Diabetic Retinopathy Clinical Research Network Comparative Effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for DME Supported through a cooperative agreement from the National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817  1

Anti-VEGF Treatment Options for Diabetic Macular Edema Aflibercept 2.0-mg (EYLEA®) Better vision outcomes at 1 year for individuals with worse vision ~ U.S. cost per injection (2014): $1850 Bevacizumab 1.25-mg (Avastin®) Not approved for DME by FDA ~ U.S. cost per injection (2014): $60 Typically repackaged into plastic syringes Ranibizumab 0.3-mg (Lucentis) ~ U.S. cost per injection (2014): $1170

Relevance: Comparing Efficacy vs. Cost-effectiveness Comparing efficacy is most relevant to the doctor-patient relationship For example, primary outcome of DRCR.net Protocol T When initial visual acuity loss was mild prior to initiating anti-VEGF therapy for DME, there were no apparent differences, on average, in visual acuity outcomes at 1 year after initiating therapy with aflibercept, bevacizumab, or ranibizumab At worse levels of initial visual acuity, aflibercept was more effective at improving vision at 1 year Comparing cost-effectiveness is most relevant to some payers and policymakers

Relevance: Efficacy vs. Cost-effectiveness In 2010, about 2 billion dollars spent for anti-VEGF for ophthalmologic purposes – 1/6th entire Medicare Part B drug budget Example: July 2011: UK National Health Service (NHS) decided not to reimburse ranibizumab as a treatment of DME April 2013: Novartis agrees to a discounted price to the UK government (details are “commercial in confidence”); NHS decides to reimburse ranibizumab Given increasing public health importance of DME and large differences in costs among different treatment alternatives for DME, a post-hoc cost-effectiveness analysis of different anti-VEGF agents for DME was undertaken by DRCR.net

Cost-Effectiveness Plane Higher Cost Worse Health (QALYs) Better Health (QALYs) Lower Cost

Cost-Effectiveness Plane Incremental Cost Less Favorable COSTS MONEY, WORSENS HEALTH COSTS MONEY, IMPROVES HEALTH x ? More Favorable DOMINATED Incremental Benefit (QALYs Gained) A SAVES MONEY, WORSENS HEALTH SAVES MONEY, IMPROVES HEALTH x/? √ B DOMINANT

Cost-Effectiveness Ratio Incremental Cost-Effectiveness Ratio (ICER): High ratios are “Bad”, low ratios are “Good” No explicit threshold, but generally . . . <$50,000/QALY considered good value >$250,000/QALY considered too expensive Additional Costs you pay for B vs. A ($$$) Additional Health Benefits you get from B vs. A (QALYs)

Purpose Determine cost-effectiveness of anti-VEGF treatment options for patients with newly-diagnosed diabetic macular edema involving the center of the macula with visual acuity loss (20/32 or worse)

Costs “Societal” perspective Direct medical costs based on actual resource use from the trial and CMS allowables Costs of each intervention Number of treatments per year from DCRC.net Protocol T Tapering of treatments without average visual acuity loss as published from DRCR.net Protocol I Costs of managing side effects Costs of caring for patients who are blind from DME

Health-Related Quality of Life Time spent in each health state is weighted by a quality multiplier to reflect quality of life Death Perfect Health 1

Sample Quality Adjustments Death Perfect Health 1 .92 – moderate angina .90 – asymptomatic HIV .87 – migraine .84 – ulcer .82 – severe angina .78 – atrioventricular blockage .61 – mild schizophrenia .53 – AIDS .45 – severe clinical depression .40 – symptomatic, drug-resistant prostate cancer .29 – severe chronic schizophrenia .07 – post-cardiac arrest, moderately impaired

Health-Related Quality of Life Note: Protocol T did not elicit participants’ quality-of-life directly But, other researchers studied large populations and found relationships between best-corrected visual acuity and quality-of-life weights used for this study Brown Tied to better-seeing eye Ex: 20/20 BCVA = 0.97 20/200 BCVA = 0.66 RESTORE Trial (ranibizumab vs. laser for DME) Tied to eye treated with anti-VEGF Utility scores for side effects (MI, CVA, death) Determined ICER of each intervention relative to one another

Mean cumulative QALYs over 1 year Results – Utility, Year 1   Mean cumulative QALYs over 1 year A vs B A vs R R vs B A B R Difference (P-value) All participants 0.869 0.849 0.857 0.020 (0.03) 0.011 (0.22) 0.008 (0.40) Visual acuity 20/50 or worse at baseline 0.835 0.823 0.829 0.012 (0.33) 0.006 (0.63) 0.006 (0.59) Visual acuity 20/32 to 20/40 at baseline 0.901 0.875 0.884 0.026 (0.02) 0.017 (0.18) 0.009 (0.55) A: aflibercept, B: bevacizumab, R: ranibizumab

