Evidence Review Group s Report Ustekinumab for treating active and progressive psoriatic arthritis

Transcription

1 Evidence Review Group s Report Ustekinumab for treating active and progressive psoriatic arthritis Produced by Centre for Reviews and Dissemination (CRD), University of York Authors Dawn Craig, Research Fellow, CRD Joanne O Connor, Research Fellow, CRD Mark Rodgers, Research Fellow, CRD Rocio Rodriguez-Lopez, Information Specialist, CRD Alison Smith, Research Fellow, CRD Nerys Woolacott, Senior Research Fellow, CRD Correspondence to Xx xxxxx xxxxxxxx Xxxxx xxx xxxxxxxx xxx xxxxxxxxxxxx Xxxxxxxxx xx xxxx xxxxxxxxxx xxxx xxxx xxx Date completed Date completed (30/10/2013) Source of funding This report was commissioned by the NIHR HTA Programme as project number HTA 12/58. Declared competing interests of the authors None Acknowledgements We would like to thank our clinical advisor, Professor Ian Bruce (Professor of Rheumatology and NIHR Senior Investigator, Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair). 1

2 We would also like to thank Professor Stephen Palmer (Professor of Health Economics, CHE) for advice and for providing comments on the ERG report. Rider on responsibility for report The views expressed in this report are those of the authors and not necessarily those of the NIHR HTA Programme. Any errors are the responsibility of the authors. This report should be referenced as follows: Craig D, O Connor J, Rodgers M, Smith A, Woolacott N. Ustekinumab for treating active and progressive psoriatic arthritis: A Single Technology Appraisal. Centre for Reviews and Dissemination, Contributions of authors Mark Rodgers, Dawn Craig and NerysWoolacott wrote the clinical effectiveness sections of the report; Alison Smith, Joanne O Connor and Dawn Craig wrote the cost effectiveness sections of the report and performed the economic modelling. Rocio Rodriguez-Lopez wrote the sections of the report dealing with search strategies and provided information support. 2

3 Table of Contents List of abbreviations 12 Glossary 15 1 Summary Critique of the decision problem in the manufacturer s submission Summary of clinical effectiveness evidence submitted by the manufacturer Ustekinumab versus conventional management Ustekinumab versus TNFα inhibitors Safety of ustekinumab Summary of the ERG s critique of clinical effectiveness evidence submitted Ustekinumab versus conventional management Summary of cost effectiveness submitted evidence by the manufacturer Summary of the ERG s critique of cost effectiveness evidence submitted ERG commentary on the robustness of evidence submitted by the manufacturer Strengths Weaknesses and areas of uncertainty Summary of exploratory and sensitivity analyses undertaken by the ERG Anti-TNFα naïve population Anti-TNFα experienced population Sequencing analysis 28 2 Background Critique of manufacturer s description of underlying health problem Critique of manufacturer s overview of current service provision 30 3 Critique of manufacturer s definition of decision problem Population Intervention Comparators Outcomes Other relevant factors 33 4 Clinical Effectiveness Critique of the methods of review(s) Searches Clinical effectiveness search Inclusion criteria Critique of data extraction Quality assessment 37 3

4 4.1.5 Evidence synthesis Critique of trials of the technology of interest, their analysis and interpretation (and any standard meta-analyses of these) Description of PSUMMIT trial methods Outcomes collected in the PSUMMIT trials Internal validity of PSUMMIT trials External validity of PSUMMIT trials Analysis of PSUMMIT trial data Summary of PSUMMIT trials results ERG commentary on PSUMMIT trials Description and evaluation of adverse event studies Critique of the indirect comparison and/or multiple treatment comparison and the trials identified and included Conclusions of the clinical effectiveness section 67 5 Cost Effectiveness Overview ERG comment on manufacturer s review of cost-effectiveness evidence ERG s summary and critique of manufacturer s submitted economic evaluation Population Interventions and comparators Anti-TNFα naïve population Anti-TNFα experienced population Conventional management therapies Model structure Perspective, time horizon and discounting Treatment effectiveness and extrapolation PASI Score PASI Score changes HAQ Score PsARC response rates HAQ score change from baseline HAQ rebound and natural disease progression Long term withdrawal Mortality Adverse events Health related quality of life Resources and costs 92 4

5 Drug acquisition costs Administration costs Medical resource utilization Health state costs (HAQ- and PASI-related costs) Adverse event costs Cost effectiveness results Cost-effectiveness results for the anti-tnfα naïve patients Cost-effectiveness results for the anti-tnfα experienced patients Model validation and face validity check Exploratory and sensitivity analyses undertaken by the ERG Conclusions of the cost effectiveness section Impact on the ICER of additional clinical and economic analyses undertaken by the ERG Overview ERG corrections and adjustments to the manufacturer s base case model Additional ERG analyses Weight based NMA vs. ITT NMA (naïve population) Alternative HAQ score rebound assumptions (naïve population) HAQ score changes from ERG NMA (naïve population) Time horizon (naïve population) Week 24 vs. 12 as the PsARC response assessment time point (naïve population) Inclusion of the cost of phototherapy in the PASI-related cost estimate (naïve population) The ERG s preferred base case for anti-tnf naïve population Anti-TNFα experienced population Sequencing of treatment ERG sequencing analysis Results of ERG sequencing analysis Budget impact model Conclusions from ERG analyses End of life Overall conclusions Anti-TNFα naïve population Anti-TNFα experienced population Implications for research References Appendices PSUMMIT outcome data for dactylitis, DLQI and SF

6 10.2 NMA trial baseline comparison as provided by the manufacturer ERG NMA compared with MS NMA PsARC response HAQ conditional on PsARC ERG re-calculated baseline HAQ and PASI score ERG additional analyses Efficacy results derived from ITT trial data where possible (anti-tnfα experienced population) HAQ rebound to natural progression (anti-tnfα experienced population) Alternative time horizons Week 12 vs. 24 PsARC assessment time point Including the cost of phototherapy Natural history of patients with psoriatic arthritis eligible for biologic therapy Introduction Methods Results Discussion Conclusion Sequencing analysis Formulas used by Rodgers et al ERG estimates based on the formulas from Rodgers et al Full results of the Sequencing analysis 169 6

7 Table of Tables Table 1: Drug survival rates at 3 years (NOR-DMARDstudy) Table 2: Drug survival rates from observational studies of Anti-TNFαs for PsA. (Taken directly from DANBIO Registry (Glintborg et al. 2013)) Table 3: Proportion of patients achieving a response in terms of ACR 20/50/70, a Good EULAR response and DAS28 remission. (Constructed from data reported from DANBIO Registry (Glintborg et al. 2013)) Table 4: Baseline characteristics of PSUMMIT trials according to prior biologic exposure Table 5 Number of patients receiving 1, 2, 3 or more previous anti-tnfs (PSUMMIT 2) Table 6: ACR, PsARC and PASI75 response rates in PSUMMIT trials Table 7: Ustekinumab 45mg vs. 90mg. Random effects meta-analyses (relative risk, 95% confidence interval) Table 8: Discontinuation of study agent due to adverse events (PSUMMITtrials) Table 9: Quality assessment of included RCTs (from Rodgers et al) Table 10: (1 of 2) Summary of trial population baseline characteristics (placebo arm only) Table 11: (2 of 2) Summary of trial population baseline characteristics (treatment arm only) Table 12 Baseline DMARD use among RCTs included in the MTC Table 13: Summary of the trials used* to conduct the MTC (Manufacturer s submission, table 1, pg 73.) Table 14 Number of patients included in weight-based NMA Table 15: PASI 75 - Proportion of responders for the anti-tnfα naïve population, using the weightbased dosing criteria compared with ITT Table 16. PASI 90 - Proportion of responders for the anti-tnfα naïve population, using the weightbased dosing criteria compared with ITT Table 17. PsARC - Proportion of responders for the anti-tnfα naive population, using the weight based dosing criteria compared with ITT Table 18: Summary of the manufacturer s economic evaluation (and signposts to MS) Table 19: NICE reference checklist Table 20: Treatment dosing regimens (adapted from Table 5, Section 4.1.1, pg. 20 in the MS) Table 21. Manufacturer and ERG baseline PASI scores Table 22. Sources used to derive PASI response rates in the MS Table 23. PASI score change for PASI 75 responders and non-responders for the anti-tnfα naïve population (taken from the manufacturer s model, Inp_Efficacy!C247:D254 ) Table 24. PASI score change for PASI 75 responders and non-responders for the anti-tnfα experienced subgroup analysis (taken from manufacturer s model, Inp_Efficacy! F247:D248 ) Table 25. Manufacturer and ERG baseline HAQ estimates Table 26. Proportion of Ustekinumab and conventional management PsARC responders for both populations

8 Table 27. HAQ score change from baseline for PsARC responders and non-responders (naïve population) Table 28. HAQ score change from baseline for PsARC responders and non-responders (experienced population) Table 29. Unit costs used in the manufacturer's model (adapted from Table 55, pg. 139 of MS) Table 30: Base-case deterministic results, anti-tnfα naïve patients (based on Table 64, Section 7.7.6, pg. 165 in the MS) Table 31: Amended base-case deterministic results, TNF naïve patients (pg. 50 in the manufacturer s response to clarification) Table 32: PSA results; mean of 10,000 simulations, anti-tnfα naïve patients (pg 50 in the manufacturer s response to clarification) Table 33. Summary of scenario analyses and results (based MS. Tables 68-34, pg174-7) Table 35: Base-case results, anti-tnfα experienced patients (based on Table 65, Section 7.7.6, pg. 165 in the MS) Table 36: Base-case results, anti-tnfα experienced patients (pg 54 in the manufacturer s response to clarification) Table 37: PSA results; mean of 10,000 simulations, anti-tnfα experienced patients (Table 67, Section 7.7.8, pg. 172 in the MS) Table 38: PSA results; mean of 10,000 simulations, anti-tnfα experienced patients (pg 54 of manufacturer s response to clarification) Table 39. Summary of scenario analyses and results (MS. Table 40, pg178) Table 41: Results comparison: TA199; TA220 and Ustekinumab submission Table 42: Comparisons with previous submissions Table 43: Corrected model probabilistic results (MS corrections and ERG baseline HAQ and PASI estimates (anti-tnfα naive population) Table 44: Corrected model probabilistic results (MS corrections and ERG baseline HAQ and PASI estimates (anti-tnfα experienced population) Table 45. Probabilistic results for model using full ITT NMA results (anti-tnfα naive population)114 Table 46. Probabilistic results for model with ITT NMA results used, excluding ustekinumab 90mg (anti-tnfα naive population) Table 47. Probabilistic results for model assuming HAQ rebounds to natural progression ("worst case scenario"; anti-tnfα naive population) Table 48. Probabilistic results for model using HAQ score change results from updated Yang NMA using 12-week PSUMMIT trial data (anti-tnfα naive population) Table 49. Probabilistic results for model using HAQ score change results from updated Yang NMA using 24-week PSUMMIT trial data (anti-tnfα naive population) Table 50. Alternative time horizons, ICER results (anti-tnfα naive population) Table 51. Alternative time horizons, ICER vs. conventional management strategy results (anti-tnf naive population) Table 52. Probabilistic results for model using week 24 weeks as the PsARC assessment time point for all treatments (anti-tnfα naïve population)

9 Table 53. Probabilistic results for model with cost of phototherapy included in the PASI-related cost estimate (anti-tnfα naive population) Table 54. ERG's preferred base case (anti-tnf naive population) Table 55: Probabilistic results for scenario analyses on the anti-tnfα experienced population Table 56: Alternative time horizons (anti-tnfα experienced population) Table 57: Cost-effective treatments for various WTP thresholds for scenario Table 58: Cost-effective treatments for various WTP thresholds for scenario Table 59: Cost-effective treatments for various WTP thresholds for scenario Table 60: Estimated budget impact (Table 86, pg 186 of MS) Table 61: Re-estimated budget impact, assuming ustekinumab has the projected market share of golimumab Table 62: Comparison of baseline characteristics NMA RCTs Table 63: MTC comparison manufacturer s data compared with ERG reanalysis for PsARC response Table 64: ERG HAQ PsARC response compared with MS estimate Table 65 ERG baseline PASI estimate for anti-tnf naive population Table 66. Standard error and standard deviations for ERG baseline PASI estimates (anti-tnfα naive population) Table 67. ERG baseline PASI estimate for the anti-tnfα experienced population Table 68. Standard deviation and standard error for ERG baseline PASI estimate (anti-tnfα experienced population) Table 694: ERG baseline HAQ estimate for the anti-tnfα naive population Table 70. Standard deviation and standard error for ERG baseline HAQ estimates (anti-tnfα naive population) Table 71. ERG baseline HAQ score for anti-tnf experienced population Table 72. Standard deviation and standard error for ERG baseline HAQ estimate (anti-tnfα experienced population) Table 73. Probabilistic results for model using all available ITT trial results (anti-tnfα experienced population) Table 74. Probabilistic results for model using all ITT trial results for ustekinumab 45mg only (anti- TNFα experienced population) Table 75. Probabilistic results for model assuming HAQ rebounds to natural progression ("worst case scenario"; anti-tnfα experienced population) Table 76. Probabilistic results for model using 5 year time horizon (anti-tnfα naive population) Table 77. Probabilistic results for model using 5 year time horizon (anti-tnfα experienced population) Table 78. Probabilistic results for model using 10 year time horizon (anti-tnfα naive population) 159 Table 79. Probabilistic results for model using 10 year time horizon (anti-tnfα experienced population) Table 80. Probabilistic results for model using 20 year time horizon (anti-tnfα naïve population) 159 9

