Evidence-Based Evaluation on Off-Label Drug Use Policies in 15 Countries_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Lingli ,  LI Youping ^1,2 , ZENG Linan ¹ , LIANG Yi ² , HU Die ^2,3 , LIU Yi ^2,3 , LV Juan ^2,3

1. Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, China;2. West China Second University Hospital, Sichuan University, Chengdu 610041, China;3. West China School of Pharmacy, Sichuan University, Chengdu 610041, China;

Corresponding author：

LI Youping, Email: yzmylab@hotmail.com

Keywords：

Off-label drug use; Policy; Systematic review

DOI：

10.7507/1672-2531.20120069

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective 　To evaluate the related laws, regulations and guidelines about off-label drug use in several countries, so as to provide evidence for regulating off-label drug use in China.
Methods 　The following 3 Chinese databases as CBM, CNKI and VIP, 11 foreign databases including EMbase, PubMed and so on, 15 countries’ official websites of pharmaceutical administration department or academic organization, and WHO website were searched to obtain the related laws, regulations and guidelines about off-label drug use. By adopting the system evaluation method and self-defined index evaluation, the quality of the included literatures was evaluated in three aspects: literatures’ type, content relevance and timeliness. Seven researchers independently extracted data by Excel which included basic information of literatures, preconditions of off-label drug use, medicines categories that could be off-labelly used, regulations and legal responsibility in off-label drug use. And finally the descriptive analysis was conducted.
Results 　A total of 4 735 literatures were retrieved, 104 of which were finally included, including 89 at grade A quality level (85.58%) and 15 was at grade B (14.42%). The analysis showed that, a) Seven countries had laws related to off-label drug use: America, Germany, Italy, Netherland, New Zealand, India and Japan. Except India, the rational off-label drug use was allowed in the other 6 countries. The right to prescribe off-label drug was defined in Britain and Ireland; b) Medical staff had to take the responsibility of off-label drug use in the country where the duty regulations were formulated; and c) Ten countries published guidelines or statements related to off label drug use by their official departments and academic organizations. And the regulation included the following procedures: firstly, to obtain the relative information and evidence; secondly, to get the informed consent; thirdly, to be approved by the ethics committee and/or pharmacy administration committee; fourthly, to record the reasons and effectiveness of off-label use; fifthly, to monitor the adverse reactions of off-label drug use. Besides monitoring the medical institutes, the pharmaceutical companies had also be monitored which included the following 3 aspects: a) to require companies to train specialized staffs to answer the questions related to off-label drug use; b) to open the contact information of medical departments of companies; and c) to prohibit preaching and advertising the off-label drug use.
Conclusion　 Off-label drug use has its rationality and necessity. To protect the safety of patients, avoid the risk for hospitals and medical staffs, it requires formulating relative regulations soon in order to manage the off-label drug use in China. As a developing country, China is different from the developed countries in health care system. Therefore, when formulating the regulations, it is necessary to perform evidence-based evaluation on each country’s laws, regulations and guidelines about off-label drug use, with Chinese national conditions and experts’ opinions in combination. After a regulation is preliminarily drawn up, it needs to be put into pilot practice, and then revised and spread to the whole country.

Citation： ZHANG Lingli,LI Youping,ZENG Linan,LIANG Yi,HU Die,LIU Yi,LV Juan. Evidence-Based Evaluation on Off-Label Drug Use Policies in 15 Countries. Chinese Journal of Evidence-Based Medicine, 2012, 12(4): 426-435. doi: 10.7507/1672-2531.20120069 Copy

