1. Biological Differentiation Part II Dubai, United Arab Emirates January 19th, 2009 Prof. Joachim R. Kalden Director emeritus Dept. of Internal Medicine III Div. of Molecular Immunology Nikolaus-Fiebiger-Center University 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] Cost  Acquisition  Delivery  Training  Monitoring  Cost to patient  Travel  Time off work  Adverse events  Healthcare professional visits  State benefits  Lost taxes  Productivity loss 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

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 SMR (or SMR ratio) at follow up (95% CI) 2 years 3 years 4 years Anti-TNF exposed (n = 921) All 1.2 (0.64-1.75) 1.20 (0.74-1.75) 1.50 (1.03-1.96) Men 1.65 (0.57-2.74) 1.79 (0.85-2.72) 1.86 (1.00-2.72) Women 0.94 (0.33-1.55) 0.88 (0.38-1.37) 1.29 (0.75-1.83) Non Anti-TNF exposed (n = 652) All 1.51 (0.99-2.04) 1.54 (1.11-1.96) 1.50 (1.14-1.86) Men 1.18 (0.45-1.90) 1.24 (0.63-1.85) 1.19 (0.68-1.70 Women 1.74 (1.01-2.47) 1.73 (1.15-2.31) 1.70 (1.21-2.19) SMR ratio (anti-TNF exposed vs not exposed) All 0.79 (0.42-1.44) 0.78 (0.47-1.27) 1.00 (0.66-1.49) Men 1.41 (0.51-4.04) 1.44 (0.65-3.16) 1.56 (0.78-3.05) Women 0.54 (0.22-1.22) 0.50 (0.24-0.99) 0.76 (0.44-1.28)  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. Importance of Resource Use Reduction  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 Pre-treatment Cost of Care Post-treatment Cost of Care Net Cost Cost Offsets Drug Costs Total 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 857 593 332 113 0 200 400 600 800 1000 Surgery-Related Hospitalization Non-Surgery Hospitalization Total Number of Days Pre - Post Anti-TNF Treatment 56 22 20 28 10 8 0 20 30 40 50 60 Orthopaedic Procedures Major Joint Replacement Hand Surgery Percent Per Patient Year 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 * P<0.05, E versus MTX †P<0.05, combination versus MTX ‡ P<0.05, combination versus E * ACR 20 ACR 50 ACR 70 months 86†85†‡ 69†‡ 71†‡ 67†‡ 43†‡ 49†‡ 85 0 20 40 60 80 100 122436122436122436 % of Patients MTXEMTX+E TEMPO. Data on file. Wyeth.

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

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

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) Unadjusted Adjusted For Demographics, RA Status, Occupation, Industry Diff = 16% (95% CI 7-26%) Diff = 20% (95% CI 9-32%) 72 71 54 55 020406080 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) Unadjusted Adjusted For Demographics, RA Status, Occupation, Industry Diff = 5.4 (95% CI 1.1, 9.7) Diff = 7.4 (95% CI 2.6, 12.3) Yelin Ed et al. A&R 2003:48(11):3046-54

24. P<0.0001 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 1.64 0.72 0.83 0 0.4 0.8 1.2 1.6 2 2.4 Baseline (n=596) 6 months (n=577) 12 months (n=596) Mean # of Times Missed Work for Half a Day or More in Prior Month 0 0.4 0.8 1.2 1.6 2 2.4 1.43 0.66 0.83 0 0.4 0.8 1.2 1.6 2 2.4 Baseline (n=895) 6 months (n=875) 12 months (n=596) Combination Mean # of Times Missed Work for Half a Day or More in Prior Month Gibofsky A et al. Curr Med Res Opin 2006;22:169-83.

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

26. Pharmacoeconomic evaluations - why bother…?

27.  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. Value Framework An Illustration of QALYs 1 QALY UTILITY VALUE 0 1.0 YEARS 4 0.5 21 1 QALY Gain= 1 QALY Gains from Mortality Benefits Gain =1 QALY Gains from QoL Benefits

32. Independent Cost Effectiveness Review Latest Results from NICE Appraisal – Nov 2006 TNF Cost Effectiveness calculated after 2 DMARD failures in combination with MTX Late RA data Early RA data HAQ progression No HAQ progression HAQ progression No HAQ progression adalimumab£64,000£30,200£30,200 etanercept£49,800£24,600£28,500>£20,000 infliximab£139,000£39,400£30,400

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 1.Reduce time off work? 2.Improve quality of work? 3.Reduce other heath care costs? 4.Reduce mortality in women? 5.All of these?

39. In RA - it is cost effective to 1.Withhold TNF inhibitors totally and only use low cost drugs? 2.Revert back to a DMARD after 1 TNF inhibitor failure? 3.Swap TNF inhibitor if first agent fails? 4.Maintain patients on TNF inhibitors when no clinical response? 5.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