Reportlinker Adds Advances in the Design and Regulation of Adaptive Clinical Trials

Dec 08, 2010, 13:35 ET from Reportlinker

NEW YORK, Dec. 8, 2010 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

Advances in the Design and Regulation of Adaptive Clinical Trials

As the pharma industry comes under increasing pressure to replenish revenues which are under threat from generic competition, there is an increased focus on technologies and trial designs which aim to maximize success and reduce development time. This report reviews the use of adaptive designs across all phases of development. Dose-ranging and seamless trials are explored through case studies of important adaptive trials. Regulation by the FDA and EMA is covered in detail. The report also reviews logistical and technological aspects of adaptive designs as well as presenting an outlook for their use in drug development.

Scope of this research

• Learn how the largest companies are applying adaptive methods to improve drug development.

• Identify situations in which adaptive trials could benefit drug development in your company.

• Analyze the importance of adaptive trials in the context of a drug's development program and a company's portfolio of compounds.

• Assess how the FDA's draft guidelines on adaptive trials are influencing companies to use adaptive trials in their drug development programs.

• Evaluate the providers of key skills and technologies for adaptive trials.

Research and analysis highlights

The large majority of adaptive trials currently being undertaken in the pharma industry are Phase 2 – 'Learning' – trials that aim to establish the most effective dose and the dose response curve. Exploratory trials may also aim to combine proof of concept with dose finding, stop early for futility or investigate biomarkers and patient subsets.

Ground-breaking research using adaptive designs with biomarkers is currently shaping the future of research in the field of oncology. The highly collaborative I SPY2 study may deliver changes to the field on a number of levels such as demonstrating the feasibility of cooperation at this level and the efficiency of the adaptive design.

Companies are learning how to implement adaptive studies in the confirmatory stages of drug development and regulators are developing their views on what is acceptable. Interaction with regulators to gain acceptance for a particular design and implementation plan, and proper documentation of decisions and actions, are a key success factors.

Key reasons to purchase this research

• What is the current regulatory position on the use of adaptive trials in the exploratory and confirmatory stages of drug development?

• Where and how have adaptive trials been used by the industry already? Which companies are pioneering their use?

• How can adaptive trials improve drug development?

• What are the costs associated with adaptive trials? Can they save money?

• How can adaptive trials be used in clinical trials with biomarkers?

Table of Contents

About the authors 2

Disclaimer 2

Executive summary 9

Introduction 9

Adaptive trials in the 'learn' development phase 10

Adaptive trials in the 'confirm' development phase 10

Simulation in the design of adaptive trials 11

Logistics and technology requirements for adaptive trials 12

Regulation of adaptive trials 13

Outlook for adaptive trials 14

Chapter 1 Introduction 16

Summary 16

Introduction 17

Defining adaptive clinical trials 17

Why adapt? 19

Redesigning drug development 22

Potential advantages of adaptive trials 23

Companies working together 24

Report outline 26

Chapter 2 Adaptive trials in the 'learn' development phase 27

Summary 27

Introduction 28

Finding the right dose 28

The Adaptive Dose-Ranging Studies Working Group 29

Case studies 31

Pfizer's ASTIN study 31

Dose-ranging study in neuropathic pain (Pfizer) 34

Dose-finding study of anti-migraine compound (Merck & Co) 35

Adaptive dose finding study (Wyeth) 36

A Bayesian dose-finding trial in patients with diabetes (Wyeth) 39

A Bayesian adaptive randomization seamless Phase IIa/b study (Abbott Labs) 40

Adaptive Phase I oncology trials: the continual re-assessment method 40

Biomarkers and adaptation in the 'learn' phase 41

Adaptive trials with predictive biomarkers 42

Adaptive signature designs 43

Adaptive randomization designs 44

Case study: Biomarker-Integrated Approaches of Targeted Therapy of Lung Cancer Elimination (BATTLE) Trial 44

