Skip to main content
SpringerLink
Log in

Today’s Challenges in Pharmacovigilance

What can we Learn from Epoetins?

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Highly publicized safety issues of medicinal products in recent years and the accompanying political pressure have forced both the US FDA and the European Medicines Agency (EMA) to implement stronger regulations concerning pharmacovigilance. These legislative changes demand more proactive risk management strategies of both pharmaceutical companies and regulators to characterize and minimize known and potential safety concerns. Concurrently, comprehensive surveillance systems are implemented, intended to identify and confirm adverse drug reactions, including the creation of large pharmacovigilance databases and the cooperation with epidemiological centres. Although the ambitions are high, not much is known about how effective all these measures are, or will be. In this review we analyse how the pharmacovigilance community has acted upon two adverse events associated with the use of erythropoiesis-stimulating agents: the sudden increase in pure red cell aplasia and the possible risk of tumour progression associated with these products. These incidents provide important insight for improving pharmacovigilance, but also pose new challenges for regulatory decision making.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Table I

Similar content being viewed by others

References

  1. Singh D. Merck withdraws arthritis drug worldwide. BMJ 2004 Oct 9; 329(7470): 816

    Article  PubMed  Google Scholar 

  2. Charatan F. Bayer decides to withdraw cholesterol lowering drug. BMJ 2001 Aug 18; 323(7309): 359a

    Article  Google Scholar 

  3. Waller PC, Evans SJ. A model for the future conduct of pharmacovigilance. Pharmacoepidemiol Drug Saf 2003 Jan–Feb; 12(1): 17–29

    Article  PubMed  Google Scholar 

  4. Cohen D. Rosiglitazone: what went wrong? BMJ 2010; 341: c4848

    Article  PubMed  Google Scholar 

  5. Edwards IR. What are the real lessons from Vioxx? Drug Saf 2005; 28(8): 651–8

    Article  PubMed  CAS  Google Scholar 

  6. Lenzer J. FDA is incapable of protecting US ‘against another Vioxx’. BMJ 2004 Nov 27; 329(7477): 1253

    Article  PubMed  Google Scholar 

  7. Fraunhofer Institute for Systems and Innovation Research (ISI). Assessment of the European community system of pharmacovigilance. Karlsruhe: Fraunhofer Institute, 2006

    Google Scholar 

  8. Furberg CD, Levin AA, Gross PA, et al. The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med 2006 Oct 9; 166(18): 1938–42

    Article  PubMed  Google Scholar 

  9. Eichler HG, Abadie E, Raine JM, et al. Safe drugs and the cost of good intentions. N Engl J Med 2009 Apr 2; 360(14): 1378–80

    Article  PubMed  CAS  Google Scholar 

  10. European Commission. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use [online]. Available from URL: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2004_27/dir_2004_27_en.pdf [Accessed 2010 Dec 15]

  11. European Commission. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency [online]. Available from URL: http://ec.europa.eu/health/files/eudralex/vol-1/reg_2004_726_cons/reg_2004_726_cons_en.pdf [Accessed 2010 Dec 15]

  12. Food and Drug Administration. Guidance for industry: format and content of proposed risk evaluation and mitigation strategies (REMS), REMS assessments, and proposed REMS modifications. Draft guidance, 2009 Sep [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf [Accessed 2010 Jun 1]

  13. Faden LB, Milne CP. Pharmacovigilance activities in the United States, European Union and Japan: harmonic convergence or convergent evolution? Food Drug Law J 2008; 63(3): 683–700

    PubMed  Google Scholar 

  14. European Commission. Directive 2010/84/EC of the European Parliament and of the Council of 15 December 2010 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use [online]. Available from URL: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:0074:0099:EN:PDF [Accessed 2011 Mar 14]

  15. Food and Drug Administration. The Sentinel Initiative: a national strategy for monitoring medical product safety. Silver Spring (MD): Food and Drug Administration, 2008

    Google Scholar 

  16. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). What is ENCePP? [online]. Available from URL: http://www.encepp.eu/structure/index.html [Accessed 2009 Sep 24]

  17. Fontanarosa PB, Rennie D, DeAngelis CD. Postmarketing surveillance: lack of vigilance, lack of trust. JAMA 2004 Dec 1; 292(21): 2647–50

    Article  PubMed  CAS  Google Scholar 

  18. Avorn J, Schneeweiss S. Managing drug-risk information: what to do with all those new numbers. N Engl J Med 2009 Aug 13; 361(7): 647–9

    Article  PubMed  CAS  Google Scholar 

  19. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009 Nov 19; 361(21): 2019–32

    Article  PubMed  Google Scholar 

  20. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase III multicenter clinical trial. Ann Intern Med 1989 Dec 15; 111(12): 992–1000

