Innovative Clinical Trial Design and Management: Trends, success stories and impact upon R&D budgets

Published by: Business Insights

Published: May. 1, 2008 - 170 Pages

Table of Contents

Innovative Clinical Trial Design and Management

Executive Summary

Introduction

Adaptive clinical trials

Adaptive dose-finding studies

Seamless adaptive trials

Adaptive trials in drug-diagnostic co-development

Simulation, logistics and technology in adaptive trials

Regulating adaptive trials

Outlook for adaptive trials in the pharma industry

Chapter 1 Introduction

Summary

State of the industry

Rising development costs

Longer development times

Increasing complexity

Higher attrition

Increasing innovation

Innovation in drug discovery and development

Adaptive clinical trials - an introduction

Report outline

Chapter 2 Adaptive clinical trials

Summary

Introduction

Adaptive designs

Flexibility in adaptive trials

Statistics for adaptive designs

Group Sequential Designs

Stopping early for benefit - controversy

Case study: RALES - a Searle Phase 3 Group Sequential Design

Case study: CAPTURE - a Centocor study in refractory unstable angina

Case study: Proof-of-concept study in neuropathic pain - GlaxoSmithKline

Case study: PURSUIT - a Millennium Pharmaceuticals study in unstable angina

Sample size re-estimation

Case study: a group sequential study for sample size re-estimation

Case study: GlaxoSmithKline pivotal study for Advair Diskus

Response adaptive randomization

Case study: Troxacitabine in acute myeloid leukemia

Case study: Eli Lilly out-patient study in depression

Case study: Three dosing schedules of decitabine in myelodysplastic syndrome

Case studies: A study of sorafenib in different types of cancer

Bayesian methods in First in Man studies

Conclusions

Chapter 3 Adaptive dose-finding studies

Summary

Introduction

Case study: ASTIN

Case study: Phase 2 Pfizer dose-ranging study in neuropathic pain

Case study: Phase 2 Merck dose-finding study of anti-migraine compound

Case study: Phase 3 Napo Pharmaceuticals study in HIV patients with diarrhea

The PhRMA Adaptive Dose-Ranging Studies Working Group 69

Conclusions

Chapter 4 Seamless adaptive trials

Summary

Introduction

Pros, cons and controversy

Speeding up clinical development

Efficiency gains in seamless trials

When are seamless designs appropriate?

Regulatory view of seamless Phase 2b/3 studies

Case study: Phase 1/2 trials in oncology

Case study: Phase 2b/3 Novartis study in a chronic disease indication

Case study: HORIZON III an AstraZeneca study in oncology

Conclusions

Chapter 5 Adaptive trials in drug-diagnostic co-development projects

Summary

Introduction

Biomarkers and classifiers

Co-development of drugs and companion diagnostics

Pivotal Phase 3 trial designs using predictive biomarkers

Enrichment designs

Patient stratification

Sample size calculation for enrichment and stratification designs

Adaptive signature designs

Biomarker adaptive threshold determination

Case study: identifying a classifier of response to Velcade

Conclusions

Chapter 6 Simulation, logistics and technology in adaptive trials

Summary

Introduction

Preplanning and simulation

Case study: A study design and simulation using Cytel’s East® simulation package

Logistical issues

Real-time data collection

Electronic data capture (EDC)

Electronic patient reported outcomes (ePRO)

