Supplementary Appendix A: Cost-effectiveness Model: Additional Input Parameter Values

Transcription

1 Supplementary Appendix A: Cost-effectiveness Model: Additional Input Parameter Values

2 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Detailed Input Tables Table A.1: Annual Probability of Moving Between EDSS States for Patients With Relapsing-Remitting Multiple Sclerosis EDSS State at EDSS State at End of Year Start of Year EDSS = Expanded Disability Status Scale. Note: Data from dimethyl fumarate clinical trials was based on intent-to-treat placebo arms only. Source: London Ontario (Scalfari et al., 2010) (EDSS 8-9) and dimethyl fumarate clinical trial data (placebo data, EDSS 0-7, DEFINE and CONFIRM). 2

3 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.2: Annual Probability of Conversion From Relapsing-Remitting Multiple Sclerosis to Secondary Progressive Multiple Sclerosis, by EDSS State Initial EDSS State EDSS + 1 in SPMS EDSS = Expanded Disability Status Scale; SPMS = secondary progressive multiple sclerosis. Source: London Ontario (Scalfari et al., 2010). 3

4 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.3: Annual Probability of Moving Between EDSS States for Patients With Secondary Progressive Multiple Sclerosis EDSS State at EDSS State at End of Year Start of Year EDSS = Expanded Disability Status Scale. Source: London Ontario (Scalfari et al., 2010). 4

5 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.4: Annual Relapse Rate per EDSS State: Trial Based and Observational Data Based EDSS State Trial-Based Annual Relapse Rate, RRMS Adjusted Annual Relapse Rate, SPMS Observational Data Annual Relapse Rate, RRMS Observational Data Annual Relapse Rate, SPMS EDSS = Expanded Disability Status Scale; RRMS = relapsing-remitting multiple sclerosis, SPMS = secondary progressive multiple sclerosis. Sources: Trial-based rates used data on file from Biogen Idec for RRMS, as well as data from Patzold and Pocklington (1982) and Orme et al. (2007) where EDSS state-specific data were not available in the trial for RRMS. Adjusted annual relapse rate for SPMS represent observational data annual rates adjusted upwards by the ratio of the trial-based annual relapse rates for RRMS and the observational data annual relapse rates for RRMS. Observational data rates used data from Patzold and Pocklington (1982). 5

6 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.5: Calculated Mortality Multipliers of All-Cause General Population Mortality, by EDSS State EDSS State Mortality Multiplier EDSS = Expanded Disability Status Scale. Source: Calculated using linear interpolation from (Pokorski, 1997). 6

7 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.6: Studies Included in the Mixed-Treatment Comparison Analysis Studies Included in the Mixed-Treatment Comparison Analyses 1. AFFIRM trial (placebo vs. natalizumab 300 mg every 4 weeks) 2. BECOME trial (IFNβ-1b 250 mcg every other day vs. glatiramer acetate 20 mg once daily) 3. BEYOND trial (IFNβ-1b 250 mcg every other day vs. glatiramer acetate 20 mg once daily) 4. Bornstein 1987 (placebo vs. glatiramer acetate 20 mg once daily) 5. Calabrese 2011 (IFNβ-1a 30 mcg once weekly vs. IFNβ-1a 44 mcg three times each week vs. glatiramer acetate 20 mg once daily) 6. CONFIRM trial (placebo vs. glatiramer acetate 20 mg once daily vs. dimethyl fumarate 240 mg twice daily) 7. Copolymer 1 trial (placebo vs. glatiramer acetate 20 mg once daily) 8. DEFINE trial (placebo vs. dimethyl fumarate 240 mg twice daily) 9. Etemadafir 2006 (IFNβ-1a 44 mcg three times each week vs. IFNβ-1b 250 mcg every other day vs. IFNβ-1a 30 mcg once weekly) 10. European and Canadian glatiramer trial (placebo vs. glatiramer acetate 20 mg once daily) 11. EVIDENCE trial (IFNβ-1a 30 mcg once weekly vs. IFNβ-1a 44 mcg three times each week) 12. FREEDOMS trial (placebo vs. fingolimod once daily 0.5 mg once daily) 13. IFNB MS trial (placebo vs. IFNβ-1b 250 mcg every other day) 14. IMPROVE trial (placebo vs. IFNβ-1a 44 mcg three times each week) 15. INCOMIN trial (IFNβ-1a 30 mcg once weekly vs. IFNβ-1b 250 mcg every other day) 16. Knobler 1993 (placebo vs. IFNβ-1b 250 mcg every other day) 17. MSCRG trial (placebo vs. IFNβ-1a 30 mcg once weekly) 18. PRISMS trial (placebo vs. IFNβ-1a 22 mcg three times each week vs. IFNβ-1a 44 mcg three times each week) 19. REGARD trial (IFNβ-1a 44 mcg three times each week vs. glatiramer acetate 20 mg once daily) 20. TRANSFORMS trial (IFNβ-1a 30 mcg once weekly vs. fingolimod once daily 0.5 mg once daily) 21. TEMSO trial (placebo vs. teriflunomide 7 mg once daily vs. teriflunomide 14 mg once daily) IFNβ = interferon beta; MS = multiple sclerosis. a Studies 1-21 were included in the mixed-treatment comparison analysis of relative risk of relapse; studies 1, 3, 4, 6, 7, 8, 12, 18, and 21 were used in the mixed-treatment comparison analysis of hazard ratio for disability progression. 7

