Approaches to Reducing Phase II Attrition

Approaches to Reducing Phase II Attrition

Phase II is the critical development stage in which most clinical attrition occurs. This report focuses on approaches to improving R&D productivity in the pharmaceutical and biotechnology industries and considers:

• Leading-edge strategies being pursued to improve success rates of therapeutic candidates in clinical development
• The use of translational medicine studies and early clinical trial protocols designed to reduce Phase II attrition
• Survey results and expert interviews on efforts to improve R&D efficiency.

Pharmaceutical companies have been responding to a combination of major challenges that many commentators call a “perfect storm.” It is clear that the high rate of attrition in the drug development process is severely limiting the numbers of high-quality novel drug candidates, especially for innovative drugs that address unmet medical needs. In order to overcome this limitation, the industry must develop strategies that can reduce attrition during Phase II, where most attrition occurs, especially as it continues to drive up the cost of R&D to unsustainable levels.

Approaches to Reducing Phase II Attrition considers examples of leading-edge strategies being pursued to improve target selection and other aspects of drug discovery. These include development of multitargeted therapies, whole-pathway approaches, biology-driven drug discovery, analysis of multigenic complex diseases, and network pharmacology. Strategies for improving early-stage clinical studies are discussed, including the use of Phase 0 and adaptive trials, and employing early proof-of-concept trials. Ways in which some companies have adopted new corporate structures designed to increase innovation or make R&D more “biotech-like” are described.

Poorly predictive animal models constitute a major cause of drug attrition. We present two case studies in CNS and cancer, two therapeutic areas in which animal models are notorious for being poorly predictive. The CNS case study focuses on attempts to improve animal model efficacy studies, and the cancer case study focuses on industry’s adoption of improved animal models developed in academia. In these discussions, we indicate how these particular case studies may have lessons for efficacy studies in most therapeutic areas.

Well-designed translational studies may enable drugs that do not work in humans to fail early. We examine various aspects of translational studies, including definition of responder versus non-responder populations, and optimal dosing regimens; and identification of early and sensitive markers of efficacy, and of those patients who are likely to experience adverse effects. Examples of ways in which translational medicine is changing the organization of clinical trials in some companies are discussed. We also study the roles that various types of biomarkers play in translational medicine, as well as the current state of biomarker science. Case studies on stratification biomarkers in cancer are presented.

Approaches to Reducing Phase II Attrition analyzes results from a survey of current practices and views toward improving the efficiency and effectiveness of drug development. Finally, the complete transcripts of interviews conducted with experts in the field are provided. 
 

Chapter 1 - INTRODUCTION: CHALLENGES TO DRUG DEVELOPMENT TODAY

1.1. Responding to Industry Challenges by Corporate Restructuring
1.2. Responding to Industry Challenges by Large-Scale Mergers and Acquisitions
1.3. Attrition in Drug Development
The Kola and Landis Paper on Drug Attrition, 2004
Drug Approvals, R&D Costs, and Attrition Rates Since 2003
Strategies for Attacking the Phase II Attrition Problem

Chapter 2 - DRUG DISCOVERY STRATEGIES AIMED AT REDUCING PHASE II ATTRITION

2.1. Summary of the Target Evaluation Process
2.2. Strategies for Moving Beyond the Target Validation Paradigm
Developing Agents That Address Multiple Targets
Whole-Pathway Approaches to Drug Discovery
Biology-Driven Drug Discovery
Other Means of Going Beyond the Target Validation Paradigm
2.3. Target Generation at Pfizer’s Biotherapeutics & Bioinnovation Center
2.4. Novartis’ Pathway-Based Drug Discovery Strategy
2.5. Genomic Analysis of Multiple Genes, Pathways, and Networks Involved in Complex Diseases
2.6. Network Pharmacology and Rational Discovery of Multitargeted Drugs

Chapter 3 - IMPROVING ANIMAL MODEL STUDIES TO REDUCE PHASE II ATTRITION

3.1. Introduction
A Notorious Case of the Failure of Animal Studies to Predict Toxicity in Humans
The Focus of This Chapter
3.2. Case Studies on the Inadequacy of Animal Studies in Neurodegenerative Diseases
Animal Studies in Amyotrophic Lateral Sclerosis (ALS)
Animal Studies Using the “Standard Model” of ALS
Can Researchers Develop A Better Model of Sporadic ALS?
Implications of the ALS Animal Model Case for Alzheimer’s Disease (AD)
Studies in Mouse Models Transgenic For Tau
3.3. Lessons from Animal Model Studies in ALS and AD
3.4. Another Therapy for AD Based On Targeting Tau
3.5. Case Study on Adoption of Improved Mouse Models of Cancer by Industry
Aveo Pharmaceuticals and Mouse Model Technology Transfer Between Academia and Industry