1.	American Society of Hospital Pharmacists. ASHP statement on the use of medications for unlabeled uses. Am J Hospital Pharm, 1992, 49(8): 2006-2008.
2.	广东省药学会, 药品未注册用法专家共识, 2010年3月18日.
3.	Herring C, McManus A, Weeks A. Off-label prescribing during pregnancy in the UK: an analysis of 18,000 prescriptions in Liverpool Women’s Hospital. The International Journal Of Pharmacy Practice, 2010, 18(4): 226-229.
4.	Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ, 2000, 320(7227): 79-82.
5.	Hames A. Unlicensed and off-label drug use in elderly people. Age And Ageing, 2001, 30(6): 530-531.
6.	Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s Disease. N Engl J Med, 2006, 355(15): 1525-1538.
7.	Huntzinger A. FDA warns against off-label use of antipsychotic drugs. Am Fam Physician, 2005, 71(61): 2205.
8.	Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med, 2006, 166(9): 1021-1026.
9.	孙纽云, 王莉, 周军, 等. 美英加澳和中国台湾地区医疗风险管理机构、法规与运行机制的比较研究. 中国循证医学杂志, 2011, 11(2): 117-124.
10.	贾莉英, 袁蓓蓓, 王健, 等. 卫生政策系统评价方法探讨. 中国循证医学杂志, 2009, 9(10): 1037-1043.
11.	王莉, 喻佳洁, 周帮旻, 等. 17国国家药物政策的系统评价. 中国循证医学杂志, 2009, 9(7): 715-729.
12.	宋儒亮. 对超说明书用药多种意义上的完善思考. 中国处方药, 2010, 103: 26-27.
13.	Miller JL. Rules set for dissemination of off-label-use information.Am J Health-Syst Pharm, 1999, 56(3): 204-206.
14.	Verordnungsfähigkeit von zugelassenen Arzneimitteln in nicht zugelassenen Anwendungsgebieten. Richtlinie des Gemeinsamen Bundesausschusses, 2009. Available at: URL: http://www.g-ba.de/downloads/62-492-470/AM-RL-2010-09-16_4.pdf.
15.	Gijsen R, Jochemsen H, van Dijk L, et al. Frequency of ill-founded off-label prescribing in Dutch general practice. Pharmacoepidemiology and Drug Safety, 2009, 18(1): 84-91.
16.	Bernardi A, Pegoraro R. The ethics of off-label use of drugs: oncology pharmacy in Italy. Journal of Clinical Pharmacy and Therapeutics, 2008, 33(2): 95-99.
17.	Aguggia M, Cavallini M, Varetto L. Medical-legal issues in headache: penal and civil Italian legislation, working claims, social security, off-label prescription. Neurol Sci, 2006, 27(suppl 2): S198-S202.
18.	Medsafe. Patient consent and off-label use of medicines (April 1998). Available at: URL: http://www. medsafe.govt.nz/profs/RIss/unapp.asp.
19.	Sharma DC. Indian experts protest against off-label drug use. Medline and Health Policy. 2004.
20.	「医師法」（昭和23年7月30日法律第二百一号）（1948）最終改正：平成19年6月27日法律第九六号（2008）. Available at:URL:http:// www.law.e-gov.go.jp.
21.	立法機関.「薬事法」（昭和35年8月10日法律第百四十五号）(1960年)最終改正：平成18年6月21日法律第八四号（2007）. Available at: URL:http:// www.law.e-gov.go.jp.
22.	厚生労働省健康政策局研究開発振興課，厚生労働省医薬安全局審査管理課. 「適応外使用に係る医療用医薬品の取り扱いについて」　平成11年2月1日（2000年）. Available at:http:// www.mhlw.go.jp.
23.	MHRA. Off-label use or unlicensed medicines: prescribers’ responsibilities. Drug Safety Update, 2009, 9(2): 6.
24.	Irish Medicines Board, FAQ Categories. Question: Can a registered medical doctor/dentist use a medicine off-label? Available at: URL: http://www.imb.ie/EN/FAQs.aspx? page=1&categoryid= &letter=C&q= &faqid=154&pagecategoryid=-1.
25.	FDA.“Off-Label”and Investigational Use of Marketed Drugs, Biologics, and Medical Devices - Information Sheet.Guidance for Institutional Review Boards and Clinical Investigators（2010）.Available at: URL:http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm.
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28.	Australian Government Department of Health and Ageing.Changes to the Definition of Therapeutic Substance. (Nov.2010). Available at: URL: http://www.health.gov.au/internet/mbsonline/publishing.nsf/Content/News-201001-Therapeutic-Substance.
29.	Medsafe. Unapproved Use of Medicines. Prescriber Update, 2003, 24(1): 8-11.
30.	寺岡章雄, 津谷喜一郎. 未承認薬のコンパッショネート使用. Jpn Pharmacol Ther薬理と治療, 2010, 38(2): 109-150.
31.	国立医薬品食品衛生研究所安全情報部. 医薬品安全性情報（2009/05/28）. Available at: URL: http://www.nihs.go.jp/dig/sireport/index.html.