8 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.7: Estimation of Annual Disease-Modifying Therapy Acquisition Cost Treatment Dimethyl fumarate Glatiramer acetate, 20 mg OD Glatiramer acetate, 40 mg TIW Fingolimod Administration Method, Recommended Dose, Number of Doses per Pack Oral, 240 mg twice a day, 60 doses per pack Injection 20 mg daily, 30 doses per pack 40 mg three times a week, 12 doses per pack Oral, 500 micrograms daily, 28 doses per pack Number of Packs per Year WAC Cost per Pack Annual Treatment Cost (USD) 12.2 $5,460 $66, $6,110 $74, $5,008 $65, $5,442 $70,752 OD = once a day; TIW = three times a week; USD = United States dollars; WAC = wholesale acquisition cost. All costs reported in 2015 US dollars ($). Source: First Data Bank, April 8,

9 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.8: Annual Administration Costs for Each Disease-Modifying Therapy Considered in the Model Treatment Annual Administration Cost (First Year) Resource Use Glatiramer acetate $ Self-administered, taught by nurse (3 hours of day nurse s time) Fingolimod Dimethyl fumarate $0.00 Assumption: oral DMTs have no associated administration cost Annual Administration Cost (Second Year) Resource Use $36.64 Self-administered, but continuing issues requiring 1 hour nurse time per year throughout administration $0.00 Assumption: oral DMTs have no associated administration cost DMTs = disease-modifying therapies. All costs reported in 2015 United States dollars. Source: personal communication from a US neurologist (2013); Bureau of Labor Statistics (2012); Bureau of Labor Statistics (2015). 9

10 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.9: Annual Monitoring Costs for Each Disease-Modifying Therapy Considered in the Model (USD) Treatment Annual Monitoring Cost in First Year of Treatment Resource Use Dimethyl fumarate $ Neurology visits 4 Complete blood counts 4 Liver panels Annual Monitoring Cost in Subsequent Years of Treatment Resource Use $ Neurology visits 4 Complete blood counts 4 Liver panels Glatiramer acetate $ Neurology visits $ Neurology visits Fingolimod $ Neurology visits 1 Complete blood count 1 Liver panel 2 Ophthalmologist visits First-dose patient observation by health care professional 2 Electrocardiograms $ Neurology visits 1 Complete blood count 1 Liver panel USD = United States dollars. All costs reported in 2015 US dollars. Sources: personal communication from a US neurologist (2013); Gilenya prescribing information (2012); OptumInsight (2013); Novartis Pharmaceuticals UK, Ltd. (2011); Novartis press release (2012); Tecfidera prescribing information (2013). 10