Interactive voice recognition and interactive web response

Companies involved in real-time data collection

Maintaining data confidentiality

Minimizing operational bias and assuring consistency between study stages

Clinical supply management

Case study: simulating drug supply

Summary - logistical considerations for adaptive trials

Conclusions

Chapter 7 Regulating adaptive trials

Summary

Introduction

FDA guidance on adaptive designs

EMEA guidance on adaptive designs

PhRMA working groups

Conclusions

Chapter 8 Outlook for adaptive trials in the pharma industry

Summary

Introduction

Adaptive trials and success rates in clinical drug development

Costs in adaptive clinical trials

Time means money

Costs in a dose-finding clinical trial

Cost savings in a seamless Phase 2b/3 trial

Cost savings in a random adaptive allocation trial

Costs in a sample size re-estimation study

Costs of clinical trials in pharmacogenomics

Pharma’s uptake of adaptive designs

Outlook for adaptive trials

Chapter 9 Appendix

Primary research methodology

Index

Glossary

Glossary

List of Figures

Figure 1.1: New drug approvals versus R&D costs, 1995-2006

Figure 1.2: Trend towards longer drug development times, 1997 to 2005

Figure 1.3: Increasing complexity of clinical trial

Figure 1.4: Change in attrition rates, 1994 to 2000

Figure 1.5: Increasing innovation in drug development

Figure 1.6: Attrition rates and development times by drug novelty status

Figure 2.1: Summary of motivations for using adaptive trials

Figure 2.2: Examples of motivations for adapting clinical trials

Figure 2.3: Advantages and disadvantages of increasing the flexibility of adaptive trial designs

Figure 2.4: Bayes Theorem explained

Figure 2.5: How Bayesian statistics work

Figure 2.6: Data from interim monitoring visits during the RALES study

Figure 2.7: The random play-the-winner trial design

Figure 2.8: Response adaptive randomization - case study with troxacitabine

Figure 3.1: Advantages of adaptive dose-finding studies over traditional methods

Figure 3.2: Structure of the ASTIN study

Figure 3.3: Data from the ASTIN study

Figure 4.1: Structure of an adaptive seamless clinical trial

Figure 4.2: Key aims of each phase of drug development

Figure 4.3: Seamless trials in Phases 1, 2 and 3

Figure 4.4: When to use seamless adaptive Phase 2b/3 designs

Figure 4.5: Novartis’ ongoing seamless adaptive Phase 2b/3 study design

Figure 5.1: Examples of targeted treatments and their companion diagnostics

Figure 5.2: Definitions of predictive and prognostic biomarkers

Figure 5.3: Co-development of a drug and companion diagnostic

Figure 5.4: Types of study design for use in drug-diagnostic co-development

Figure 5.5: The enrichment design

Figure 5.6: Including classifier positive and negative patients: stratification

Figure 5.7: Marker-based strategy for patient stratification

Figure 5.8: Adaptive signature designs

Figure 5.9: Discovery and testing of a predictive classifier for Velcade

Figure 6.1: Case study: stopping probabilities calculated using Cytel’s East software

Figure 6.2: Integrative electronic systems in adaptive trial designs

Figure 6.3: Working Group proposal for sponsor involvement in decision making

Figure 6.4: Working Group proposal for selection decisions

Figure 6.5: Choosing an adaptive design: infrastructure and process requirements

Figure 8.1: Attrition rates and costs in drug development

Figure 8.2: Adaptive trials may help to restore success rates

Figure 8.3: Adaptive trials may help to restore success rates

Figure 8.4: Cost savings in a hypothetical seamless Phase 2b/3 adaptive trial

List of Tables

Table 1.1: Advantages and disadvantages of using adaptive clinical trial designs

Table 1.2: How adaptive designs can fight attrition

Table 2.1: Group sequential study design may save time

Table 2.2: Consequences of incorrect planning- treatment difference and/or standard deviation

Table 2.3: Comparison of simple randomization and response-adaptive randomization

Table 2.4: Results of a response adaptive randomization study in depression

Table 3.1: Bayesian designs can investigate more doses

Table 4.1: Advantages and disadvantages of seamless adaptive designs

Table 5.1: Efficiency of enrichment study designs

Table 5.2: Comparison of number of patients needed for enrichment designs: gefitinib example

Table 5.3: Free software available for calculating sample sizes in pharmacogenomic studies

Table 6.1: Integrity and validity in adaptive clinical trials

Table 6.2: Companies offering statistical expertise for adaptive trials

Table 6.3: Providers of software, tools and services for adaptive trials

Table 6.4: Clinical trial supply simulation software providers

Table 8.1: Cost savings for various options in COPD trial

Table 8.2: Retrospective analysis identifies benefits of an adaptive design

Table 8.3: Effect of HER2 testing on the development of Herceptin

Table 8.4: Potential additional sales for a drug targeted to 25% of patients tested

Table 8.5: Phase distribution of case studies, PhRMA Adaptive Designs Working Group

Table 8.6: Indications in which Bayesian adaptive designs have been used

Abstract

Innovative Clinical Trial Design and Management

Trends, success stories and impact upon R&D budgets

Report overview Key findings...