32.	JansenRM, Gouws C. Clinical, legal and ethical implications of the intra-ocular (off-label) use of bevacizumab (Avastin)–a South African perspective. S Afr Med J, 2009, 99(6): 446-449.
33.	ASHP. ASHP Guidelines on the Pharmacy and Therapeutics Committee and the Formulary System. Formulary Management-Guidelines (2008): 142-151.
34.	IMB. Question: Should a registered medical doctor/dentist inform the IMB when they supply an unauthorised medicine? Available at:URL: http://www.imb.ie/EN/FAQs.aspx?page=1&categoryid=&letter=S&q=&faqid=152&pagecategoryid=-1.
35.	Brockmeyer NH, Brucklacher U, Potthoff A, et al.Off-label use in dermatology in Germany: What has changed since 2004? J Dtsch Dermatol Ges. 2009, 7(11): 938-945.
36.	厚生労働省ワーキンググループ. ワーキンググループ検討結果報告書. 平成18年1月19日（2007）. Available at: URL: http://www.mhlw.go.jp.
37.	Levêque D. Off -label use of anticancer drugs. Lancet Oncol, 2008, 9(11): 1102-1107.
38.	ASHP. ASHP Drug Information:off label uses.2010. Available at: URL:http://www.Ahfsdrug information.com/off_label/overview.aspx.
39.	Johnson PE. Pharmaceutical reimbursement:An overview. Am J Health-Syst Pharm, 2008, 65 (Suppl 1): S4-S10.
40.	British National Formulary(BNF-57), BMJ Group and RPS Publishing. 2009.
41.	BMJ Group. British national formulation for children. 2009.
42.	Gazarian M, Kelly M, McPhee JR, et al. Health Care Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2006, 185(10): 544-548.
43.	A Working Group of NSW TAG Inc. Off-Label Use of Registered Medicines and Use of Medicines under the Personal Importation Scheme in NSW Public Hospitals (September 2003).
44.	FDA. Social Media Working Group. Pharmaceutical Industry Approaches for Engagement in Online Communities 2009. Available at: URL:http://www.fda.gov/downloads/AboutFDA/Centers Offices/ CDER/ UCM 194608.pdf.
45.	Cohen PJ. “Off-label” use of prescription drugs: Legal, clinical and policy considerations. Eur J Anaesthesiol, 1997, 14(3): 307-309.
46.	Interim Report of the Review of Unlicensed Medicines. Review of UK regulatory arrangements established under Article 5.1 of European Directive 2001/83/EC.
47.	张恩娟. 科学管理, 为超说明书用药“保驾护航”. 中国处方药, 2010, 103(3): 23-25.
48.	FDA. Guidance for Industry - Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices(2009). Available at: URL:http://www.fda.gov/oc/op/goodreprint.htm.
49.	Anonymous. FDA Releases Draft Guidance on Reprint Practices for Dissemination of Articles on Drugs or Medical Devices.(February 25，2008). Available at: http://www.wsgr.com/wsgr/Display.aspx?SectionName=publications/PDFSearch/clientalert_FDA-Guidance.htm.
50.	Tanne JH. FDA is criticised for poor oversight of drug companies’promotion of off-label drug use. BMJ, 2008, 337: a1163.
51.	FDA. Measures Undertaken to Address Concerns about Marketing of Unapproved Drugs(2010). Available at: URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm079099.htm.
52.	Cheng AC, Robinson PM, Harvey K. Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2007, 186(7): 379-380.
53.	Akaza H, Ohashi Y, Shimada Y, et al. Post launch studies. Gan To Kagaku Ryoho, 2002, 29(32): 2037-2048.
54.	Johnson PE. Pharmaceutical reimbursement: an overview. Am J Health-Syst Pharm,2008, 65(suppl 1): S4-S10.
55.	Kaa K. Medicare challenges and solutions: reimbursement issues in treating the patient with colorectal cancer. J Manag Care Pharm, 2007, 13(6 suppl C): S19-S26.
56.	American Society of Hospital Pharmacists. ASHP statement on the use of medications for unlabeled uses. Am J Hosp Pharm, 1992, 49(13): 2006-2008.
57.	Allen C Cheng, Priscilla M Robinson and Ken Harvey. Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2007, 186(7): 379-380.
58.	张钰莹, 于丽. 超说明书用药理与法的考量.中国处方药, 2010, 103(3): 71-72.
59.	李玉珍, 任晓蕾. 超说明书用药,医疗机构需谨慎对待. 中国社区医师, 2011-04-22,23.