11 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.10: List of Cost-effectiveness Model Assumptions Cost-effectiveness Model Assumptions The memory-less feature of Markov models: all patients in a particular health state had the same probability of transitioning, regardless of any previous experience. Annual cycles were used for the model as they were seen to have a suitable length for modeling the disease. Costs and utilities were applied to a midyear estimate of the cohort distribution to avoid over- or underestimation in the model. Disability progression and relapses were modeled independently, with independent treatment effects being applied to each. Patients were not allowed to switch between different DMTs, but only were allowed to discontinue treatment altogether. Patients who discontinued treatment were assumed to follow natural disease progression. The adverse events included in the model were only those that were present in the dimethyl fumarate trial, a conservative assumption. The model did not include transitions to EDSS state 10 (i.e., MS-related death) in the transition matrices. Rather, it used the mortality multiplier by MS state to account for the increased mortality. Relapses were not divided into different levels of severity, but were all assumed to have the same effects on cost and utility. In the model, relapses were allowed to have a differing quality-of-life impact depending on the EDSS state, which could be interpreted as a measure of relapse severity. In the base case, the impact was the same for all EDSS states. The treatment effect was assumed to be constant and not degrade over time in the base case, but the model was constructed to allow for alternative assumptions. Treatments had no direct effect on the risk of conversion to SPMS. Patients were assumed to discontinue treatment when they reached EDSS 7 or higher in the base case. In a sensitivity analysis, they were allowed to discontinue treatment after conversion to SPMS if that came before reaching an EDSS of 7. As a consequence of the model structure, treatments had an indirect effect on mortality in the model, since delaying progression to higher EDSS states avoided the higher mortality multipliers associated with risk of mortality from MS. As a consequence of the model structure, treatments had an indirect effect on conversion to SPMS (independent of any direct treatment effect on SPMS conversion), since delaying progression to higher EDSS states avoided the higher SPMS conversion risks. It was assumed in the model that a patient who received treatment would incur the disutility and cost associated with adverse events, for each year in the simulation. This may overestimate the impact of adverse events, as patients with severe/frequent adverse events may withdraw from treatment. In each cycle of the model, mortality was calculated based on the patient distribution at the start of the cycle. This means the models minimally underestimated mortality. This had the most effect when looking at a time horizon of 1 year. DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; SPMS = secondary progressive multiple sclerosis. 11

12 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Table A.11: Alternative Utility Scores per EDSS State EDSS Status Clinical Presentation, Disease Type No relapse RRMS SPMS Relapse RRMS SPMS EDSS = Expanded Disability Status Scale, RRMS = relapsing-remitting multiple sclerosis, SPMS = secondary progressive multiple sclerosis. Source: Kobelt et al. (2006) linear interpolation of values for EDSS < 4, EDSS 4 to 6 and EDSS > 6. 12

13 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values References Bureau of Labor Statistics (BLS). Consumer price index (CPI) for medical care Available at: Accessed June 26, Bureau of Labor Statistics (BLS). Occupational employment statistics Available at: Accessed June 26, Copaxone [prescribing information]. North Wales (PA): Teva Pharmaceuticals USA; Available at: Accessed February 26, First Data Bank, April 8, 2015 Fox RJ, Miller DH, Phillips JT, et al.; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12): Gilenya [prescribing information]. East Hanover (NJ): Novartis Pharmaceuticals Corp; Available at: Accessed February 26, Gold R, Kappos L, Arnold DL, et al.; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12): IFNB Multiple Sclerosis Study Group [No authors listed]. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology Jul;45(7): Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3): Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):

14 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Kappos L, Radue EW, O Connor P, et al.; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5): Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66(11): Novartis Pharmaceuticals UK, Ltd. Fingolimod for the treatment of relapsing-remitting multiple sclerosis in adults: NICE single technology appraisal O Connor P, Wolinsky JS, Confavreux C, et al.; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med Oct 6;365(14): doi: /NEJMoa OptumInsight. The essential RBRVS: a comprehensive listing of RBRVS values for CPT and HCPCS codes. OptumInsight, Inc; Orme M, Lerrigan J, Tyas D, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health. 2007;10: Panitch H, Goodin DS, Francis G, et al.; EVIDENCE Study Group (Evidence of Interferon Dose-Response: European North American Comparative Efficacy); University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon beta- 1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59(10): Patzold U, Pocklington PR. Course of multiple sclerosis. First results of a prospective study carried out of 102 MS patients from Acta Neurol Scand. 1982;65(4): Pokorski RJ. Long-term survival experience of patients with multiple sclerosis. J Insur Med. 1997;29(2): Polman CH, O Connor PW, Havrdova E, et al.; AFFIRM Investigators. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9): PRISMS Study Group [No authors listed]. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352(9139): PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group [No authors listed]. PRISMS-4: long term efficacy of interferon-b-1a in relapsing MS. Neurology. 2001;56(12):

