Overview

1. Biological DifferentiationPart IIDubai, United Arab EmiratesJanuary 19th, 2009Prof. Joachim R. KaldenDirector emeritusDept. of Internal Medicine IIIDiv. of Molecular ImmunologyNikolaus-Fiebiger-CenterUniversity of Erlangen-Nuremberg

2. Overview • Value for TNF antagonists in RA • Economic evaluation for biologics in RA • ENBREL & QoL of RA patients • Measurement of RA impact • Cost-effectiveness of ENBREL vs. biologics • Impact of biologics on QALY

3. What is Value for a Healthcare Intervention?

4. Value • Does a healthcare intervention save lives or reduce disease? • Does the healthcare intervention save cost in a health system? • Does the healthcare intervention get people back to normal living or work? • Does the healthcare intervention do all the above better than the existing therapies?

5. Value Value = • [cost][benefit] Benefit • Clinical • Reduced number active joints • Reduced damage • Reduced mortality • Reduced cardiovascular events • Reduced osteoporosis • Reduced fatigue • Quality of life • Reduced disability • Reduced depression • Improved work output • Improved social life • Intangible benefits Cost • Acquisition • Delivery • Training • Monitoring • Cost to patient • Travel • Time off work • Adverse events • Healthcare professional visits • State benefits • Lost taxes • Productivity loss

6. Need to Communicate with Payors • Competitive world - we must be advocates for our patients for healthcare resource!! • “Key” areas - cardiology, oncology etc etc • New expensive drugs hitting the market in “key” areas • Still major unmet need for rheumatology patients • Make sure that rheumatology maintains its “share of voice” • Built on a principle of large amounts of good data in many countries examining the impact of these agents over the last 5 years

7. Treatment with TNF-blockers and mortality risk in patients with rheumatoid arthritis

8. Objective • To assess mortality in patients with RA treated with TNF inhibitors, compared to a standard RA population. • 921 RA patients started on TNF inhibitors in 1999 or later recruited from regional register of RA patients to cohort. • Patient and disease characteristics including HAQ scores gathered from regional register. • Total cohort linked to national register for cause of death. • Overall mortality rates in those treated with TNF inhibitors compared to those not treated with TNF inhibitors estimated using standardised mortality ratios (SMRs).

9. Results • Mortality ratios generated using Swedish national data as reference. • TNF inhibitor treated patients appear to have reduced SMR compared to those not treated with TNF inhibitors.

10. Conclusions • Critical role for inflammation in RA associated premature mortality • Anti-TNF therapy may reduce mortality in RA

11. Reductions in Healthcare Resource Use

12. Traditional Model (HTA): What does the net cost of drug buy you in health benefits? Emerging Model (Policy Model): Can help shape policy by alleviating payors’ budgetary concerns Importance of Resource Use Reduction Net Cost Total Cost of Care Drug Costs Pre-treatment Cost of Care Cost Offsets Post-treatment Cost of Care Pre – Treatment Total cost of Care Post – Treatment Total cost of Care

13. Use of TNF therapy associated with a decline in resource Use • Subjects on etanercept or infliximab (Mar99 to Jun00) • Four rheumatology centers in Helsingborg, Kristianstad, Trelleborg, and Lund (n=116) • Pre – Post comparison implemented at 12 months Pre - Post Anti-TNF Treatment Pre - Post Anti-TNF Treatment 56 1000 60 857 50 800 593 40 600 Total Number of Days 28 Percent Per Patient Year 30 332 22 400 20 20 10 113 200 8 10 0 0 Surgery-Related Non-Surgery Orthopaedic Major Joint Hand Surgery Hospitalization Hospitalization Procedures Replacement Kobelt et al :Annals of the Rheumatic Diseases 2004;63:4-10

14. Biologics have a profound effect on the quality of life of patients with RA

15. ACR Responses (LOCF): TEMPO MTX E MTX+E ACR 20 ACR 50 ACR 70 100 86† 85†‡ 85 80 71†‡ 69†‡ 67†‡ 60 49†‡ 49†‡ * 43†‡ % of Patients 40 20 0 12 24 36 12 24 36 12 24 36 months *P<0.05, E versus MTX †P<0.05, combination versus MTX ‡P<0.05, combination versus E TEMPO. Data on file. Wyeth.

16. HAQ Values (LOCF) 1.1 1.1 †‡ †‡ 0.8 †‡ †‡ † †‡ †‡ †‡ † †‡ † † †P<0.05, combination vs MTX ‡P<0.05, combination vs E TEMPO. Data on file. Wyeth.

