研究背景與目的
糖尿病足潰瘍為糖尿病中較嚴重的併發症之一，於全世界的盛行率為 6.3%，
而在台灣的盛行率則為 0.52%，足部潰瘍患者常見的併發症包括感染、壞疽甚
至截肢，疾病對病患以及政府而言都帶來龐大的經濟負擔。糖尿病足潰瘍的治
療選擇相當有限，現有的用藥僅有 1997 年美國 FDA(food and drug
administration)核准的 becaplermin，目前亦無標準的治療準則與程序，臨床上仍
以支持性傷口照護為主，並按照病患疾病特徵予以個人化照顧。近期於台灣取
得藥證的新藥 ON101，於第三期臨床試驗中顯示在治療糖尿病足潰瘍上，有協
助傷口癒合的療效。然而考量 ON101 高價格以及疾病本身帶來的經濟負擔，若
要評估 ON101 的介入是否為成本效益的治療選擇，藥物經濟效益的評估是必須
的；此外目前在台灣亦缺乏研究糖尿病足潰瘍的成本效益分析研究，因此也無
法得知足部潰瘍及其併發症對台灣造成經濟衝擊的嚴重程度。
本研究希望以台灣醫療保健部門的角度，評估以台灣為研究背景設定的
WTP(willingness-to-pay)下， ON101 合併標準照護相較於單純標準照護是否為一
個具有成本效益的治療選擇。
研究方法
本研究利用馬可夫模型，模擬糖尿病足潰瘍病患分別使用 ON101 合併標準
照護與單純標準照護間之臨床療效與費用，並以台灣醫療保健部門為觀察角度，
總觀察時間為五年。研究中使用的模型包含非感染性糖尿病足潰瘍及其相關併
發症(感染性足部潰瘍、壞疽、截肢、死亡)與癒合，共 6 個健康狀態；研究中
參數(健康狀態之轉換機率、醫療品質與健康效用)的來源包括文獻回顧以及
ON101 第三期臨床試驗結果。主要觀察臨床療效為病患生活品質校正生命年，II
療效以及醫療費用皆以 3%作為折現率，並以 2020 年美元呈現。研究針對基礎
分析結果進行單因子敏感度分析、情境性敏感度分析以及機率性敏感度分析。
研究結果
經過五年模擬， ON101 合併標準照護相較於單純標準照護能增加病患的生
活品質校正生命年(0.044 QALY)以及減少醫療總費用(每人省下 2,584 美元)，表
示每一個糖尿病足潰瘍患者在 ON101 介入下，每增加一單位的 QALY 還能省下
$58,298 美元，為節省成本的治療選擇；一系列的敏感性分析和基礎研究分析的
結果具一致性。依照 WTO 建議，以 1~3 倍人均 GDP 為 WTP 的情況下，有 95-
98%的機會 ON101 合併標準照護是符合成本效益的治療選擇。相較於標準照護，
ON101 合併標準照護的介入在其他臨床療效上亦有其優勢，包括增加癒合速度
與待在癒合狀態時間，以及減少糖尿病足潰瘍相關併發症: 感染性足部潰瘍、壞
疽以及截肢。
研究結論
本研究顯示對於糖尿病足部潰瘍患者，使用 ON101 的介入治療相較於單純
標準照護能帶來較佳的醫療效果且能減少醫療花費，是個節省成本的治療選擇，
因此對於政府而言， ON101 的使用或許有助於減少健康照護系統的醫療及財政
負擔。相信本篇研究能增加健康照護系統對於糖尿病足部潰瘍的重視，以利於
後續更多相關研究的發展。

Diabetic foot ulcer (DFU) is one of the severe complications of diabetes, which
causes impaired quality of life of patients and considerable economic burden to
healthcare system. This study utilized a Markov model with one-month cycle in a 5-
year time horizon to evaluate the cost-effectiveness of ON101 added-on to standard care in comparison with standard care alone for DFU patients from the perspective of Taiwan’s healthcare sector. Clinical outcomes and cost were discounted at 3% and cost values were presented in 2020 USD. After 5-year simulation, in terms of qualityadjusted life year (QALY), the results demonstrated more effective (0.044 QALY) and less costly of $2,584 per person with the intervention of ON101 along with standard care compared to standard care alone. The results of probabilistic sensitivity analysis showed that the intervention of ON101 added-on to standard care yielded a high probability (95~98%) of being a cost-effective option than the use of standard care alone regardless of different willingness-to-pay (WTP) thresholds (i.e., $30,038~$90,114) for one to three times of gross domestic product per capita in Taiwan, respectively). In conclusion, the use of ON101 along with standard care may be considered as a cost-saving treatment for DFU patients in Taiwan, which may further inform the healthcare system to allocate the limited healthcare resources and support the decision of drug pricing related reimbursement policies for ON101 in the health insurance program.

1. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis. Annals of Medicine. 2017;49(2):106-116.
2. Tai CH, Hsieh TC, Lee RP, Lo SF. Prevalence and Medical Resource of Patients with Diabetic Foot Ulcer: A Nationwide Population-Based Retrospective Cohort Study for 2001-2015 in Taiwan. Int J Environ Res Public Health. 2021;18(4).
3. Chen H-Y, Kuo S, Su P-F, Wu J-S, Ou H-T. Health Care Costs Associated With Macrovascular, Microvascular, and Metabolic Complications of Type 2 Diabetes Across Time: Estimates From a Population-Based Cohort of More Than 0.8 Million Individuals With Up to 15 Years of Follow-up. Diabetes Care. 2020;43(8):1732-1740.
4. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157:107843.
5. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53.
6. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. New England Journal of Medicine. 2017;376(24):2367-2375.
7. Moulik PK, Mtonga R, Gill GV. Amputation and Mortality in New-Onset Diabetic Foot Ulcers Stratified by Etiology. Diabetes Care. 2003;26(2):491-494.
8. Milne TE, Schoen DE, Bower VM, Burrows SA, Westphal C, Gurr JM. Healing times of diabetic foot ulcers: investigating the influence of infection and peripheral arterial disease. J Diab Foot Complications. 2013;5:29-38.
9. Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. J Intern Med. 1993;233(6):485-491.
10. Huang YY, Lin CW, Yang HM, Hung SY, Chen IW. Survival and associated risk factors in patients with diabetes and amputations caused by infectious foot gangrene. J Foot Ankle Res. 2018;11:1.
11. Lin C-W, Armstrong DG, Lin C-H, et al. Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period. BMJ Open Diabetes Research & Care. 2019;7(1):e000795.
12. Yazdanpanah L, Shahbazian H, Nazari I, et al. Incidence and Risk Factors of Diabetic Foot Ulcer: A Population-Based Diabetic Foot Cohort (ADFC Study)-Two-Year Follow-Up Study. Int J Endocrinol. 2018;2018:7631659.
13. International Best Practice Guidelines. Wound Management in Diabetic Foot Ulcers, 2013.
14. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabetic medicine : a journal of the British Diabetic Association. 2018;35(1):78-88.
15. Sørensen MLB, Jansen RB, Wilbek Fabricius T, Jørgensen B, Svendsen OL. Healing of Diabetic Foot Ulcers in Patients Treated at the Copenhagen Wound Healing Center in 1999/2000 and in 2011/2012. Journal of Diabetes Research. 2019;2019:6429575.
16. Jeyaraman K, Berhane T, Hamilton M, Chandra AP, Falhammar H. Mortality in patients with diabetic foot ulcer: a retrospective study of 513 cases from a single Centre in the Northern Territory of Australia. BMC Endocr Disord. 2019;19(1):1.
17. Noor S, Zubair M, Ahmad J. Diabetic foot ulcer--A review on pathophysiology, classification and microbial etiology. Diabetes Metab Syndr. 2015;9(3):192-199.
18. 沈惠民, 林東亮, 鍾進燈, 許惠恒. 糖尿病足之臨床評估與治療. 內科學誌. 2011;22(4):254-265.
19. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3266.
20. Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: A critical review. Diabetes/Metabolism Research and Reviews. 2020;36(S1):e3272.
21. Monteiro-Soares M, Russell D, Boyko EJ, et al. Guidelines on the classification of diabetic foot ulcers (IWGDF 2019). Diabetes/Metabolism Research and Reviews. 2020;36(S1):e3273.
22. Ince P, Abbas ZG, Lutale JK, et al. Use of the SINBAD Classification System and Score in Comparing Outcome of Foot Ulcer Management on Three Continents. Diabetes Care. 2008;31(5):964-967.
23. Health NIf, Excellence C. Diabetic foot problems: prevention and management: National Institute for Health and Care Excellence (NICE); 2015.
24. Jeffcoate WJ, Price PE, Phillips CJ, et al. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes. Health Technol Assess. 2009;13(54):1-86, iii-iv.
25. Wu L, Norman G, Dumville JC, O'Meara S, Bell-Syer SE. Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews. Cochrane Database Syst Rev. 2015;2015(7):Cd010471.
26. Botros M, Kuhnke J, Embil J, et al. Best practice recommendations for the prevention and management of diabetic foot ulcers. Wounds Canada: North York. 2017.
27. Armstrong DG, McCulloch D, de Asla R. Management of diabetic foot ulcers. Edits: JF, Mills JL, Nathan DM, eds. UpToDate. 2019.
28. Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Annals of the New York Academy of Sciences. 2018;1411(1):153-165.
29. R.O.C. DAot. DAROC Clinical Practice Guidelines for Diabetes Care- 2018. 2018.
30. Game FL, Apelqvist J, Attinger C, et al. Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes/Metabolism Research and Reviews. 2016;32(S1):154-168.
31. Wang A, Lv G, Cheng X, et al. Guidelines on multidisciplinary approaches for the prevention and management of diabetic foot disease (2020 edition). Burns Trauma. 2020;8:tkaa017.
32. Internal Clinical Guidelines t. National Institute for Health and Care Excellence: Clinical Guidelines. Diabetic Foot Problems: Prevention and Management. London: National Institute for Health and Care Excellence (UK) Copyright © 2015 National Institute for Health and Care Excellence.; 2015.
33. Jeffcoate WJ, Vileikyte L, Boyko EJ, Armstrong DG, Boulton AJM. Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers. Diabetes Care. 2018;41(4):645-652.
34. Sharma R, Sharma SK, Mudgal SK, Jelly P, Thakur K. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcer, a systematic review and meta-analysis of controlled clinical trials. Sci Rep. 2021;11(1):2189.
35. Goyal M, Reeves ND, Rajbhandari S, Ahmad N, Wang C, Yap MH. Recognition of ischaemia and infection in diabetic foot ulcers: Dataset and techniques. Computers in Biology and Medicine. 2020;117:103616.
36. Aldana PC, Khachemoune A. Diabetic Foot Ulcers: Appraising Standard of Care and Reviewing New Trends in Management. Am J Clin Dermatol. 2020;21(2):255-264.
37. Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care. 1998;21(5):822-827.
38. Ziyadeh N, Fife D, Walker AM, Wilkinson GS, Seeger JD. A matched cohort study of the risk of cancer in users of becaplermin. Adv Skin Wound Care. 2011;24(1):31-39.
39. Goodridge D, Trepman E, Embil JM. Health-related quality of life in diabetic patients with foot ulcers: literature review. J Wound Ostomy Continence Nurs. 2005;32(6):368-377.
40. Arshad M, Arshad S, Arshad S, Abbas H. The quality of life in patients with diabetic foot ulcers. Disability and Rehabilitation. 2020;11:101.
41. Edmonds M, Manu C, Vas P. The current burden of diabetic foot disease. Journal of Clinical Orthopaedics & Trauma. 2021;17:88-93.
42. Polikandrioti M, Vasilopoulos G, Koutelekos I, et al. Quality of Life in Diabetic Foot Ulcer: Associated Factors and the Impact of Anxiety/Depression and Adherence to Self-Care. Int J Low Extrem Wounds. 2020;19(2):165-179.
