Contribution of Modeling and Simulation Studies in the Regulatory Review: A European Regulatory Perspective

  • Siv Jönsson
  • Anja Henningsson
  • Monica Edholm
  • Tomas Salmonson
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 1)


Modeling and simulation of pharmacokinetic and pharmacodynamic/response data has been increasingly advocated during drug development, to allow more efficient utilization of collected clinical data and to support informed decision making, e.g., regarding future study designs and dosing strategies in subpopulations. This chapter reflects the view of the Swedish Medical Products Agency, one of the European regulatory bodies, on how M&S studies contribute in the regulatory review. The availability of European guidelines related to modeling and simulation is discussed and some insight is provided into the types of recommendations given, together with a few examples.


Systemic Exposure Dose Recommendation European Medicine Agency Population Pharmacokinetic Analysis European Union Legislation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Monique Wakelkamp is gratefully acknowledged for providing linguistic review.


  1. Aarons L, Karlsson MO, Mentre F, Rombout F, Steimer JL, van Peer A (2001) Role of modelling and simulation in phase I drug development. Eur J Pharm Sci 13:115–122PubMedCrossRefGoogle Scholar
  2. Balant LP, Gex-Fabry M (2000) Modelling during drug development. Eur J Pharm Biopharm 50:13–26PubMedCrossRefGoogle Scholar
  3. Barrett JS, Fossler MJ, Cadieu KD, Gastonguay MR (2008) Pharmacometrics: a multidisciplinary field to facilitate critical thinking in drug development and translational research settings. J Clin Pharmacol 48:632–649PubMedCrossRefGoogle Scholar
  4. Bhattaram VA, Booth BP, Ramchandani RP, Beasley BN, Wang Y, Tandon V, Duan JZ, Baweja RK, Marroum PJ, Uppoor RS, Rahman NA, Sahajwalla CG, Powell JR, Mehta MU, Gobburu JV (2005) Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J 7:E503–E512PubMedCrossRefGoogle Scholar
  5. Bhattaram VA, Bonapace C, Chilukuri DM, Duan JZ, Garnett C, Gobburu JV, Jang SH, Kenna L, Lesko LJ, Madabushi R, Men Y, Powell JR, Qiu W, Ramchandani RP, Tornoe CW, Wang Y, Zheng JJ (2007) Impact of pharmacometric reviews on new drug approval and labeling decisions–a survey of 31 new drug applications submitted between 2005 and 2006. Clin Pharmacol Ther 81:213–221PubMedCrossRefGoogle Scholar
  6. Blesch KS, Gieschke R, Tsukamoto Y, Reigner BG, Burger HU, Steimer JL (2003) Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience. Invest New Drugs 21:195–223PubMedCrossRefGoogle Scholar
  7. Bonate PL (2000) Clinical trial simulation in drug development. Pharm Res 17:252–256PubMedCrossRefGoogle Scholar
  8. Breimer DD, Danhof M (1997) Relevance of the application of pharmacokinetic-pharmacodynamic modelling concepts in drug development. The ‘wooden shoe’ paradigm. Clin Pharmacokinet 32:259–267PubMedCrossRefGoogle Scholar
  9. Chaikin P, Rhodes GR, Bruno R, Rohatagi S, Natarajan C (2000) Pharmacokinetics/pharmacodynamics in drug development: an industrial perspective. J Clin Pharmacol 40:1428–1438PubMedGoogle Scholar
  10. Chien JY, Friedrich S, Heathman MA, de Alwis DP, Sinha V (2005) Pharmacokinetics/pharmacodynamics and the stages of drug development: role of modeling and simulation. AAPS J 7:E544–E559PubMedCrossRefGoogle Scholar
  11. Committee for Medicinal Products for Human Use (CHMP) (2007) Guideline on reporting the results of population pharmacokinetic analyses. CHMP/EWP/185990/06. Available for Accessed 10 October 2010
  12. Derendorf H, Meibohm B (1999) Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. Pharm Res 16:176–185PubMedCrossRefGoogle Scholar