    PubMed  CAS  Google Scholar 

  21. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008 Feb 27; 299(8): 914–24

    Article  PubMed  CAS  Google Scholar 

  22. Gascón P. Evaluating erythropoietic agents for the treatment of anaemia in the oncology setting. Eur J Cancer 2005; 41(17): 2601–12

    Article  PubMed  Google Scholar 

  23. Aranesp® (darbepoetin alfa): prescribing information. Thousand Oaks (CA): Amgen, 2002

  24. Sunder-Plassmann G, Hörl WH. Effect of erythropoietin on cardiovascular diseases. Am J Kidney Dis 2001; 38 (4 Suppl. 1): S20–5

    Article  PubMed  CAS  Google Scholar 

  25. Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009; 60: 181–92

    Article  PubMed  CAS  Google Scholar 

  26. McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetinassociated pure red cell aplasia: past, present, and future considerations. Transfusion 2008 Aug; 48(8): 1754–62

    Article  PubMed  Google Scholar 

  27. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002 Feb 14; 346(7): 469–75

    Article  PubMed  CAS  Google Scholar 

  28. Casadevall N, Dupuy E, Molho-Sabatier P, et al. Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 1996 Mar 7; 334(10): 630–3

    Article  PubMed  CAS  Google Scholar 

  29. Bergrem H, Danielson BG, Eckardt KU, et al. A case of antierythropoietin antibodies following recombinant human erythropoietin treatment. In: Bauer C, Koch KM, Scigalla P, et al., editors. Erythropoietin: molecular physiology and clinical applications. New York: Marcel Dekker, 1993

    Google Scholar 

  30. Peces R, de la Torre M, Alcazar R, et al. Antibodies against recombinant human erythropoietin in a patient with erythropoietin-resistant anemia. N Engl J Med 1996 Aug 15; 335(7): 523–4

    Article  PubMed  CAS  Google Scholar 

  31. Prabhakar SS, Muhlfelder T. Antibodies to recombinant human erythropoietin causing pure red cell aplasia. Clin Nephrol 1997 May; 47(5): 331–5

    PubMed  CAS  Google Scholar 

  32. Schellekens H, Jiskoot W. Erythropoietin-associated PRCA: still an unsolved mystery. J Immunotoxicol 2006 Sep 1; 3(3): 123–30

    Article  PubMed  CAS  Google Scholar 

  33. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005 Jun; 67(6): 2346–53

    Article  PubMed  Google Scholar 

  34. Rossert J, Muirhead N, White L, et al. An active postmarketing surveillance (PMS) plan to prospectively monitor the incidence of pure red cell aplasia (PRCA) among patients receiving epoetin alfa therapy or other erythropoietins [abstract]. Nephrol Dial Transplant 2006; 21 Suppl. 4: iv153

    Google Scholar 

  35. Anagnostou A, Lee ES, Kessimian N, et al. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 1990 Aug; 87(15): 5978–82

    Article  PubMed  CAS  Google Scholar 

  36. Grote T, Yeilding AL, Castillo R, et al. Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2005 Dec 20; 23(36): 9377–86

    Article  PubMed  CAS  Google Scholar 

  37. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003 Oct 18; 362(9392): 1255–60

    Article  PubMed  CAS  Google Scholar 

  38. Dubray B, Mosseri V, Brunin F, et al. Anemia is associated with lower local-regional control and survival after radiation therapy for head and neck cancer: a prospective study. Radiology 1996 Nov; 201(2): 553–8

    PubMed  CAS  Google Scholar 

  39. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005 Sep 1; 23(25): 5960–72

    Article  PubMed  CAS  Google Scholar 

  40. Untch M, Fasching PA, Bauerfeind I, et al. PREPARE trial. A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed epirubicin/ cyclophosphamide followed by paclitaxel +/−darbepoetin alfa in primary breast cancer: a preplanned interim analysis of efficacy at surgery. J Clin Oncol 2008 May 20; 26 (15 Suppl.): 517

    Article  Google Scholar 

  41. Oncologic Drugs Advisory Committee. FDA briefing document. 2008 Mar13. Silver Spring (MD): FDA [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4345b2-01-FDA.pdf [Accessed 2011 Feb 17]

  42. European Medicines Agency. EMEA recommends a new warning for epoetins for their use in cancer patients [press release]. 2008 Jun 26 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/press/pr/33396308en.pdf [Accessed 2010 Dec 15]

  43. Procrit label/Epogen label [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/103234s5164lbl.pdf2008 [Accessed 2009 Jun 3]

  44. Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or darbepoetin for patients with cancer: meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; (3): CD007303

  45. Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med 2007 Jun 14; 356(24): 2445–8