17. ACR20 ACR50 ACR70 * 80 80 80 Week 52 * 73 69 # 70 70 70 * Week 104 * 62 63 59 60 60 60 56 54 * * 50 47 46 46 50 50 50 43 42 37 40 40 40 28 28 28 30 30 30 26 20 20 20 10 10 10 0 0 0 ADA +MTX ADA MTX ADA +MTX ADA MTX ADA +MTX ADA MTX Adalimumab (PREMIER): 52 and 104 weeks % patients *P<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone # P=0.043 for MTX vs adalimumab, others NS

18. How Can We Measure the impact of RA at Home and Work?

19. Impact of RA on Work Disability? • Work loss is common in RA • Approximately 25% to 50% of patients with RA stop working within a decade of disease onset • Between 50% and 90% stop working before age 65 • Economic evaluation of impact on work • Employment to unemployment • Missed days of work (Absenteeism) • Productivity loss (Presenteeism) • Changing occupation • Several factors contribute to work loss • Biopsychosocial – support structure, type of job (white vs. blue collar; management vs. clerical), education • Economic incentive and disincentive to work • Clinical factors: joint damage, pain, fatigue, sleep loss • Missed days of work is important marker of future work loss

20. Work ability and disability in rheumatology • Patients with RA have reduced productivity, increased lost work days and retire early • Systematic review (Burton et al 2006): 66% of RA patients experienced work loss in previous 12 months with median duration of 39 days • Approximately one third of RA patients stop work early • Begins early after onset • In FIN-RACo in first 5 yrs of disease (Puolakka et al, ARD 2006): • 75% lose work days • Mean productivity loss per year (human capital) €7217 • Work loss related to HAQ and increasing erosions

21. Effect of TNF inhibitors • RAPOLO results (Yelin et al A&R 2003) • Compared cohort taking etanercept with control RA group • Patients receiving etanercept worked on average 7.4 h more per week • Canadian study (Farahani et al, J Rheumatol, 2006) • Compared cohort taking etanercept with control RA group • In 1st 6m, lost work days significantly less in etanercept than control group 2.5d v 7.8d (P=0.03). Difference not significant at 12 months • Days with reduced productivity significantly less in etanercept than control group at both 6 and 12 months (32.9 v 45.8; 60.7 v 86.5, both P=0.02)

22. Impact on Current Employment Probability of Current Employment Among Enbrel/non-Enbrel Users (%) (n=497) Diff = 16% (95% CI 7-26%) 55 Unadjusted 71 Adjusted For Demographics, RA Status, Occupation, Industry 54 Diff = 20% (95% CI 9-32%) 72 0 20 40 60 80 RAPOLO (n=238) RA Panel (n=259) Yelin Ed et al. A&R 2003:48(11):3046-54

23. Improvement in Presenteeism Quantity of Current Employment (hours/week), Among All Employed At Diagnosis (n=497) Diff = 5.4 (95% CI 1.1, 9.7) Unadjusted Adjusted For Demographics, RA Status, Occupation, Industry Diff = 7.4 (95% CI 2.6, 12.3) Yelin Ed et al. A&R 2003:48(11):3046-54

24. Reduction in Absenteeism • RADIUS 2: long-term US registry of adults patients with RA who initiated or added etanercept to their treatment at enrollment • Enrolled 5,000 patients from both academic & community practices • For patients who reported that they were employed in some way at baseline, the number of missed workdays was analysed Monotherapy P<0.0001 2.4 2.4 P<0.0001 2 2 1.64 1.6 1.6 Mean # of Times Missed Work for Half a Day or More in Prior Month 1.2 1.2 0.83 0.72 0.8 0.8 0.4 0.4 0 0 Baseline 6 months 12 months (n=596) (n=577) (n=596) Combination P<0.0001 2.4 P<0.0001 2 1.43 1.6 Mean # of Times Missed Work for 1.2 Half a Day or More in Prior Month 0.83 0.66 0.8 0.4 0 Baseline 6 months 12 months Gibofsky A et al. Curr Med Res Opin 2006;22:169-83. (n=895) (n=875) (n=596)

25. For patients who reported that they were employed at baseline, the number of missed workdays was analysed Reduction in Need to Seek Less Demanding Job Montherapy Montherapy P<0.0001 40 40 P<0.0001 35 35 28.5 28.5 30 30 25 25 % of Patients who had to take a less % of Patients who had to take a less physically demanding job physically demanding job 20 20 15 15 14.7 14.7 15 15 10 10 5 5 0 0 Baseline (n=463) Baseline (n=463) 6 months 6 months 12 months 12 months (n=446) (n=446) (n=463) (n=463) Combination Combination P<0.0001 40 40 P<0.0001 35 35 28.3 28.3 30 30 25 25 % of Patients who had to take a less % of Patients who had to take a less physically demanding job physically demanding job 20 20 14.6 14.6 14.6 14.6 15 15 10 10 5 5 0 0 Baseline (n=685) Baseline (n=685) 6 months 6 months 12 months 12 months (n=666) (n=666) (n=685) (n=685) Gibofsky A et al. Curr Med Res Opin 2006;22:169-83.