15 Appendix A: Cost-effectiveness Model: Additional Input Parameter Values Sadovnick AD, Ebers GC, Wilson RW, Paty DW. Life expectancy in patients attending multiple sclerosis clinics. Neurology. 1992;42(5): Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7): Tecfidera [prescribing information]. Cambridge (MA): Biogen Idec Inc.; Available at: Accessed April 16,

16 Supplementary Appendix B: Cost-effectiveness Model: Adverse Events

17 Appendix B: Cost-effectiveness Model: Adverse Events Estimates of Adverse Event Incidence, Cost, and Utility Losses for Each Disease-Modifying Treatment The annual costs and disutility associated with adverse events (AEs) for each diseasemodifying treatment (DMT) was estimated based on the percentage of people experiencing each type of AE, the percentage of those AEs that were serious, the costs for serious and nonserious AEs, and the disutility and duration of each adverse event. The treatment-specific annual incidence of AEs was calculated from the pivotal clinical studies in relapsing-remitting multiple sclerosis (RRMS) (see Table B.1). AEs were included in the model (see Table B.2) if they met the following criteria: the most common AEs listed on the delayed-release dimethyl fumarate label (Tecfidera prescribing information, 2013) ( 5% incidence in any treatment group of delayed-release dimethyl fumarate studies) or the common delayed-release dimethyl fumarate AEs on the label that have been reported in the published literature. AEs that had an incidence at least 3% higher in the total delayedrelease dimethyl fumarate group than in the placebo group were also included, even if overall incidence in the delayed-release dimethyl fumarate arm was less than 5%. The AEs included for comparators were only those reported in delayed-release dimethyl fumarate studies. The proportion of each AE that was serious (grade 3 or 4) was also estimated using trial data (see Table B.3). For each common included AE, the number of reported serious events was used to calculate the proportion of events that were serious for patients on each treatment. Separate quality-of-life and cost implications were assigned to these serious events. The number of serious AEs was available only from the CONFIRM and DEFINE studies. Therefore, the following approach was taken: For delayed-release dimethyl fumarate, the proportions of AEs that were serious were taken from the dimethyl fumarate twice-daily arms of the CONFIRM and DEFINE clinical studies. Where data were available from more than one study regarding same event, a weighted average was taken. For glatiramer acetate, the proportion of AEs that were serious was taken from the glatiramer acetate arm of the CONFIRM clinical study. For fingolimod, the proportions of AEs that were serious were taken from the fingolimod 0.5 mg arm of the TRANSFORMS and FREEDOMS clinical studies. Where data were available from more than one study regarding same event, a weighted average was taken. The cost of treating each nonserious or serious AE was included in the model and was calculated from the expected resource use of treating a patient with a specific adverse event, taken from publicly available literature, validated by clinical expert opinion, and 2

18 Appendix B: Cost-effectiveness Model: Adverse Events multiplied by appropriate unit costs (see Table B.4). In some situations for example, where publicly available data were not available clinical experts provided the resource use estimates. The average annual cost for the treatment of all AEs for a patient on each DMT was calculated based on the estimates of annualized incidence of each AE, the proportion of AEs that were serious for that DMT, the cost for each serious AE, and the cost for each nonserious AE. The disutility from AEs was obtained from a variety of sources or assumed where no data were available (see Table B.5). The duration for each AE each year was based on clinical opinion (see Table B.6). The average annual quality-adjusted life-year (QALY) loss for all AEs for a patient on each DMT was calculated based on the estimated annualized incidence of each AE, the proportion of AEs that were serious for that treatment, the utility loss for each serious AE, and the utility loss for each nonserious AE. The average annual cost and QALYs lost for each DMT are shown in Table B.7. The incidence (and hence cost and disutility) of AEs was assumed to remain constant for all years that the patient takes the DMT (see Table B.8). 3