Results – Costs, Year 1

Results – Costs, Year 1

Results – Costs, Year 1

Results – Costs, Year 1, All Participants

Results – Costs, Year 1, Initial Visual Acuity 20/50 Or Worse

Results – Costs, Year 1, Initial Visual Acuity 20/32 to 20/40

Results – Cost-effectiveness, 1 Yr   Cost (2015 USD) Utility (QALYs) Cost-effectiveness vs. bevacizumab ($/QALY)* All patients Bevacizumab $4,100 0.849 – Ranibizumab $18,600 0.857 $1,730,000 Aflibercept $26,100 0.869 $1,100,000 Baseline visual acuity 20/50 or worse $5,000 0.823 $20,400 0.829 $2,450,000 $28,100 0.835 $1,870,000 Baseline visual acuity 20/32 to 20/40 $3,200 0.875 $16,900 0.884 $1,500,000 $24,100 0.901 $798,000

Results – Cost-effectiveness Projections

Results – Cost-effectiveness, 10 Yr   Cost (2015 USD) Utility (QALYs) Cost-effectiveness vs. bevacizumab ($/QALY)* All patients Bevacizumab $39,800 6.80 – Ranibizumab $79,400 6.87 $603,000 Aflibercept $102,500 6.98 $349,000 Baseline visual acuity 20/50 or worse $40,700 6.60 $81,200 6.65 $817,000 $104,500 6.82 $287,000 Baseline visual acuity 20/32 to 20/40 $38,900 7.01 $77,700 7.09 $506,000 $100,600 7.14 $474,000

Injection Cost Thresholds, 1 Yr   1-year horizon Current drug cost per dose (2015 USD) All patients Ranibizumab $1,170 Aflibercept $1,850 Baseline visual acuity 20/50 or worse

Injection Cost Thresholds, 1 Yr   1-year horizon Current drug cost per dose (2015 USD) Cost producing cost-effectiveness of $100,000/QALY All patients Ranibizumab $1,170 $100 Aflibercept $1,850 $240 Baseline visual acuity 20/50 or worse $94 $250

Injection Cost Thresholds, 1 Yr   1-year horizon Current drug cost per dose (2015 USD) Cost producing cost-effectiveness of $100,000/QALY Relative reduction from current cost All patients Ranibizumab $1,170 $100 91% Aflibercept $1,850 $240 87% Baseline visual acuity 20/50 or worse $94 92% $250

Injection Cost Thresholds, 10 Yr   10-year horizon Current drug cost per dose (2015 USD) Cost producing cost-effectiveness of $100,000/QALY Relative reduction from current cost All patients Ranibizumab $1,170 $230 80% Aflibercept $1,850 $570 69% Baseline visual acuity 20/50 or worse $190 84% $700 62%

Limitations Extrapolating the findings of the DRCR.net trial beyond year one Using best-corrected visual acuity alone as a surrogate for the impact of DME on health- related quality-of-life Visual needs may be varied from patient to patient Utilities assigned to best-corrected visual acuity alone may underestimate impact on health-related quality of life

Conclusions Over 1-year study period, for individuals with worse initial visual acuity, incremental cost-effectiveness ratios (ICERs) of aflibercept and ranibizumab when compared with bevacizumab were $1.9 million and $2.5 million per quality-adjusted life-year (QALY) Overall ICERs projected over 10 years when compared with bevacizumab were $350,000/QALY for aflibercept and $600,000/QALY for ranibizumab

Conclusions (continued) For treatment of eyes with worse initial visual acuity, anti-VEGF agent cost per injection would have to decrease by 62% for aflibercept or 84% for ranibizumab for those therapies to have ICERs of $100,000/QALY relative to bevacizumab if evaluated over a 10-year time horizon

Relevance Aflibercept 2.0-mg and ranibizumab 0.3-mg are unlikely to be cost-effective relative to bevacizumab for treatment of DME unless their prices decline substantially These results highlight the challenges when safety and efficacy results (of importance to patients and physicians providing their treatment) are at odds with cost-effectiveness results (of importance to some payers and policymakers)

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 52 clinical study sites Study participants who volunteered to participate in this trial DRCR.net Data and Safety Monitoring Committee DRCR.net investigators and staff 31