implementing adaptive clinical trials
DESCRIPTION
Presentation of the webinar on adaptive clinical trials conducted on November 16th 2011, by Clinovo.TRANSCRIPT
Clinovo
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Sunnyvale, CA 94085
+1 800 987 6007
www.clinovo.com
Implementing Adaptive Clinical Trials
Webinar – Wednesday, November 16th, 9 AM PST
2© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
Clinovo’s free webinar series
Every month, Clinovo hosts several webinars covering various topics:
� Medidata Rave® Advanced Use
� Open Source For Clinical Trials
� CDISC® Data Conversion
� Adaptive Clinical Trials
3© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
4© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
Joe Laver
Senior Director of Biometrics
Clinovo
Pascal Royet
VP of Business Operations
Clinovo
Today’s Speakers
5© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
� Introduction
� When should we use adaptive clinical trials?
� Key benefits
� Planning ahead for an adaptive clinical trial
Today’s Agenda
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The contents of this document are confidential and proprietary to Clinovo
Definition
� Adaptive clinical trials allow pre-planned modifications to
the study when opportunities arise
• Adaptive randomization design
• Group sequential design
• Sample size re-estimation design
• Drop-the-loser design
• Adaptive dose-finding design
• Biomarker-adaptive design
• Adaptive treatment-switching design
• Hypothesis-adaptive design
• Adaptive seamless phase II/III design
• Multiple-adaptive: two or more of the above design
Some types of adaptive
designs
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The contents of this document are confidential and proprietary to Clinovo
Some Facts
Mentioned in Oxford University Press’ Biometrika December 1933
Work on sequential clinical trials 1940’s - 1950’s
Declared an “urgent need” in the FDA’s Critical Path Initiative 2004
Among the FDA’s Critical Path Opportunities Report 2006
US PhRMa working group on adaptive trials reports 2006
Guidance for Industry on Adaptive Design Clinical Trials for Drugs and
Biologics issued by the FDAFebruary 2010
“A study that includes a prospectively planned opportunity
for modification of one or more specified aspects of the
study design and hypotheses based on analysis of data
(usually interim data) from subjects in the study.”
Definition of adaptive design from the FDA Guidance
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The contents of this document are confidential and proprietary to Clinovo
Why Adaptive Clinical Trials
� Clinical trials have become increasingly complex….
38%
49%54% 58%
-21%-30%
-40%
-20%
0%
20%
40%
60%
80%
Unique Procedures Total Procedures Execution Burden Total Eligibility
Criteria
Volunteer Enrollment
Rates
Volunteer Retention
Rates
Change in Clinical Trials: Resources, Length and Participation,2000-03 to 2004-07
Source: 2011 profile, PhRMA Pharmaceutical Industry
Pharmaceutical study, Jan 22,2011. New York Times
9© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
Why Adaptive Clinical Trials
� … Expensive …
$19.0$22.7
$26.0$29.8 $31.0
$34.5$37.0
$39.9 $43.4$47.9 $47.4 $46.4
$49.4
$0
$10
$20
$30
$40
$50
$60
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Source: 2011 profile, PhRMA Pharmaceutical Industry
Pharmaceutical study, Jan 22,2011. New York Times
High failure rates: 50-75% in late stage
Total R&D as a percentage total sales: 17%
PhRMA Member Companies’ R&D Expenditures (Billions of Dollars)
� … and Risky
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The contents of this document are confidential and proprietary to Clinovo
Agile Clinical Development
� Enhance study performance
� Improve speed
� Minimize risks
Characteristics of Adaptive Design
Adaptive
Design Dynamic
Sequential
learning
Simulation
Robust
Real-TimeBayesianIntegrity
Validity
Cost-efficient
Systematic
Data-Driven
Optimized
Flexible
Streamlined
Decision-
Oriented
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The contents of this document are confidential and proprietary to Clinovo
When should we use adaptive design?
� When is it most appropriate to run an adaptive clinical trial?
When you have a lot to learn about the drug and the
disease in your target population
You do not have the time or money to simply recruit
enough subjects in a simple way to answer your
questions
And there are outcomes early enough in treatment to
adapt to
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The contents of this document are confidential and proprietary to Clinovo
When should we use adaptive design?
� When in a drug's development is the most appropriate time
to conduct an adaptive clinical trial?
� Any phase where there is significant uncertainty over the drug
behavior
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The contents of this document are confidential and proprietary to Clinovo
When should we use adaptive design?
� What indications particularly lend themselves to the use of
adaptive clinical trials?
� Quick response (<25% of recruitment period)
� Range of doses available
� Subjects are expensive
0
50
100
150
200
250
300
350
1 2 3 4 5 6 7 8 9 10 11 12 13 14
# S
ubje
cts
/ Res
pons
es
Months into trial
Example Cumulative Subjects and Responses
Monthly recruitment
Total Recruitment
2 Month Response
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The contents of this document are confidential and proprietary to Clinovo
When should we use adaptive design?
What indications particularly lend themselves to the use of
adaptive clinical trials?
Stroke, Alzheimer's, Schizophrenia
Diabetes, cholesterol lowering
Cancer
Orphan indications
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The contents of this document are confidential and proprietary to Clinovo
When should we use adaptive design?
� What indications don’t lend themselves to the use of
adaptive clinical trials?
� Very long time to final response
� Very swift recruitment
� Population change over duration of trial
� Subjects are cheap
� Want to learn equally about all treatment arms
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Key Benefits of Adaptive Design
� Savings in every phase of development
� Shorter timelines
� Higher probability of success
� Improved flexibility
� Responsiveness
� The right drug to the right patient
Sources: Health Decision Webinar “Top 10 Benefits of Adaptive Design”, Jan 25, 2011
Mark Chang, “Enhancing the quality of clinical trials”, Pharma Focus Asia
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The right drug to the right patient
� Better characterization of the drug efficacy and toxicity
� More data on the dose of interest
� Better characterization of the dose behavior
� Faster/smarter overall development through better targeted
trials
� Optimization of dose allocation
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Other Benefits
� Better Ethics
� Fewer subjects allocated to ineffective or over-toxic treatment arms
� Fewer subjects used in studies that fail
� Better Science
� Can try more doses
� Explore other dimensions – combinations, indications, sub-
populations
� Better Business
� Swifter curtailment of failing compound
� Better information -> better decisions at the next phase
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Impact on the development program
� Consider trial in whole development program
� Need to think about the next trial earlier and longer
� Need to integrate the development team
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Advanced Technology
� Need more powerful forecasting systems
� To simulate trial scenarios & patient enrolment
� To project time-phased patient demand for clinical supplies
� Need for advanced technology to manage the clinical trial
� Central randomization
� Dynamic treatment allocation
� Automated dose titration
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Challenges
� Longer Design Time
� Need to identify candidate trial
� Design less “off-the-shelf”
� Design needs interaction with clinical team
� Design needs simulation and optimization
� More Integrated Trial Management System
� Quick capture of key responses
� Frequent modification of randomization
� Drug Supply
� Need to be able to deliver more doses
� Need to be able to use central randomization
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The contents of this document are confidential and proprietary to Clinovo
23© 2011 Clinovo. All Rights Reserved.
The contents of this document are confidential and proprietary to Clinovo
Contact us
Pascal Royet
VP of Business Operations
Joe Laver
Senior Director of Biometrics
Upcoming webinars
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