19 Appendix B: Cost-effectiveness Model: Adverse Events Table B.1: Pivotal Clinical Studies in RRMS Adverse Event Incidence Rates Taken from the Following Studies 1. AFFIRM trial (placebo vs. natalizumab 300 mg every 4 weeks) 2. BECOME trial (IFNβ-1b 250 mcg every other day vs. glatiramer acetate 20 mg once daily) 3. BEYOND trial (IFNβ-1b 250 mcg every other day vs. glatiramer acetate 20 mg once daily) 4. Bornstein 1987 (placebo vs. glatiramer acetate 20 mg once daily) 5. Calabrese 2011 (IFNβ-1a 30 mcg once weekly vs. IFNβ-1a 44 mcg three times each week vs. glatiramer acetate 20 mg once daily) 6. CONFIRM trial (placebo vs. glatiramer acetate 20 mg once daily vs. dimethyl fumarate 240 mg twice daily) 7. Copolymer 1 trial (placebo vs. glatiramer acetate 20 mg once daily) 8. DEFINE trial (placebo vs. dimethyl fumarate 240 mg twice daily) 9. European and Canadian glatiramer trial (placebo vs. glatiramer acetate 20 mg once daily) 10. FREEDOMS trial (placebo vs. fingolimod once daily 0.5 mg once daily) 11. REGARD trial (IFNβ-1a 44 mcg three times each week vs. glatiramer acetate 20 mg once daily) 12. TRANSFORMS trial (IFNβ-1a 30 mcg once weekly vs. fingolimod once daily 0.5 mg once daily) RRMS = relapsing-remitting multiple sclerosis. Source: Biogen Idec data on file (2013). 4

20 Appendix B: Cost-effectiveness Model: Adverse Events Table B.2: Annual Incidence of Adverse Events Included in the Model Adverse Events Dimethyl Fumarate Glatiramer Acetate Fingolimod Abdominal pain 5.14% 0.62% NA Abdominal pain upper 5.37% 0.62% NA ALT increased 3.13% 1.77% 4.88% Arthralgia 4.63% 3.70% 3.19% ACB 0.34% 0.31% 1.11% Back pain 6.66% 4.69% 6.06% Bradycardia 0.00% 0.31% 1.09% Chest pain 0.61% 1.75% 0.47% Cough 2.65% 1.40% 4.93% Depression 3.71% 4.92% 4.43% Diarrhea 7.62% 2.18% 6.98% Fatigue 6.66% 7.61% 8.05% Flu-like symptoms 0.68% 4.68% 3.50% Flushing 19.97% 1.63% NA Gastroenteritis 2.92% 0.77% NA Headache 9.56% 8.96% 16.56% Influenza 3.77% 3.49% 6.18% Leukopenia 0.48% 0.00% 0.75% Lower RTI 0.14% 0.15% 4.77% Nausea 6.60% 4.08% 7.89% Pain in extremity 4.06% 4.67% 4.13% Pruritus 4.34% 6.45% NA Rash 4.06% 2.01% 6.89% UTI 7.64% 4.93% 5.63% ACB = atrioventricular conduction block; ALT = alanine transaminase; NA = not available indicates where data were not reported or found in the systematic review; RTI = respiratory tract infection; UTI = urinary tract infection. Source: Biogen Idec data on file (2013). 5

21 Appendix B: Cost-effectiveness Model: Adverse Events Table B.3: Percentage of Adverse Events That Were Recorded as Serious Adverse Events Dimethyl Fumarate Glatiramer Acetate Fingolimod Abdominal pain 7.41% NA 0.00% Abdominal pain upper NA NA NA ALT increased NA NA NA Arthralgia 5.00% NA 0.00% ACB NA NA 100.0% Back pain 2.67% NA 4.00% Bradycardia 0.00% NA 72.35% Chest pain 0.00% NA NA Cough NA NA NA Depression 1.84% 6.67% NA Diarrhea NA NA NA Fatigue NA NA NA Flu-like symptoms 0.00% NA NA Flushing 0.65% NA NA Gastroenteritis 14.29% NA NA Headache 0.00% NA NA Influenza 0.00% NA NA Leukopenia NA NA NA Lower RTI NA NA NA Nausea 2.50% NA NA Pain in extremity NA NA NA Pruritus 0.00% NA NA Rash NA NA NA UTI 0.90% NA 5.88% ACB = atrioventricular conduction block; ALT = alanine transaminase; NA = not available indicates where data were not reported or found in the systematic review; RTI = respiratory tract infection; UTI = urinary tract infection. Source: Biogen Idec data on file (2013). 6