    Article  PubMed  CAS  Google Scholar 

  46. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002; 94: 1211–20

    Article  PubMed  CAS  Google Scholar 

  47. Caro JJ, Maribel S, Alexandra W, et al. Anemia as an independent prognostic factor for survival in patients with cancer. Cancer 2001; 91(12): 2214–21

    Article  PubMed  CAS  Google Scholar 

  48. Newland AM, Black CD. Tumor progression associated with erythropoiesis-stimulating agents. Ann Pharmacother 2008; 42(12): 1865–70

    Article  PubMed  CAS  Google Scholar 

  49. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006 May 17; 98(10): 708–14

    Article  PubMed  CAS  Google Scholar 

  50. Adamson JW. Erythropoietic-stimulating agents: the cancer progression controversy and collateral damage to the blood supply. Transfusion 2009; 49(5): 824–6

    Article  PubMed  Google Scholar 

  51. Weinberg PD, Hounshell J, Sherman LA, et al. Legal, financial, and public health consequences of HIV contamination of blood and blood products in the 1980s and 1990s. Ann Intern Med 2002 Feb 19; 136(4): 312–9

    PubMed  Google Scholar 

  52. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood 2009 Apr 9; 113(15): 3406–17

    Article  PubMed  CAS  Google Scholar 

  53. Muirhead N, Bargman J, Burgess E, et al. Evidence-based recommendations for the clinical use of recombinant human erythropoietin. Am J Kidney Dis 1995; 26 (2 Suppl. 1): S1–24

    Article  PubMed  CAS  Google Scholar 

  54. Levin A, Beaulieu MC. TREAT: implications for guideline updates and clinical care. Am J Kidney Dis 2010; 55(6): 984–7

    Article  PubMed  Google Scholar 

  55. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006 Nov 16; 355(20): 2085–98

    Article  PubMed  CAS  Google Scholar 

  56. Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002 Oct 1; 20(19): 4083–107

    Article  PubMed  CAS  Google Scholar 

  57. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 2008 Jan 1; 26(1): 132–49

    Article  PubMed  CAS  Google Scholar 

  58. Meyboom RH, Olsson S. Pharmacovigilance. In: Mulder GJ, Dencker L, editors. Pharmaceutical toxicology. London: Pharmaceutical Press, 2006: 229–41

    Google Scholar 

  59. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28(10): 851–70

    Article  PubMed  Google Scholar 

  60. Marmont A, Peschle C, Sanguineti M, et al. Pure red cell aplasia (PRCA): response of three patients of cyclophosphamide and/or antilymphocyte globulin (ALG) and demonstration of two types of serum IgG inhibitors to erythropoiesis. Blood 1975 Feb 1; 45(2): 247–61

    PubMed  CAS  Google Scholar 

  61. Casati S, Passerini P, Campise MR, et al. Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis. BMJ (Clin Res Ed) 1987 Oct 24; 295(6605): 1017–20

    Article  CAS  Google Scholar 

  62. Collins AJ, Li S, Adamson JW, et al. Assessment of pure red cell aplasia in US dialysis patients: the limits of the Medicare data. Am J Kidney Dis 2004 Mar; 43(3): 464–70

    Article  PubMed  Google Scholar 

  63. Rades D, Schild SE, Yekebas EF, et al. Epoetin-alpha during radiotherapy for stage III esophageal carcinoma. Cancer 2005 Jun 1; 103(11): 2274–9

    Article  PubMed  CAS  Google Scholar 

  64. Glaser CM, Millesi W, Kornek GV, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001 Jul 1; 50(3): 705–15

    Article  PubMed  CAS  Google Scholar 

  65. Vandenbroucke JP. Observational research, randomised trials, and two views of medical science. PLoS Medicine 2008 Mar 11; 5(3): e67

    Article  PubMed  Google Scholar 

  66. Egberts TC. Signal detection: historical background. Drug Saf 2007; 30(7): 607–9

    Article  PubMed  Google Scholar 

  67. Platt R, Wilson M, Chan KA, et al. The new Sentinel Network: improving the evidence of medical-product safety. N Engl J Med 2009 Aug 13; 361(7): 645–7

    Article  PubMed  CAS  Google Scholar 

  68. Shankar G, Pendley C, Stein KE. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotech 2007; 25(5): 555–61

    Article  CAS  Google Scholar 

  69. Clarke A, Deeks JJ, Shakir SA. An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets. Drug Saf 2006; 29(2): 175–81

    Article  PubMed  Google Scholar 

  70. European Medicines Agency. Questions and answers on the recommendation to suspend the marketing authorisation for Raptiva [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/raptiva/RaptivaQ&A_1552509en.pdf [Accessed 2010 Dec 15]

