Submission to Applied Health Economics and Health Policy Systematic Assessment of Decision-analytic Models for Chronic Myeloid Leukemia Ursula Rochau 1,2 , Ruth Schwarzer 1,2 , Beate Jahn 1,2 , Gaby Sroczynski 1,2 , Martina Kluibenschaedl 1,2 , Dominik Wolf 3,4 , Jerald Radich 5 , Diana Brixner 1,2,6 , Guenther Gastl 3 , Uwe Siebert 1,2,7,8 1 Division of Public Health Decision Modelling, Health Technology Assessment and Health Economics, ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria; 2 Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria; 3 Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Austria; 4 Internal Medicine III, University of Bonn, Germany; 5 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 6 Department of Pharmacotherapy and Program in Personalized Health Care, University of Utah, Salt Lake City, Utah, USA; 7 Center for Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USA; 8 Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 1
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static-content.springer.com10.1007/s402… · Web viewAWP = Average wholesale prices; BMT = Bone marrow transplantation; BNF = British National Formulary; CEA = Cost-effectiveness
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Submission to Applied Health Economics and Health Policy
Systematic Assessment of Decision-analytic Models for Chronic
Myeloid Leukemia
Ursula Rochau1,2, Ruth Schwarzer1,2, Beate Jahn1,2, Gaby Sroczynski1,2, Martina
A restricted search was performed in EconLit via Harvard (update search date:
8.9.2013) and Tufts CEA Registry. Econlit: TI=cml OR TI=(leukemia or leukaemia)
A broader search was performed inTufts CEA Registry.
TI: CML OR Chronic Myeloid Leukemia OR Chronic Myeloid Leukaemia OR chronic
myelogenous leukemia OR chronic myelogenous leukaemia
3
Table II: Summary of Cost-Effectiveness Results and Conclusions of Included Studies[1, 2]
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
Pre-imatinib era
Beck et al. 2001[3],university medical centers in North America & Europe
CEA, CUA, U.S.$, estimated 2000
Efficacy: RCT (FCMLG)QoL/Utilities: Updated Kattan et al. 1996[4]Costs: Updated Kattan et al. 1996[4]
Benefits and costs: 3%
ICER discountedIFNα vs. HU: $23,491/ LY Cytarabine+IFNα vs. HU: $22,708/ LYCytarabine+IFNα vs. IFNα: $20,881/ LY ICUR discountedIFNα vs HU: $30,930/ QALY Cytarabine+IFNα vs. HU: $27,994/ QALY Cytarabine+IFNα vs. IFNα: $22,056/ QALY
ICER discountedIFNα vs. HU: $18,000/ LY Cytarabine+IFNα vs. HU: $17,400/ LYCytarabine+IFNα vs. IFNα: $16,000/ LY
ICUR discountedIFNα vs. HU: $23,700/ QALY Cytarabine+IFNα vs. HU: $21,450/ QALY Cytarabine+IFNα vs. IFNα: $16,900/ QALY
“For all plausible ranges of the efficacy of IFNα and cytarabine, the combination therapies are cost-effective with respect to chemotherapy alone.” Further,” the increment in costs with cytarabine added to IFNα is more than offset by the extra increment in QALE.”
Kattan et al. 1996[4],university medical centers North America & Europe
CEA, CUA, U.S.$, estimated 1995
Efficacy: RCTs, published studies, clinician panelQoL/Utilities: Clinical panel: Direct scalingCosts: U.S./ 2 European cancer centers, clinical-cost accounting systems
Benefits and costs: 5%
ICER discountedIFNα vs. HU: $39,078/ year of life savedICUR discountedIFNα vs. HU: $51,317/ QALY
ICER discountedIFNα vs. HU: $26,500/ year of life savedICUR discountedIFNα vs. HU: $34,800/ QALY
“Compared with HU, IFNα is, in most clinical scenarios, a cost-effective initial therapy for patients with chronic-phase CML who can tolerate the drug.”
Liberato et al. 1997[5],Italy
CUA, U.S.$, 1995
Efficacy: RCTs, published studies QoL/Utilities: 10 physicians: VAS Costs: Retail drug prices; published literature, expert panel judgments
Benefits and costs: 5%
ICUR discountedIFNα Scenario A vs. chemotherapy: $131,981/ QALY IFNα Scenario B vs. chemotherapy: $93,640/ QALY
ICUR discountedIFNα Scenario A vs. chemotherapy: $89,500/ QALY IFNα Scenario B vs. chemotherapy: $63,500/ QALY
“In conclusion, IFNα adds an effective option to the treatment of CML, but is expensive in the most common protocols.”