22 Appendix B: Cost-effectiveness Model: Adverse Events Table B.4: Cost of Adverse Events Included in the Analysis Adverse Event Cost per Nonserious Event Source Abdominal pain $ Based on 1 specialist visit (CPT code 99214) Abdominal pain upper $ Based on 1 specialist visit (CPT code 99214) ALT increased $ liver function tests after ALT increase noted in routine serum chemistry tests Arthralgia $ Based on 1 specialist visit (CPT code 99214) ACB $ Based on 2 specialist visits (CPT code 99214) and ECG Back pain $ Based on 1 specialist visit (CPT code 99214) Bradycardia $ Based on 2 specialist visits (CPT code 99214) and ECG Cost per Serious Event Source $ Based on 2 specialist visits (CPT code 99215) and liver function study $ Based on 2 specialist visits (CPT code 99215) and liver function study $ specialist visits (CPT code 99215) and 4 liver function tests after ALT increase noted in routine serum chemistry tests $ Based on 2 specialist visits (CPT code 99215) $5, Hospital or outpatient pacemaker implant (70% outpatient) $ Based on 2 specialist visits (CPT code 99215) plus an MRI $5, Hospital or outpatient pacemaker implant (70% outpatient) Chest pain $ Based on 1 specialist visit $ Based on 2 specialist visits (CPT code 99215), ECG, and enzyme tests Cough $ Based on 1 specialist visit (CPT code 99214) Depression $ Based on 2 specialist visits (CPT code 99214) and antidepressants $ Based on 1 specialist visit (CPT code 99215) $18, Based on 2 specialist visits (CPT code 99215) and hospital stay for electroconvulsive therapy Diarrhea $0.00 Assumption: no cost $ Based on 1 specialist visit (CPT code 99215) Fatigue $0.00 Assumption: no cost $0.00 Assumed no cost 7

23 Appendix B: Cost-effectiveness Model: Adverse Events Adverse Event Flu-like symptoms Cost per Nonserious Event Source $ Based on 1 specialist visit (CPT code 99214) Cost per Serious Event Source $ Based on 1 specialist visit (CPT code 99215), chest x-ray, and complete blood count Flushing $0.00 Assumption: no cost $ Based on 1 specialist visit (CPT code 99215) Gastroenteritis $ Based on 2 specialist visits (CPT code 99214) Headache $ Based on 1 specialist visit (CPT code 99214) Influenza $ Based on 1 specialist visit (CPT code 99214) and a rapid influenza test Leukopenia $ Based on 1 specialist visit (CPT code 99214) and 2 complete blood counts after leukopenia noted in routine blood tests Lower RTI $ Based on 1 specialist visit (CPT code 99214), a chest x-ray and a rapid influenza test Nausea $ Based on 1 specialist visit (CPT code 99214) and Phenergan Pain in extremity $ Based on 1 specialist visit (CPT code 99214) Pruritus $ Based on 1 specialist visit (CPT code 99214) Rash $ Based on 2 specialist visits (CPT code 99214) $9, Hospital stay for gastroenteritis with complications $ Based on 1 specialist visit (CPT code 99215) and an MRI $5, Based on hospital stay for influenza or pneumonia $ Based on 1 specialist visit (CPT code 99215) and 4 complete blood counts after leukopenia noted in routine blood tests $5, Based on hospital stay for influenza or pneumonia $ Based on 1 specialist visit (CPT code 99215), promethazine, and hydration $ Based on 1 specialist visit (CPT code 99215) and an MRI $ Based on 2 specialist visits (CPT code 99215) and topical medicine $7, Based on hospitalization for Stevens- Johnson syndrome 8

24 Appendix B: Cost-effectiveness Model: Adverse Events Adverse Event Cost per Nonserious Event Source UTI $ Based on 1 specialist visit (CPT code 99214), lab culture, and ciprofloxacin Cost per Serious Event Source $6, Based on hospital stay for UTI ACB = atrioventricular conduction block; ALT = alanine transaminase; CPT = Current Procedural Terminology; ECG = electrocardiogram; MRI = magnetic resonance imaging; RTI = respiratory tract infection; UTI = urinary tract infection. All costs presented in May 2015 US dollars. Resource use based on interviews with 2 US physicians, a neurosurgeon and a neurologist. Source: Biogen Idec data on file (2013); OptumInsight, Inc. (2013); unit costs inflated to May 2015 US dollars using the consumer price index for medical care from Bureau of Labor Statistics (2015). 9

