Implementing Adaptive Clinical Trials Webinar – Wednesday, November 16th, 9 AM PST
Clinovo 1208 E. Arques Avenue, Suite 114 Sunnyvale, CA 94085 contact@clinovo.com +1 800 987 6007 www.clinovo.com
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
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Today’s Speakers Joe Laver Senior Director of Biometrics Clinovo
Pascal Royet VP of Business Operations Clinovo
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Today’s Agenda Introduction When should we use adaptive clinical trials? Key benefits Planning ahead for an adaptive clinical trial
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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 6 © 2011 Clinovo. All Rights Reserved. The contents of this document are confidential and proprietary to Clinovo
Some Facts Mentioned in Oxford University Press’ Biometrika Work on sequential clinical trials
December 1933 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 FDA
February 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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Why Adaptive Clinical Trials
Clinical trials have become increasingly complex‌. Change in Clinical Trials: Resources, Length and Participation,2000-03 to 2004-07
80% 60% 40% 20%
49%
54%
58%
38%
0% -21%
-20%
-30%
-40% Unique Procedures
Total Procedures
Execution Burden
Total Eligibility Criteria
Volunteer Enrollment Volunteer Retention Rates Rates
Source: 2011 profile, PhRMA Pharmaceutical Industry Pharmaceutical study, Jan 22,2011. New York Times
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Why Adaptive Clinical Trials
… Expensive … PhRMA Member Companies’ R&D Expenditures (Billions of Dollars) $60
$47.9
$50 $40 $30 $20
$19.0
$22.7
$26.0
$29.8
$31.0
$34.5
$37.0
$39.9
$43.4
$47.4
$46.4
$49.4
$10 $0 1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
… and Risky High failure rates: 50-75% in late stage Total R&D as a percentage total sales: 17%
Source: 2011 profile, PhRMA Pharmaceutical Industry Pharmaceutical study, Jan 22,2011. New York Times
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Agile Clinical Development Enhance study performance Improve speed Minimize risks Characteristics of Adaptive Design Streamlined
Optimized
Flexible
Data-Driven
Validity Simulation
Adaptive Design
Systematic Dynamic
DecisionOriented
Sequential learning
Robust
Cost-efficient
Integrity
Bayesian
Real-Time
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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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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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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 Example Cumulative Subjects and Responses 350
# Subjects / Responses
300 250 200
Monthly recruitment
150
Total Recruitment 2 Month Response
100 50 0 1
2
3
4
5
6 7 8 9 Months into trial
10
11
12
13
14
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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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When should we use adaptive design? What indications donâ&#x20AC;&#x2122;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 â&#x20AC;&#x201C; combinations, indications, subpopulations
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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Contact us Pascal Royet
Joe Laver
VP of Business Operations
Senior Director of Biometrics
pascal.royet@clinovo.com
joe.laver@clinovo.com
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