Lessons from gefitinib-induced interstitial lung disease in Japan: Problems in approval, pharmacovigilance, and regulatory decision-making procedures
Objective: The objective of this study was to identify problems in the approval, pharmacovigilance, and post-approval regulatory decision-making procedures involving gefitinib and to propose countermeasures to prevent further drug-induced suffering in Japan in the future.
Methods: We comprehensively reviewed reports regarding gefitinib published during the period from 2000 to 2006 by regulatory agencies, the manufacturer of the gefitinib-containing drug, cancer clinical study groups, and a scientific society.
Results: We identified the following major problems in the approval, pharmacovigilance, and regulatory decision-making procedures: 1) the results of animal experiments and pre-marketing clinical trials, and reports of adverse drug reactions from other countries were not properly reflected in the label; 2) indications for the drug were expanded without strict evaluation of the external validity of pre-marketing clinical trials; and 3) despite many serious cases of interstitial lung disease (ILD) being spontaneously reported, well-designed post-marketing surveillance was not immediately performed.
Conclusions: We propose a mandatory total registry of all drug users and surveillance (i.e. a prospective outcome study) as one of the rational solutions for preventing further drug-induced suffering in Japan.
2. AstraZeneca. Information about Iressa tablets 250. (in Japanese). http://www.info.pmda.go.jp/shinyaku/g020706/index.html? (accessed 2006 August 2)
3. AstraZeneca. The trend in the incidence of interstitial lung diseases and interstitial pneumonia. February 10, 2003 (in Japanese). http://www.astrazeneca.co.jp/activity/other/detail/03_02_10b.html (accessed 2006 August 2)
4. Ministry of Health, Labour and Welfare. The trend in the incidence of interstitial lung diseases and interstitial pneumonia possibly related to the use of gefitinib reported to Ministry of Health, Labour and Welfare and Pharmaceuticals and Medical Devices Agency: Tabulation by the day of reporting until December 28, 2005. January 20, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/01/dl/s0120-4b.pdf (accessed 2006 August 2)
5. Ministry of Health, Labour and Welfare. The reported number of interstitial lung diseases and interstitial pneumonia after gefitinib therapy. April 26, 2006 (in Japanese). http://www.mhlw.go.jp/houdou/2006/04/h0426-1.html (accessed 2006 March 30)
6. AstraZeneca. The results and discussions of the prospective study (Special Surveillance) for Iressa® tablets 250. August 2004 (in Japanese). http://www.mhlw.go.jp/shingi/2005/01/s0120-4.html (accessed 2006 March 30)
7. Evans TL. Highlights from the Tenth World Conference on Lung Cancer: The Oncologist 2004; 9 (2), 232–238.
8. Ministry of Health, Labour and Welfare. State of the implementation of measures for the safe use of Iressa, including disclosure of safety information. January 20, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/01/dl/s0120-4d.pdf (accessed 2006 August 2)
9. Ministry of Health, Labour and Welfare. An opinion on evaluation of the results of ISEL study and future countermeasures for the use of Iressa. March 24, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/03/s0324-12.html (accessed 2006 August 2)
10. Ministry of Health, Labour and Welfare. A list of adverse drug reactions reported before approval of Iressa. December 25, 2002 (in Japanese). http://www.mhlw.go.jp/shingi/2003/05/dl/s0502-1m1.pdf (accessed 2006 August 2); http://www.mhlw.go.jp/shingi/2003/05/dl/s0502-1m2.pdf (accessed 2006 August 2)
11. Ministry of Health, Labour and Welfare. Minutes of the fourth official meeting to discuss the gefitinib problem. March 24, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/03/txt/s0324-6.txt (accessed 2006 August 2)
12. Pharmaceuticals and Medical Devices Evaluation Center. The report of new drug application review for Iressa. May 9, 2002 (in Japanese). http://220.127.116.11/shinyaku/g0207/06/67022700_21400AMY00188_110_1.pdf (accessed 2006 August 2)
13. FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa®) Tablets. Oncologist 2003; 8: 303-306.
14. AstraZeneca. Label for Iressa® 250 tablets, first edition. July 2002 (in Japanese).
15. AstraZeneca. The Emergency Safety Information for Iressa. October 15, 2002 (in Japanese). http://www.info.pmda.go.jp/kinkyu_anzen/kinkyu20021015.pdf (accessed 2006 August 2)
16. AstraZeneca. A report of early post-marketing pharmacovigilance: Iressa® tablets 250. March 2003 (in Japanese).
17. AstraZeneca. Comments on recent news reports. March 12, 2003 (in Japanese). http://www.astrazeneca.co.jp/activity/other/detail/03_03_11.html (accessed 2006 August 2)
18. AstraZeneca. The final report of the Professional Meeting regarding interstitial lung diseases and interstitial pneumonia induced by the use of gefitinib (Iressa® tablets). March 26, 2003 (in Japanese).