  13. Edholm M, Gil Berglund E, Salmonson T (2008) Regulatory aspects of pharmacokinetic profiling in special populations: a European perspective. Clin Pharmacokinet 47:693–701PubMedCrossRefGoogle Scholar
  14. EU Legislation – Eudralex, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (Consolided version: 30/12/2008). Accessed 10 October 2010
  15. EU Legislation – Eudralex, Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use. Accessed 10 October 2010
  16. EU Legislation – Eudralex, The rules governing medicinal products in the European Union Volume 2A: Notice to applicants and regulatory guidelines for medicinal products for human use. Accessed 10 October 2010
  17. European Commission. Accessed 10 October 2010
  18. European Medicines Agency (2007) European public assessment report for Celsentri, procedure no. EMEA/H/C/811. 10 October 2010
  19. European Medicines Agency (2008) European public assessment report for Bridion, procedure no.EMEA/H/C/000885. Accessed 10 October 2010
  20. European Medicines Agency (2009) European public assessment report for Keppra, procedure no. EMEA/H/C/000277/II/0097. Accessed 10 October 2010
  21. European Medicines Agency. Accessed 2 May 2010
  22. European Medicines Agency. Scientific guidelines for human medicinal products. Clinical efficacy and safety guidelines. Accessed 10 October 2010
  23. European Medicines Agency. Scientific guidelines for human medicinal products. Multidisciplinary guidelines. Accessed 10 October 2010
  24. Food and Drug Administration (2004) Innovation or stagnation: challenge and opportunity on the critical path to new medical products. Accessed 2 May 2010
  25. Food and Drug Administration (2006) Innovation or stagnation: Critical path opportunities report. Accessed 2 May 2010
  26. Gieschke R, Steimer JL (2000) Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development. Eur J Drug Metab Pharmacokinet 25:49–58PubMedCrossRefGoogle Scholar
  27. Gobburu JV, Marroum PJ (2001) Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making. Clin Pharmacokinet 40:883–892PubMedCrossRefGoogle Scholar
  28. Gobburu JV, Sekar VJ (2002) Application of modeling and simulation to integrate clinical pharmacology knowledge across a new drug application. Int J Clin Pharmacol Ther 40:281–288PubMedGoogle Scholar
  29. Grasela TH, Dement CW, Kolterman OG, Fineman MS, Grasela DM, Honig P, Antal EJ, Bjornsson TD, Loh E (2007) Pharmacometrics and the transition to model-based development. Clin Pharmacol Ther 82:137–142PubMedCrossRefGoogle Scholar
  30. Holford N, Karlsson MO (2007) Time for quantitative clinical pharmacology: a proposal for a pharmacometrics curriculum. Clin Pharmacol Ther 82:103–105PubMedCrossRefGoogle Scholar
  31. Holford NH, Kimko HC, Monteleone JP, Peck CC (2000) Simulation of clinical trials. Annu Rev Pharmacol Toxicol 40:209–234PubMedCrossRefGoogle Scholar
  32. Jacqmin P, McFadyen L, Wade JR (2008) A receptor theory-based semimechanistic PD model for the CCR5 noncompetitive antagonist maraviroc. Br J Clin Pharmacol 65(suppl 1):95–106PubMedCrossRefGoogle Scholar
  33. Jadhav PR, Zhang J, Gobburu JV (2009) Leveraging prior quantitative knowledge in guiding pediatric drug development: a case study. Pharm Stat 8:216–224PubMedCrossRefGoogle Scholar
  34. Lalonde RL, Kowalski KG, Hutmacher MM, Ewy W, Nichols DJ, Milligan PA, Corrigan BW, Lockwood PA, Marshall SA, Benincosa LJ, Tensfeldt TG, Parivar K, Amantea M, Glue P, Koide H, Miller R (2007) Model-based drug development. Clin Pharmacol Ther 82:21–32PubMedCrossRefGoogle Scholar
  35. Lesko LJ (2007) Paving the critical path: how can clinical pharmacology help achieve the vision? Clin Pharmacol Ther 81:170–177PubMedCrossRefGoogle Scholar