4
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Efficacy: 4 RCTsQoL/Utilities: Not evaluatedCosts: Published literature
Benefits and costs: 5%
ICER discountedIFNα vs. control group 1)German trial: $130,866/ LY 2)English trial: $180,724/ LY 3)Italian trial: $236,617/ LY 4)Japanese trial: $317,214/ LY
ICER discountedIFNα vs. control group 1)German trial: $93,461/ LY 2)English trial: $129,068/ LY 3)Italian trial: $168,985/ LY 4)Japanese trial: $226,545/ LY
“Our cost-effectiveness study gave a 'negative' result because our findings showed that an unselected use of IFNα in CML has an unfavorable pharmacoeconomic ranking.”
Imatinib era
Chen et al. 2009[7],China
CEA, CUA, RMB, estimated 2008
Efficacy: RCTs (incl. IRIS), published studiesQoL/Utilities: Reed et al. 2004[8]Costs: Retail price, unit costs top tier hospitals
Benefits and costs: 3.5%
ICER discounted Imatinib vs. IFNα: $20,463/ LYICUR discounted Imatinib vs. IFNα: $20,126/ QALY
ICER discounted Imatinib vs. IFNα: RMB74,908/ LYICUR discounted Imatinib vs. IFNα: RMB73,674/ QALY
“This study confirms that imatinib is more cost-effective than IFNα from the Chinese public health-care system perspective“.
Dalziel et al. 2004[9],U.K.
CUA, £, 2002
Efficacy: RCTs, published studiesQoL/Utilities: Patients (IRIS): EQ-5D (Imatinib, IFNα), estimates clinical panel from Kattan et al. 1996[4], (HU)Costs: BNF, SUHT, NHS Trust databases
Benefits: 1.5%, Costs: 6%
ICUR discounted (undiscounted) Imatinib vs. IFNα: $52,108/ QALY ($63,217/ QALY)Imatinib vs. HU: $173,033/ QALY ($167,393/ QALY)
ICUR discounted (undiscounted) Imatinib vs. IFNα: £26,180/ QALY (£31,761/ QALY)Imatinib vs. HU: £86,934/ QALY (£84,100/ QALY)
“Imatinib appears to be more effective than current standard drug treatments in terms of cytogenetic response and PFS, with fewer side-effects.”
Gordois et al. 2003[10]U.K.
CUA, £, 2001
Efficacy: RCTs, published studies, clinician panelQoL/Utilities: 6 clinicians using the EQ-5DCosts: Chartered Institute of Public Finance and Accountancy, Dept. of Health, 6 NHS Trusts, published literature
Benefits: 1.5%, Costs: 6%
ICUR discountedAccelerated Phase Imatinib vs. comparator: $59,408/ QALY Blast Crisis Phase Imatinib vs. comparator: $85,514/ QALY
ICUR discountedAccelerated Phase Imatinib vs. comparator: £ 29,344/ QALY Blast Crisis Phase Imatinib vs. comparator: £42,239/ QALY
"We conclude that treatment of CML with imatinib confers considerably greater survival and quality of life than conventional treatments but at a cost."
Reed et al. CEA, Efficacy: RCTs (incl. IRIS, Benefit ICER discounted (undiscounted) ICER discounted (undiscounted) “The results of the current study
5
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
2004[8]U.S.
CUA, U.S.$, 2002
FCMLG), published studiesQoL/Utilities: Patients (IRIS): EQ-5D (imatinib, IFNα+LDAC); no data HU: imatinib utility values used Costs: Medication costs: Red Book, outpatient visits/inpatient costs: Medicare
s and costs: 3%
Imatinib vs. IFNα+LDAC: $53,841/ LYS,($48,844/ LYS)ICUR discounted (undiscounted) Imatinib vs. IFNα+LDAC: $54,091/ QALY ($51,843/ QALY)
Imatinib vs. IFNα+LDAC: $43,100/ LYS,($39,100/ LYS)ICUR discounted (undiscounted) Imatinib vs. IFNα+LDAC: $43,300/ QALY ($41,500/ QALY)
demonstrate that compared with IFNα plus LDAC, imatinib is a cost-effective first-line therapy in patients with newly diagnosed chronic-phase CML.”
Reed et al. 2008[11](update Reed et al. 2004[8]), U.S.
