Trends in Clinical Trials: Strategies to enhance clinical trial design

Pharma is experiencing tough times, facing both economic and regulatory pressures, with increasing demands for improved safety data and comparative efficacy studies. Consequently, the duration, size, complexity and ultimately cost of clinical trials is on the increase, while simultaneously, the success of late-stage clinical trials is declining.

Report Highlights
In the increasingly competitive and cost-conscious pharmaceutical environment, it is important that pharma companies develop their pipeline products as quickly and cheaply as possible, while ensuring that they receive marketing approval as well as authorization from the relevant reimbursement agencies.

Approximately 58% of Phase III clinical trials are unsuccessful, with the primary cause for failure being the inability of the trial data to demonstrate efficacy of the tested product against placebo. However, this success rate can be improved by implementing a number of different strategies discussed herein.

Most drugs that apply for approval from the FDA and the EMEA are approved by both agencies. However, a minority of applications are approved by one agency and not the other, for reasons largely based upon the design of clinical trials that form part of the submission package. Find out how to maximize the chance of approval in both markets.
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CHAPTER 1 EXECUTIVE SUMMARY 4
Scope of the report 4
Key findings 5
CHAPTER 2 CLINICAL TRIAL TRENDS 10
Overview of R&D productivity 11
Increasing duration of clinical trials 13
Most popular therapy areas for clinical trials 16
Growing size of clinical trials 18
Variation in Phase III trial size by therapy area 20
Patient enrollment set to further lengthen study duration as complexity of trials increases 21
The cost of R&D is increasing 21
Cost of clinical trials is increasing 23
Clinical trial success rates are declining 24
Pharma faces increasingly stringent regulatory requirements 25
Stricter FDA regulation for foreign clinical trial data 26
Clinical trial registry and results database 28
Financial penalties for manufacturers not complying with the new safety requirements 29
The FDA's ability to require post-marketing studies has expanded 30
Inefficient data collection and management remains a problem 31
Clinical trials are becoming increasingly globalized 31
CHAPTER 3 OPTIMIZING CLINICAL TRIAL SUCCESS 32
Reducing attrition in the clinical trial process 33
Choose your indication carefully 36
Dispose of unsuccessful products before Phase III 37
Use of adaptive clinical designs 38
Work with regulatory authorities 42
Patient recruitment and retention 43
eRecruitment is a growing phenomenon 43
Lessons to be learnt from the UK - an oncology perspective 44
Selection of niches within a patient population is advantageous 45
Use of eClinical trial technologies improves efficiency 46
Electronic data capture (eDC) increases efficiency over a paper-based system 46
Optimize clinical trial outsourcing 50
Emerging markets are presenting many cost- and time-saving opportunities for clinical trials 51
Key recommendations for optimizing clinical trial outsourcing 53
Caution over clinical trials designed for marketing rather than clinical research purposes 55
Recommendations to improve the design of open-label extension studies 56
CHAPTER 4 ANALYSIS OF CLINICAL TRIAL AND REGULATORY SUCCESSES AND FAILURES 57
Why Phase III drugs fail and what lessons can be learnt? 58
Lessons learnt from clinical trial failures 60
Alterations to clinical trial design will cast doubt over results, whether unintentional or not 60
Failure to ensure dosing regimen for active and placebo/comparator arms 62
Ensure patients recruited for a trial are at the desired stage of disease progression 62
Ensure placebo group is sufficiently large 63
Why products fail to gain regulatory approval 65
Reasons for failing to gain approval at first submission 65
Working closely with regulators improves the chance of clinical success 68
Submitting data from trials that failed to meet primary endpoints 72
Ensure that clinical trial endpoints reflect real-world treatment endpoints 73
What happens when drugs fail late-stage clinical trials 75
Options following a late-stage clinical trial failure non-approvable letter 76
AstraZeneca - bounces back from key late-stage clinical trial failures 78
CHAPTER 5 DIFFERENCES IN FDA AND EMEA APPROVAL OUTCOMES 82
Gaining approval in both the US and EU 83
Differences in FDA and EMEA approval criteria 83
Drugs approved by one agency but not the other 84
Vectibix - differing approval criteria in the US and EU 86
FDA's heightened safety concerns 89
Factors behind leading to negative opinions by the CHMP 91
Not applicable in the real-world setting 91
Long-term/maintenance data required by EMEA 93
Future changes to regulatory approval processes 93
Joint FDA-EMEA reviews unlikely 94
Future direction of the EU Clinical Trial Directive 95
CHAPTER 6 BIBLIOGRAPHY 97
Publications and online articles 97
Datamonitor resources 109
Databases 109
Abbreviations 110
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Table 1: Ranking of therapy areas in terms of growth in number of clinical trials performed between 2005 and 2007 17
Table 2: Pros and cons of implementing an adaptive clinical trial design 41
Table 3: Considerations when selecting a suitable contract research organization (CRO) 53
Table 4: Reasons for the failure of Phase III drugs 58
Table 5: Opportunities for interaction between the FDA and drug sponsors during clinical development 69
Table 6: AstraZeneca's key late-stage clinical trial failures, 2006-08 78
Table 7: Drugs approved by one regulatory agency but not the other 85
Figure 1: Leading causes of delays at clinical trial centers in the US, 2003 and 2005 12
Figure 2: Evaluation of clinical trial duration by indication and phase of development, 2001-06 15
Figure 3: Numbers of enrollees by therapy area for Phase III clinical trials conducted in the US in 2007-08 20
Figure 4: Key causes of patient enrollment delays 21
Figure 5: With declining return on investment, successful launches have never been more important for pharmaceutical companies, 1990-2004 22
Figure 6: Clinical trials with a high degree of complexity are more costly, 2006 24
Figure 7: Evaluation of clinical trial to launch success rates by indication and phase, 2001-06 25
Figure 8: NIH recommendations for improving clinical trial design 35
Figure 9: Faster drug developers terminate development drugs earlier 37
Figure 10: Factors affecting Go or No-Go decisions for progressing to Phase III 38
Figure 11: Reasons for adopting adaptive clinical trials 39
Figure 12: Perceived barriers to the adoption of adaptive clinical trials 41
Figure 13: Factors to be considered when designing an adaptive clinical trial 42
Figure 14: Lack of available cash is the primary barrier to electronic data capture 48
Figure 15: Implementation of eDC is expected to rise, 2006 49
Figure 16: Predictions for future usage of CROs over the next 5 years, 2008 50
Figure 17: Country trends in participation in clinical trials, 2008 51
Figure 18: Advantages and disadvantages of conducting clinical trials in emerging market countries 52
Figure 19: Recommendations to improve the design of open-label extension studies 56
Figure 20: Why Phase III drugs fail - therapy area analysis 59
Figure 21: Safety issues account for one-third of all problems experienced during the FDA approval process, 2002-04 66
Figure 22: Hurdles to successful clinical development and subsequent regulatory approval 68
Figure 23: The EMEA is finalizing ever more procedures in an increasingly shorter time, 2005-07 70
Figure 24: Drug development following Phase III failures across the seven major markets, 1998-2008 77
Figure 25: Clinical trials required for FDA and EMEA approval 88
Figure 26: Questions raised over the FDA's heightened safety focus 91
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