathways to Efficient Drug Development, Biomarkers qualified by the FDA for use in drug
                                                           development ................................................................................................................................ 27
                                              Table 9:     Pathways to Efficient Drug Development, Biomarkers qualified by the EMA for use in drug
                                                           development ................................................................................................................................ 27
                                              Table 10:    Pathways to Efficient Drug Development, Ongoing Public-Private Partnerships for Biomarker
                                                           Identification and Qualification .................................................................................................... 28
                                              Table 11:    Pathways to Efficient Drug Development, Pharmaceutical Companies Involved in the Predictive
                                                           Safety Testing Consortium, IMI SAFE-T Project and the Biomarkers Consortium Kidney Project 30
                                              Table 12:    Pathways to Efficient Drug Development, Ongoing and Completed Projects being Undertaken by
                                                           The Biomarkers Consortium ......................................................................................................... 31
                                              Table 13:    Pathways to Efficient Drug Development, Open Innovation Platforms to Enhance Drug Discovery
                                                           ...................................................................................................................................................... 33
                                              Table 14:    Pathways to Efficient Drug Development, Disease Specific Models Developed by the FDA ........ 39
                                              Table 15:    Pathways to Efficient Drug Development, Pharmacometric Consultancies ................................. 41
                                              Table 16:    Pathways to Efficient Drug Development, Examples of Companies Offering Accelerator Mass
                                                           Spectrometry Services .................................................................................................................. 45
                                              Table 17:    Pathways to Efficient Drug Development, Eli Lilly’s Long-Term Service Providers ....................... 49
                                              Table 18:    Pathways to Efficient Drug Development, Open Innovation Business Models that Place Research
                                                           Results in the Public Domain ........................................................................................................ 51
                                              Table 19:    Pathways to Efficient Drug Development, Examples of Pharmaceutical Corporate Venture
                                                           Capital Funds ................................................................................................................................ 53
                                              Table 20:    Pathways to Efficient Drug Development, New Companies Launched by Enlight Bioscience ...... 54
                                              Table 21:    Pathways to Efficient Drug Development, Projects Funded by Pfizer’s Centers for Therapeutic
                                                           Innovation .................................................................................................................................... 55
                                              Table 22:    Pathways to Efficient Drug Development, Examples of Recent Collaborations Between Academia
                                                           and the Pharmaceutical Industry ................................................................................................. 56
                                              Table 23:    Pathways to Efficient Drug Development, AstraZeneca Compounds Made Available for Research
                                                           (December 2011) .......................................................................................................................... 58




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                                                                                                                                                                                             Page 7
Table of Contents




                                              1.2        List of Figures
                                              Figure 1:  Pathways to Efficient Drug Development, Number of New Drug and Biologic FDA Approvals and
                                                         Global R&D Expenditure by the Pharmaceutical Industry (2004-2011) ......................................... 9
                                              Figure 2: Pathways to Efficient Drug Development, Drivers for Innovation in the Pharmaceutical Industry
                                                         ...................................................................................................................................................... 10
                                              Figure 3: Pathways to Efficient Drug Development, The Rising Cost of Drug Development 1975-2005 ..... 10
                                              Figure 4: Pathways to Efficient Drug Development, Changes in Clinical Trial Parameters between 2000-
                                                         2003 and 2004-2007..................................................................................................................... 11
                                              Figure 5: Pathways to Efficient Drug Development, Failure Rates According to Therapeutic Area in Phase II
                                                         and Phase III/Submission .............................................................................................................. 13
                                              Figure 6: Pathways to Efficient Drug Development, History of the European Innovative Medicines
                                                         Initiative and its Strategic Research Agenda ................................................................................ 18
                                              Figure 7: Pathways to Efficient Drug Development, European Innovative Medicines Initiative: Strategic
                                                         Research Agenda (updated 2012) ................................................................................................ 19
                                              Figure 8: Pathways to Efficient Drug Development, New Drug Applications Filed with the FDA Centre for
                                                         Drug Evaluation and Research (1996-2011) ................................................................................. 20
                                              Figure 9: Pathways to Efficient Drug Development, Key Areas of Precompetitive Research ...................... 21
                                              Figure 10: Pathways to Efficient Drug Development, Disease, Drug and Trial Models: Pharmacometrics in
                                                         Drug Development ....................................................................................................................... 39
                                              Figure 11: Pathways to Efficient Drug Development, The I-SPY2 Adaptive Clinical Trial............................... 44




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                                                                                                                                                                                             Page 8
State of the Industry




                                              2                             State of the Industry
                                              2.1                           Introduction
                                              Over the past 15 years the number of New Drug Applications (NDAs) and Biologics License Applications
                                              (BLAs) approved by the US Food and Drug Administration (FDA) has fallen steadily, despite ever increasing
                                              R&D expenditure (Figure 1). The gap between investment and success, measured in terms of new drug
                                              approvals, has caused the industry to rethink its business strategies in order to regain profit levels. In 2011,
                                              a total of 30 new drugs or biologics were approved, indicating that the industry may have entered a new
                                              and more positive phase, and spending on R&D continued to increase, rising to $68.3 billion. In the first
                                              quarter of 2012, a further eight NDAs were approved.