Case study: I-SPY2 45

Conclusions 47

Chapter 3 Adaptive trials in the 'confirm' development phase 49

Summary 49

Introduction 50

'Seamless' confirmatory trials 51

Case studies 52

Eli Lilly case study 52

Novartis case study 1 55

Novartis case study 2 58

AstraZeneca case study 59

Napo Pharmaceuticals case study 61

Cempra Pharmaceuticals case study 61

Pros and cons of seamless designs 62

Regulatory view 62

White space 64

When are seamless designs appropriate? 65

Sample size re-estimation in confirmatory trials 66

Conclusions 68

Chapter 4 Simulation in the design of adaptive trials 70

Summary 70

Introduction 71

Clinical trial simulations 71

Including pharmacometric data 73

Providers of clinical trial simulation software 74

Berry Consultants 75

Cytel Inc 76

Documenting simulations 76

Statisticians in drug development 77

Conclusions 77

Chapter 5 Logistics and technology requirements for adaptive trials 79

Summary 79

Introduction 80

Suppliers of clinical technologies 81

Consolidation within the industry 82

Endpoint selection and real-time data collection 83

Technologies for data collection and their integration 83

Case study: Timaeus (Cmed Technology Ltd) 85

Electronic data capture (EDC) 85

Standards in EDC 86

Special considerations for safety parameters 87

Interactive voice recognition and interactive web response 87

Electronic patient reported outcomes (ePRO) 88

Cleaning data 88

Testing data flow 89

Clinical supply management 89

Key challenges in supply chain management 89


Simulation 90

Case study – clinical trial supply scenario simulation 91

Case study – Wyeth dose finding trial 91

Documenting design decisions 92

Conclusions 93

Chapter 6 Regulation of adaptive trials 94

Summary 94

Introduction 95

The EMA position on adaptive designs 95

FDA draft guidance on adaptive designs 96

Bayesian statistics 97

Regulatory documents 97

Interacting with the FDA 97

Industry response to the draft guidelines 99

Causes for regulatory concern 99

Type 1 error rate control 100

Maintaining confidentiality 100

Conclusions 104

Chapter 7 Outlook for adaptive trials 106

Summary 106

Introduction 107

Impact of adaptive clinical trials on costs and success in drug development 107

Cost savings associated with stopping early 108

Modeling costs and the probability of success 109

Portfolio planning for clinical trials with biomarkers 111

Organizational changes for adaptive trials 113

Outlook for adaptive trials 114

Conclusions 115

Appendix 117

Primary research methodology 117

Acknowledgments 118

Glossary 119

Bibliography 121

Table of figures

Figure 1: Summary of strategic motivations for using adaptive trials 20

Figure 2: Examples of strategic motivations for adapting clinical trials 21

Figure 3: The 'learn and confirm' model of drug development 23

Figure 4: Types of dose finding adaptive trial design tested by the PhRMA Adaptive Dose-Ranging Studies Working Group in 2009 30

Figure 5: Structure of the ASTIN study 32

Figure 6: Data from the ASTIN study 33

Figure 7: Design of an adaptive dose finding study with telcagepant (Merck & Co) 35

Figure 8: The adaptive signature design 43

Figure 9: Design of the BATTLE study to identify molecular signatures targeted by drugs for non-small cell lung cancer 45

Figure 10: Overview of the I-SPY2 trial design 46

Figure 11: Design of operationally and inferentially seamless trials 51

Figure 12: Key elements of Eli Lilly's seamless Phase II/III study in patients with type 2 diabetes 53

Figure 13: Design Eli Lilly's seamless Phase IIb/III study in patients with type 2 diabetes 54

Figure 14: Key elements of Novartis' seamless Phase IIb/III study in COPD 56

Figure 15: Novartis' completed seamless adaptive Phase IIb/III study design 57

Figure 16: Seamless adaptive Phase IIb/III trial designs; Novartis case study 59

Figure 17: HORIZON III Phase II/III clinical study 60

Figure 18: When to use seamless adaptive Phase IIb/III designs 66

Figure 19: The clinical trial design simulation process 72

Figure 20: Information utilized in model-based drug development 73

Figure 21: Choosing an adaptive design: infrastructure and process requirements 81

Figure 22: Providers of clinical technologies to support adaptive trials 82

Figure 23: Automated implementation for adaptive designs 84

Figure 24: Acceptance of different adaptive designs 97

Figure 25: Relationship between the size of Phase IIb and the probability of success in Phase III 110

Figure 26: Relationship between the size of Phase IIb and the product's expected net present value 111

Table of tables

Table 1: Definitions of adaptive clinical trials 18

Table 2: Advantages and disadvantages of using adaptive clinical trial designs 24

Table 3: Bayesian designs can investigate more doses 34

Table 4: Comparison of features of different designs for a dose finding study 37

Table 5: Adaptive dose finding study comparisons: probabilities of success and potential cost savings 38

Table 6: Definitions of four key types of biomarker 41

Table 7: Advantages and disadvantages of seamless adaptive designs 62

Table 8: Consequences of incorrect planning for treatment difference and/or standard deviation 67

Table 9: Leading companies offering statistical expertise for adaptive trials 75

Table 10: Cost savings associated with stopping early for futility 109

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Nicolas Bombourg



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