43. Rice JB, Desai U, Cummings AKG, Birnbaum HG, Skornicki M, Parsons NB. Burden of Diabetic Foot Ulcers for Medicare and Private Insurers. Diabetes Care. 2014;37(3):651-658.
44. Raghav A, Khan ZA, Labala RK, Ahmad J, Noor S, Mishra BK. Financial burden of diabetic foot ulcers to world: a progressive topic to discuss always. Ther Adv Endocrinol Metab. 2018;9(1):29-31.
45. Kerr M, Barron E, Chadwick P, et al. The cost of diabetic foot ulcers and amputations to the National Health Service in England. Diabetic Medicine. 2019;36(8):995-1002.
46. Reeder CE. Overview of pharmacoeconomics and pharmaceutical outcomes evaluations. Am J Health Syst Pharm. 1995;52(19 Suppl 4):S5-8.
47. 楊忠霖. 伴隨臨床試驗同步進行藥物經濟研究. 當代醫藥法規月刊. 2017;77.
48. Thomas D, Hiligsmann M, John D, Al Ahdab OG, Li H. Chapter 18 - Pharmacoeconomic Analyses and Modeling. In: Thomas D. Clinical Pharmacy Education, Practice and Research: Elsevier; 2019.
49. Rai M, Goyal R. Chapter 33 - Pharmacoeconomics in Healthcare. In: Vohora D, Singh G. Pharmaceutical Medicine and Translational Clinical Research. Boston: Academic Press; 2018.
50. Organization WH. The world health report 2002: reducing risks, promoting healthy life: World Health Organization; 2002.
51. 財團法人醫藥品查驗中心. 醫療科技評估方法學指引. 2013.
52. Jain R, Grabner M, Onukwugha E. Sensitivity analysis in cost-effectiveness studies: from guidelines to practice. Pharmacoeconomics. 2011;29(4):297-314.
53. Persson U, Willis M, Odegaard K, Apelqvist J. The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data. Value Health. 2000;3 Suppl 1:39-46.
54. Redekop WK, McDonnell J, Verboom P, Lovas K, Kalo Z. The cost effectiveness of Apligraf treatment of diabetic foot ulcers. Pharmacoeconomics. 2003;21(16):1171-1183.
55. Flack S, Apelqvist J, Keith M, Trueman P, Williams D. An economic evaluation of VAC therapy compared with wound dressings in the treatment of diabetic foot ulcers. J Wound Care. 2008;17(2):71-78.
56. Ragnarson Tennvall G, Apelqvist J. Prevention of diabetes-related foot ulcers and amputations: a cost-utility analysis based on Markov model simulations. Diabetologia. 2001;44(11):2077-2087.
57. Cheng Q, Lazzarini PA, Gibb M, et al. A cost-effectiveness analysis of optimal care for diabetic foot ulcers in Australia. International Wound Journal. 2017;14(4):616-628.
58. Wu B, Wan X, Ma J. Cost-effectiveness of prevention and management of diabetic foot ulcer and amputation in a health resource-limited setting. Journal of Diabetes. 2018;10(4):320-327.
59. Tesar T, Szilberhorn L, Nemeth B, Nagy B, Wawruch M, Kalo Z. Cost-Utility Analysis of Heberprot-P as an Add-on Therapy to Good Wound Care for Patients in Slovakia with Advanced Diabetic Foot Ulcer. Frontiers in Pharmacology. 2017;8(946).
60. Lund CI. A Cost-utility analysis of Diabetic Foot Ulcer treatment in Norway: A Markov model2018.
61. Linertová R, Del Pino-Sedeño T, Pérez LG, et al. Cost-effectiveness of Platelet-Rich Plasma for Diabetic Foot Ulcer in Spain. Int J Low Extrem Wounds. 2020:1534734620903239.