19. AstraZeneca. Label for IressaTM (gefitinib tablets) 250mg, first edition. May 2, 2003. http://www.fda.gov/cder/foi/label/2003/021399lbl.pdf (accessed 2006 August 2)
20. AstraZeneca. A report of monitoring of adverse drug reaction: Iressa® tablets 250. September 2003 (in Japanese).
21. AstraZeneca. A report of adverse drug reaction: Iressa® tablets 250. October 2003 (in Japanese).
22. AstraZeneca. A list of adverse drug reactions: Iressa® tablets 250. April 2004 (in Japanese).
23. AstraZeneca. The report of general toxicity studies. February 25, 2005. http://med.astrazeneca.co.jp/iressasp/index.html (accessed 2006 August 2)
24. AstraZeneca. The estimated number of patients administered Iressa tablets. March 24, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/03/dl/s0324-11d.pdf (accessed 2006 August 2)
25. AstraZeneca. The answer about EGFR mutation related iressa from AstraZeneca. March 17, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/03/s0317-4.html (accessed 2006 August 2)
26. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 261: 137-9.
27. Seto T, Yamamoto N. Interstitial lung diseases (ILD) induced by gefitinib in patients with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group (WJTOG) epidemiological survey. proc ASCO 2004; (Abstract#7064).
28. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung caner treated with gefitinib. Lung Cancer 2004; 45: 93-104.
29. Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group. proc ASCO 2004; (Abstract#7063).
30. Nakagawa M, Teramukai S, Tada H, et al. Hypoalbumia as a risk factor of interstitinal lung disease (ILD) during gefitinib treatment in patients with non-small cell lung cancer (NSCLC) : A JMTO study. proc ASCO 2005; 23: 667s. (Abstract#7190).
31. Japan Lung Cancer Society. Statement on gefitinib. Japanese Journal of Lung Cancer 2003; 43: 780-4 (in Japanese).
32. Japan Lung Cancer Society. The guideline for Iressa use. February 19, 2005. (in Japanese).
33. Fukuoka M, Yano S, Giaccone G, et al. Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated patients With Advanced Non-Small-Cell Lung Cancer (The IDEAL 1 Trial), J Clin Oncol 2003; 21: 2237-2246.
34. Natale RB, Skarin A, Maddox AM, et al. Improvement in symptoms and quality of life for advanced non-small-cell lung cancer patients receiving ZD1839 in IDEAL 2, Proc ASCO 2002; 21:1167.
35. Suzuki H, Aoshiba K, Yokohori N, Nagai A. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Augments a murine Model of Pulmonary Fibrosis. Cancer Res 2003; 63: 5054-5059.
36. Mainichi Newspapers. Concealment of the results of animal experiments. February 7, 2003 (in Japanese).
37. Physicians’ Desk Reference® (PDR®), 60 edition. Thomson, 2006; 685-686.
38. Kasper D, Fauci A, Longo D, Braunwald E, Hauser S, Jameson L. Harrison's Principles of Internal Medicine, 16th edition. McGraw-Hill, 2005; 1554.
39. Danson S, Blackhall F, Hulse P, Ranson M. Interstitial lung disease in lung cancer - Separating disease progression from treatment effects. Drug Saf 2005;28(2):103-13.
40. Camus P. Interstitial lung disease in patients with non-small-cell lung cancer: causes, mechanisms and management. Br J Cancer. 2004 Aug;91 Suppl 2:S1-2.
41. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71(4):301-26.
42. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2006 Jun 1;24(16):2549-56.
43. Camus P, Kudoh S, Ebina M. Interstitial lung disease associated with drug therapy. British Journal of Cancer, (2004), 91, (Suppl 2).
44. Inside Nikkei Biobiz 2002/10/29. Iressa and interstitial pneumonia. (in Japanese).
45. Hama Rokuro, Beppu Hirokuni, Fukushima Masanori. The request for cancel of gefitinib. February 28, 2003 (in Japanese). http://www.npojip.org/iressa/iressa10-r1.html (accessed 2006 August 2)
46. Janet Woodcock. Letter to FDA expressing concerns about the pending approval of the cancer drug gefitinib (IRESSA) (HRG Publication #1665). May 1, 2003. http://www.citizen.org/publications/print_release.cfm?ID=7242 (accessed August 2, 2006)
47. Merck & Co., Inc. Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. September 30, 2004. http://www.vioxx.com/rofecoxib/vioxx/consumer/index.jsp (accessed August 2, 2006)
