Adaptive Designs

Outstanding scientific credibility How better convert investment in new science
to therapeutic reality - FDA
Modernization Act of 1997 (conditions when one pivotal study is enough) Janet Woodcock’s report in 2004 Investment & progress in basic biomedical science has far surpassed investment and progress in the medical product development process. The development process - the critical path to patients - is becoming a serious bottleneck to delivery of new products (use of evaluation tools and infrastructure of the last century to develop this century’s advances) Critical Path Initiative (initiated in 2004, ongoing) Critical path opportunities list - Advanced innovative trial designs (use of prior experience or accumulated information in trial design), optimisation via innovative technology Guidelines: Adaptive Trial Designs (draft planned 2008 - postponed until September 2009)
Outstanding scientific credibility Why this talk?
Group sequential tests (e.g. 3 SE stopping or Peto rule) ISCB – September 06 Consulting opportunities – Cardinal Systems Big buzz in the pharmaceutical industry (Novartis) Growing trend in RCT methodological research
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One 4-arm trial: Bonferroni & Dunnett
Outstanding scientific credibility
• Primary endpoint is binary, measured at week 4 • Expect 30% response on the placebo arm • Require 25% improvement for drug to be marketable • Require 80% power with a 2-sided level of 5% (one-sided α=2.5) • Bonferroni (conservative) : use α=0.05/3=0.0166
Adaptive treatment switching design Multiple adaptive design = a combination of 2+ of the aforementioned (flexible but very messy) (Chow & Chang, 2008)
Sydney, AUSTRALIA | Beijing, CHINA | Hyderabad, INDIA | London, UK
Adaptive designs
Dr Stephane Heritier, Associate Professor of Biostatistics The George Institute for International Health Affiliated with the University of Sydney
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Outstanding scientific credibility Outline
What is an adaptive design (AD)? Regulatory background A seamless design vs standard practise for phase II/III dev. Underlying Principles SYMPHONY – consultancy work with Cardinal Systems Comments from the FDA/EMEA Conclusions
In particular, interim study data and other (external) information are used to decide on whether and how to modify aspects of the study, without undermining the validity and integrity of the trial.
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Problems with options 1) and 2)
Outstanding scientific credibility
Option 1) : - We do not select the dose (cost/time) Option 2) : - Data from Phase II cannot be combined with the data from Phase III - Often excessive delay between terminating Phase II & starting Phase III Running two separate trials is inefficient and costly if one integrated trial can achieve the same goals
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Outstanding scientific credibility Different “adaptations”
Sample size re-assessment Seamless phase II/III design (dose selection) Adaptive dose finding design Biomarker adaptive design Adaptive hypothesis design switching endpoints switching from superiority to non-inferiority or vice versa changing the type of study
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The dose selection case – standard vs adaptive
Outstanding scientific credibility
Setting Orphan Drug indication for a HIV associated neurological disease Only a limited pool of potential patients ( One well controlled pivotal trial will suffice) Prior to Phase II study 3 possible doses were identified, 125 mg, 250 mg and 500 mg No evidence of a dose relationship
EMEA are a bit more demanding than the FDA in practise!
Why so much interest in the pharma industry?
Outsta来自百度文库ding scientific credibility
Getting GOOD drug to the market QUICKLY Reduce drug-development time significantly Decrease overall number of patients in trial and number of patients assigned to control group (if inferior) Verify/modify initial design assumptions Remain flexible in terms of timing and number of interim analyses Allow for flexible reactions to unexpected events Adaptations are something that clinicians are naturally asking for
(critical value Cα=2.394)
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Outstanding scientific credibility What is an adaptive design
Definition (EMEA.CPMP) A study design is called adaptive if statistical methodology allows the modification of a design element (e.g. sample-size, randomisation ratio, number of treatment arms) at an interim analysis with full control of the type I Error
What are the options?
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3 options were considered
Outstanding scientific credibility
1) Single 4-arm trial (3 dose groups + placebo) 2) Two separate trials: run a 4 arm phase II trial to select the best dose. Then run a second independent phase III 2-arm trial 3) Seamless Phase II/III trial: start with 4 arms; select best dose at interim; continue with 2 arms; combine data from both stages
Outstanding scientific credibility EMEA
The European Medicines Agency Road Map to 2010: Preparing the Ground for the Future Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan (draft made available in 2006, CHMP/EWP/2459/02)