10 Table 81. Probabilistic results for model using 20 year time horizon (anti-tnfα experienced population) Table 82. Probabilistic results for model using 40 year time horizon (anti-tnfα naive population) 160 Table 83. Probabilistic results for model using a 40 year time horizon (anti-tnfα experienced population) Table 84. Probabilistic results for model using week 12 weeks as the PsARC assessment time point for all treatments (anti-tnfα naïve population) Table 85. Probabilistic results for model using week 12 weeks as the PsARC assessment time point for all treatments (anti-tnfα experienced population) Table 86. Probabilistic results for model using week 24 weeks as the PsARC assessment time point for all treatments (anti-tnfα experienced population) Table 87. Probabilistic results for model including the cost of phototherapy in the PASI-related cost (anti-tnfα experienced population) Table 88: Initial PsARC response given patient discontinued first course because of a lack of efficacy (manufacturer s data derived from model: Cells Inp_Efficacy!C22:C39 ) Table 89: Withdrawal rates after three months, given patient discontinued first course of treatment because of lack of efficacy( manufacturer s estimates derived from model: Cells Inp_Outomes!C16:D20 ) Table 90: Withdrawal rates after three months, given patient discontinued first course of treatment because of an adverse event (manufacturer s estimates derived from model: Cells Inp_Outomes!C16:D20 ) Table 91: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to inefficacy (the manufacturer s data was used from PSUMMIT2 for ustekinumab and the ERG estimates were used for the other comparators) Table 92: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to adverse events Table 93: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to inefficacy (ERG estimates were used for all comparators)

11 Table of Figures Figure 1: ACR20 response through week 52 (PSUMMIT1) Figure 2: ACR20 response through week 52 (PSUMMIT2) Figure 3: PsARC response through week 52 (PSUMMIT1) Figure 4: PsARC response through week 52 (PSUMMIT2) Figure 5: PASI 75 response through week 52; randomised subjects with 3% BSA psoriasis skin involvement at baseline (PSUMMIT2) Figure 6: PASI 75 response through week 52; randomised subjects with 3% BSA psoriasis skin involvement at baseline (PSUMMIT1) Figure 7: Decision tree structure (Figure 20, Section 7.2.2, pg. 97 in the MS) Figure 8: Markov model structure (Figure 31, Section 7.2.2, pg. 98 in the MS)

12 List of abbreviations ACR American College of Rheumatology response criteria ADEPT AE BAD BNF BSA BSR CEAC CI CrI DLQI DMARD EMA ERG EQ-5D HAQ HRQoL ICER IMPACT ITT Adalimumab Effectiveness in Psoriatic Arthritis Trial Adverse event British Association of Dermatologists British National Formulary Body surface area British Society of Rheumatologists Cost-effectiveness acceptability curve Confidence interval Credible Interval Dermatology Life Quality Index Disease modifying anti-rheumatic drug European Medicines Agency Evidence Review Group EuroQol-5D Health Assessment Questionnaire Health-related quality of life Incremental cost-effectiveness ratio Infliximab Multinational Psoriatic Arthritis Controlled Trial Intention-to-treat 12

13 MS MTC MTX N/A NHS NICE NMA NOAR NSAID OLS OR PASI PsA PSA PsARC QALYs RCT RR SD SF-36 SPC STA Manufacturer s submission Mixed treatment comparison Methotrexate Not applicable National Health Service National Institute for Health and Clinical Excellence Network Meta-Analysis Norfolk Arthritis Register Nonsteroidal anti-inflammatory drug Ordinary Least Square Odds Ratio Psoriasis Area and Severity Index Psoriatic arthritis Probabilistic sensitivity analysis Psoriatic Arthritis Response Criteria Quality adjusted life years Randomised Controlled Trial Relative risk Standard deviation Short Form Questionnaire 36 Items Summary of product characteristics Single Technology Appraisal 13

14 TNF Tumour necrosis factor 14

15 Glossary Adverse effect An abnormal or harmful effect caused by and attributable to exposure to a chemical (e.g. a drug), which is indicated by some result such as death, a physical symptom or visible illness. An effect may be classed as adverse if it causes functional or anatomical damage, causes irreversible change in the homeostasis of the organism, or increases the susceptibility of the organism to other chemical or biological stress. Ankylosing spondylitis A rheumatic disease that affects the spine and may lead to some degree of stiffness in the back. As the inflammation goes and healing takes place, bone grows out from both sides of the vertebrae and may join the two together; this stiffening is called ankylosis. Arthritis A term meaning inflammation of the joint(s), but which is often used to include all joint disorders. Sometimes joints are damaged through the disease process of arthritis. Articular Of or relating to the joints. Biologic therapies Medical preparations derived from living organisms. Includes anti-tnfα drug and other new drugs which target the pathologically active T cells involved in psoriasis, and psoriatic arthritis. Confidence interval (CI) The typical ( Classical or Frequentist ) definition is the range within which the "true" value (e.g. size of effect of an intervention) would be expected to lie if sampling could be repeated a large number of times (e.g. 95% or 99%). Corticosteroid 15

16 A synthetic hormone similar to that produced naturally by the adrenal glands that is available in pill, topical, and injectable forms. Cost-benefit analysis An economic analysis that converts the effects or consequences of interventions into the same monetary terms as the costs and compares them using a measure of net benefit or a cost-benefit ratio Cost-effectiveness analysis An economic analysis that expresses the effects or consequences of interventions on a single dimension. This would normally be expressed in natural units (e.g. cases cured, life-years gained, additional strokes prevented). The difference between interventions in terms of costs and effects is typically expressed as an incremental cost-effectiveness ratio (e.g. the incremental cost per life-year gained). Cost-utility analysis The same as a cost-effectiveness analysis but the effects or consequences of interventions are expressed in generic units of health gain, usually quality-adjusted life years (QALYs). Crohn's disease An inflammatory condition of the digestive tract; rheumatic diseases are often associated with it and ulcerative colitis is related to it. C-reactive protein (CRP) Concentrations of this protein in the blood can be measured as a test of inflammation or disease activity. Ciclosporin A medication originally developed to prevent the immune system from rejecting transplanted organs, which has also proved helpful in treating psoriasis. Disease-modifying anti-rheumatic drugs (DMARDs) DMARDs are drugs capable of modifying the progression of rheumatic disease. The term is, however, applied to what are now considered to be traditional disease modifying drugs, in particular sulphasalazine, methotrexate and ciclosporin, as well as azathioprine, cyclophosphamide, 16

17 antimalarials, penicillamine and gold. The newer agent leflunomide may be included as a DMARD. The biologics such as etanercept and infliximab are not generally referred to as DMARDS. Effect size A generic term for the estimate of effect for a study. Emollient An agent that holds moisture in the skin, and by doing so softens or soothes it. Erythrocyte sedimentation rate (ESR) One of the tests designed to measure the degree of inflammation. Fixed effect model A statistical model that stipulates that the units under analysis (e.g. people in a trial or study in a metaanalysis) are the ones of interest, and thus constitute the entire population of units. Only within-study variation is taken to influence the uncertainty of results (as reflected in the confidence interval) of a meta-analysis using a fixed effect model. Heterogeneity In systematic reviews heterogeneity refers to variability or differences between studies in the estimates of effects. A distinction is sometimes made between "statistical heterogeneity" (differences in the reported effects), "methodological heterogeneity" (differences in study design) and "clinical heterogeneity" (differences between studies in key characteristics of the participants, interventions or outcome measures). Immunomodulator A substance that alters the body s immune response. Intention-to-treat An intention-to-treat analysis is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received it or not. Methotrexate 17

18 One of the oldest chemotherapy drugs used to treat cancer; used in the treatment of psoriasis. Mixed treatment comparison Mixed treatment comparison (also known as network meta analysis) is a form of meta-analysis used to strengthen inference concerning the relative efficacy of two treatments. It uses data based on direct comparisons (A vs. B and B vs. C trials) and indirect comparisons (A vs C trials) also, it facilitates simultaneous inference regarding all treatments in order to select the best treatments. Monoclonal antibody An antibody produced in a laboratory from a single clone that recognizes only one antigen. Non-steroidal anti-inflammatory drugs (NSAIDs) Consists of a large range of drugs of the aspirin family, prescribed for different kinds of arthritis which reduce inflammation and control pain, swelling and stiffness. Network meta analysis See Mixed treatment comparison PASI score Psoriasis Area Severity Index score, a number representing the size, redness, thickness, and scaliness of a person s psoriasis. Placebo An inactive substance or procedure administered to a patient, usually to compare its effects with those of a real drug or other intervention, but sometimes for the psychological benefit to the patient through a belief that s/he is receiving treatment. Plaque psoriasis The most common form of psoriasis, also known as psoriasis vulgaris, recognized by red, raised lesions covered by silvery scales. About 80% of psoriasis patients have this type. Psoriasis 18

19 A chronic skin disease characterized by inflammation and scaling. Scaling occurs when cells in the outer layer of skin reproduce faster than normal and pile up on the skin s surface. It is understood to be a disorder of the immune system. Psoriatic arthritis This disease is characterized by stiffness, pain, and swelling in the joints especially of the hands and feet. It affects about 23% of people with psoriasis. Early diagnosis and treatment can help inhibit the progression of joint deterioration. Quality Adjusted Life Year (QALY) An index of health gain where survival duration is weighted or adjusted by the patient s quality of life during the survival period. QALYs have the advantage of incorporating changes in both quantity (mortality) and quality (morbidity) of life. Quality of Life A concept incorporating all the factors that might impact on an individual s life, including factors such as the absence of disease or infirmity as well as other factors which might affect their physical, mental and social well-being. Random effects model A statistical model sometimes used in meta-analysis in which both within-study sampling error (variance) and between-studies variation are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. Randomised controlled trial (RCT) (Synonym: randomised clinical trial) An experiment in which investigators randomly allocate eligible people into intervention groups to receive or not to receive one or more interventions that are being compared. Relative Risk (RR) (synonym: risk ratio) The ratio of risk in the intervention group to the risk in the control group. The risk (proportion, probability or rate) is the ratio of people with an event in a group to the total in the group. A relative risk of one indicates no difference between comparison groups. For undesirable outcomes an RR that is less than one indicates that the intervention was effective in reducing the risk of that outcome. 19

20 Remission A lessening or abatement of the symptoms of a disease. Rheumatoid arthritis A chronic autoimmune disease characterized by pain, stiffness, inflammation, swelling, and, sometimes, destruction of joints. Sensitivity analysis An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used. Statistical significance An estimate of the probability of an association (effect) as large or larger than what is observed in a study occurring by chance, usually expressed as a P-value. T cell A type of white blood cell that is part of the immune system that normally helps protect the body against infection and disease. Topical agent A treatment such as a cream, salve, or ointment that is applied to the surface of the skin. Tumor necrosis factor (TNF) One of the cytokines, or messengers, known to be fundamental to the disease process that underlies psoriasis. It often plays a key role in the onset and the continuation of skin inflammation. Variance A measure of the variation shown by a set of observations, defined by the sum of the squares of deviations from the mean, divided by the number of degrees of freedom in the set of observations. 20

21 1 Summary 1.1 Critique of the decision problem in the manufacturer s submission The decision problem addressed in the manufacturer s submission was largely appropriate and matched the scope. It should be noted that the manufacturer focused on the effectiveness of ustekinumab in two subgroups of patients with PsA: (1) anti-tnfα naïve patients and (2) anti-tnfα experienced patients (i.e. those who had previously received one or more TNFα inhibitors). The submission considered a different comparison for each of these subgroups: (1) ustekinumab versus licensed TNFα inhibitors for anti-tnfα naïve patients; and (2) ustekinumab versus conventional management (excluding the use of anti-tnfα inhibitors) for anti-tnfα experienced patients. Neither of these scenarios fully reflect UK clinical practice where a number of anti-tnfαs can be tried in (no fixed) sequence. The ERG noted that ustekinumab versus a second biologic might be a more appropriate comparison for the substantial proportion of experienced patients who had received only a single prior TNFα inhibitor. Comparison with only conventional management implies that a longer sequence of anti-tnf treatment has failed. 1.2 Summary of clinical effectiveness evidence submitted by the manufacturer Ustekinumab versus conventional management The majority of evidence presented on the efficacy of ustekinumab for PsA in the MS was derived from two methodologically similar RCTs (PSUMMIT 1 and PSUMMIT 2) comparing 45mg and 90mg doses of ustekinumab against placebo (plus conventional non-biologic management). Data from these trials suggest that ustekinumab is a more effective treatment than conventional management over weeks in terms of both joint (ACR 20/50/70, PsARC) and skin (PASI 75/90) response, and that these benefits are likely to persist for at least 52 weeks. No data is available on longer term radiographic progression. On the basis of the available subgroup data from the PSUMMIT 2 trial, there is no convincing evidence of a substantial difference in the efficacy of ustekinumab between anti-tnfα experienced patients and patients who had not received any prior anti-tnfα treatment. Treatment effects were not significantly different for 45mg and 90mg doses of ustekinumab Ustekinumab versus TNFα inhibitors In the absence of head-to-head comparisons between alternative anti-tnfα agents, the manufacturer conducted a network meta-analysis (NMA) incorporating nine placebo controlled RCTs to estimate the relative efficacy between the five biologic agents of interest: adalimumab (2 RCTs), etanercept (2 21