The costs associated with developing drugs have risen dramatically over the past decade and fewer drugs are obtaining regulatory approval. The pharmaceutical industry is continually exploring new ways of improving drug developments and one area of focus is adaptive clinical trial designs. These innovative clinical trial designs use accumulating data to guide potential modifications to the study as it progresses, without undermining the validity and integrity of the trial. The advantages of such designs include the reduced length and cost of clinical trials, lower patient numbers and the ability to stop a trial early where a drug has not shown efficacy.

‘Innovative Clinical Trial Design and Management’ is a new report published by Business Insights that explores the major types of adaptive design and their role in dose-finding. The report investigates seamless Phase 2/3 trials and adaptive trials in pharmacogenomics, assesses the logistical implications of adaptive trial implementations and reviews the current regulatory standpoints of the FDA and EMEA. Detailed case studies of recent adaptive clinical trials are provided and the companies offering statistical expertise in this area are profiled. This report also includes a breakdown of the potential cost and time savings that innovative trial designs can offer throughout the clinical development process.

Use detailed case studies to explore recent adaptive trial implementations, identify the companies pioneering and supporting innovative designs and understand the most effective planning and logistics strategies...

Key findings...

Major pharma companies are implementing adaptive trials to improve dose-finding in the Phase 2 setting. The use of adaptive clinical trials will increase across the industry over the next 2-3 years.

Adaptive clinical trial designs are more effective than traditional designs in cases where there is uncertainty surrounding the dose, effect size and variability, clinical endpoint or patient populations.

The planning and execution of adaptive designs is more complex than the traditional approach. Successful implementations require teams of statisticians, data managers, clinicians and drug supply and logistics managers to work together as early as possible.

Predictive biomarkers have been found to require detailed prospective analysis far earlier in the clinical development process, and with the same clarity as traditional drug approvals. Post-hoc correlations were previously thought to be good enough for identifying the biomarkers used to predict the patients most likely to respond well to a new treatment.

Regulatory authorities are supportive of adaptive trials, particularly in the Phase 2 setting. However, there are concerns over the confidentiality of data and companies have been asked to demonstrate that the parties involved in running the study will remain unaware of ongoing adaptations.

Key questions answered...

• How can adaptive trials improve the success rates of clinical drug projects?
• How are pharma companies implementing adaptive trials and what major hurdles can prevent such implementations?
• What is the position of the FDA and EMEA in regards to different types of adaptive trial?
• How can logistical and strategic planning be managed most effectively?
• Which companies are offering services to support adaptive clinical trials?
• Which companies are co-developing drugs and diagnostic products?

Key issues examined by this report...

• Adaptive trial implementations. The aim of adaptive trials is to improve the information value of clinical trials whilst maintaining their integrity and validity. The use of adaptive trials in the early phases of drug development should yield better information and lead to the earlier termination of unsuccessful compounds.
• Dose finding improvements. The availability of new Bayesian study designs that acknowledge prior information and allow for the testing of a wider range of doses has enabled more accurate dose-finding. This may have important consequences for the success of future Phase 3 clinical programs
• Seamless trial speed. Major pharma companies are interested in the prospect of combining drug development phases into ‘seamless trials’, with the potential to reduce the length of clinical development programs in the Phase 2b/3 setting
• Regulatory issues. Engaging with the FDA/EMEA during the protocol design stages of an adaptive trial is important, especially for studies intended for use in packages of pivotal clinical data. The EMEA’s current position on adaptive clinical trial design is summarized within a reflection paper published in October 2007, while draft FDA guidance is expected in 2008.

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