  71. Hauben M, Aronson JK. Gold standards in pharmacovigilance: the use of definitive anecdotal reports of adverse drug reactions as pure gold and high-grade ore. Drug Saf 2007; 30(8): 645–55

    Article  PubMed  Google Scholar 

  72. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58(5): 295–300

    PubMed  CAS  Google Scholar 

  73. Steinbrook R. Haemoglobin concentrations in chronic kidney disease. Lancet 2006 Dec 23; 368(9554): 2191–3

    Article  PubMed  Google Scholar 

  74. Arbuckle RB, Griffith NL, Iacovelli LM, et al. Continued challenges with the use of erythropoiesis-stimulating agents in patients with cancer: perspectives and issues on policyguided health care. Pharmacotherapy 2008 May; 28 (5 Pt 2): 1–15S

    Article  Google Scholar 

  75. Bennett CL, Nebeker JR, Lyons EA, et al. The Research on Adverse Drug events And Reports (RADAR) project. JAMA 2005 May 4; 293(17): 2131–40

    Article  PubMed  CAS  Google Scholar 

  76. Mackey AC, Green L, Liang L-C, et al. Hepatosplenic T-cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007; 44(2): 265–7

    Article  PubMed  Google Scholar 

  77. Pelosini M, Focosi D, Rita F, et al. Progressive multifocal leukoencephalopathy: report of three cases in HIV-negative hematological patients and review of literature. Ann Hematol 2008; 87(5): 405–12

    Article  PubMed  Google Scholar 

  78. Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide: the FDA’s review of a new antidiabetic therapy. N Engl J Med 2010 Mar 4; 362(9): 774–7

    Article  PubMed  CAS  Google Scholar 

  79. Valerie B, Emily B, Gillian R. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002; 360(9337): 942–4

    Article  Google Scholar 

  80. European Medicines Agency. Public statement on Acomplia: withdrawal of the marketing authorisation in the European Union [online]. Available from URL: http://www.ema.europa.eu/humandocs/PDFs/EPAR/acomplia/3945709en.pdf [Accessed 2010 Jun 29]

  81. Tuffs A. German agency suspects that insulin analogue glargine increases risk of cancer. BMJ 2009; 339: b2774

    Article  PubMed  Google Scholar 

  82. Wise L, Parkinson J, Raine J, et al. New approaches to drug safety: a pharmacovigilance tool kit. Nat Rev 2009 Oct; 8(10): 779–82

    CAS  Google Scholar 

Download references

Acknowledgements

All authors declare no conflicts of interest relevant to the subject matter or materials discussed in the review. This study was performed in the context of the Escher project (T6-202), a project of the Dutch Top Institute Pharma. The Division of Pharmacoepidemiology and Clinical Pharmacology, employing authors Hans C. Ebbers, Aukje K. Mantel-Teeuwisse and Hubert G. Leufkens, has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, the private-public funded Top Institute Pharma (www. tipharma.nl; includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board and the Dutch Ministry of Health. H. Schellekens participated in meetings and publications sponsored by Amgen, Johnson & Johnson, Roche, Sandoz and Hospira. Part of his research is directly or indirectly sponsored by Roche and Amgen. E. Moors has no conflicts of interest to declare.

The authors wish to thank Professor Nicole Casadevall for the fruitful discussions and her insights of the events surrounding PRCA. The authors are indebted to the national centres contributing data to the WHO-UMC International Drug Monitoring Programme. The opinions and conclusions, however, are not necessarily those of the various centres or of the WHO.

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or any other regulatory agency, or one of its committees or working parties.

Author information

Authors and Affiliations

  1. Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, the Netherlands

    Hans C. Ebbers,  Aukje K. Mantel-Teeuwisse & Hubert G. Leufkens

  2. Medicines Evaluation Board, The Hague, the Netherlands

    Aukje K. Mantel-Teeuwisse & Hubert G. Leufkens

  3. Department of Innovation and Environmental Sciences, Copernicus Institute, Utrecht University, Utrecht, the Netherlands

    Ellen H. M. Moors & Huub Schellekens

  4. Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmaceutics, Utrecht University, Utrecht, the Netherlands

    Huub Schellekens

Authors
  1. Hans C. Ebbers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aukje K. Mantel-Teeuwisse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ellen H. M. Moors
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huub Schellekens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hubert G. Leufkens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aukje K. Mantel-Teeuwisse.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ebbers, H.C., Mantel-Teeuwisse, A.K., Moors, E.H.M. et al. Today’s Challenges in Pharmacovigilance. Drug-Safety 34, 273–287 (2011). https://doi.org/10.2165/11586350-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11586350-000000000-00000

Keywords

Search

Navigation