48. Horton R. Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet. 2004; 364: 1995-6.
49. Dieppe PA, Ebrahim S, Martin RM, Juni P. Lessons from the withdrawal of rofecoxib. BMJ 2004;329:867-868.
50. ICH harmonized tripartite guideline pharmacovigilance planning E2E. November 18, 2004. http://www.nihs.go.jp/dig/ich/efficacy/e2e/e2e_041118_e.pdf (accessed August 2, 2006))
51. Strom BL (ed.). Pharmacoepidemiology (3rd edn), John Wiley & Sons Inc, 2000.
52. Hartzema AG, Porta MS, Tilson HH. Pharmacoepidemiology: An Introduction (3rd edn). Harvey Whitney Books, 1998.
53. J. Jpn. Soc. Cancer Ther. 1986; 21(5): 929-942 (in Japanese).
54. New Drug Approval Summary No.1 Irinotecan hydrochloride. 1st. Society of Japanese Pharmacopoeia, 1994; 47-49: (in Japanese).
55. Taiho Pharmaceutical. Drug Interview Form TS-1 capsule 20・25, 10th. 2004; 112 (in Japanese).
56. Fukuoka M, Kudo S, Kato H, Nakada K, Nishiwaki Y. A nested case-control study to determine the relative risk of and risk factors for interstitial lung disease in a cohort of NSCLC patients treated with and without gefitinib. Medicine and Drug Journal 2005; 41, 790-795. (in Japanese).
57. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527-37.
58. AstraZeneca. AstraZeneca Announces US Label Change For IRESSA® (gefitinib) And New Distribution Program. June 17, 2005. http://www.astrazeneca-us.com/modules/PRMS/display.asp?id=571650 (accessed 2006 August 2)
59. AstraZeneca. Gefitinib (IressaTM) marketing authorisation application withdrawn in EU. January 4, 2005. http://www.astrazeneca.com/pressrelease/4442.aspx (accessed 2006 August 2)
60. National Cancer Institute. Clinical Trial of Gefitinib for Advanced Lung Cancer Closes Early. April 18, 2005. http://www.nci.nih.gov/newscenter/pressreleases/gefitinibNSCLC (accessed 2006 August 2)
61. Cufer T, Vrdoljak E. Results from a Phase II, open-label, randomized study (SIGN) comparing gefitinib with docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. proc ASCO 2005; 23: 629s. (abstract#7035).
62. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005 ; 97: 339-346.
63. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, and Mitsudomi T. Mutations of the Epidermal Growth Factor Receptor Gene in Lung Cancer: Biological and Clinical Implications. Cancer Res 2004; 64: 8919-8923.
64. Kaneda H, Tamura K, Kurata T, Uejima H, Nakagawa K, Fukuoka M. Retrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer. Lung Cancer 2004; 46:247-254.
65. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005; 23(11):2513-20.
66. Ministry of Health, Labour and Welfare. Staff roster. January 10, 2005. (in Japanese). http://www.mhlw.go.jp/general/sosiki/kanbu/050110.html (accessed 2006 August 2)
67. Ministry of Health, Labour and Welfare. Minutes of Pharmaceutical Subcommittee II of the Pharmaceutical Affairs, Food, and Health Council. May 24, 2002. (in Japanese). http://www.mhlw.go.jp/shingi/2002/05/txt/s0524-2.txt (accessed 2006 August 2)
68. Fukushima M. Clinical trials in Japan. Nature Medicine 1995; 1 :12-13.
69. Fukushima M. The overdose of drugs in Japan. Nature 1989; 342: 850-851.
70. Ministry of Health, Labour and Welfare. Fukushima Masanori. Future directions for gefitinib use. March 7, 2005. (in Japanese). http://www.mhlw.go.jp/shingi/2005/03/dl/s0310-3i.pdf (accessed 2006 August 2)
71. Ministry of Health, Labour and Welfare. The states of the implement about approval conditions. January 20, 2005 (in Japanese). http://www.mhlw.go.jp/shingi/2005/01/dl/s0120-4c.pdf (accessed 2006 August 2)
72. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-32.
73. OSI Pharmaceuticals Inc. Label Tarceva® (erlotinib). October 18, 2005. http://www.fda.gov/medwatch/safety/2005/Nov_PI/Tarceva2_PI.pdf (accessed 2006 August 2)
74. Yamamoto N, Yamada Y, Shimoyama T, et al. A phase I study of erlotinib HCl in Japanese patients with various types of solid tumors. proc ASCO 2003; 22: 225. (abstract#903).
75. Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib (Tarceva) in a patient who previously tolerated gefitinib (Iressa). J Oncol Pharm Pract. 2005;11(3):127-30.
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