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Reduce & Repeat
Non-Clinical Statistics Conference 2014, BruggeOctober 2014
More Precise XC50s Using Fewer Wells (in vitro) and Fewer Animals (in vivo)
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Innovative Medicines | Discovery Sciences
Raw Conc-Response Data
2 Jonathan Bright | September 2014
Innovative Medicines | Discovery Sciences
Only Half of the Concs
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Innovative Medicines | Discovery Sciences
Only Half of the Replicates
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Innovative Medicines | Discovery Sciences
Only Half of the Concs and Half of the Replicates
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Innovative Medicines | Discovery Sciences
Only Half of the Concs and Half of the Replicates and Half of the Controls
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Innovative Medicines | Discovery Sciences
IC50 and 95% Confidence Interval
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Innovative Medicines | Discovery Sciences
Findings #1
• For a “well-behaved” assay, the resource (wells) may be dramatically reduced with little impact on either the estimate of the XC50 or its confidence interval
• “Well-behaved”- Max and min controls that safely position the curve top and
bottom- Conc-response data that have the right sort of sigmoid
shape- Acceptable to overlook details such as biphasic and partial
inhibition• May be exploited
- Throughput- Cost- Compound use
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Innovative Medicines | Discovery Sciences
Second Set of Raw Conc-Response Data
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Innovative Medicines | Discovery Sciences
IC50 and 95% Confidence Interval
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Innovative Medicines | Discovery Sciences
IC50 and 95% Confidence Interval
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Innovative Medicines | Discovery Sciences
Findings #2
• Run-to-run differences in XC50 are massive compared to the small changes in XC50 that occur as a result of reducing the resource (wells) on any given run
• Put in terms of components of variation- Between run variation dominates within-run variation- Within-run variation changes hardly at all as the number of
concs and number of replicates changes• May be exploited
- Reduce the resource per run- Repeat- Average
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
IC50 vs Run
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Innovative Medicines | Discovery Sciences
In Vivo
• A situation similar to the in vitro case has been observed, whereby study-to-study differences are the main component of variation
- Was it a “good day” or a “bad day” for compound X• 2 Start Strategy (Brian Middleton)
- Start half the planned animals (reduce)- Independently run the second half (repeat)- Average
• Gives a superior estimate of the e.g. XC50 or XD50• Provides in some cases a chance to change doses for the
second start
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Innovative Medicines | Discovery Sciences
Summary
• In both in vitro and in vivo settings there are large run-to-run or study-to-study differences when a compound is retested
- Root cause analysis• Exploit by
- reducing the resource (wells or animals) on a given occasion- repeating the experiment- averaging across the experiments
• Reduce- Throughput, cost and compound benefits
• Reduce and Repeat- Precision benefit +
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Innovative Medicines | Discovery Sciences
Acknowledgement and Reference
• Siller H, Taylor JD, Middleton B. Two-start design within a Sephadex inflammatory model – A means to generate reliable ED50 data whilst significantly reducing the number of animals used. Pulm Pharmacol Ther 2012; 25:223-227.
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Innovative Medicines | Discovery Sciences
Extra Slide
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Innovative Medicines | Discovery Sciences23 Jonathan Bright | September 2014
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