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

Executive Summary

Headache for Pharma as R&D Spending Climbs While Number of Approved Molecules Falls

Low research and development (R&D) productivity, combined with the patent cliff and a stringent US Food and Drug Administration (FDA) approval process, is resulting in climbing expenditure without the corresponding output, states the latest report from industry experts GBI Research.

The company's new report* says that, despite efforts made by pharmaceutical firms to cut down on costs, R&D expenditure expanded at a Compound Annual Growth Rate (CAGR) of 6% from $26 billion in 2000 to $50 billion by the end of 2011. Conversely, the number of new molecular entities (NME) approved during this same period has dropped on average, decreasing at a CAGR of 1%.

R&D is a core and integral part of the pharmaceutical industry, but poor productivity means there may soon be a drought in the R&D pipeline. GBI Research estimates that currently as much as 55% of the entire late stage pipeline is made up of life cycle management (LCM) projects, while a 28% share of the industry's top 20 companies' pipelines is devoted to LCM research.

To compound the frustrations of the industry, the FDA has adopted a stricter drug approval policy. Following controversies regarding products such as Vioxx and Exubera, as well as product recalls for 'Made in China' drugs, the agency has been more cautious in analyzing the risks and benefits of drugs before approving them, slowing down or cutting out potentially marketable treatments.

Additionally, the patent cliff has damaged company revenues, severely curbing the selling power of blockbuster medications and opening the market to generics. The reduction in NME approvals has meant the big pharmaceutical firms are less able to offset the loss of revenue resulting from patent expirations, with new drugs offering therapeutic superiority to the generic versions of their predecessors.

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

In this report, GBI Research has studied various hurdles at different stages of drug development that can halt a drug's progress. The report provides detailed information about the need for accelerated drug development.

This report was built using data and information sourced from proprietary databases, primary and secondary research, and in-house analysis conducted by GBI Research's team of industry experts.

Abstract

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

Summary

GBI Research's new report, "Accelerating Drugs to Market - Despite Challenges, Adaptive Clinical Trials Reduce Drug Development Costs and Time to Market", 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.

This report is built using data and information sourced from proprietary databases, primary and secondary research, and in-house analysis by GBI Research's team of industry experts.

The process of drug development starts from the initial discovery and ends with a final medication. This is an expensive, lengthy and incremental process. The main objective of the process is to identify a molecule with the potential for producing the desired effect in the human body, and to establish the quality, safety and efficacy of the molecule for treating patients. In the present scenario drug development takes about 12 years, for a molecule to progress from the laboratory and enter the pharmaceutical market. It is estimated that out of 5,000 compounds which enter the preclinical stage of development, only five compounds will be successful enough to be tested on humans, and only one among them will be approved. The slow pace of drug development greatly affects the pharmaceutical industry and patients who are in need of new therapeutics to treat their illness.

The current process of drug development begins with the synthesis of molecules, which targets specific proteins in living cells. It is followed by in vitro tests to identify any specific toxicity associated with the synthesized molecules. The compounds which make it through this stage will go further and will be tested for in vivo toxicology studies. The information gathered from these studies is utilized for planning and conducting clinical trials in human subjects.

It is important for biopharmaceutical companies to launch their products more quickly in the market, as this will lead to early revenue generation from the product. As a large number of drugs fail at the later stages of drug development, pharmaceutical companies try to maintain their revenues by launching new drugs at the earliest possible time. The decline in the total number of new drug approvals by the regulatory bodies and the patent expirations for major blockbuster drugs are forcing pharmaceutical companies to consider ways in which the time and cost of clinical trials can be reduced without affecting their quality.

Scope

  • The report presents various tools and strategies which can help to accelerate a drug to market.
  • The report provides detailed information about the need for accelerated drug development.
  • The report outlines misconceptions regarding accelerated drug development.
  • The report provides information on trends in drug transition and strategies and models adopted to accelerate drug transition through the various stages of development.
  • Description of the methods for optimum patient recruitment and retention in a clinical trial.
  • Analysis of efficient clinical trial site management so that completion of a trial is done on time.

Reasons to buy

  • Develop strategies to implement the use of various technologies for advancing drug discovery and development in an efficient manner.
  • Understand the use of biomarkers and surrogate endpoints, improvised clinical trial designs and better recruitment and retention of subjects in clinical trials, in order to avoid drug lags in various phases of development.
  • Prioritize design elements of study protocols and balance the overall protocol.
  • Ensure efficient clinical trial outcomes by implementing CDISC standards.
  • Understand the utility of operationally seamless Phase II/III design for instantaneous transition of the drug from Phase II to Phase III.

TOC

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
    • 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
  • 9.5 Contact Us 63
  • 9.6 Disclaimer 63

List of Tables

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

List of Figures

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 24
  • Figure 10: Lead Generation Strategies and Technologies in Drug Discovery, Evotec's Approach to Identifying Novel Beta Secretase-1 Inhibitor Using the Fragment-Based Approach 26
  • Figure 11: Accelerating Drugs to Market, Benefits And Challenges In Imaging Technique 29
  • Figure 12: Accelerating Drugs to Market, Service Providers in Combinatorial Chemistry and 3D Molecular Modeling 31
  • Figure 13: Accelerating Drugs to Market, Service Providers of Omics Technology and Bioinformatics 34
  • Figure 14: Accelerating Drugs to Market, Strategic or Tactical Advantages in Early Stage Drug Development Outsourcing 36
  • Figure 15: Accelerating Drugs to Market, Preclinical ADMET Studies - Current System 39
  • Figure 16: Accelerating Drugs to Market, Site Initiation Process, 2011 47
  • Figure 17: Accelerating Drugs to Market, Key Factors Responsible for Study Timeline Reduction by SMOs 49
  • Figure 18: Accelerating Drugs to Market, Clinical Trial Supply Management System 51
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