25 Appendix B: Cost-effectiveness Model: Adverse Events Table B.5: Disutility of Each Adverse Event Considered in the Model Adverse Event Disutility per Nonserious Event Source Disutility per Serious Event Source Abdominal pain 0 Assumption 0 Assumption Abdominal pain upper 0 Assumption 0 Assumption ALT increased 0 Assumption 0 Assumption Arthralgia 0 Assumption 0.25 Assumption: same as nonserious back pain ACB NICE submission (Novartis Pharmaceuticals UK Ltd, 2011) NICE submission (Novartis Pharmaceuticals UK Ltd, 2011) Back pain 0.25 Parsons (2006) 0.50 Assumption Bradycardia 0 Assumption 0 Assumption Chest pain 0.25 Assumption 0.50 Assumption Cough 0 Assumption Depression 0.16 Weighted average of values from NICE guidelines (NICE, 2009) Diarrhea 0 Assumption Fatigue 0 Assumption Flu-like symptoms 0.63 Assumption (same loss of utility as influenza) 0.56 Weighted average of values from NICE guidelines (NICE, 2009) 0.63 Assumption (same loss of utility as influenza) Flushing 0 Assumption 0 Assumption Gastroenteritis : gain in QoL of patient with IBS treated (NICE, 2008a) Headache Xu et al. (2011); value for mild migraine pain : gain in QoL of patient with IBS treated (NICE, 2008a) Xu et al. (2011); value for severe migraine pain Influenza 0.63 van Hoek et al. (2011) 0.67 van Hoek et al. (2011) Leukopenia 0 Assumption 10

26 Appendix B: Cost-effectiveness Model: Adverse Events Adverse Event Disutility per Nonserious Event Source Lower RTI 0.05 NICE respiratory infection guidelines, disutility of 0.05 for sore throat (NICE, 2008b) Disutility per Serious Event Source Nausea 0 Assumption 0 Assumption: no loss in QoL Pain in extremity 0.25 Assumption Pruritus 0 Assumption 0 Assumption: no loss in QoL Rash 0 Assumption UTI 0.1 Natalizumab NICE submission (Biogen Idec, 2006) 0.1 Natalizumab NICE submission (Biogen Idec, 2006) indicates that data were not reported or found in systematic review; ACB = atrioventricular conduction block; ALT = alanine transaminase; IBS = irritable bowel syndrome; NICE = National Institute for Health and Care Excellence; QoL = quality of life; RTI = respiratory tract infection; UK = United Kingdom; UTI = urinary tract infection. Source: Biogen Idec data on file (2013). 11

27 Appendix B: Cost-effectiveness Model: Adverse Events Table B.6: Duration of Each Adverse Event Considered in the Model Duration of Adverse Event Nonserious Event Duration of Serious Event Source Abdominal pain 10.5 days 24.5 days Physician estimate Abdominal pain upper 10.5 days 24.5 days Physician estimate ALT increased 28 days 28 days Physician estimate Arthralgia 10.5 days 24.5 days Physician estimate ACB 1 day 1 day NICE submission (Novartis Pharmaceuticals UK Ltd, 2011); physician indicated variable Back pain 10.5 days 24.5 days Physician estimate Bradycardia 14 days 14 days Assumption, physician estimate indicated variable Chest pain 7 days 14 days Physician estimate Cough 7 days 14 days Physician estimate Depression 75 days days Physician estimate Diarrhea 10.5 days 24.5 days Physician estimate Fatigue days days Assumption (physician estimate indicated months) Flu-like symptoms 1 day a week for 26 weeks 1 day a week, 52 weeks Physician estimate Flushing 10.5 days 24.5 days Physician estimate Gastroenteritis 10.5 days 24.5 days Physician estimate Headache 10.5 days 24.5 days Physician estimate Influenza 8.75 days 8.75 days van Hoek et al. (2011) Leukopenia 28 days days Physician estimate indicated weeks and months Lower RTI 11.7 days 11.7 days Moore et al. (2008), physician estimate indicated days Nausea 10.5 days 24.5 days Physician estimate Pain in extremity 7 days 28 days Assumption, physician indicated days and weeks Pruritus 10.5 days 24.5 days Physician estimate Rash 28 days days Assumption, physician indicated weeks and months UTI 5 days 5 days Physician estimate ACB = atrioventricular conduction block; ALT = alanine transaminase; NICE = National Institute for Health and Care Excellence; RTI = respiratory tract infection; UK = United Kingdom; UTI = urinary tract infection. Source: UK physician interviews; Biogen Idec data on file (2013). 12