22 RCTs), infliximab (2 RCTs), golimumab (1 RCT) and ustekinumab (2 RCTs). These trials appear to represent the complete relevant body of evidence for the included comparators. Trials of all five agents had a common comparator, placebo, which allowed a network to be established. An NMA was undertaken for the anti-tnfα naïve population only, which reflected the population included in all of the trials, with the exception of the treatment experienced subgroup in PSUMMIT2. Separate networks were constructed for three outcomes: PASI75, PASI90 and PsARC. These three outcomes were considered for two time points weeks and 24 weeks. Overall the results of the NMA found that *********** **** had the lowest or one of the lowest response rates for skin (PASI 75 and 90) and joints (PsARC). For PASI 75 response, ********** was the most effective treatment, and for PASI 90 response ********** was the most effective treatment. For all analyses, ********* achieved the greatest proportion of PsARC responders, followed by ******************** and **********. The manufacturer made no attempt to compare the effectiveness of ustekinumab with TNFα inhibitors among anti-tnfα experienced patients Safety of ustekinumab Four data sources were used to investigate adverse events associated with ustekinumab: (1) the PSUMMIT trials; (2) five-year extensions of four RCTs of ustekinumab for psoriasis; (3) the observational Psoriasis Longitudinal Assessment and Registry (PSOLAR) study; and (4) an observational study from the British Society for Rheumatology Biologics Register (BSRBR) for anti- TNFα therapies in PsA. With the exception of a slightly higher proportion of injection site reactions for 90mg observed in the PSUMMIT trials (1% 90mg vs. 0.6% 45mg vs. 0.4% placebo), the included trial data did not suggest any obvious excess in adverse events, serious adverse events or treatment discontinuation for ustekinumab treated patients. 1.3 Summary of the ERG s critique of clinical effectiveness evidence submitted Ustekinumab versus conventional management The PSUMMIT trials comparing ustekinumab against conventional management were of adequate methodological quality, though interruption of the placebo-controlled phase at week 16 (where participants were allowed to cross-over to an alternative treatment arm) and the termination of the 22

23 controlled phase altogether at 24 weeks provided only a very brief comparison for a chronic condition such as PsA. However, the results obtained over this short period are likely to be valid. The three-arm design of the PSUMMIT trials meant that a substantial proportion of participants were randomised to an unlicensed ustekinumab dose (i.e. 90mg in patients 100kg). However, efficacy estimates for the 45mg and 90mg ustekinumab arms were similar, and there did not appear to be an excess of adverse events associated with the higher dose. Analyses of the anti-tnfα experienced population were based on a subgroup of just 180 or fewer patients from the PSUMMIT 2 trial. The number of prior TNFα inhibitors and duration of prior treatment varied among patients within this subgroup, so data for patients who could be considered truly anti-tnfα refractory is scarce. The additional adverse event studies appear to be appropriate sources for establishing longer term safety information on ustekinumab (albeit in a psoriasis population) and anti-tnfα treatment in PsA. Other than the PSUMMIT trials, the manufacturer did not assess the quality of these adverse event studies, and the possibility of observational data being confounded by differing selection criteria across treatments cannot be excluded. RCTs included in the NMA were of a consistent and adequate quality. There was some heterogeneity; in particular prior DMARD exposure was variable across trials, though where reported the mean number of prior DMARDs was typically fewer than two. On this basis it would appear that, while baseline disease severity is broadly comparable across trials, the NMA population may be less severe than that routinely considered for biologic treatment in practice. The manufacturer assumed that in practice, ustekinumab patients will be treated according to weightbased dosing criteria ( i.e. 45mg for patients with body weight 100kg; and 90mg for those with body weight >100kg), and so excluded PSUMMIT trial patients not meeting these criteria from their NMA. However, it is not clear to the ERG that this is entirely in line with the licence (which permits but does not mandate 90mg in patients >100 kg) or the manner in which the trials were conducted. Furthermore, this resulted in a significant amount of data being lost from the analyses. Nevertheless, despite some limitations in the NMA presented by the manufacturer, the degree of clinical heterogeneity between the included trials in terms of joint and skin disease severity and functional status was reasonable and the assumption of exchangeability between the trials for the purposes of the analyses was considered acceptable. Overall, the ERG believes that it was appropriate to undertake the network meta-analysis and the results obtained by the manufacturer were robust when compared with the results of the ERG analysis. 23

24 1.4 Summary of cost effectiveness submitted evidence by the manufacturer The manufacturer presented a decision model, which was based on previously published models. It comprised two elements: a short-term decision tree, which evaluated patients initial response to treatment; followed by a longer-term Markov model which captured the longer term costs and consequences of treatments. They evaluated treatments over a lifetime horizon, from a NHS/PSSRU perspective. Treatment response, in the base case, was determined by PsARC response. For all comparators response was determined at 12 weeks, but for ustekinumab it was determined at 24 weeks, based on dosing requirements; this was tested in a sensitivity analysis. Patients who did not achieve a response at the appropriate time point were considered non-responders and moved to conventional management. After the initial response point a constant withdrawal rate was applied to account for withdrawals due to lack of efficacy and adverse events in the long run. Health states within the Markov model captured both the joint (PsARC) and skin (PASI) components of PsA, as both of these are related to quality-of-life and costs. PASI score changes were dependent on achieving a PASI 75 response; HAQ (functional status measure) scores were dependent on achieving a PsARC response. Both HAQ and PASI scores were incorporated into health-related quality-of-life through the use of published mapping equations. Resource use data were taken from a previous submission. Drug prices were taken from the BNF (2013). Health state costs were estimated as a function of HAQ and PASI through the use of previously published work. Deterministic and probabilistic results were presented. In addition, numerous scenario analyses were undertaken. The manufacturers presented analyses for two populations: anti-tnfα naïve patients and anti-tnfα experienced patients (i.e. those who had previously received one or more TNFα inhibitors). For anti- TNFα naïve patients ustekinumab was compared with conventional management, adalimumab, etanercept, golimumab and infliximab. This analysis utilised effectiveness evidence from the manufacturers NMA, a previous ERG NMA, and PSUMMIT data (naïve population only). In addition, they also utilised data on resource use, HAQ rebound, HAQ natural history and the relationship between HAQ, PASI and EQ-5D from the previous Rodgers et al. submission. For anti-tnfα naïve patients when a full probabilistic incremental analysis was undertaken both adalimumab and ustekinumab were found to be dominated. That is, both of these treatments were more costly and less effective when compared with the next most costly alternative. Golimumab achieved an ICER of 12,235; the ICERs for etanercept and infliximab both exceeded 100,

25 Probabilistic results did not differ significantly from the deterministic results. The probabilistic ICERs for each of the pairwise comparisons with conventional management strategies ranged from 13,134 to 40,068 with the ICER for ustekinumab compared with conventional management strategies being 23,048. Golimumab, etanercept and adalimumab all had lower pairwise ICERs. For anti-tnfα experienced patients, ustekinumab was compared with conventional management only. This analysis utilised evidence from a sub-group of the PSUMMIT 2 trial. In addition, they also utilised data on resource use, HAQ rebound, HAQ natural history and the relationship between HAQ, PASI and EQ-5D from the previous Rodgers et al. Submission to NICE for an appraisal of anti-tnfs for psoriatic arthritis. For anti-tnfα experienced patients, ustekinumab achieved a probabilistic ICER of 29,451 when compared with conventional management. Sensitivity analysis undertaken for both the naïve and experienced evaluations did not significantly change the results obtained. 1.5 Summary of the ERG s critique of cost effectiveness evidence submitted The model met the NICE reference standard and is in line with the NICE scope. The structure of the model was based on previous submissions and the ERG felt that it was appropriate. Both the manufacturer and the ERG undertook a number of sensitivity analyses in an attempt to explore some of the uncertainty in data inputs. In general these analyses did not have a significant impact on the results obtained but the ERG feels that some of these analyses represented a more realistic base case and have presented this as a preferred analysis for the modelling of the anti-tnf naive population. Due to a lack of data to evaluate the anti-tnfα experienced population and the inappropriate single comparator no preferred analysis is presented, rather the ERG have elected to explore the issue of sequencing (see Section 1.7). 1.6 ERG commentary on the robustness of evidence submitted by the manufacturer Strengths The short-term estimates of efficacy for all agents against placebo were derived from RCTs of adequate methodological quality and are likely to be reliable. The manufacturer s NMA was robust, with little variation in estimates from the ITT, weight-based, or combined-dose analyses. The model structure was appropriate and the evaluation met the NICE reference case Weaknesses and areas of uncertainty 25

26 Ustekinumab was not compared with other licensed biologics for the anti-tnfα experienced population. The manufacturer suggested that that ustekinumab provides a novel treatment option when anti-tnfα treatment has failed, and so the relevant comparator in anti-tnfα experienced patients would be conventional treatment without any biologic component. However the model used evidence derived from a population who had experienced anti-tnfs but not failed them as a class. Whilst observational evidence suggests diminishing response rates and treatment persistence associated with the sequential use of anti-tnfα agents, no robust evidence for the relative efficacy of ustekinumab and anti-tnfs when used as second or later-line therapy is available. *** *** ******* ******* **** **** ********* ****** *** **** *********** **** *********** ** ******** **** ***** *********** *** ** ******** ** ********* ** ******* ******* *** ********** ********* ** ******** ** * ** * * ** * ** * ** **** ********* ****** ***** **** ***** *** ***** ** ******** ******** *** *********** ** ********* *********** ********. The ERG tried to address this issue in an additional cost-effectiveness analysis incorporating sequential use of anti- TNFs, but this was based on a number of strong assumptions and suboptimal data. Given the lack of comparative data for second-line biologic treatment, a head-to-head trial of ustekinumab versus TNFα inhibitor therapy in this population may be warranted. Any such trial should clearly distinguish between prior anti-tnfα experience and anti-tnfα class failure in its selection of participants. The ERG believes that some uncertainty still remains due to a lack of robust evidence on some key model parameters. These include: The natural history of HAQ score change. This parameter was taken from a previous publication (Bojke et al; Rodgers et al.) and is based on a secondary analysis of data from the NOAR database. The analysis was undertaken in 2009 and a number of limitations were highlighted by the ERG at that time. In 2009 it represented the best available evidence; it is not clear to the ERG that it remains the best available evidence. Rebound to HAQ on withdrawal from treatment. An alternative scenario has been presented in this submission, but no further evidence has been presented to support which is most likely to reflect clinical reality. HAQ and PASI related costs. These data were also taken from a previous submission. Whilst this allows for consistent comparison the limitations of these data were fully discussed in the previous submission and no attempt has been made to address the limitations. A relatively large though statistically non-significant PASI75 benefit was observed in the anti-tnfα experienced subgroup in PSUMMIT 2. This may be an artefact of the small number of patients in the analysis and could be confirmed or refuted in a properly powered trial in this patient population. 26

27 1.7 Summary of exploratory and sensitivity analyses undertaken by the ERG The ERG found that the baseline HAQ and baseline PASI were incorrectly calculated. Therefore, a corrected model was presented. This corrected model estimated that for the anti-tnfα naïve population, the probabilistic ICER for ustekinumab vs. conventional management was 23,508 and that ustekinumab was dominated in the incremental analysis. For the anti-tnfα experienced population the probabilistic ICER for ustekinumab vs. conventional management was estimated as 29,451. All further analyses undertaken by the ERG used this corrected version of the model. Several sensitivity analyses were then undertaken for both the anti-tnfα naïve and the anti-tnfα experienced populations as well as an exploratory sequencing analysis Anti-TNFα naïve population The analyses undertaken for the naïve population are listed below, with probabilistic ICER results for ustekinumab for vs. conventional management and for the incremental analysis presented for each: Full ITT NMA results for all treatments used: Ustekinumab vs. conventional management ICER: 23,480 Incremental analysis ICER: Dominated Full ITT NMA results, except for ustekinumab 90mg used: Ustekinumab vs. conventional management ICER: 23,542 Incremental analysis ICER: Dominated Assumption that HAQ rebounds to natural progression used: Ustekinumab vs. conventional management ICER: 41,500 Incremental analysis ICER: Dominated HAQ score change estimates from updated Yang NMA using 12-week PSUMMIT trial data used: Ustekinumab vs. conventional management ICER: 23,140 Incremental analysis ICER: Dominated HAQ score change estimates from updated Yang NMA using 24-week PSUMMIT trial data used Ustekinumab vs. conventional management ICER: 22,987 Incremental analysis ICER: Dominated 27