1. American Society of Hospital Pharmacists. ASHP statement on the use of medications for unlabeled uses. Am J Hospital Pharm, 1992, 49(8): 2006-2008.
2. 广东省药学会, 药品未注册用法专家共识, 2010年3月18日.
3. Herring C, McManus A, Weeks A. Off-label prescribing during pregnancy in the UK: an analysis of 18,000 prescriptions in Liverpool Women’s Hospital. The International Journal Of Pharmacy Practice, 2010, 18(4): 226-229.
4. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ, 2000, 320(7227): 79-82.
5. Hames A. Unlicensed and off-label drug use in elderly people. Age And Ageing, 2001, 30(6): 530-531.
6. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s Disease. N Engl J Med, 2006, 355(15): 1525-1538.
7. Huntzinger A. FDA warns against off-label use of antipsychotic drugs. Am Fam Physician, 2005, 71(61): 2205.
8. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med, 2006, 166(9): 1021-1026.
9. 孙纽云, 王莉, 周军, 等. 美英加澳和中国台湾地区医疗风险管理机构、法规与运行机制的比较研究. 中国循证医学杂志, 2011, 11(2): 117-124.
10. 贾莉英, 袁蓓蓓, 王健, 等. 卫生政策系统评价方法探讨. 中国循证医学杂志, 2009, 9(10): 1037-1043.
11. 王莉, 喻佳洁, 周帮旻, 等. 17国国家药物政策的系统评价. 中国循证医学杂志, 2009, 9(7): 715-729.
12. 宋儒亮. 对超说明书用药多种意义上的完善思考. 中国处方药, 2010, 103: 26-27.
13. Miller JL. Rules set for dissemination of off-label-use information.Am J Health-Syst Pharm, 1999, 56(3): 204-206.
14. Verordnungsfähigkeit von zugelassenen Arzneimitteln in nicht zugelassenen Anwendungsgebieten. Richtlinie des Gemeinsamen Bundesausschusses, 2009. Available at: URL: http://www.g-ba.de/downloads/62-492-470/AM-RL-2010-09-16_4.pdf.
15. Gijsen R, Jochemsen H, van Dijk L, et al. Frequency of ill-founded off-label prescribing in Dutch general practice. Pharmacoepidemiology and Drug Safety, 2009, 18(1): 84-91.
16. Bernardi A, Pegoraro R. The ethics of off-label use of drugs: oncology pharmacy in Italy. Journal of Clinical Pharmacy and Therapeutics, 2008, 33(2): 95-99.
17. Aguggia M, Cavallini M, Varetto L. Medical-legal issues in headache: penal and civil Italian legislation, working claims, social security, off-label prescription. Neurol Sci, 2006, 27(suppl 2): S198-S202.
18. Medsafe. Patient consent and off-label use of medicines (April 1998). Available at: URL: http://www. medsafe.govt.nz/profs/RIss/unapp.asp.
19. Sharma DC. Indian experts protest against off-label drug use. Medline and Health Policy. 2004.
20. 「医師法」（昭和23年7月30日法律第二百一号）（1948）最終改正：平成19年6月27日法律第九六号（2008）. Available at:URL:http:// www.law.e-gov.go.jp.
21. 立法機関.「薬事法」（昭和35年8月10日法律第百四十五号）(1960年)最終改正：平成18年6月21日法律第八四号（2007）. Available at: URL:http:// www.law.e-gov.go.jp.
22. 厚生労働省健康政策局研究開発振興課，厚生労働省医薬安全局審査管理課. 「適応外使用に係る医療用医薬品の取り扱いについて」　平成11年2月1日（2000年）. Available at:http:// www.mhlw.go.jp.
23. MHRA. Off-label use or unlicensed medicines: prescribers’ responsibilities. Drug Safety Update, 2009, 9(2): 6.
24. Irish Medicines Board, FAQ Categories. Question: Can a registered medical doctor/dentist use a medicine off-label? Available at: URL: http://www.imb.ie/EN/FAQs.aspx? page=1&categoryid= &letter=C&q= &faqid=154&pagecategoryid=-1.
25. FDA.“Off-Label”and Investigational Use of Marketed Drugs, Biologics, and Medical Devices - Information Sheet.Guidance for Institutional Review Boards and Clinical Investigators（2010）.Available at: URL:http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm.
26. General Medical Council. Good Practice in Prescribing Medicines. 2008-09.
27. MEB. off-label-use Human medicine-Medicinal products-off label use. off-label-use. Available at: URL:http://www.cbg-meb.nl/CBG/en/human-medicines/medicinal%20products/Off-label%20use/default.htm.
28. Australian Government Department of Health and Ageing.Changes to the Definition of Therapeutic Substance. (Nov.2010). Available at: URL: http://www.health.gov.au/internet/mbsonline/publishing.nsf/Content/News-201001-Therapeutic-Substance.
29. Medsafe. Unapproved Use of Medicines. Prescriber Update, 2003, 24(1): 8-11.
30. 寺岡章雄, 津谷喜一郎. 未承認薬のコンパッショネート使用. Jpn Pharmacol Ther薬理と治療, 2010, 38(2): 109-150.
31. 国立医薬品食品衛生研究所安全情報部. 医薬品安全性情報（2009/05/28）. Available at: URL: http://www.nihs.go.jp/dig/sireport/index.html.
