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Reduce & Repeat

Reduce & Repeat. More Precise XC50s Using Fewer Wells (in vitro) and Fewer Animals (in vivo). Non-Clinical Statistics Conference 2014, Brugge October 2014. Raw Conc -Response Data. Only Half of the Concs. Only Half of the Replicates. Only Half of the Concs and Half of the Replicates.

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Reduce & Repeat

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  1. Reduce & Repeat More Precise XC50s Using Fewer Wells (in vitro) and Fewer Animals (in vivo) Non-Clinical Statistics Conference 2014, Brugge October 2014

  2. Raw Conc-Response Data Innovative Medicines | Discovery Sciences

  3. Only Half of the Concs Innovative Medicines | Discovery Sciences

  4. Only Half of the Replicates Innovative Medicines | Discovery Sciences

  5. Only Half of the Concs and Half of the Replicates Innovative Medicines | Discovery Sciences

  6. Only Half of the Concs and Half of the Replicates and Half of the Controls Innovative Medicines | Discovery Sciences

  7. IC50 and 95% Confidence Interval Innovative Medicines | Discovery Sciences

  8. 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 Innovative Medicines | Discovery Sciences

  9. Second Set of Raw Conc-Response Data Innovative Medicines | Discovery Sciences

  10. IC50 and 95% Confidence Interval Innovative Medicines | Discovery Sciences

  11. IC50 and 95% Confidence Interval Innovative Medicines | Discovery Sciences

  12. 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 Innovative Medicines | Discovery Sciences

  13. IC50 vs Run Innovative Medicines | Discovery Sciences

  14. IC50 vs Run Innovative Medicines | Discovery Sciences

  15. IC50 vs Run Innovative Medicines | Discovery Sciences

  16. IC50 vs Run Innovative Medicines | Discovery Sciences

  17. IC50 vs Run Innovative Medicines | Discovery Sciences

  18. IC50 vs Run Innovative Medicines | Discovery Sciences

  19. 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 Innovative Medicines | Discovery Sciences

  20. 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 + Innovative Medicines | Discovery Sciences

  21. 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. PulmPharmacolTher 2012; 25:223-227. Innovative Medicines | Discovery Sciences

  22. Extra Slide Innovative Medicines | Discovery Sciences

  23. Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com Innovative Medicines | Discovery Sciences

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