28 24 week PsARC assessment point for all treatments was used: Ustekinumab vs. conventional management ICER: 30,495 Incremental analysis ICER: Dominated Phototherapy cost was included: Ustekinumab vs. conventional management ICER: 22,455 Incremental analysis ICER: Dominated In addition, 5, 10, 20 and 40 year time horizons were estimated. Ustekinumab was dominated for each time horizon, when compared with the next best non-dominated alternative. When compared with conventional management, the ICER for ustekinumab varied from 55,029 (5 year time horizon) to 23,509 (52 year time horizon). In Section 6, a preferred base case for the anti-tnfα naïve population was also presented. When compared with conventional management, the ICER for ustekinumab was 23,246. When compared with the next best non-dominated alternative, ustekinumab was dominated Anti-TNFα experienced population The analyses undertaken for the experienced population are listed below, with probabilistic ICER results presented for each: Available ITT trial results for all treatments used: ICER estimated as 29,797 ITT trial results used for ustekinumab 45mg arm only: ICER estimated as 29, week PsARC assessment point for all treatments: ICER estimated as 39, week PsARC assessment point for all treatments: ICER estimated as 32,162 Phototherapy cost was included: ICER estimated as 28,670 Assumption that HAQ rebounds to natural progression: ICER estimated as 52,408 5 year time horizon: ICER estimated as 69, year time horizon: ICER estimated as 46, year time horizon: ICER estimated as 32, year time horizon: ICER estimated as 29, Sequencing analysis In addition to the sensitivity analysis undertaken, an exploratory analysis into the sequencing of biologic treatments was presented. There are a number of caveats to this analysis (See Section 6.3.x) The ICERs for second-line treatment, when the first-line treatment had failed, either due to lack of 28

29 efficacy or due to adverse events were calculated. Within this analysis, ustekinumab was never estimated to be cost-effective at a willingness to pay threshold of 30,000, although these results were subject to significant uncertainty. 29

30 2 Background 2.1 Critique of manufacturer s description of underlying health problem. The manufacturer provided a brief but accurate overview of psoriatic arthritis (PsA). They state that both indications for ustekinumab (psoriasis and PsA) cover approximately 27,000 patients in England and Wales, though it should be noted that only 7,000 of these are patients with PsA. 2.2 Critique of manufacturer s overview of current service provision The manufacturer s submission (MS) provided an accurate overview of the treatment pathway for active and progressive PsA patients, based on the current clinical pathway recommended by British Society of Rheumatology (BSR) and existing NICE guidance on the use of TNFα inhibitors in PsA. The manufacturer provided details of the anti-tnfα agents (etanercept, infliximab, adalimumab and golimumab) that are currently used for the treatment of active and progressive PsA in UK clinical practice. The MS briefly discussed sequential use of TNFα inhibitors, referencing observational evidence that showed lower response rates and treatment persistence after switching from one TNFα inhibitor to another. 1, 2 As this is an important issue in the prescribing of anti-tnfαs in PsA the ERG examined these studies, and they are briefly summarised below. Fagerli et al. 2013: 1 : This small (n=439) uncontrolled observational study, appeared to include all patients with inflammatory arthropathies from five centres in Norway. It was not reported whether these were specialist centres or what proportion of PsA patients in Norway were treated in these centres. It is therefore not clear whether the included patients are representative of all PsA patients in Norway that received anti-tnfαs, and by extension how typical they are of UK patients. Of note is that the diagnostic criteria for PsA were more lax than is typical such that not all patients had swollen joints. The study sample comprised all patients who started an anti-tnfα in 2001 or later. As the anti- TNFαs available has grown over the subsequent 12 years, the actual anti-tnfαs experienced by these patients may not reflect the likely experience of a typical current cohort starting their first or second anti-tnfα in All the patients appeared to be included in the analysis, however, it is not completely clear that the non-switchers continued to take their 1 st anti-tnfα, rather than merely not starting a second. The most common 1 st anti-tnfα was etanercept (50%), with adalimumab the next most common (29%). It was not reported if these proportions varied over the duration of the study. Table 1 shows drug survival rates at three years for switchers and patients who remained on their first treatment. 30

31 Table 1: Drug survival rates at 3 years (NOR-DMARDstudy) Anti-TNFαs % drug survival All patients (n=439) Those who stayed on 1 st treatment (n=344) Those who switched to 2nd treatment (n=95) 1 st 57% 71% 17% 2 nd % Glintborg et al., 2013: 2 The population in this uncontrolled observational study was apparently unselected, comprising a Danish registry started in 2000 and containing more than 90% of all adults with rheumatic disease in Denmark who were treated with a biologic (TNFα inhibitor). It was approved by the Danish Health and Medicines Authority. The registry included patients treated between 2000 and 2012 receiving a biologic marketed for PsA, and on entry to the registry patients had to be starting their first anti-tnfα. Patients using anti-tnfαs in clinical trials were not included. There was no checking of the data but the participating centres were subject to audit. The analysis of response rates did not include those who switched from first anti-tnfα after 2 years. Kaplan-Meyer curves were used to assess drug survival (i.e. staying on given anti-tnfα). The most common 1 st anti-tnfα was adalimumab (45%), with the next most common being infliximab (30%), followed by etanercept (22%) and golimumab (3%). The most frequently used 1 st anti-tnfα varied over time: from 2001 to 2006 it was infliximab; from it was adalimumab. Etanercept was the most common 2 nd and 3 rd anti-tnfα. Table 2 and Table 3 show median drug survival rates and treatment response for first, second and third TNFα inhibitor therapy. Table 2: Drug survival rates from observational studies of Anti-TNFαs for PsA. (Taken directly from DANBIO Registry (Glintborg et al. 2013)) Anti- TNFαs Withdrawn Patients still treated ( n) after Still on treatment after 2 years 0 2 yrs 4 yrs 6 yrs 8 yrs 10 yrs Median drug survival (95% CI) 1 st % 2.2 (1.9, 2.5) 2 nd % 1.3 (1.0, 1.6) 3rd % 1.1 (0.7, 1.5) 31

32 Table 3: Proportion of patients achieving a response in terms of ACR 20/50/70, a Good EULAR response and DAS28 remission. (Constructed from data reported from DANBIO Registry (Glintborg et al. 2013)) Anti-TNFαs Response criteria ACR 20 ACR 50 ACR 70 Good EULAR response DAS28 remission 1 st 47% 33% 17% 45% 43% 2 nd 22% 13% 5% 19% 34% 3rd 18% 6% 2% 17% 22% The results of these two observational studies demonstrate that for a subgroup of patients whose drug survival on a 1 st anti-tnfα is short, a substantial proportion of patients nevertheless appear to benefit from switching TNFα inhibitors. However, treatment response to a second and later anti-tnfα is lower than to a first. There is uncertainty around how generalisable these results are to current use of anti-tnfαs in UK clinical practice. 3 Critique of manufacturer s definition of decision problem 3.1 Population The manufacturer specified the relevant population as people with active and progressive PsA who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs) or TNF-α inhibitors. This matches the population specified in the NICE scope, though the licence (Marketing Authorisation) only states that ustekinumab is indicated in PsA patients with an inadequate response to DMARDs; there is no mention of TNF-α inhibitors. The ERG queried whether the population included patients with predominant axial disease, but the manufacturer confirmed that such patients were not included in the population. 32

33 3.2 Intervention The scope and decision both simply define ustekinumab as the intervention of interest. Ustekinumab is a human monoclonal antibody that acts as a cytokine inhibitor through targeting interleukin-12 (IL- 12) and interleukin-23 (IL-23). The product licence states that ustekinumab alone or in combination with methotrexate (MTX) is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate. The recommended posology is an initial dose of 45mg administered subcutaneously, followed by a 45mg dose four weeks later, and then every 12 weeks thereafter. Alternatively, 90mg may be used in patients with a body weight greater than 100 kg: the licence does not mandate strict weight-based dosing Comparators The MS reflects the NICE scope in specifying the following comparators: a) alternative TNF- inhibitors, and b) conventional management strategies for active and progressive psoriatic arthritis excluding TNF- inhibitors. In their submission, the manufacturer presents two evaluations: (1) all of the licensed treatments are compared, along with conventional management, in anti- TNF- naïve patients (i.e. all are considered as alternative first-line options); (2) ustekinumab is compared with conventional management alone in a population who have experience of prior TNF- inhibitor therapy (i.e. ustekinumab is considered the only choice for any patient with an inadequate response to a previous biologic treatment). However, this second analysis more closely resembles a scenario where ustekinumab is the only available option after all reasonable TNF- inhibitor therapy options have been exhausted (i.e. end of line). The manufacturer does not present any evidence on the effectiveness of ustekinumab relative to an alternative to second- or third-line TNF- inhibitor for patients who have failed an initial anti- TNF- agent. 3.4 Outcomes Outcomes addressed in the stated decision problem matched those in the NICE scope, namely: disease activity, effect on concomitant skin condition, functional capacity, joint damage, disease progression, adverse effects of treatment, and health related quality of life. The actual measures used (e.g. American College of Rheumatology (ACR) criteria, PsA Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI) response, Disability Index of the Health Assessment Questionnaire (HAQ- DI), modified van der Heijde-Sharp Score, SF-36) are similar to those used in earlier evaluations of biologic therapy in PsA. 3.5 Other relevant factors 33

34 The MS emphasises ustekinumab s novel mechanism of action, stating that this IL-12/IL-23 inhibitor..through its unique mode of action, provides PsA patients with a new option. This is especially important for patients who have failed on previous treatment with TNFαs. This statement raises questions about the definition of failure for TNFα inhibitors as a class, and the strength of evidence to support the use of ustekinumab in patients who have failed on one or more previous TNFα inhibitors. These issues are discussed in Section 4.2 of this report. 34

35 4 Clinical Effectiveness This section contains a critique of the methods of the review(s) of clinical effectiveness data, followed by a description and critique of the trials included in the review, including a summary of their quality and results and the results of any synthesis of studies. 4.1 Critique of the methods of review(s) The MS reported a systematic review conducted to determine the clinical efficacy and tolerability of ustekinumab and the specified comparator treatments for active PsA Searches Clinical effectiveness search The MS described the search strategies used to identify relevant clinical effectiveness studies about the use of ustekinumab (Stelara ) for treating active and progressive psoriatic arthritis. Search strategies were only briefly described in the main body of the submission, however full details were provided on request (clarification A2). The electronic databases MEDLINE and MEDLINE In-Process (via Ovid), EMBASE (via Ovid), and the Cochrane Library: Cochrane database of systematic reviews, register of clinical trials (CENTRAL), NHS HEED, HTA, DARE, CINAHL, Science Citation Index (Web of Science) and Conference Proceedings Index (Web of Science) were searched to identify clinical trials and systematic reviews on the use of ustekinumab and other comparators. In addition to the formal searches, reference lists of systematic reviews and meta-analyses identified were scanned for additional trials of relevance to the research question. Unpublished data on the clinical efficacy of ustekinumab from Janssen were also included. Searches were conducted in October 2012 and subsequently updated in July Search strategies for each database were documented in Section 10.2 appendix 2. There were no date or language limits. Overall the searches were appropriate and well documented, and included the use of both subject indexing terms (MeSH and EMTREE) and free text searching. Field searching, Boolean operators and truncation were used where required. All the databases required by NICE were searched. However, medical society and regulatory body websites were not searched. The search strategies used in the manufacturer's submission were limited to clinical trials and systematic reviews by applying appropriate methodological search filters, however a search for other 35

36 study designs such as cohort or case control studies might have provided useful supplementary information about safety Inclusion criteria Clinical efficacy: RCTs (parallel, cross-over, open-label, single- or double-blinded) evaluating ustekinumab for the treatment of active PsA in adults, reporting relevant clinical, quality of life, or safety outcomes were included in the review. Eligible interventions appeared to be ustekinumab and relevant TNFα inhibitors (etanercept, infliximab, adalimumab, and golimumab). Inclusion criteria relating to comparators were not explicitly reported, though it appears that TNFα inhibitors and conventional management were eligible, as stated in the decision problem. The stated inclusion criteria were appropriate. PRISMA flow diagrams were reported for both original and update searches, though reasons for excluding four studies from the quantitative synthesis were not reported. In response to a query from the ERG, the manufacturer clarified that one of these was the RESPOND study, which was excluded because it compared infliximab+mtx versus MTX alone and so could not be connected to the network used for the MTC (see clarification A3). The three remaining studies were ongoing trials of agents not licenced for use in PsA (apremilast and brodalumab). The justifications for excluding these trials seem appropriate. Adverse events: Alongside clinical efficacy trial data, the MS presented observational data and psoriasis trial data relating to adverse events. However, no inclusion criteria were reported for this set of studies. In response to the ERG s request for clarification, the manufacturer stated sources that were recently published and relevant to the decision problem were selected and included in the original submission (see clarification A23), apparently confirming that no explicit inclusion criteria were applied to safety evidence. The ERG compared the sources for adverse effects data with the Medical Review report from the FDA (2009) and found that they included all available at that time plus all that were predicted to be available at a later date, with the exception of data from the planned Pregnancy Research Initiative or Nordic Database Initiative. 4 It is not clear whether these data were available for inclusion in the MS. However, PsA data on anti-tnfα therapy from the British Society for Rheumatology Biologics Register was included; while an appropriate source of adverse event data, populations may not have been directly comparable across these different sources (see Section 4.2). 36

