1. Strategies for Comparative Efficacy Trials
Report Details:
Published:August 2012
No. of Pages: 81
Price: Single User License – US$3800
Clinicians and patients want to be able to compare new drugs with those already available to
inform evidence-based medicine, and reimbursement authorities require comparative data to
support their decisions. This report discusses the role of comparative efficacy trials and the
challenges in their design, with particular attention to the question of comparator selection.
Features and benefits
•Understand the role that comparative efficacy plays in the evaluation of new drugs.
•Review the various types of trial design that can provide comparative data and assess the
purpose for which each is most suited.
•Identify decision-making processes for guiding key choices in the design of pivotal comparative
efficacy trials.
•Understand the importance of comparator selection and the consequences of later
disagreements with external authorities.
•Review the factors that need to be considered in making a comparator selection.
Highlights
The choice of active control group for a comparative trial can be difficult due to variation in the
standard of care across different geographic regions and changing medical practices.
Numerous recent appraisals by the UK’s National Institute for Health and Clinical Excellence
(NICE) and Germany’s Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG)
have demonstrated the critical stance that is being readily taken by these bodies with regard to
comparator selection.
Scientific advice from regulators and, where possible, from health technology assessors or
reimbursement authorities can be extremely useful in guiding clinical development planning,
especially in the choice of comparator.
Your key questions answered
•What is driving the use of comparative efficacy trials and what role do they play in approval and
reimbursement decisions?

2. •How should an active comparator and other features of comparative efficacy trials be chosen?
•Can the range of comparators be expected to extend beyond pharmaceutical interventions?
•Which regulatory and reimbursement authorities are willing to offer scientific advice in the design
of a comparative efficacy trial?
•To what extent have drug evaluation committees shown flexibility in disagreements about the
optimum comparator?
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Major points covered in Table of Contents of this report include
Table Of Contents
EXECUTIVE SUMMARY
Key findings
The impetus to conduct comparative efficacy trials
Summary
Availability of comparative data during regulatory review
Addressing uncertainty
FDA
EMA
Differences in approach in the US and EU
Research ethics
Efficacy or effectiveness: when should comparative trials be conducted?
Case study: antihypertensives
Clinical trial designs
Summary
Introduction
Superiority trials
Non-inferiority trials
FDA versus EMA guidance
Comparative efficacy and biocreep
Three-arm trials
Adaptive trials
Subgroup analysis
Case study: subgroup analysis within a non-inferiority trial
Placebo effects
Biosimilars
Pragmatic clinical trials
Observational studies

3. Network meta-analyses
Simultaneous consideration of benefits and harms
Conclusions
Trial optimization
Summary
Introduction
Recent examples of challenges in comparator selection
AstraZeneca’s Faslodex rejected by NICE on the basis of indirect comparison
IQWiG and NICE judge GlaxoSmithKline’s Benlysta to have been inadequately compared
Biogen Idec’s Fampyra highlights challenges of comparison with non-pharmacological treatment
IQWiG disagrees with GlaxoSmithKline regarding comparators for Trobalt
Eisai’s Halaven considered inadequately compared despite following EMA protocol
Comparison with experimental treatments not demanded by the FDA but view of reimbursers is
uncertain
A late-arriving statin has adequate comparator data for regulatory approval but proving
differentiation is another matter
Selection of active control group for the comparative trial
Use of existing knowledge
Decision-making techniques
Reflecting on the range of interventions
Patient populations, outcomes, and other study variables
Scientific advice
Conclusions
Outlook
Summary
Introduction
Comparative efficacy: a regulatory requirement?
Regulators and reimbursement authorities: working together
Progressive approvals
Conclusion
Appendix
Methodology
Acknowledgements
Glossary
Abbreviations
References
Disclaimer
List Of Tables

4. Table: New medicines with premarketing randomized active-controlled trials (1995–2005)
Table: New medicines without premarketing randomized active-controlled trials (1995–2005)
Table: Trials described in approval packages in the US and EU (2005–07)
Table: Comparator information available for drugs approved in the EU (2009–10)
Table: New medicines (1999–2005) with an improved efficacy
Table: Therapeutic areas in which response to placebo varies widely between trials
Table: Advantages and disadvantages of using adaptive clinical trial designs
Table: Sample sizes for a three-arm randomized controlled trial or an adaptive Phase III/IV trial
Table: Possible trial designs providing comparative efficacy data
Table: Possible trial designs providing comparative effectiveness data
Table: Statins available in the US
Table: Scenarios for requirements for comparative efficacy in regulatory approval
Table: The future role of The Joint Initiative for Medicines: coordinating the EMA, HTA, and
competent bodies
List Of Figures
Figure: New molecular entities with comparative efficacy data available in FDA approval packages
(2000–10)
Figure: Recommendations from the Presidential Commission for the Study of Bioethical Issues
Figure: Defining efficacy and effectiveness
Figure: Designs of studies for efficacy and effectiveness
Figure: Adaptive Phase III/IV trial design
Figure: Factors determining choice of active control in a clinical trial
Figure: Effects of increased calls for comparative efficacy trials on drug development
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