A New Paradigm for Clinical Development: The Clinical Trial in 2015

SUMMARY

A New Paradigm for Clinical Development:

The Clinical Trial in 2015

A New Paradigm for Clinical Development: The Clinical Trial in 2015 outlines an innovative and imaginative strategy for reinventing clinical development, and demonstrates why a complete overhaul of the clinical trials process is feasible from a conceptual, technical and logistical point of view.

The current clinical evaluation process is fraught with inefficiencies, resulting in numerous compound failures and exploding development costs. Until recently, the industry has reacted to the clinical evaluation problem essentially by "streamlining" the existing processes and by introducing information technology in a cautious and evolutionary fashion. While the FDA's Critical Path Initiative of 2004 showed that the agency is willing to take the lead in working with representatives from industry and academia towards a remedy, this report suggests that a more radical solution is needed.

A New Paradigm for Clinical Development: The Clinical Trial in 2015 proposes a bidirectional approach to accelerate the clinical process and make it more effective. These two avenues, which can be summarized as revamping trial design and as truly pervasive modelling and monitoring driven by information technology, are fundamentally different from each other but need to be implemented in a closely linked fashion. Though radical in effect, none of these changes would involve concepts or technologies that are unknown today.

According to the strategy laid out in the report, the following changes are required:

• Phase I will assume a new role as a brief confirmatory testing stage for the model for drug-human interactions that the sponsor has proposed.
• Phases II and III will merge into a single advanced-stage human testing phase involving fewer patients than today, relying on relatively small patient populations that are highly homogenous with respect to key criteria of pharmacological response.
• Systematic post-marketing studies and a significantly improved and extended post-marketing surveillance system that goes far beyond adverse event reporting will be integrated into a post-marketing monitoring phase that documents real-life use of the newly licensed drug.

These new processes will be made possible through holistic mathematical models such as the virtual patient, extensive biomarker monitoring, and pervasive computing. With a full implementation of all envisaged changes by the year 2015, the stage would be set for a new world of drug development:

• The pre-approval clinical trial phase might be shortened to about three years and 40-50 percent of all candidate compounds that enter this stage could complete it, with the majority of the failures occurring in the early human validation phase.
• The crucial function of the advanced-stage human testing phase will be to determine whether efficacy is sufficiently superior over the established standard of therapy to warrant the cost of launch and the mandated post-marketing monitoring.
• Developers recoup development costs earlier and enjoy a longer life cycle under patent protection, but also benefit from more and closer attention to real-life use of the newly licensed drug.

About the Author

Hermann A.M. Mucke, Ph.D. spent 17 years in academia and industry before he founded H.M. Pharma Consultancy (www.hmpharmacon.com) in 2000 to become an independent pharmaceutical consultant, analyst and science author. His last industry position was Vice President R&D in a European pharmceutical company which he helped to take public on the Frankfurt Stock Exchange in 1999. Since then, Dr. Mucke, who holds a Ph.D. in biochemistry from the University of Vienna (Austria) became a consultant and advisory board member for several European and U.S. pharmaceutical companies, and a regular reviewer of drugs and patents for Thomson Current Drugs and Ashley Publications. He has served as an outside expert author for CHA since 2004. Dr. Mucke is based in Vienna and can be reached at h.mucke@hmpharmacon.com , or by fax at +43 1 494 9989.

TABLE OF CONTENTS

Chapter 1. Clinical Trials Today

1.1. More Targets, More Research and Development Spending, More Candidate Drugs?and Fewer New Products

1.2. The Clinical Trial Process: From Phase I to Phase IV

1.3. A Strategic Problem Analysis

• Why Do Phase III Trials Fail So Frequently?
• High-Profile Market Recalls: The Worst-Case Scenario Enacted
• Approved but Not Effective in All Eligible Patients

Chapter 2. Current Strategies for Clinical Streamlining

2.1. Cost-Effective Solutions for Clinical Go/No-Go Decisions

• Better Disease Models that Are Predictive of Human Exposure
• Human Microdosing: "Phase Zero"

2.2. Optimized Project Planning

2.3. Recruiting the "Right" Patients More Quickly?and Keeping Them

• Maximizing Outpatient Compliance
• "Offshoring" Clinical Trials

2.4. "Information-Rich" Trial Design and Biomarkers

• Pharmacogenomics
• Biomarkers for Clinical Monitoring

2.5. Electronic Data Capture: Heading for the "E-Trial"

• Digitizing the Case Report Form
• Interactive Voice Response Systems and Web-Supported Trials
• The E-Trial: A "Revolutionary Evolution"

2.6. Mining Clinical Databases

Chapter 3. Forces Shaping Future Clinical Trials

3.1. The Confounding Mega-Trends

3.2. Paradigm Changes Rather than Technological Leaps at the Clinical Inflection Point

3.3. Systems Biology as a Key to Understanding Disease and Patients' Reactions to Drugs

• The Virtual Patient: A "Crash Dummy" for the Pharmaceutical Industry

3.4. Beyond Today's Biomarkers

• Molecular Fingerprinting and Metabolomics
• Functional Endpoints Defined by Molecular Imaging
• Theranostics: The Co-Evolvement of Drugs and Diagnostics

3.5. Pervasive Computing: Can a New Type of Information Technology Bring Trials to New Shores?

• Clinical Data Management Systems (CDMS)
• The Omnipresent Radiofrequency Tags
• Grid Computing, Virtual Trial Organizations, and Data Interchange

Chapter 4. Regulatory Agencies in an Era of Change

4.1. The FDA Takes the Initiative

• The FDA's "Exploratory Investigational New Drug Application" Guideline
• The FDA's Critical Path Document
• The Biomarker Bootstrap Situation
• The FDA and the Emerging E-Trial Modalities

4.2. The Thorough QT Trial: An Example for International Coordination of Clinical Study Reform

4.3. The Dwindling Role of the Placebo

4.4. Focused Postmarketing Surveillance Instead of Megatrials

Chapter 5. A Scenario for Clinical Trials in the Year 2015

Chapter 6. Corporate Profiles

• Clinphone Group
• Compugen
• Entelos, Inc.
• eTrials Worldwide, Inc.
• Gene Network Sciences
• IBM Healthcare and Life Sciences
• Lifetree Technology LLC

References

Index