37 4.1.3 Critique of data extraction Clinical efficacy: Details of data extraction methods (such as procedures used to avoid errors and bias) were not reported in the MS. Therefore ERG could not comment on the robustness of the data extraction methods in general. Adverse events: It appears that adverse event data were not extracted systematically; in response to a request from the ERG, the manufacturer provided additional data on serious infections and injectionsite reactions that were not reported in the original MS (see clarification C4) Quality assessment Clinical efficacy: The manufacturer s quality assessment was adapted from CRD guidance 5 covering: randomisation, allocation concealment, similarity of groups at outset, blinding, differential dropout, selective reporting of outcomes, and use of intention to treat analysis. This tool was appropriate. However, it appears that this was only applied to the ustekinumab trials; the quality of other RCTs included in the NMA was not assessed in the MS (see Section 4.4). The ERG queried why, despite two near identical sample size calculations, the sample size for PSUMMIT 2 is only half that of PSUMMIT 1 (clarification A6). The only apparent difference between the sample size calculations was the assumption of a slightly larger proportion of patients receiving MTX at baseline in PSUMMIT 2 (60% vs. 50% in PSUMMIT 1). It is unclear whether this would explain the large difference in sample sizes, but in their response to the clarification, the manufacturer provided tables showing that both trials were adequately powered to detect the overall observed difference between treatment groups on ACR20. Adverse events: With the exception of the PSUMMIT trials, the manufacturer did not appear to assess the quality of studies included in the adverse events section of the MS. Observational evidence can be subject to confounding and selection bias, though these issues are considered in the summary below Evidence synthesis Direct evidence of clinical efficacy: The original MS presented data on the anti-tnfα naïve subpopulation separately for each of the two PSUMMIT trials, alongside separate anti-tnfα experienced subgroup data from PSUMMIT 2. Since the two PSUMMIT trials had almost identical protocols, the ERG considered it appropriate to combine these trials in a meta-analysis, and requested that the manufacturer present pooled outcomes for two populations: (i) anti-tnfα naïve patients only and (ii) all randomised patients, regardless of prior anti-tnfα exposure (see clarification A10). A critique of the PSUMMIT trials and their synthesis is given in Section 4.4 of this report. 37

38 Network meta-analysis: The original MS presented combined data on the anti-tnfα naïve subpopulation from the two PSUMMIT trials with data from RCTs evaluating TNFα inhibitors in a network meta-analysis (NMA), details of which are presented in Section 4.4 of this report. 4.2 Critique of trials of the technology of interest, their analysis and interpretation (and any standard meta-analyses of these) Three double-blind RCTs evaluating ustekinumab were retrieved from the searches (C0743T10, PSUMMIT 1 and PSUMMIT 2). 6-8 All three trials compared ustekinumab against placebo. However, concomitant therapies (DMARDs, NSAIDs and oral corticosteroids) were permitted for all patients, and since the majority of patients received concomitant therapies ***** **** **** ********* **** ******), these placebo groups are likely to reflect conventional non-biologic management strategies for the treatment of active PsA in patients in whom DMARDs have been tried unsuccessfully. The CO743T10 RCT 6 was excluded from the analysis because the ustekinumab dosing schedule (63 or 90mg every week for four weeks) differed from the licenced posology. Exclusion on this basis seems justifiable. The remaining trials (PSUMMIT 1 and 2) both use the recommended posology Description of PSUMMIT trial methods PSUMMIT 1 7 is a multicentre, double-blind, placebo-controlled RCT in which 615 adults with active psoriatic arthritis ( 5 tender and 5 swollen joints, C-reactive protein 3 0 mg/l) were randomly assigned to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered blinded early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they received again at week 28 and every 12 weeks thereafter. Blinding was maintained up to and including 24 weeks. The planned duration of exposure to study agent including follow-up for safety was 100 weeks. PSUMMIT 2 8 appeared to employ almost identical methodology to PSUMMIT 1, with three main differences: (i) around half the total number of patients were randomised (n=312); (ii) planned follow-up was for just 60 weeks and; (3) at least 150 but not more than 180 included subjects could have been treated with single or multiple biologic anti-tnfα therapy (at least eight weeks of etanercept, adalimumab, golimumab, certolizumab pogol, or at least 14 weeks of infliximab). Consequently, 58% of PSUMMIT 2 patients (n=180) had been exposed to at least one TNFα inhibitor prior to enrolment; these patients constitute the entire anti-tnfα experienced subpopulation discussed in the MS and in this report Outcomes collected in the PSUMMIT trials 38

39 The primary outcome of both PSUMMIT trials was the proportion of patients achieving a 20% improvement in tender or swollen joint counts using the American College of Rheumatology assessment criteria (ACR20) at 24 weeks. Secondary joint response outcomes were ACR50, ACR70, Psoriasis Area and Severity Index (PASI) 75 response at week 24 among patients with 3% body surface area (BSA) psoriasis at baseline, physical functional status measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI), and radiographic progression assessed by changes in modified van der Heijde-Sharp Score (vdh-s) of the hands and feet. Though inconsistently reported in the original MS, the manufacturer clarified that modified PsA Response Criteria (PsARC) at week 24 was also collected as secondary outcome (response to clarification C2). Though not listed as primary or secondary outcomes, the MS also provided 24 week data from the PSUMMIT trials on dactylitis, enthesitis, health related quality of life (SF-36) and adverse events. Since the clinicaltrials.gov records 9, 10 do not list all the outcomes known to have been collected in these trials and in the absence of complete protocols, it was not possible to assess whether there was selective reporting of secondary/tertiary outcomes in the MS. However, for the main joint/skin response measures, selective reporting of outcomes is not an issue Internal validity of PSUMMIT trials Baseline comparability of groups: The manufacturer s critical appraisal rated the PSUMMIT 1 and 2 trials as high quality. Insufficient data are available for the ERG to properly verify each item, but based on the limited available information in the MS, related publications, 6, 7 and response to clarifications (see clarification A4), these ratings appear to be reliable. Table 13 (p.38) in the MS suggested that patient groups were broadly comparable across the PSUMMIT trials in terms of prognostic factors at baseline. The ERG asked for similar baseline data for the anti-tnfα naïve and anti-tnfα experienced subgroups from PSUMMIT 2 (see response to clarification A5). This revealed similar baseline characteristics for the anti-tnfα naïve populations in both PSUMMIT trials. As might be expected, duration of PsA was greater in the PSUMMIT 2 anti-tnfα experienced subgroup relative to the anti-tnfα naïve groups (by around two years on average). Anti-TNF experienced patients also appeared to be slightly ******* at baseline, and a ************* ******* ********** ** **** ******** were randomised to ustekinumab in this subgroup (see Table 4 below). Early escape and crossover between treatment groups: In both PSUMMIT trials, for patients who escaped early at week 16 (due a lack of joint improvement), week 16 data were carried forward to week 24. Therefore, complete observations were only available up to 16 weeks. If it is assumed that patients on active treatment were more likely to have responded during weeks than those on placebo, the treatment benefit of ustekinumab might have been underestimated at 24 weeks. However, 39

40 the ERG requested that response data over time were provided for ACR20, PsARC and PASI75 for both PSUMMIT trials (clarification A12), and the supplied data suggested that relative effects across treatment groups were fairly consistent over weeks. The ERG asked for the proportion of patients escaping early in each treatment group (clarification A15). The manufacturer s response showed that for both PSUMMIT trials, *** ********** ** ******** ******** ***** **** ******* ****** ******** *** ******* **** **** **** ****** ********* ***** ** ********** **** *** *********** **** ************ ***** ** ****** ** *** ******* *****. However, for the majority of patients, the recommended posology of ustekinumab is an initial dose of 45 mg administered subcutaneously, followed by a 45 mg dose four weeks later, and then every 12 weeks thereafter. It is unlikely that poorly-responding patients in clinical practice would be considered treatment failures at 16 weeks after having received only the initial 45mg dose of ustekinumab. Even if this were the case, the licence would only allow the option of switching to the higher 90mg dose for patients weighing more than 100 kg. At week 24, all remaining patients in the placebo groups crossed-over to receive 45mg ustekinumab. Consequently, the PSUMMIT trials cannot provide evidence on the effects of ustekinumab relative to placebo/conventional management after 24 weeks. 40

41 Table 4: Baseline characteristics of PSUMMIT trials according to prior biologic exposure TRIAL PSUMMIT2 PSUMMIT 1 Prior anti-tnfα use anti-tnfα experienced anti-tnfα naive anti-tnfα naive Ustekinumab Ustekinumab Ustekinumab Ustekinumab Ustekinumab 45 Ustekinumab 90 Treatment arm Placebo Placebo 45 mg 90 mg 45 mg 90 mg mg mg Placebo Age, mean years (SD) **** ****** **** ****** **** ****** **** ****** **** ****** **** ****** 47.1 (12.6) 46.8 (11.8) 47.4 (12.3) Sex, % male **** **** **** **** **** **** Race, % Caucasian **** **** **** **** ***** ***** Weight, mean kg (SD) **** ****** **** ****** **** ****** **** ****** **** ****** **** ****** 87.8 (20.6) 89.8 (21.5) 87.5 (21.7) Duration of PsA, mean *** ***** *** ***** *** ***** *** ****** *** ***** *** ***** years (SD) 6.1 (6.8) 7.0 (7.6) 6.7 (7.5) Duration of PsO, mean **** ****** **** ****** **** ****** **** ****** **** ****** **** ****** years (SD) 14.9 (13.0) 15.5 (12.1) 15.9 (12.8) Treatment history, % use DAS28, mean (SD) PASI score, mean (SD) Swollen Joint Count, mean (SD) Tender Joint Count, mean (SD) ****** ***** **** ***** ****** **** ****** ***** **** ***** ****** **** ****** ***** **** ***** ****** **** ****** ***** **** ***** ****** **** ****** ***** **** ***** ****** **** ****** ***** **** ***** ****** **** DMARD: 79.5; NSAID: 89.3 DMARD: 78.4; NSAID: 90.6 DMARD: 80.6; NSAID: 87.8 ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ***** ***** ***** ***** ***** ***** 5.1 (0.9) 5.2 (0.9) 5.2 (1.1) ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ***** ***** ***** ***** ***** ***** 11.5 (11.8)* 10.6 (8.5)* 11.7 (10.3)* **** ****** **** ****** **** ****** **** ***** **** ***** **** ***** 12.5 (7.8) 12.9 (8.3) 15.0 (10.2) **** ****** **** ****** **** ****** **** ****** **** ****** **** ****** 22.2 (13.9) 23.2 (13.7) 25.1 (15.0) Enthesitis, n (%) ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ***** ***** ***** ***** ***** ***** 142 (69.3) 154 (75.5) 145 (70.4) Dactylitis, n (%) ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ** ** ******** ***** ***** ***** ***** ***** ***** 101 (49.3) 99 (48.5) 96 (46.6) CRP mg/l, mean (SD) **** ****** **** ****** **** ****** **** ****** **** ****** **** ****** 16.9 (17.8) 18.0 (18.0) 15.9 (19.1) 41

42 TRIAL PSUMMIT2 PSUMMIT 1 Prior anti-tnfα use anti-tnfα experienced anti-tnfα naive anti-tnfα naive Ustekinumab Ustekinumab Ustekinumab Ustekinumab Ustekinumab 45 Ustekinumab 90 Treatment arm Placebo Placebo 45 mg 90 mg 45 mg 90 mg mg mg **** **** **** **** **** **** ****** ***** ****** ***** ****** ***** ****** ***** ****** ***** ****** ***** (5.10; 7.60) (5.05; 7.80) Patient s assessment of pain (VAS; 0-10 cm) Patient s global assessment of disease activity (VAS; 0-10 cm) Physician s global assessment of disease activity (VAS 0-10 cm) HAQ disability index (0 3) Psoriasis on 3% body surface area **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** **** ****** ***** ** ******* ** ******* ** ******* ** ******* ** ******* ** ******* 5.70 (4.40; 7.00) 6.50 (5.00; 7.60) 1.25 (0.75; 1.75) 6.30 (4.85; 7.35) 6.80 (5.30; 7.90) 1.25 (0.75; 1.63) Placebo 6.40 (4.80; 7.60) 5.85 (4.60; 7.30) 6.40 (4.90; 7.50) 1.25 (0.75; 1.75) 145 (70.7%) 149 (73.4%) 146 (70.9%) 42