CEA, CUA, U.S.$, 2006
Efficacy: Reed et al. 2004[8]., update IRISQoL/Utilities: Reed et al.2004[8]Costs: Medications: AWP Red Book, WAC, Medi-Span; outpatient visits/ inpatient costs: Medicare
Benefits and costs: 3%
ICER discounted (undiscounted) Imatinib vs. IFNα+LDAC using AWP: $59,679/ LY ($53,657/ LY); using WAC: $48,124/ LY ($43,868/ LY) ICUR discounted (undiscounted) Imatinib vs. IFNα+LDAC using AWP: $63,656/ QALY ($60,050/ QALY); using WAC: $51,370/ QALY ($49,106/ QALY)
ICER discounted (undiscounted) Imatinib vs. IFNα+LDAC using AWP: $53,535/ LY ($48,133/ LY) using WAC: $43,170/ LY ($39,352/ LY) ICUR discounted (undiscounted) Imatinib vs. IFNα+LDAC using AWP: $57,103/ QALY ($53,868/ QALY) using WAC: $46,082/ QALY ($44,051/ QALY)
“Although the analysis revealed that the original survival estimates were conservative, the updated cost-effectiveness ratios were consistent with, or slightly higher than, the original estimates, depending on the method for assigning costs to study medications.”
Warren et al. 2004[12],U.K.
CUA , £, 2001
Efficacy: RCTs, published studiesQoL/Utilities: Panel of clinicians: EQ-5DCosts: BNF, NHS reference costs, Personal Social Services Research Unit, authors' assumptions
Benefits: 1.5%, Costs: 6%
ICUR discounted Imatinib vs. HU: $77,880/ QALY
ICUR discounted Imatinib vs. HU: £38,468/ QALY
"In the present model analysis, imatinib as a second-line treatment for patients with chronic phase CML was found to offer considerable health benefits to patients, but at a cost to the payer."
Second-generation TKIsGhatnekar et al.
CEA, CUA, €,
Efficacy: RCT (12 week head-to-head), published literature
Benefits and
ICER discountedDasatinib vs. Imatinib: $8,167/ LY
ICER discountedDasatinib vs. Imatinib: €6,332/ LY
“The results indicate that dasatinib treatment in CML
6
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
2010[13],Sweden
2008 QoL/Utilities: 100 U.K. lay persons: TTO using the EQ-5DCosts: Treatment practice: 2 Swedish hematologists; Unit cost: FASS, regional tariffs and fees, income distribution survey, consumption and production in Sweden
costs: 3%
ICUR discounted Dasatinib vs. Imatinib: $8,873/ QALY
ICUR discounted Dasatinib vs. Imatinib: €6,880/ QALY
patients resistant to standard dose imatinib in Sweden is a cost-effective treatment in comparison to imatinib 800 mg/daily. Dasatinib is expected to generate greater health benefits at a cost per QALY of about €6,880 with a life-long societal perspective.”
Hoyle et al, 2011[14] (Rogers et al. 2012[15]),U.K.
CEA, CUA, £,2009-2010
Efficacy: several trials from systematic reviewQoL/Utilities: adopted from Reed[8, 11]Costs: Expert opinion, trials, BNF, Curtis
Benefits and costs: 3.5%
Imatinib intolerant:ICER discountedDasatinib vs. IFNα : $76,107/ LY Nilotinib vs. IFNα : $108,833/ LYICUR discountedDasatinib vs. IFNα : $131,132/ QALY Nilotinib vs. IFNα: $166,175/ QALYImatinib resistantICER discountedDasatinib vs. high dose-imatinib: $74,841/ LYNilotinib vs. high dose-imatinib: Nilotinib dominatesICUR discounted Dasatinib vs. high dose-imatinib$145,226/ QALYNilotinib vs. high dose-imatinib: Nilotinib dominates
Imatinib intolerant:ICER discountedDasatinib vs. IFNα: £47,951/ LY Nilotinib vs. IFNα: £68,570/ LYICUR discounted Dasatinib vs. IFNα: £82,619/ QALYNilotinib vs. IFNα: £104,698 QALYImatinib resistant: ICER discountedDasatinib vs. high dose-imatinib: £47,153/ LY Nilotinib vs. high dose-imatinib: Nilotinib dominatesICUR discounted Dasatinib vs. high dose-imatinib: £91,499/ QALYNilotinib vs. high dose-imatinib: Nilotinib dominates
“Whilst clinical data remains immature, the cost-effectiveness of dasatinib and nilotinib for imatinib-resistant people is highly uncertain. Both nilotinib and dasatinib are highly unlikely to be cost-effective versus IFNα for people intolerant to imatinib.”
