Innovations and Trends in Clinical Trials: Microdosing (Phase 0 Trials), Adaptive Trials, Phase IV Trials and the Role of Information Technology

Innovations and Trends in Clinical Trials: Microdosing (Phase 0 Trials), Adaptive Trials, Phase IV Trials and the Role of Information Technology

The clinical trials industry has clear potential for strong growth in the future, driven by technological and scientific advances. This trend is complemented by the development of new trial designs, with a view to rationalizing and accelerating the drug discovery process by identifying failures at an earlier stage.

This report provides detailed information regarding new developments in the field of clinical trials as well as an assessment of the impact these new technologies and designs are having and will have on the pharmaceutical and biotech industries.

Key Findings

• Overall, a number of trends are set to influence the field of clinical trials. Phase 0 (human microdosing) will become more common and more desirable, while Phase I is likely to morph into a shorter testing stage.
• Similarly, seamless designs are the future of the combined Phase II and III, cutting development times and associated costs. The latter change would advance the trend already observed in the field, with many trials designed to test efficacy and safety concurrently.
• Additionally, post-marketing studies will gain importance as patient, ethical and regulatory demands increase, as much as the methods for toxicology testing becomes more sophisticated. Such changes will be supported by the use of existing and new technology.

• Human microdosing clearly holds significant promise as an analytical tool. In the coming years, as research methods and technology involved in Phase 0 trials become more sophisticated, human microdosing may be applied to a number of drugs that could potentially be administered consecutively.
• Looking further into the future, the trend of combining adaptive designs with the goals of Phase IIb and Phase III trials is likely to become the norm. This type of trial, described as ‘seamless adaptive’, will aim to become even more time-efficient, although it may carry higher risks for first-in-class drugs.
• Phase IV trials will continue to grow at an estimated annual rate of over 20 percent. According to some estimates, companies are likely to invest over US$12 billion in this area in the course of 2007. Phase IV trials will be increasingly used to expand a drug’s indications, its geographical reach, as well as to disseminate information to medical professionals, regulatory authorities and patients alike.

Key Features of This Report

• Analysis of emerging clinical trial innovations, including microdosing (Phase 0 trials), adaptive trials, Phase IV clinical trials and information technology trends in the sector
• Integrated discussion and analysis of regulatory activities affecting new clinical trial designs and information technology in clinical trials
• A discussion of the future trends in the clinical trials marketplace, shaped by medical and technological advances as well as demographic and epidemiological changes and industry needs
• Profiles of the leading companies active in microdosing (Phase 0), adaptive trials, Phase IV trials and information technology
• Overview of the clinical trials industry
• In-depth information and analysis regarding different types and phases of clinical trials, including their brief history

Table of Contents

1 Methodology and Executive Summary
1.1 Report Objectives
1.2 Report Methodology
1.3 Executive Summary
1.3.1 Microdosing
1.3.2 Adaptive Design
1.3.3 Phase IV Post Marketing Trials
1.3.4 Information Technology
1.3.5 Clinical Trials Outlook

2 Clinical Trials – Background
2.1 Introduction to Clinical Trials
2.2 Clinical Trials Marketplace
2.3 Types of Clinical Trials
2.4 Phases of Clinical Trials
2.5 Brief History of Clinical Trials
2.6 Need for Innovation in the Pharmaceutical Industry
2.7 Need for Maximization of Drug Development
2.8 Major Limitations of Present Clinical Trial Designs
2.8.1 Cost
2.8.2 Inflexibility
2.8.3 Time
2.8.4 Use of Animals
2.8.5 Early Trial Failures
2.8.6 Pharmacogenomics

3 Clinical Trials – Overview of New Developments
3.1 Present Situation
3.2 Regulatory Environment
3.3 Need for Changes
3.4 Likely Future Trends in Clinical Trials
3.5 Partnerships in the Realm of Clinical Trials

4 Phase 0 Clinical Trials
4.1 Overview
4.2 Human Microdosing - Technology
4.2.1 Accelerator Mass Spectometry (AMS)
4.2.1.1 Key Study Details
4.2.2 Positron Emission Tomography (PET)
4.2.2.1 Key Study Details
4.2.3 Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS)
4.2.4 Liquid Scintillation Counting (LSC)
4.2.4.1 Key Study Details
4.3 Regulatory Issues
4.4 Recent Changes in Regulatory Environment
4.5 Microdosing Versus Conventional Clinical Trial Methods - Advantages and Disadvantages
4.6 Microdosing and the Use of Animals
4.7 Examples of Phase 0 Clinical Trials
4.7.1 Neurocrine Biosciences
4.7.1.1 Key Study Details
4.7.2 Radiant Research
4.7.2.1 Key Study Details
4.7.3 Resverlogix
4.7.3.1 Key Study Details
4.7.4 Speedel Pharmaceuticals
4.7.4.1 Key Study Details
4.7.5 Tripep
4.7.5.1 Key Study Details
4.7.6 Vitalea Science
4.7.6.1 Key Study Details
4.7.7 Xceleron
4.7.7.1 Key Study Details
4.8 Future of Phase 0 Clinical Trials