43 4.2.4 External validity of PSUMMIT trials Prior DMARD use: Current NICE guidance for TNFα inhibitor therapy recommends: The psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs, administered either individually or in combination. However, though all patients included in the PSUMMIT trials were required to have active arthritis despite current or previous DMARD and/or NSAID therapy, around 20% of patients in PSUMMIT 1 and 14% of patients in PSUMMIT 2 had never received any DMARD therapy prior to enrolment (Response to clarification A8). Consequently PsA patients in the PSUMMIT studies may have less severe disease than PsA patients considered eligible for biologic treatment in practice (see Section 4.4 for further discussion of this issue). The most commonly used prior DMARDs **** ************ ****** ************* ***** *** *********** *****. The proportions were similar across treatment groups and appear to be representative of routine clinical practice. Concomitant medication use: In response to a request from the ERG, the manufacturer clarified that *** ** ******** ** *** ******* ******* ********* ** ******* **** *** ** ******** ******** *********** ****** *** *** ******** ***************. These rates were broadly similar across treatment groups and are likely to reflect rates seen in clinical practice. Prior TNFα inhibitor use: For the anti-tnfα experienced subpopulation, the MS included only data from a subgroup of patients in the placebo-controlled PSUMMIT 2 trial. There was no direct or indirect comparative evidence on the efficacy of ustekinumab relative to TNF- inhibitors in this subpopulation, so the MS only evaluates ustekinumab against conventional management strategies for the patients who have experience with TNF- inhibitors. This would be the appropriate comparator in a scenario where TNF- inhibitors are considered to have been ineffective or intolerable**** ************ ****** ************* ***** *** *********** ***** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** ***********While the existing NICE guidance does not explicitly mention sequential treatment, in clinical practice a second TNF- inhibitor (usually one of the monoclonal antibodies) is commonly used if response is not achieved with the initial agent (frequently etanercept). Therefore, the ERG believes that the proper comparison for many of the anti-tnfα experienced patients would be ustekinumab versus a second- or third line TNF- inhibitor. The *** of anti-tnfα experienced patients in PSUMMIT 2 with 3 TNF- inhibitors are more likely to represent a truly anti-tnfα refractory population in which conventional management would be an appropriate comparator (see Section 5). However, separate outcome data were not available for these patients, and the ***** ****** ** ******** may make any results unreliable. 43

44 Table 5 Number of patients receiving 1, 2, 3 or more previous anti-tnfs (PSUMMIT 2) Placebo Ustekinumab 45mg Ustekinumab 90mg Total Randomized subjects who were previously treated with biologic anti-tnfα agent(s) ** ** ** *** 1 previous anti-tnf ** ***** ******* ** ***** ** ***** 2 previous anti-tnfs ** ***** ** ***** ** ***** ** ***** 3 previous anti-tnfs ** ***** ** ***** ** ***** ** ***** Duration of treatment for a prior anti-tnfα inhibitor also varied; **** ***** **** ** ******** ***** had experience of less than one year, *** had one to three years experience, and *** had three or more years experience (see response to clarification A8) Analysis of PSUMMIT trial data Section 6.5 of the MS presented outcome data from the PSUMMIT trials in a number of tables and figures, though this presentation was somewhat inconsistent and incomplete. The main points were: The results were reported variously by trial (PSUMMIT 1 and 2) and by prior anti-tnfα experience. All results should have been reported by trial in the first instance. Results were not reported as relative effects and confidence intervals or other measures of variance were frequently not reported. Longer-term follow-up was not consistently reported; though 52 week data were presented for PASI75, and detailed follow-up data over multiple timepoints were presented for ACR20, the remaining outcomes were only reported at 24 weeks. No results were reported for the pre-planned subgroup analyses of demographics, baseline disease characteristics or concomitant or prior use of medications. Results from a meta-analysis for the main outcomes were not presented. Given the similarity of the PSUMMIT trials, meta-analyses would have been appropriate, provided greater statistical power and allowed formal exploration of heterogeneity of estimates from the anti- TNFα naïve and experienced populations. In its request for clarifications, the ERG requested that the manufacturer: report the findings of the previously described subgroup analyses (A7); provide pooled data across the PSUMMIT 1 and 2 trials for anti-tnfα naive and all randomised patient groups (A10); report relative measures of effect 44

45 with 95% confidence intervals (A11); report response-over-time data in a consistent manner across outcomes (A12); report post-24 week data consistently across outcomes (A13); provide numerous missing confidence intervals and p values (A14) and; report discontinuation rates due to adverse events for both PSUMMIT trials (A25). The manufacturer responded to each of the ERG s requests and these data are summarised in Section Summary of PSUMMIT trials results 24 week outcome data: Though the manufacturer provided relative measures of effect and 95% CIs for pooled PSUMMIT data, on closer inspection of the spreadsheet the ERG noticed that the point estimates were based on simple additive calculations and confidence intervals were typed values without any underlying formulae. It was therefore unclear whether these pooled data took the relative weight of each PSUMMIT trial into account. However, the ERG conducted separate metaanalyses that provided almost identical results to the manufacturer s estimates, so these estimates appear to be reliable. Where available, pooled relative risks from the PSUMMIT trials (provided in response to clarifications A10-A14) are discussed here, alongside anti-tnfα experienced subgroup data from the PSUMMIT 2 trial. Pooled estimates incorporating all PSUMMIT patients are considered the primary analysis for each outcome, with any variations in subgroup estimates discussed in relation to this primary analysis. Response rates and relative risks for each analysis are reported in Table 6 and response rates over time are shown in Figure 1 to Figure 5. The manufacturer confirmed that their subgroup analyses were not adjusted for multiple testing (see response to clarification A7), nor did they report any test for interaction between the anti-tnfα naïve and experienced subgroups. The ERG calculated these values and corresponding relative risk reductions (RRRs) and reports them below. Since the response-over-time data in Figure 1 to Figure 5 show separate response rates for 45mg and 90mg ustekinumab treatment groups and the product licence implies the option of choosing one of these doses for heavier patients, the ERG also conducted analyses comparing ustekinumab doses with one another using standard meta-analytic techniques (see Table 7). ACR20/50/70: For randomised patients as a whole, ustekinumab was associated with a statistically significant improvement on the primary outcome of ACR20 response relative to placebo at 24 weeks (45% vs. 22%; RR 2.06, 95% CI 1.64 to 2.59). While the relative risk of response was slightly larger for the anti-tnfα experienced subgroup than the anti-tnfα naïve subgroup (Table 6), this difference was not statistically significant (test of interaction z=-0.58, p=0.57; RRR 0.82, 95% CI 0.41 to 1.63), suggesting no good evidence for a different treatment effect in anti-tnfα naïve and experienced 45

46 patients. There was no obvious difference between ustekinumab doses or interactions between dose and prior anti-tnfα experience (Table 7). As would be expected, fewer patients in all groups showed ACR50 and ACR70 response; though the relative benefit of ustekinumab increased as proportionally fewer placebo patients met these increasingly stringent response criteria (see Table 6). Estimates of relative ACR50 and ACR70 response were slightly larger for the anti-tnfα naïve subgroup, though again the difference did not indicate any significant subgroup effect (ACR50 z=0.49, p=0.62; ACR70 z=0.32, p=0.75). PsARC: Overall, ustekinumab was also associated with a statistically significant improvement in PsARC response relative to placebo at 24 weeks (58% vs. 35%; RR 1.65, 95% CI 1.40 to 1.95). Despite a marginally greater relative benefit in the anti-tnfα experienced subgroup, there was no good evidence for a difference in treatment effect between anti-tnfα naïve and experienced patients (z=-0.86, p=0.39; RRR 0.81, 95% CI 0.50 to 1.31). A small statistically non-significant trend favoured 90mg over 45mg among anti-tnfα naïve patients (RR 0.88, 95% CI 0.76 to 1.02) but not among anti-tnfα experienced patients (RR 1.18, 95% CI 0.83, 1.69). Given the licenced posology allows 90mg ustekinumab in patients with a body weight greater than 100 kg, the slightly poorer PsARC response to this higher dose observed among the heavier anti-tnfα experienced subgroup (47% for 90mg versus 55% for 45mg) is surprising. However, the overall effects of different ustekinumab doses do not differ significantly, and the data are too sparse to draw any clear conclusions about possible interactions between ustekinumab dose and prior TNFα inhibitor treatment. PASI75: Among patients with 3% BSA psoriasis skin involvement at baseline, ustekinumab was associated with a statistically significant improvement in PASI75 response relative to placebo at 24 weeks (57% vs. 9%; RR 6.51, 95% CI 4.25 to 9.96). The relative risk of PASI75 response was much larger for the anti-tnfα experienced subgroup than for the anti-tnfα naïve subgroup (RR 23.5 vs. 5.6; Table 6). This was driven by the almost complete lack of response among anti-tnfα experienced patients randomised to placebo. However, confidence intervals for the experienced subgroup were extremely wide and the difference between anti-tnfα naïve and experienced patient subgroups was not statistically significant (test of interaction z=-1.41, p=0.16; RRR 0.24, 95% CI 0.03 to 1.75). Regardless of whether patients were anti-tnfα naïve or experienced, the observed effect was similar for 45mg and 90mg ustekinumab doses (Table 7). HAQ-DI: Ustekinumab was also associated ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *** ******** ***** suggesting a beneficial effect on functional status. As with other outcomes, there was no obvious evidence of a different treatment effect in anti-tnfα naïve and experienced patients. 46

47 Radiographic progression: The MS reported (Section 6.5, table 23) ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** However, since baseline radiographic scores were not reported in the MS or response to clarifications, it is difficult to establish whether the observed changes were clinically meaningful. Unlike other outcomes, the manufacturer did not report these data separately for anti-tnfα experienced population. Soft tissue conditions: The response to clarifications confirmed that patients receiving ustekinumab was associated had a ************* *********** ***** ********** ** ********** *** ********** relative to placebo at 24 weeks. The observed effects were similar between anti-tnfα naïve and experienced patient subgroups (see Appendix) Dermatology Life Quality Index: Among patients with 3% BSA psoriasis skin involvement at baseline, median change from baseline DLQI score was ************* ******* for ustekinumab than for placebo at 24 weeks (***** *** *********** ***** *** **see Appendix). This meets most published definitions of a meaningful clinically important difference, 11 though the absolute severity values at baseline and follow-up were not reported so these changes cannot be interpreted in context. SF-36: ************* *********** ******* **** ******** SF-36 physical and mental component scores were reported for all randomised patients, as well as for anti-tnfα naïve and experienced patient subgroups (see Appendix). However, the lack of baseline data precluded interpretation of the clinical meaningfulness of these changes. 47

48 Table 6: ACR, PsARC and PASI75 response rates in PSUMMIT trials Trial results (% responders) Relative risk vs placebo (95% CIs) Placebo UST 45mg UST 90mg Comb. UST 45mg 90mg Comb. ACR 20 response at 24 weeks PSUMMIT 1 Anti-TNFα naïve (N=615) 22.8% 42.4% 49.5% 46.0% 1.86 (1.38, 2.50) 2.17 (1.63, 2.87) 2.01 (1.53, 2.65) PSUMMIT 2 Anti-TNFα naïve (N=132) 28.6% 53.5% 55.3% 54.4% 1.87 (1.08, 3.26) 1.94 (1.33, 3.33) 1.91 (1.14, 3.19) PSUMMIT 2 Anti-TNFα experienced (N= 180) 14.5% 36.7% 34.5% 35.6% 2.53 (1.27, 5.03) 2.38 (1.18, 4.79) 2.45 (1.28, 4.70) PSUMMIT 1 & 2 Anti-TNFα naïve (n= 747) 23.8% 44.4% 50.6% 47.5% 1.86 (1.43, 2.42) 2.13 (1.65, 2.74) 2.00 (1.57, 2.54) PSUMMIT 1 & 2 All randomised patients N=927) 21.9% 42.9% 47.6% 45.2% 1.95 (1.53, 2.50) 2.17 (1.71, 2.76) 2.06 (1.64, 2.59) ACR 50 response at 24 weeks PSUMMIT 1 Anti-TNFα naïve (N= % 24.9% 27.9% 26.4% 2.85 (1.72, 4.70) 3.20 (1.95, 5.24) 3.02 (1.89, 4.84) PSUMMIT 2 Anti-TNFα naïve (N=132) 7.1% 20.9% 31.9% 26.7% 2.93 (0.85, 10.08) 4.47 (1.39, 14.36) 3.73 (1.19, 11.71) PSUMMIT 2 Anti-TNFα experienced (N=180 ) 6.5% 15.0% 15.5% 15.3% 2.33 (0.76, 7.15) 2.41 (0.78, 7.39) 2.36 (0.84, 6.68) PSUMMIT 1 & 2 Anti-TNFα naïve (n= 747) 8.5% 24.2% 28.7% 26.5% 2.86 (1.80, 4.55) 3.39 (2.15, 5.33) 3.12 (2.02, 4.82) PSUMMIT 1 & 2 All randomised patients N=927) 8.1% 22.4% 26.2% 24.3% 2.78 (1.81, 4.27) 3.25 (2.14, 4.95) 3.01 (2.02, 4.50) ACR 70 response at 24 weeks PSUMMIT 1 Anti-TNFα naïve (N=615) 2.4% 12.2% 14.2% 13.2% 5.02 (1.96, 12.87) 5.86 (2.31, 14.83) 5.44 (2.21, 13.39) 48