Loveman et al. 2012[16]
CEA,
CUA , £, 2009-2010
Parameters mostly adopted from Hoyle et al.[14] (Rogers et al.[15]), Drug costs: BNF
Costs and benefits 3.5%
ICUR discounted:Nilotinib vs. HU: $41,956/ QALY
Dasatinib vs. Nilotinib: $79,385/ QALY
ICUR discountedNilotinib vs.HU: £26,434 / QALYDasatinib vs. nilotinib: £50,016 / QALYRemaining strategies were dominated
“Nilotinib and dasatinib are slightly more cost-effective than high-dose imatinib because of slightly lower costs and better
7
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
Remaining strategies were dominated effectiveness than high-dose imatinib.”“It is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to the great uncertainty around data inputs.”
Pavey et al. 2012[17]
CEA, CUA, £, 2011-2012
Efficacy: several trials from systematic reviewQoL/Utilities: adapted from Reed[8], Lee[18], Dalziel[9]Costs: BNF, MIMS, Oxford
Outcomes 2009 survey, (NSRC), Curtis, trials and manufacturer submissions
Costs and benefits 3.5%
Scenario 1ICER discountedNilotinib vs. imatinib: $17,657/ LYDasatinib vs. imatinib: $301,643/ LYNilotinib vs. dasatinib: $-142,728/ LYICUR discounted:Nilotinib vs. imatinib: $36,786/ QALYDasatinib vs. imatinib: $609,172/ QALYNilotinib vs. dasatinib: Dasatinib dominatedScenario 2ICUR discounted:Nilotinib vs. imatinib: $29,429/ QALYDasatinib vs. imatinib: $376,686/ QALYNilotinib vs. dasatinib: Dasatinib dominatedScenario 3ICER discountedImatinib+2LNilo vs. nilotinib: Nilotinib cost-savingImatinib+2LNilo vs. dasatinib+2LNilo: $295,757/ LY
Scenario 1ICER discountedNilotinib vs. imatinib: £12,000/ LYDasatinib vs. imatinib: £205,000/ LYDasatinib vs. nilotinib: Dasatinib dominatedICUR discounted:Nilotinib vs. imatinib: £25,000/ QALYDasatinib vs. imatinib: £414,000/ QALYDasatinib vs. nilotinib: Dasatinib dominatedScenario 2ICUR discounted:Nilotinib vs. imatinib: : £20,000/ QALYDasatinib vs. imatinib: £256,000/ QALYDasatinib vs. nilotinib: : Dasatinib dominatedScenario 3ICER discountedImatinib+2LNilo vs. nilotinib: Nilotinib cost-savingImatinib+2LNilo vs. dasatinib+2LNilo: £201,000/ LYNilotinib vs. dasatinib+2LNilo: £356,000/
“… assuming the use ofsecond-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib for most scenarios. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY are used, compared with imatinib and nilotinib.
8
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
Nilotinib vs. dasatinib+2LNilo: $523,829/ LYICUR discounted:Imatinib+2LNilo vs. nilotinib: $282,515/ QALYImatinib+2LNilo vs. dasatinib+2LNilo: $662,144/ QALYNilotinib vs. dasatinib+2LNilo: $507,643/ QALYScenario 4Imatinib+2LNilo vs. nilotinib: $67,686/ QALYImatinib+2LNilo vs. dasatinib+2LNilo: $442,900/ QALYNilotinib vs. dasatinib+2LNilo: $183,929/ QALY
LYICUR discounted:Imatinib+2LNilo vs. nilotinib: £192,000/ QALYImatinib+2LNilo vs. dasatinib+2LNilo: £450,000/ QALYNilotinib vs. dasatinib+2LNilo: £345,000/ QALYScenario 4Imatinib+2LNilo vs. nilotinib: £46,000/ QALYImatinib+2LNilo vs. dasatinib+2LNilo: £301,000/ QALYNilotinib vs. dasatinib+2LNilo: £125,000/ QALY
BMT/ peripheral SCT
Breitscheidel 2008[19],Germany
CUA, €, 2005
Efficacy: RCT (IRIS), published studies QoL/Utilities: Patients (IRIS) EQ-5D (Imatinib); clinical panel: STG (rescaled, Lee et al. 1997[18], SCT)Costs: Red Book, DRG, EBM
Benefits and costs: 3%
ICUR discounted (undiscounted) Imatinib vs. MUD-SCT: $92,594/ QALY ($102,752/ QALY)
ICUR discounted (undiscounted) Imatinib vs. MUD-SCT: €69,764/ QALY (€77,410/ QALY)
“Imatinib is more costly but more effective (as measured in QALYs) over a 5-year time horizon. The resulting ICER of €77,410/ QALY is higher than commonly cited thresholds.”