28 Appendix B: Cost-effectiveness Model: Adverse Events Table B.7: Estimates of Annual Adverse Event Costs and Quality-Adjusted Life-Years Lost Treatment Annual AE Cost USD Annual Loss in QALYs From AEs Dimethyl fumarate $ Glatiramer acetate $ Fingolimod $ AE = adverse event; QALY = quality-adjusted life-year; USD = United States dollars. All costs reported in May 2015 US dollars ($). Source: Biogen Idec data on file, 2013; costs derived using values in Tables B2, B3 and B4. Table B.8: List of Assumptions Related to Adverse Events Cost-effectiveness Model Assumptions The adverse events included in the model were only those that were present with a frequency of at least 5% or a difference of > 3% compared to placebo in the dimethyl fumarate trials, a conservative assumption. It was assumed in the model that a patient who received treatment would incur the disutility and cost associated with adverse events, for each year in the simulation. This may overestimate the impact of adverse events, as patients with severe/frequent adverse events may withdraw from treatment. 13

29 Appendix B: Cost-effectiveness Model: Adverse Events References Biogen Idec Inc. Natalizumab (Tysabri) for the treatment of adults with highly active relapsing remitting multiple sclerosis: single technology appraisal (STA) submission to the National Institute for Health and Clinical [Care] Excellence Biogen Idec. Cost-effectiveness analysis of Tecfidera in patients with relapsing remitting multiple sclerosis. Version 18.0 Technical Report. Data on file, October Bureau of Labor Statistics (BLS). Consumer price index (CPI) for medical care Available at: Accessed June 26, Copaxone [prescribing information]. North Wales (PA): Teva Pharmaceuticals USA; Available at: Accessed February 26, Fox RJ, Miller DH, Phillips JT, et al.; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12): Gilenya [prescribing information]. East Hanover (NJ): Novartis Pharmaceuticals Corp; Available at: Accessed February 26, Gold R, Kappos L, Arnold DL, et al.; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12): Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7): Kappos L, Radue EW, O Connor P, et al.; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5): Moore M, Little P, Rumsby K, et al. Predicting the duration of symptoms in lower respiratory tract infection. Br J Gen Pract. 2008;58(547):

30 Appendix B: Cost-effectiveness Model: Adverse Events National Institute for Health and Clinical [Care] Excellence (NICE). Depression: the treatment and management of depression in adults Available at: Accessed February 26, National Institute for Health and Clinical [Care] Excellence (NICE). Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. 2008a. Available at: Accessed February 26, National Institute for Health and Clinical [Care] Excellence (NICE). Respiratory tract infections antibiotic prescribing: prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. 2008b. Available at: Accessed February 26, Novartis Pharmaceuticals UK, Ltd. Fingolimod for the treatment of relapsing-remitting multiple sclerosis in adults: NICE single technology appraisal OptumInsight. The essential RBRVS: a comprehensive listing of RBRVS values for CPT and HCPCS codes. OptumInsight, Inc; Parsons G. Acupuncture was better than no acupuncture but did not differ from minimal (sham) acupuncture for chronic low back pain at 8 weeks. Evid Based Nurs. 2006;9(4):111. Tecfidera [prescribing information]. Cambridge (MA): Biogen Idec Inc.; Available at: Accessed April 16, van Hoek AJ, Underwood A, Jit M, et al. The impact of pandemic influenza H1N1 on healthrelated quality of life: a prospective population-based study. PLoS One. 2011;6(3):e Xu R, Insinga RP, Golden W, Hu XH. EuroQol (EQ-5D) health utility scores for patients with migraine. Qual Life Res. 2011;20(4):