49 PSUMMIT 2 Anti-TNFα naïve (N=132) 4.8% 9.3% 12.8% 11.1% 1.95 (0.38, 10.10) 2.68 (0.57, 12.57) 2.33 (0.53, 10.18) PSUMMIT 2 Anti-TNFα experienced (N= 180) 1.6% 5.0% 5.2% 5.1% 3.10 (0.33, 28.98) 3.21 (0.34, 29.96) 3.15 (0.39, 25.60) PSUMMIT 1 & 2 Anti-TNFα naïve (n= 747) 2.8% 11.7% 13.9% 12.8% 4.14 (1.85, 9.28) 4.94 (2.24, 10.91) 4.54 (2.11, 9.77) PSUMMIT 1 & 2 All randomised patients N=927) 2.6% 10.4% 12.3% 11.3% 4.03 (1.89, 8.60) 4.77 (2.26, 10.05) 4.40 (2.14, 9.02) PsARC response at 24 weeks PSUMMIT 1 Anti-TNFα naïve (N=615) 37.4% 56.1% 64.7% 60.4% 1.50 (1.21, 1.86) 1.73 (1.41, 2.12) 1.62 (1.33, 1.96) PSUMMIT 2 Anti-TNFα naïve (N=132) 38.1% 55.8% 57.4% 56.7% 1.47 (0.92, 2.34) 1.51 (0.95, 2.38) 1.49 (0.97, 2.28) PSUMMIT 2 Anti-TNFα experienced (N=180) 25.8% 55.0% 46.6% 50.8% 2.13 (1.32, 3.44) 1.80 (1.09, 2.99) 1.97 (1.25, 3.11) PSUMMIT 1 & 2 Anti-TNFα naïve (N=747) 37.5% 56.0% 63.3% 59.7% 1.49 (1.23, 1.82) 1.69 (1.40, 2.03) 1.59 (1.34, 1.90) PSUMMIT 1 & 2 All randomised patients (N=927) 35.2% 55.8% 60.2% 58.0% 1.59 (1.33, 1.90) 1.71 (1.44, 2.04) 1.65 (1.40, 1.95) PASI 75 response at 24 weeks PSUMMIT 1 Anti-TNFα naïve (N=440) 11.0% 57.2% 62.4% 59.9% 5.22 (3.22, 8.47) 5.70 (3.53, 9.19) 5.46 (3.41, 8.76) PSUMMIT 2 Anti-TNFα naïve (N=106) 10.0% 58.3% 62.5% 60.5% 5.83 (1.93, 17.67) 6.25 (2.08, 18.78) 6.05 (2.04, 17.98) PSUMMIT 2 Anti-TNFα experienced (N=135) 2.0% 45.5% 48.8% 47.1% 22.7 (3.18, ) (3.42, ) (3.34, ) PSUMMIT 1 & 2 Anti-TNFα naïve (N=546) 10.8% 57.5% 62.4% 60.0% 5.32 (3.42, 8.29) 5.78 (3.73, 8.97) 5.56 (3.61, 8.57) PSUMMIT 1 & 2 All randomised patients (N=681) 8.8% 55.1% 60.0% 57.6% 6.23 (4.03, 9.62) 6.78 (4.40, 10.44) 6.51 (4.25, 9.96) 49

50 Table 7: Ustekinumab 45mg vs. 90mg. Random effects meta-analyses (relative risk, 95% confidence interval) Outcome (24 weeks) PSUMMIT 1 PSUMMIT 2 (naïve) PSUMMIT 2 (experienced) Pooled PSUMMIT trials ACR (0.69, 1.06) 0.97 (0.66, 1.41) 1.06 (0.65, 1.73) 0.90 (0.76 to 1.07) PsARC 0.87 [0.74, 1.02) 0.97 (0.68, 1.40) 1.18 (0.83, 1.69) 0.94 (0.79, 1.11) PASI (0.76, 1.11) 0.93 (0.65, 1.35) 0.93 (0.59, 1.46) 0.92 (0.79, 1.08) Post-24 week outcome data: The original MS only reported response-over-time data up to 52 weeks for the primary outcome of ACR20. In response to a clarification from the ERG, the manufacturer also provided this data for PsARC and PASI75. These data are reproduced in Figure 1-Figure 5 below. After crossing over to active treatment at 24 weeks, ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** The timing of these changes confirms the basic efficacy of ustekinumab treatment. ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** ********* ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** *********** ***** *** In their response to a point for clarification, the manufacturer stated that post-24 week modified van der Heijde Sharp score data were not yet available, so the longer-term effects of ustekinumab on radiographic progression of joint disease cannot be established. Subgroup analyses: The authors described a series of subgroup analyses, summary data for which were supplied in response to a request from the ERG (clarification A7). The manufacturer confirmed that these analyses were not adjusted for multiple testing. *********** ********** ********* ********* ** ******* *********** ******* ********* ***** ** ************* ******** ******* *************** ** *********** ** ***** *** ** ********************** *** 50

51 *********** ***** *** *********** ***** *** **** The main subgroup analysis comparing anti- TNFα naïve and experienced subgroups has been commented on throughout the preceding sections. 51

52 Figure 1: ACR20 response through week 52 (PSUMMIT1) Figure 2: ACR20 response through week 52 (PSUMMIT2) * 52

53 Figure 3: PsARC response through week 52 (PSUMMIT1) Figure 4: PsARC response through week 52 (PSUMMIT2) 53

54 Figure 6: PASI 75 response through week 52; randomised subjects with 3% BSA psoriasis skin involvement at baseline (PSUMMIT1) Figure 5: PASI 75 response through week 52; randomised subjects with 3% BSA psoriasis skin involvement at baseline (PSUMMIT2) 54

55 4.2.7 ERG commentary on PSUMMIT trials The majority of evidence presented on the efficacy of ustekinumab for PsA in the MS was derived from two methodologically similar trials (PSUMMIT 1 and PSUMMIT 2) comparing 45mg and 90 mg doses of ustekinumab against conventional management (excluding the use of anti-tnfα inhibitors). These trials were of adequate methodological quality, though the interruption of the placebocontrolled phase at week 16 and the termination of the controlled phase altogether at 24 weeks provided only a very brief comparison for a chronic condition such as PsA. However, the available data suggest that ustekinumab is a more effective treatment than conventional management over this short period in terms of both joint and skin response, and that these benefits are likely to persist for at least 52 weeks. No data is available on longer term radiographic progression. PSUMMIT 2 differs from other RCTs of biologics in that it specifically included a subgroup of patients who had received prior treatment with TNFα inhibitors. On the basis of the PSUMMIT trial data, there is no convincing evidence of a substantial difference in the efficacy of ustekinumab between these anti-tnfα experienced patients and patients who had not received any prior anti-tnfα treatment. The relatively large PASI75 benefit observed in the anti-tnfα experienced subgroup may be an artefact of the small number of patients in the analysis and should be confirmed in a properly powered trial in this specific patient population. Any such future trial should clearly distinguish between prior anti-tnfα experience and anti-tnf- treatment failure in order to establish an appropriate comparator. A second- or third line TNF- inhibitor might have been a more clinically meaningful comparator than conventional management for many of the anti-tnfα experienced patients included in PSUMMIT Description and evaluation of adverse event studies As stated in the MS, four data sources were used to investigate adverse events associated with ustekinumab: (1) the PSUMMIT trials; (2) five-year extension of four RCTs of ustekinumab for psoriasis; (3) the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study; and (4) an observational study from the British Society for Rheumatology Biologics Register (BSRBR) for anti- TNFα therapies in PsA. These appear to be appropriate sources to establish longer term safety information on ustekinumab (albeit in a psoriasis population) and anti-tnfα treatment in PsA. Other than the PSUMMIT trials, the manufacturer did not assess the quality of these studies. 55

56 With the exception of a slightly higher proportion of injection site reactions for 90mg observed in the PSUMMIT trials (1% 90mg vs. 0.6% 4mg vs. 0.4% placebo), the included trial data did not suggest any obvious excess in adverse events, serious adverse events or treatment discontinuation for ustekinumab treated patients. The PSOLAR study indicated similar unadjusted rates of major adverse cardiovascular events, and a possible trend toward lower rates of serious infections for ustekinumab relative to anti-tnfα therapy (0.98 per 100 patient-years, 95% CI 0.73 to 1.28), though such observational data can be confounded by differing selection criteria across treatments. The original MS only reported discontinuation rates due to adverse events for PSUMMIT1. The same data for PSUMMIT 2 were provided on request from the ERG (clarification A25). *********** ***** *** ************ ***** *** ************ ***** *** ************ ***** *** ************ ***** *** ************ ***** *** * Table 8: Discontinuation of study agent due to adverse events (PSUMMITtrials) Placebo Placebo -> ustekinumab 45 mg Ustekinumab 45 mg Ustekinumab 90 mg All ustekinumab PSUMMIT 1 through week 24 7/25 (3.4%) 0/58 (0%) 3/205 (1.5%) 3/204 (1.5%) 6/467 (1.3%) PSUMMIT 1 through week 52-3/189 (1.6%) 5/205 (2.4%) 7/204 (3.4%) 15/598 (2.5%) PSUMMIT 2 through Week 24 ****** ******* * ***** ****** ***** ****** ***** ****** PSUMMIT 2 through Week 60 * **** ****** ***** ****** ***** ****** ****** ****** 56

57 4.3 Critique of the indirect comparison and/or multiple treatment comparison and the trials identified and included The decision problem required ustekinumab to be compared with the other biologic agents licensed for the treatment of PsA in UK: adalimumab, etanercept, infliximab and golimumab. The systematic review by the manufacturer identified nine trials of these agents plus the two previously discussed trials of ustekinumbab. All nine trials were placebo controlled with no head to head comparisons of the anti-tnfαs. In the absence of head-to-head comparisons between alternative anti-tnfα agents, it was appropriate that the manufacturer used a network meta-analysis (NMA also known as MTC) approach to estimate the relative efficacy between the five agents of interest: adalimumab, etanercept, infliximab, golimumab and ustekinumab. Trials of all five agents had a common comparator, placebo, which allowed a network to be established. NMA was only undertaken for the anti-tnfα naïve population, which reflects the population included in the all the trials, other than the treatment experienced subgroup in PSUMMIT2. Table 9 presents the ERG s quality assessment of these trials, as such an assessment had not been included in the manufacturer s submission. All nine trials were double-blind placebo controlled RCTs and in general were of good quality. A full discussion of the ustekinumab PSUMMIT trials is presented in Section 4.2. The time point at which response was assessed varied across the trials: the ustekinumab trials assessed response at 24 weeks whereas the trials for the anti-tnfαs first assessed response at 12, 14 or 16 weeks, although assessments were also made at 24 weeks for all agents (although not in all trials). 57

58 Table 9: Quality assessment of included RCTs (from Rodgers et al) 12 Quality assessment criteria Etanercept Infliximab Adalimumab Golimumab Ustekinumab Mease 2000 Mease 2004 IMPACT IMPACT 2 ADEPT Genovese 2007 GO-REVEAL PSUMMIT 1 PSUMMIT 2 Eligibility criteria Y Y Y Y Y Y Y Y Y specified? Power calculation? Y Y Y Y Y Y Y Y Y Adequate sample size? Y Y Y Y Y Y Y Y Y Number randomised Y Y Y Y Y Y Y Y Y stated? True randomisation? Y Y Y Y Y Y Y Y Y Double-blind? Y Y Y Y Y Y Y Y Y Allocation of treatment Y Y Y Y NR Y Y Y Y concealed? Treatment administered Y Y Y Y Y Y Y Y Y blind? Outcome assessment Y Y Y Y Y Y NR Y Y blind? Patients blind? Y Y Y Y Y Y Y Y Y Blinding successful? NR NR NR NR NR NR NR NR NR Adequate baseline details Y Y Y Y Y Y Y Y Y presented? Baseline comparability? Y Y Y Y Y Y Y Y Y Similar co-interventions? Y Y Y Y Y Y Y Y Y Compliance with Y Y Y Y Y Y Y Y Y treatment adequate? All randomised patients Y Y Y Y Y Y Y Y Y accounted for? Valid ITT analysis? Y Y Y Y Y Y Y Y Y > 80% patients in followup Y Y Y Y Y Y Y Y Y assessment? Quality rating Good Good Good Good Good Good Good Good Good Y=Yes; N=No; NR=Not reported 58