26. Pharmacoeconomic evaluations - why bother…?

27. Pharmacoeconomic evaluations - why bother…? • Resources are scarce • People, time, facilities, equipment, knowledge • Medications are expensive • Over 20 therapies with cost > $4000 per year • Assists in making the decision process explicit • Can take into account preferences and attributes

28. How can we measure cost-effectiveness of drugs?

29. Rheumatoid Arthritis Health Economics Methodology • Models based on DMARD and biologic sequences being compared over a period beyond clinical trial timeframes • Lifetime of disease model often taken to reflect chronicity of disease, time of diagnosis, and age profile of patients • Majority of models now have incremental cost per quality adjusted life year as primary outcome measure • Cost per QALY is derived from relationship between change in HAQ and QoL from observational databases • HTA bodies make economic analysis comparisons based on analysis of data from key clinical trials • N.B. Data on “real world use” of TNFs not counted in costs in economic analysis • – no account of dose change taken into account

30. Quality Adjusted Life Years (QALY) • QALY: composite measure of quality and quantity of life • Health benefit of a healthcare intervention • Reduced mortality, and/or • Improved health • QALY used because it allows comparisons across diseases and interventions • QALY support decision on healthcare resources • Best use of limited resources: • Fund interventions that offer more QALYs for marginal unit of money spent • Thresholds for cost-effectiveness • US: $50-100K for an incremental QALY • UK: £30k for an incremental QALY

31. UTILITY VALUE 1 QALY 1.0 Gain =1 QALY Gains from QoL Benefits Gain= 1 QALY 0.5 Gains from Mortality Benefits 0 YEARS 1 2 4 Value FrameworkAn Illustration of QALYs 1 QALY

32. Independent Cost Effectiveness Review Latest Results from NICE Appraisal – Nov 2006 TNF Cost Effectiveness calculated after 2 DMARD failures in combination with MTX

33. What do you do when a patient fails a TNF Inhibitor? Switching to a different TNF antagonist or to any other available biologic

34. Independent Cost Effectiveness Review Latest Results from NICE Appraisal – Nov 2006 • ‘Speculative’ analysis carried out to explore possible bias from using mix of RCT & observational data in the model • Analysis based on data from RCTs of TNFα inhibitor monotherapy in the cases of adalimumab and etanercept and combination therapy in the case of infliximab • In the analysis it was assumed that effectiveness was reduced by 30% to reflect the lesser effectiveness of a second TNFα inhibitor as seen in the BSRBR • Estimates of incremental cost effectiveness: ~ £30,000 per QALY when etanercept used as a second TNFα inhibitor and ~£50,000 per QALY when adalimumab and infliximab used as a second TNF α inhibitor

35. Cost Effectiveness of Sequential Use vs Standard DMARD Sequence Cost Effectiveness Analysis NICE 2006

36. Conclusion • Independent UK HTA review has calculated etanercept as the most cost effective TNF agent • It is cost effective to prescribe an anti TNF after another TNF has failed • Etanercept has beneficial cost effectiveness profile when used as a switch agent • Etanercept also has beneficial cost effectiveness profile vs Rituximab in TNF failure • Ongoing studies will further elucidate the real life costs of different biologics

37. Future developments

38. TNF blockers • Reduce time off work? • Improve quality of work? • Reduce other heath care costs? • Reduce mortality in women? • All of these?

39. In RA - it is cost effective to • Withhold TNF inhibitors totally and only use low cost drugs? • Revert back to a DMARD after 1 TNF inhibitor failure? • Swap TNF inhibitor if first agent fails? • Maintain patients on TNF inhibitors when no clinical response? • Allow orthopaedic surgeons to fully manage disease?

40. Summary • Limited resources for healthcare • Arthritis often seen as low priority • Biologic therapies most effective in RA • We must argue for our pts! • TNF inhibitors cost effective • Early disease • More advanced disease • To swap after 1 TNF inhibitor failure • Cost-effectiveness measures further with experience • Payors make the big choices - we must use the increasing ammunition of evidence to support our patients