32. JansenRM, Gouws C. Clinical, legal and ethical implications of the intra-ocular (off-label) use of bevacizumab (Avastin)–a South African perspective. S Afr Med J, 2009, 99(6): 446-449.
33. ASHP. ASHP Guidelines on the Pharmacy and Therapeutics Committee and the Formulary System. Formulary Management-Guidelines (2008): 142-151.
34. IMB. Question: Should a registered medical doctor/dentist inform the IMB when they supply an unauthorised medicine? Available at:URL: http://www.imb.ie/EN/FAQs.aspx?page=1&categoryid=&letter=S&q=&faqid=152&pagecategoryid=-1.
35. Brockmeyer NH, Brucklacher U, Potthoff A, et al.Off-label use in dermatology in Germany: What has changed since 2004? J Dtsch Dermatol Ges. 2009, 7(11): 938-945.
36. 厚生労働省ワーキンググループ. ワーキンググループ検討結果報告書. 平成18年1月19日（2007）. Available at: URL: http://www.mhlw.go.jp.
37. Levêque D. Off -label use of anticancer drugs. Lancet Oncol, 2008, 9(11): 1102-1107.
38. ASHP. ASHP Drug Information:off label uses.2010. Available at: URL:http://www.Ahfsdrug information.com/off_label/overview.aspx.
39. Johnson PE. Pharmaceutical reimbursement:An overview. Am J Health-Syst Pharm, 2008, 65 (Suppl 1): S4-S10.
40. British National Formulary(BNF-57), BMJ Group and RPS Publishing. 2009.
41. BMJ Group. British national formulation for children. 2009.
42. Gazarian M, Kelly M, McPhee JR, et al. Health Care Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2006, 185(10): 544-548.
43. A Working Group of NSW TAG Inc. Off-Label Use of Registered Medicines and Use of Medicines under the Personal Importation Scheme in NSW Public Hospitals (September 2003).
44. FDA. Social Media Working Group. Pharmaceutical Industry Approaches for Engagement in Online Communities 2009. Available at: URL:http://www.fda.gov/downloads/AboutFDA/Centers Offices/ CDER/ UCM 194608.pdf.
45. Cohen PJ. “Off-label” use of prescription drugs: Legal, clinical and policy considerations. Eur J Anaesthesiol, 1997, 14(3): 307-309.
46. Interim Report of the Review of Unlicensed Medicines. Review of UK regulatory arrangements established under Article 5.1 of European Directive 2001/83/EC.
47. 张恩娟. 科学管理, 为超说明书用药“保驾护航”. 中国处方药, 2010, 103(3): 23-25.
48. FDA. Guidance for Industry - Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices(2009). Available at: URL:http://www.fda.gov/oc/op/goodreprint.htm.
49. Anonymous. FDA Releases Draft Guidance on Reprint Practices for Dissemination of Articles on Drugs or Medical Devices.(February 25，2008). Available at: http://www.wsgr.com/wsgr/Display.aspx?SectionName=publications/PDFSearch/clientalert_FDA-Guidance.htm.
50. Tanne JH. FDA is criticised for poor oversight of drug companies’promotion of off-label drug use. BMJ, 2008, 337: a1163.
51. FDA. Measures Undertaken to Address Concerns about Marketing of Unapproved Drugs(2010). Available at: URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm079099.htm.
52. Cheng AC, Robinson PM, Harvey K. Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2007, 186(7): 379-380.
53. Akaza H, Ohashi Y, Shimada Y, et al. Post launch studies. Gan To Kagaku Ryoho, 2002, 29(32): 2037-2048.
54. Johnson PE. Pharmaceutical reimbursement: an overview. Am J Health-Syst Pharm,2008, 65(suppl 1): S4-S10.
55. Kaa K. Medicare challenges and solutions: reimbursement issues in treating the patient with colorectal cancer. J Manag Care Pharm, 2007, 13(6 suppl C): S19-S26.
56. American Society of Hospital Pharmacists. ASHP statement on the use of medications for unlabeled uses. Am J Hosp Pharm, 1992, 49(13): 2006-2008.
57. Allen C Cheng, Priscilla M Robinson and Ken Harvey. Off-label use of medicines: consensus recommendations for evaluating appropriateness. MJA, 2007, 186(7): 379-380.
58. 张钰莹, 于丽. 超说明书用药理与法的考量.中国处方药, 2010, 103(3): 71-72.
59. 李玉珍, 任晓蕾. 超说明书用药,医疗机构需谨慎对待. 中国社区医师, 2011-04-22,23.

Chinese Journal of Evidence-Based Medicine

Evidence-Based Evaluation on Off-Label Drug Use Policies in 15 Countries

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