  36. Lockwood P, Ewy W, Hermann D, Holford N (2006) Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer’s disease. Pharm Res 23:2050–2059PubMedCrossRefGoogle Scholar
  37. Manolis E, Pons G (2009) Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Brit J Clin Pharmacol 68:493–501CrossRefGoogle Scholar
  38. Meibohm B, Derendorf H (2002) Pharmacokinetic/pharmacodynamic studies in drug product development. J Pharm Sci 91:18–31PubMedCrossRefGoogle Scholar
  39. Miller R, Ewy W, Corrigan BW, Ouellet D, Hermann D, Kowalski KG, Lockwood P, Koup JR, Donevan S, El-Kattan A, Li CS, Werth JL, Feltner DE, Lalonde RL (2005) How modeling and simulation have enhanced decision making in new drug development. J Pharmacokinet Pharmacodyn 32:185–197PubMedCrossRefGoogle Scholar
  40. Minto C, Schnider T (1998) Expanding clinical applications of population pharmacodynamic modelling. Br J Clin Pharmacol 46:321–333PubMedCrossRefGoogle Scholar
  41. Olson SC, Bockbrader H, Boyd RA, Cook J, Koup JR, Lalonde RL, Siedlik PH, Powell JR (2000) Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis. Clin Pharmacokinet 38:449–459PubMedCrossRefGoogle Scholar
  42. Powell JR, Gobburu JV (2007) Pharmacometrics at FDA: evolution and impact on decisions. Clin Pharmacol Ther 82:97–102PubMedCrossRefGoogle Scholar
  43. Reigner BG, Williams PE, Patel IH, Steimer JL, Peck C, van Brummelen P (1997) An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche. Clin Pharmacokinet 33:142–152PubMedCrossRefGoogle Scholar
  44. Rosario MC, Jacqmin P, Dorr P, van der Ryst E, Hitchcock C (2005) A pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc. Clin Pharmacol Ther 78:508–519PubMedCrossRefGoogle Scholar
  45. Rosario MC, Poland B, Sullivan J, Westby M, van der Ryst E (2006) A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc. J Acquir Immune Defic Syndr 42:183–191PubMedCrossRefGoogle Scholar
  46. Rosario MC, Jacqmin P, Dorr P, James I, Jenkins TM, Abel S, van der Ryst E (2008) Population pharmacokinetic/pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV-positive patients. Br J Clin Pharmacol 65(suppl 1):86–94PubMedCrossRefGoogle Scholar
  47. Rowland M, Tucker G, Peck C (2011) Physiologically based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 51 (expected, Epub ahead of print 18 January 2010)Google Scholar
  48. Sheiner LB (1997) Learning versus confirming in clinical drug development. Clin Pharmacol Ther 61:275–291PubMedCrossRefGoogle Scholar
  49. Sheiner LB, Steimer JL (2000) Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 40:67–95PubMedCrossRefGoogle Scholar
  50. Stanski DR, Rowland M, Sheiner LB (2005) Getting the dose right: Report from the Tenth European Federation of Pharmaceutical Sciences (EUFEPS) conference on optimizing drug development. J Pharmacokinet Pharmacodyn 32:199–211PubMedCrossRefGoogle Scholar
  51. Veyrat-Follet C, Bruno R, Olivares R, Rhodes GR, Chaikin P (2000) Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization. Clin Pharmacol Ther 68:677–687PubMedCrossRefGoogle Scholar
  52. Wang Y, Bhattaram AV, Jadhav PR, Lesko LJ, Madabushi R, Powell JR, Qiu W, Sun H, Yim DS, Zheng JJ, Gobburu JV (2008) Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006. J Clin Pharmacol 48:146–156PubMedCrossRefGoogle Scholar
  53. Zhang L, Sinha V, Forgue ST, Callies S, Ni L, Peck R, Allerheiligen SR (2006) Model-based drug development: the road to quantitative pharmacology. J Pharmacokinet Pharmacodyn 33:369–393PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Siv Jönsson
    • 1
  • Anja Henningsson
  • Monica Edholm
  • Tomas Salmonson
  1. 1.Medical Products AgencyUppsalaSweden

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