62. Maunoury F, Oury A, Fortin S, Thomassin L, Bohbot S, on behalf of the Explorer S. Cost-effectiveness of TLC-NOSF dressings versus neutral dressings for the treatment of diabetic foot ulcers in France. PLOS ONE. 2021;16(1):e0245652.
63. Siebert U. When should decision-analytic modeling be used in the economic evaluation of health care? The European Journal of Health Economics, formerly: HEPAC. 2003;4(3):143-150.
64. de Oliveira FFM, Torres AF, Gonçalves TB, et al. Efficacy of Plectranthus amboinicus (Lour.) Spreng in a Murine Model of Methicillin-Resistant Staphylococcus aureus Skin Abscesses. Evid Based Complement Alternat Med. 2013;2013:291592-291592.
65. Gohil KJ, Patel JA, Gajjar AK. Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all. Indian J Pharm Sci. 2010;72(5):546-556.
66. Cheng H. Evaluate the Efficacy and Safety of ON101 Cream for the Treatment of Chronic Diabetic Foot Ulcers. (2012, November 23 - 2020, May 11); Identifier NCT01898923. Available at: https://ClinicalTrials.gov/show/NCT01898923.
67. Briggs A, Sculpher M. An Introduction to Markov Modelling for Economic Evaluation. PharmacoEconomics. 1998;13(4):397-409.
68. Carter MJ. Dehydrated human amnion and chorion allograft versus standard of care alone in treatment of Wagner 1 diabetic foot ulcers: a trial-based health economics study. Journal of Medical Economics. 2020:1-11.
69. Kuo S, Yang C-T, Chen H-Y, Ou H-T. Valuing health states of people with type 2 diabetes: Analyses of the nationwide representative linked databases. Journal of Diabetes Investigation.n/a(n/a).
70. Redekop WK, Stolk EA, Kok E, Lovas K, Kalo Z, Busschbach JJ. Diabetic foot ulcers and amputations: estimates of health utility for use in cost-effectiveness analyses of new treatments. Diabetes Metab. 2004;30(6):549-556.
71. Christman AL, Selvin E, Margolis DJ, Lazarus GS, Garza LA. Hemoglobin A1c predicts healing rate in diabetic wounds. J Invest Dermatol. 2011;131(10):2121-2127.
72. Fesseha BK, Abularrage CJ, Hines KF, et al. Association of Hemoglobin A(1c) and Wound Healing in Diabetic Foot Ulcers. Diabetes Care. 2018;41(7):1478-1485.
73. Lane KL, Abusamaan MS, Voss BF, et al. Glycemic control and diabetic foot ulcer outcomes: A systematic review and meta-analysis of observational studies. Journal of diabetes and its complications. 2020;34(10):107638-107638.
74. Al-Rubeaan K, Al Derwish M, Ouizi S, et al. Diabetic foot complications and their risk factors from a large retrospective cohort study. PLoS One. 2015;10(5):e0124446.
75. Fu X-L, Ding H, Miao W-W, Chen H-L. Association Between Cigarette Smoking and Diabetic Foot Healing: A Systematic Review and Meta-Analysis. The International Journal of Lower Extremity Wounds. 2018;17(4):247-257.
76. Xia N, Morteza A, Yang F, Cao H, Wang A. Review of the role of cigarette smoking in diabetic foot. Journal of Diabetes Investigation. 2019;10(2):202-215.
77. Kim S-Y, Kim TH, Choi J-Y, et al. Predictors for Amputation in Patients with Diabetic Foot Wound. Vasc Specialist Int. 2018;34(4):109-116.
78. Vera-Cruz PN, Palmes PP, Tonogan L, Troncillo AH. Comparison of WIFi, University of Texas and Wagner Classification Systems as Major Amputation Predictors for Admitted Diabetic Foot Patients: A Prospective Cohort Study. Malays Orthop J. 2020;14(3):114-123.
79. Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the patient's perspective. Ther Clin Risk Manag. 2008;4(1):269-286.
80. Cabeceira HDS, Souza D, Juliano Y, Veiga DF. Work ability and productivity in patients with diabetic foot. Clinics (Sao Paulo). 2019;74:e421.