Chapter 4 - OVERVIEW OF TRANSLATIONAL MEDICINE AND ITS USE IN DRUG DEVELOPMENT

4.1. Defining Responder and Nonresponder Populations
4.2. Defining the Optimal Dosing Regimen
4.3. Identifying Early, Sensitive Markers of Efficacy
4.4. Identifying Patients Who Are Likely to Experience Adverse Effects
4.5. Translational Medicine Is Changing the Organization of Clinical Trials in Some Companies
Lilly’s Chorus
Wyeth’s “Learn and Confirm” Organization of Drug Development
Lessons from the Lilly and Wyeth Cases

Chapter 5 - BIOMARKERS AND THEIR ROLE IN TRANSLATIONAL MEDICINE

5.1. Introduction
5.2. Types of Biomarkers
Translational (Bridging) Biomarkers
Toxicity Biomarkers
Stratification Biomarkers in Cancer: Case Studies on Epidermal Growth Factor Receptor (EGFR) Antagonists in Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer
5.3. Biomarkers Still an Early-Stage Technology
5.4. The Biomarkers Consortium and Improving Biomarker Science

Chapter 6 - NEW STRATEGIES FOR EARLY-STAGE CLINICAL TRIAL DESIGN

6.1. Phase 0 Clinical Trials
Phase 0 Studies at the National Cancer Institute
European-Based Phase 0 Studies Led by Xceleron
The Ethics of Phase 0 Studies
What Can Be Expected From Phase 0 Microdosing Studies?
6.2. Adaptive Clinical Trials
6.3. Proof-of-Concept Clinical Trials

Chapter 7 - OUTLOOK FOR STRATEGIES TO REDUCE PHASE II ATTRITION

7.1. Discussion of Insight Pharma Reports’ Phase II Attrition Survey—January/February 2009
7.2. General Conclusions
References
Appendix
EXPERT INTERVIEWS
A.1. Charles Gombar, PhD, Vice President, R&D Strategy and Business Improvement, Wyeth
Evan Loh, MD, Vice President, Clinical R&D, Wyeth
A.2. Peter Lassota, PhD, Divisional Vice President, Imaging Biology & Oncology, Caliper Life Sciences
A.3. Bruce H. Littman, MD, President, Translational Medicine Associates, LLC
A.4. Daniel M. Skovronsky, MD, PhD, Founder and CEO, Avid Radiopharmaceuticals
Company Index with Web Addresses

TABLES

Table 1.1. Major Challenges to the Pharmaceutical Industry in 2008/2009
Table 1.2. NCE and BLA Approvals by the US FDA, 1996–2008
Table 3.1. Transgenic Tau Models as Enablers of Drug Discovery and Development in the Tau Pathway of Alzheimer’s Disease
Table 3.2. Barriers to Adoption of Advanced Mouse Models of Cancer by Industry
Table 4.1. Questions To Be Answered In Translational Studies
Table 5.1. Selected Major Types of Biomarkers
Table 5.2. Ongoing Projects and Project Concepts in Development at the Biomarkers Consortium

FIGURE

Figure 2.1. The Canonical Wnt Pathway

SURVEY EXHIBITS

Question 1: Please classify your organization.
Question 2: What aspect(s) of the drug development process do you work in?
Question 3: What class(es) of drugs do you work on?
Question 4: Do you see Phase II attrition as a major issue in your company?
Question 5: What do you see as the major reasons for low productivity and high cost of drug development?
Question 6: Has your company adopted a program of translational medicine aimed at improving the efficiency and effectiveness of early drug development?
Question 7: If you have adopted a translational medicine program, has it been helping you to accelerate movement of promising drug candidates into mid-stage clinical trials and to weed out unpromising candidates?
Question 8: Does your company conduct the following types of clinical trials?
Question 9: If you conduct any of the types of clinical trials listed in question 8, which do you find useful in accelerating your development process?
Question 10: Does your company outsource your early-stage clinical trials to CROs that specialize in that stage of development?
Question 11: Do you find the FDA helpful in assisting you in designing and implementing your early-stage development programs?
Question 12: Do you work with academic laboratories in improving aspects of your translational medicine programs (e.g., biomarkers, improved animal models)?