Lee et al. 1997[18],IBMTR, NMDP U.S.
UA Efficacy: Published studies, clinician panelQoL/Utilities: 12 physicians: STGCosts: Not evaluated
Benefits: 3%, Costs: not evaluated
Unadjusted LE (in years)1)No BMT: 5.312)BMT within 1 year: 17.01 3)BMT at 1 to 2 years: 13.26 4)BMT at 2 to 3 years: 11.90 5)BMT at >3 years: 12.65 QALE discounted (in years)
“These results support the use of early unrelated donor bone marrow transplantation for most patients with CML.”
9
Author, year, country
Study type, currency, index year
Data sources Annual discount rate
Cost-effectiveness/ utility relation in US $ (October 2011) ¥, †
Cost-effectiveness/ utility relation Conclusions
1)No BMT: 4.74 2)BMT within 1 year: 10.07 3)BMT at 1 to 2 years: 8.11 4)BMT at 2 to 3 years: 7.51 5)BMT at >3 years: 8.08
Lee et al. 1998[20],U. S.
CUA , US$, 1996
Efficacy: Meta-analysis of 7 RCTs, Lee et al. 1997[18]QoL/Utilities: Lee et al. 1997[18]Costs: Medical costs: accounting systems BWH, FHCRC; Medication costs: AWP, Red Book, pPatient records, published studies
Benefits and costs: 3%
ICUR discountedBMT vs. IFNα: $74,196/ QALY BMT vs. HU: $79,495/ QALY
ICUR discountedBMT vs. IFNα: $51,800/ QALY BMT vs. HU: $55,500/ QALY
“Unrelated donor transplantation for CML is expensive in absolute costs, but because it prolongs life substantially for some patients, the ratio of costs to effectiveness is in the range of other well-accepted medical interventions.”
Skrepnek and Ballard 2005[21],U.S.
CEA U.S.$, 2004
Efficacy: RCTs (incl. IRIS), published studiesQoL/Utilities: Not evaluatedCosts: Fee Reference, Physicians' Fee and Coding Guide, average wholesale prices; expert clinical opinion; published data
Benefits: n.r., Costs: 5%
ICER discounted Markov cohort analysis: Imatinib vs. BMT: -$90,167/ survival Monte Carlo microsimulation: Imatinib vs. BMT: -$5,948/ survival
ICER discounted Markov cohort analysis: Imatinib vs. BMT: -$75,789/ survival Monte Carlo microsimulation: Imatinib vs. BMT: -$5,000/ survival
"In most cases, imatinib was both less costly and more efficacious than BMT in the 2-year treatment of CML."
Legend:AWP = Average wholesale prices; BMT = Bone marrow transplantation; BNF = British National Formulary; CEA = Cost-effectiveness
analysis; CML = Chronic myeloid leukemia; CUA = Cost-utility analysis; Curtis = Unit Costs of Health and Social Care; DRG = Diagnosis
10
Related Groups; EBM = German Common Tariff Scale (Einheitlicher Bewertungsmaßstab der kassenärztlichen Bundesvereinigung); EQ-5D
= EuroQol 5D questionnaire; FASS = Pharmaceutical specialties in Sweden; FCMLG = French Chronic Myeloid Leukemia Study Group; HU
= Hydroxyurea; IBMTR = International Bone Marrow Transplant Registry; ICER = Incremental cost-effectiveness ratio; ICUR = Incremental
cost-utility ratio; IFNα = Interferon-alpha; IRIS = International Randomized Study of Interferon and STI571; LE = Life expectancy; LY =Life
year; LYS =Life years saved; LDAC = Low-dose cytarabine; MIMS = Monthly Index of Medical Specialties; MUD-SCT = Allogeneic stem cell
transplantation with a matched unrelated donor; NHS = National Health Service; NMDP = National Marrow Donor Program; NHS = National
Health Service; PFS = Progression-free survival; QALE = quality-adjusted life expectancy; QALY = Quality-adjusted life year; QoL = Quality