5 Adaptive Trials
5.1 Overview
5.2 Forms of Adaptive Trials
5.2.1 Scientifically Predetermined Outcome
5.2.2 Continual Reassessment Method (CRM)
5.2.3 Adaptive Randomization
5.2.4 Group Sequential Trial
5.3 Regulatory Issues
5.4 Recent Examples of Adaptive Trials
5.5 Adaptive Versus Controlled Clinical Trials – Advantages and Disadvantages
5.6 Future of Adaptive Clinical Trials
5.7 Adaptive Clinical Trials - Company Overviews
5.7.1 Bristol-Myers Squibb (BMS)
5.7.2 Eli Lilly
5.7.3 Novartis
5.7.4 Pfizer
5.7.5 Tessella
5.7.6 Wyeth

6 Phase IV Clinical Trials
6.1 Overview
6.2 Regulatory Issues
6.2.1 Completion of Promised Post-Marketing Studies
6.2.2 Clinical Trials Registries
6.2.3 Results Disclosure
6.3 Examples of Comparative Phase IV Studies
6.3.1 Strattera
6.3.2 Magnex
6.3.3 Avonex
6.4 Examples of Indication Extension Phase IV Studies
6.4.1 Remicade
6.4.2 Velcade
6.4.3 Humira
6.4.4 Visicol
6.5 Examples of Product Withdrawals Following Phase IV Studies
6.5.1 Lipobay/Baycol
6.5.2 Rezulin
6.5.3 Vioxx
6.6 Future of Phase IV Trials

7 Information Technology in Clinical Trials
7.1 Overview
7.2 Regulatory Developments
7.3 Benefits of Information Technology
7.4 Examples of IT in Clinical Trials
7.5 Electronic Data Capture (EDC)
7.5.1 Market Value and Potential
7.5.2 Main Benefits of EDC
7.5.3 Key Therapeutic Areas for EDC Application
7.5.4 Companies Using EDC
7.6 Clinical Trials Management System (CTMS)
7.6.1 Advantages and Disadvantages of CTMS
7.6.2 Companies Developing CTMS
7.7 Clinical Data Management System (CDMS)
7.7.1 CDMS Subtypes
7.7.1.1 Database Management System (DBMS)
7.7.1.2 Case Report Form (CRF) Designs
7.7.1.3 Data Entry Interface
7.7.1.4 Reporting/Analysis
7.7.2 Companies Involved in CDMS Design
7.8 Clinical Trials and the Internet
7.9 Security, Confidentiality and Ethical Concerns

8 Company Profiles
8.1 Pharmaceutical Companies
8.1.1 Bayer
8.1.2 Bristol-Myers Squibb (BMS)
8.1.3 Eli Lilly
8.1.4 InKine Pharmaceuticals
8.1.5 Johnson & Johnson (J&J)
8.1.6 Merck & Co
8.1.7 Novartis
8.1.8 Pfizer
8.1.9 Wyeth
8.2 Biopharmaceutical Companies
8.2.1 Biogen Idec
8.2.2 Cambridge Antibody Technology (CAT)
8.2.3 Millennium
8.2.4 Neurocrine Biosciences
8.2.5 Pharmaceutical Profiles
8.2.6 Radiant Research
8.2.7 Resverlogix Corporation
8.2.8 Speedel Pharmaceuticals
8.2.9 Tripep AB
8.2.10 Vitalea Science
8.2.11 Xceleron
8.3 Medical Device Companies
8.3.1 Asthmatx
8.4 Pharmaceutical Software Companies
8.4.1 DATATRAK
8.4.2 etrials
8.4.3 Phase Forward
8.4.4 Tessella Support Services

Glossary of Terms

Appendix : Regulatory Guidance

Tables
Table 2.1 Types of Phase I Trials
Table 2.2 Phases of Clinical Trials
Table 2.3 Total Expected Sample Sizes for Alternative Clinical Research Programs
Table 2.4 Regulatory Agencies for Pharmaceutical Products in Major Global Markets
Table 2.5 Areas of Animal Use
Table 4.1 Advantages and Disadvantages of AMS
Table 4.2 Advantages and Disadvantages of Human Microdosing
Table 4.3 Benefits of Microdosing in Relation to Studies on Animals
Table 4.4 Drugs Tested with Human Microdosing in the CREAM Trial
Table 5.1 Advantages and Disadvantages of Adaptive Clinical Trials
Table 7.1 IT in Clinical Trials
Table 7.6 Examples of Applying IT to Improve Clinical Trials Performance
Table 7.3 Improvement of Process and Increase of Business Value through the Adoption
of e-Solutions
Table 7.4 Technology Map for Clinical Trials
Table 7.5 Benefits of IT in Clinical Trials
Table 7.2 Reasons Cited for Not Adopting New Data Collection Methods

Graphs
Graph 2.1 Decreasing R&D Productivity
Graph 2.2 R&D Costs and Research Productivity
Graph 4.1 Semilogarithmic Plot of the Plasma Concentration/Time Profile of Midazolam
Graph 7.1 Impact of Technology on Clinical Trials
Graph 7.2 Cost Comparisons (in US$mn) of EDC Budgets of Four Clinical Trials with
Corresponding Paper Model and EDC L2TTP
Graph 7.3 Comparison of Efficiency of EDC versus Paper Data Collection

Figures
Figure 2.1 Overview of the Activities Involved in Modern Drug Discovery and Development
Figure 2.2 Phases of Pre-clinical and Clinical Development
Figure 5.1 Graphic Representation of Adaptive Trial Design
Figure 5.2 Re-Analysis of Pravachol Pac Clinical Trial Using Bayesian Techniques
Figure 7.1 Typical Systems That Can Be Integrated with CTMS