                                                Figure 1:                        Pathways to Efficient Drug Development, Number of New Drug and Biologic FDA Approvals
                                                                                 and Global R&D Expenditure by the Pharmaceutical Industry (2004-2011)

                                                                            40                                                                                 80

                                                                                   36




                                                                                                                                                       30
                                                                            30                                                                                 60




                                                                                                                                                                    Total Industry R&D Spending ($bn)
                                                                                                                                    26
                                                     No. of FDA Approvals




                                                                                                                          24
                                                                                                       22
                                                                                                                                              21
                                                                                             20
                                                                            20                                                                                 40
                                                                                                                18




                                                                            10                                                                                 20




                                                                             0                                                                                 0
                                                                                  2004      2005      2006     2007      2008      2009      2010     2011


                                                Source: FDA, 2011; PhRMA, 2012

                                              Looking at the data over a longer timeframe gives a different impression of industry productivity. The
                                              number of drugs approved each year during the 1970s and 1980s is similar to that of the last decade
                                              suggesting that, whilst current productivity does not match that of the 1990s, the issue may be one of
                                              approvals not generating sufficient revenue to sustain the rapid growth in R&D costs (Kaitin, 2010). With
                                              the industry increasingly reliant on revenue from a few products, many of which are now losing patent
                                              protection, the current business model is not sustainable. Further issues for the industry arise from the drop
                                              in market capitalization for the largest pharmaceutical companies. Nine of the top-tier pharmaceutical
                                              companies lost a cumulative total of $626 billion between January 2001 and September 2009 (Kaitin, 2010).
                                              Where other sectors’ values recovered in the wake of the global economic crisis that occurred during this
                                              period, those of the pharmaceutical industry have failed to rally, reflecting investors’ lack of confidence in
                                              current pipelines and the ability of the industry to bring new products to the market in the next few years.

  The industry is increasingly                These facts in combination with other industry statistics, including rising drug development costs, increasing
  reliant on revenue from a                   attrition rates, higher perceived regulatory hurdles, and a large number of patent expirations on high
  few products, many of which                 performing products, have caused the industry and regulators to work together in recent years to explore
  are losing patent protection,               improved pathways for drug discovery and development (Figure 2). This report provides an overview of the
  and the current business                    current state of the industry, key initiatives in this area and their progress towards improving the efficiency
                                              of drug development.




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                                                                                                                                                                     Page 9
State of the Industry




                                                Figure 2:        Pathways to Efficient Drug Development, Drivers for Innovation in the Pharmaceutical
                                                                 Industry




                                                                                                            Rising drug
                                                                                                         development costs




                                                                                                             Drivers for       Increasing attrition
                                                                       Patent expiration                   pharmaceutical             rates
                                                                                                         industry innovation




                                                                                                          Higher perceived
                                                                                                          regulatory hurdles




                                                Source: GBI Research



                                              2.1.1       The Rising Costs of Drug Development
                                              The costs associated with drug development have risen since 1975, when it was estimated to require
                                              around $138m to develop a single new molecular entity compared with over $1 billion in 2005 (DiMasi et
                                              al., 2003; DiMasi & Grabowski, 2007; Figure 3). Whilst some authors question the 2005 figures, suggesting
                                              they are too high (Collier, 2009), others suggest that the costs are actually higher. Herper indicates that
                                              accounting for failures on a company by company basis would lead to new drug development costs that
                                              vary from almost $12 billion per drug for AstraZeneca to $3.6 billion for Amgen (Herper, 2012). The exact
                                              figure associated with the cost of new drug development remains elusive, but it is clear that costs have risen
                                              dramatically over the last two decades.

                                                Figure 3:      Pathways to Efficient Drug Development, The Rising Cost of Drug Development 1975-2005

                                                          1975                                          1987                       2001               2005


                                                         $138m1                                        $318m1                     $802m1        $1.3 billion2


                                                Source: 1: DiMasi et al., 2003; 2: DiMasi and Grabowski, 2007

                                              One of the key reasons cited for rising drug development costs is the increasing expense associated with
                                              clinical trials. A report from the Tufts Center for the Study of Drug Development in 2010 highlighted the
                                              growing complexity of clinical trials. In the period between 2004 and 2007, clinical trials typically included
                                              more unique procedures, total procedures, execution burden and eligibility criteria compared with clinical
                                              trials undertaken between 2000 and 2003 (Figure 4). At the same time, volunteer enrolment and retention
                                              rates have fallen. These changes are particularly noticeable for Phase II studies, as companies aim to collect
                                              more data earlier in the drug development process. As the number of procedures included in trials
                                              increases, so too will the cost.




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Description: The report examines the reasons why the pharmaceutical industry is looking for improvements in efficiency whilst acknowledging that pharmaceutical R&D remains a long and risky process. It looks in detail at precompetitive research and evaluates how the industry is pulling together to research solutions to problems that are common to all companies. The report investigates innovation in the clinical drug development arena, documenting modeling and simulation based approaches to improving efficiency, as well as novel clinical trial designs. Lastly, the report examines innovation in business models within the industry that aim to help the industry to achieve its mantra of “doing more with less”, which will be critical for its future success.
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