59 Table 10: (1 of 2) Summary of trial population baseline characteristics (placebo arm only) Study PSUMMIT 1 PSUMMIT 2 Mease 2000 Mease 2004 IMPACT 1 IMPACT 2 ADEPT Genovese GO-REVEAL Placebo arm U n= 206 U n=104 E n= 30 E n=104 I n=52 I n=100 A n=162 A n=49 G n= 113 Age, mean years (SD) 47.4 (12.3) 47.6 (11.2) 43.5 (median) 47.3 (median) 45.2 (9.7) 45.2 (9.7) 49.2 (11.1) 47.7 (11.3) 47.0 (10.6) Sex, % male Weight, mean kg (SD) 89.5 (22.6) 81.4 (median) (16.5) 88.5 (21.1) - Duration of PsA, mean years (SD) 6.7 (7.5) 8.5 (8.5) 9.5 (median) 9.2 (median) 8.5 (6.4) 7.5 (7.8) 9.2 (8.7) 7.2 (7.0) 7.6 (7.9) Duration of PsO, mean years (SD) 15.9 (12.8) 15.2 (11.8) 17.5 (median) 19.7 (median) 19.4 (11.6) 16.8 (12.0) 17.1 (12.6) 13.8 (10.7) 19.0 (12.9) Number of prior DMARDs: mean (SD) 21% = 0 2% = 0 ***** * * * * **** * * * ***** * *** *** * ** - 50% = 1 19% = 2 38% = 1 48% = % = 1-2 9% = % = 3+ Treatment history % NSAID MTX Corticosteroid 87.8 **** PASI score baseline, mean (SD) 11.7 (10.3) 11.3 (9.3) 6.0 (median) (6.6) 10.2 (9.0) 8.3 (7.2) (9.5) Patients evaluable for PASI at baseline (%) HAQ (0-3) Mean (SD) 1.25 (median) 1.13 (median) 1.2 (median) 1.1 (median) 1.2 (0.7) 1.1 (0.6) 1.0 (0.7) 1.1 (0.6) 1.03 (0.55) Swollen Joint Count, mean (SD) 15.0 (10.2) 13.5 (9.9) 14.7 (median) 15.3 (median) 14.7 (8.2) 14.4 (8.9) 14.3 (11.1) 18.4 (12.1) 13.4 (9.8) Tender Joint Count, mean (SD) 25.1 (15.0) 23.4 (14.9) 19.0 (median) 22.1 (median) 20.4 (12.1) 25.1 (13.3) 25.8 (18.0) 29.3 (18.1) 21.9 (14.7) Patients with 3% BSA psoriasis at baseline; Patients with a baseline PASI score

60 Table 11: (2 of 2) Summary of trial population baseline characteristics (treatment arm only) Study PSUMMIT 1 PSUMMIT 2 Mease 2000 Mease 2004 IMPACT 1 IMPACT 2 ADEPT Genovese GO-REVEAL Treatment arm Age* U 45 mg n= (12.6) U 90 mg n= (11.8) U 45 mg n= (11.2) U 90 mg n= (12.4) E n= (median) E n= (median) I n= (11.1) I n= (12.8) A n=151 A n= 51 G 50mg n=146 G 100mg n= (12.5) 50.4 (11.1) 45.7 (10.7) 48.2 Sex, % male Duration of PsA* Duration of PsO* Number of prior DMARDs* Treatment history, % use NSAID MTX Corticosteroid 6.1 (6.8) 14.9 (13.0) ***** * * ***** * * **** * * 7.0 (7.6) 15.5 (12.1) ***** * * ***** * * **** * * 8.2 (8.6) 15.4 (11.2) ***** * * ***** * * ***** * * (7.5) 14.8 (12.7) ***** * * ***** * * ***** * * (median) 19 (median) (median) 11.7 (9.8) 8.4 (7.2) 18.3 (median) 16.9 (10.9) NR 27% = 0 40% = 1 20% = % = 0 52% = 1 37% = % = % = % = ( 10.9) 9.8 (8.3) 7.5 (7.0) 7.2 (6.8) 7.7 (7.8) 17.2 (12.0) 18.0 (13.2) 17.7 (11.9) 18.4 (12.7) % = % = % = % = PASI score baseline 11.5 (11.8) 10.6 (8.5) 13.4 (13.0) 12.1 (10.3) 10.1(median) CiC 8.6 (6.6) 11.4 (12.7) 7.4 (6.0) (8.6) 11.1 (9.5) Patients evaluable PASI baseline (%) HAQ (0-3)* Swollen Joint Count* Tender Joint Count* 1.25(median) 1.25(median ) 12.5 (7.8) 22.2 (13.9) 12.9 (8.3) 23.2 (13.7) 1.25(median ) 15.0 (9.2) 27.2 (15.4) 1.06(median) 1.3(median) 1.1(median) 1.2 (0.7) 1.1 (0.6) 1.0 (0.6) 0.9 (0.5) 0.98 (0.65) 1.05 (0.62) 14.0 (10.9) 25.9 (15.5) 14.0 (median) 15.9 (median) 22.5 (median) 20.4 (median) * unless otherwise stated Mean (SD); Patients with 3% BSA psoriasis at baseline ; Patients with a baseline PASI score (7.5) 13.9 (7.9) 14.3 (12.2) 18.2 (10.9) 14.1 (11.4) 12.0 (8.4) 23.7 (13.7) 24.6 (14.1) 23.9 (17.3) 25.3 (18.3) 24.0 (17.1) (15.7) 60

61 The validity of the NMA is built on the assumptions that no important differences exist between trials in terms of baseline characteristics such as disease severity. The population characteristics of all nine trials are summarised and compared in Table 10 and Table 11. Of interest is the between study comparability, therefore one table presents treatment arm patient characteristics, the other presents the placebo arm characteristics. For a combined table, including some further characteristics not included in the ERG tables, see manufacturer s points for clarification (C3; pg. 58, Section 6.7; also presented in Appendix 10.2). The trials are generally similar in terms of patients characteristics: age, % male, race, duration of PsA and psoriasis (where reported). Importantly they are generally similar in terms of patients joint disease severity at baseline particularly mean tender joint count and mean swollen joint count. The high standard deviations in each of the trials suggest that the variation between trials is unlikely to be of significance; however these differences are worth noting. The same can be said of the baseline HAQ score, although the use of median values in both the ustekinumab trials and the two etanercept trials make the comparison less transparent. There was a concern about the correlation between baseline HAQ scores and absolute HAQ changes in these PsA patients, given such a high variability of these HAQ values; however as in previous submissions the ERG considered the exchangeability of mean HAQ scores across the included trials in the MTC analysis to be acceptable. There were some differences in the proportions of patients evaluable for psoriasis endpoints at baseline and variation in mean PASI score between the included trials. Where reported, the PSUMMIT 1, PSUMMIT 2, IMPACT 2, GO-REVEAL, and Mease 2004 trials had higher percentages of patients evaluable for psoriasis endpoints at baseline. In contrast, the IMPACT and ADEPT trials had much lower percentages of patients evaluable for psoriasis endpoints. Thus, there might be potential interactions between different patient samples and the treatment effect when estimating the relative efficacy in terms of skin disease response. As noted in Section 4.2, a substantial minority of patients in the PSUMMIT trials had never received prior DMARDs. However, this is not unique to the PSUMMIT trials; prior DMARD exposure was variable across trials, and where reported the mean number of prior DMARDs was typically fewer than two (see Table 12). On the basis of the available information, it would appear that baseline disease severity is broadly comparable across trials, though the MTC population may be less severe than that routinely considered for biologic treatment in practice. 61

62 Table 12 Baseline DMARD use among RCTs included in the MTC Trial Drug evaluated % of patients without any prior DMARD use % receiving 1-2 prior DMARDs Mean number of prior DMARDs at baseline Treatment Control Treatment Control Treatment Control Mease 2000 Etanercept Mease 2004 Etanercept IMPACT Infliximab IMPACT 2 Infliximab ADEPT Adalimumab Genovese Adalimumab GO-REVEAL Golimumab PSUMMIT 1 Ustekinumab **** **** - - PSUMMIT 2 Ustekinumab **** **** - - Despite some limitations mentioned above, overall, in the NMA presented by the manufacturer the degree of clinical heterogeneity between the included trials in terms of joint and skin disease severity and functional status was reasonable and, the assumption of exchangeability between the trials for the purposes of the analyses is considered acceptable. Separate networks were constructed for three outcomes PASI75, PASI90 and PsARC. These three outcomes were considered for two time points weeks and 24 weeks. The period of weeks was used due to the different response criteria utilised in trials for the alternative treatments. These outcomes are appropriate and reflect those used in previous evaluations of PsA treatment. Due to data limitations not every trial measured or reported each of the outcomes at each of the time points and thus not all nine trials were included in all six networks. The trials included in the NMA are listed in Table 13, along with the outcomes for which they provide data. These trials appear to represent the complete relevant body of evidence for the comparators included. The network diagrams are presented in the manufacturer s submission (Figures 10, 11 and 12, pages 74 and 75). 62

63 Table 13: Summary of the trials used* to conduct the MTC (Manufacturer s submission, table 1, pg 73.) Week outcomes 24 Week outcomes Study Treatment arms PASI75 PASI90 PsARC PASI75 PASI90 PsARC PSUMMIT 1 Ustekinumab 45 mg Ustekinumab 90 mg PSUMMIT 2 ADEPT Genovese et al Placebo Ustekinumab 45 mg Ustekinumab 90 mg Placebo Adalimumab 40 mg Placebo Adalimumab 40 mg Placebo Mease et al Etanercept 25 mg Placebo Mease et al Etanercept 25 mg GO-REVEAL Placebo Golimumab 50 mg Golimumab 100 mg Placebo IMPACT 1 Infliximab 5 mg Placebo IMPACT 2 Infliximab 5 mg Placebo *The infliximab RESPOND trial was not included in the mixed treatment comparison because the comparator was MTX. As all other trials used placebo, it was not possible to integrate these data. The NMA was checked by the ERG. The NMA was conducted using R programming; the code was supplied and appears to be appropriate. A Bayesian random effects model was fitted to the data. Following a points for clarification request, the manufacturer confirmed that the model was run for 220,000 iterations with a burn-in of 10,000 and thinning of 100. They further stated that trace plots were examined to see how well the chain was mixing. The model achieved convergence and samples were drawn from the posterior distribution. No fit statistics were produced or considered by the manufacturer. Trace plots were not presented to the ERG. Where possible, the ERG ran its own NMA models in an attempt to validate the manufacturer s results. Full details of these are presented in appendix For adalimumab, etanercept, infliximab and golimumab data were retrieved, where available, from the trial publications. (ADEPT, Genovese et al 2007, Mease et al. 2000, Mease et al. 2004, GO-REVEAL, IMPACT 1, IMPACT 2) For ustekinumab, a separate patient level data analysis was undertaken to obtain PsARC and PASI response rates for a weight-based dosing regimen, i.e. 45mg for patients 63

64 with body weight 100kg; and 90mg for those with body weight >100kg. These data were presented in the submission alongside other NMA data. (Section 6.7, Table 35, pg. 76) To aid clarity they are presented again separately in Table 14. The manufacturer assumed that in practice patients will be treated according the weight-based dosing criteria, and therefore it was deemed appropriate to exclude subjects not treated this way in the PSUMMIT trials. However, it is not clear to the ERG that this is in line with the licence or the manner in which the trials were conducted so such an analysis is not necessarily the most appropriate one. Furthermore, a significant number of subjects in the PSUMMIT trials were not treated according to the weight based dosing rule and therefore a significant amount of data were lost from these analyses. Table 14 Number of patients included in weight-based NMA Trial Arm Number randomised (naïve) Number meeting PASI criteria 12 week total number included in weight-based analysis PASI 75 PASI 90 PsARC PSUMMIT 1 45mg PSUMMIT 1 90mg PSUMMIT 2 45mg PSUMMIT 2 90mg Trial Arm Number randomised (naïve) Number meeting PASI criteria 24 week total number included in weight-based analysis PASI 75 PASI 90 PsARC PSUMMIT 1 45mg PSUMMIT 1 90mg PSUMMIT 1 45mg PSUMMIT 1 90mg The ERG requested that the manufacturer re-run their NMA using the entire intention to treat population, as opposed to the restricted weight-based dosing population. The results for both sets of NMA results are shown in Table 15 for PASI 75 response, Table 16 for PASI 90 response and Table 17 for PsARC response. 64

65 Table 15: PASI 75 - Proportion of responders for the anti-tnfα naïve population, using the weight-based dosing criteria compared with ITT PASI 75 Response PASI 75 Response Treatment WEIGHT BASED ITT Week Week 24 Week Week 24 Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Ustekinumab 45mg ***** **** ***** **** ***** **** ***** **** Ustekinumab 90mg ***** **** ***** **** **** **** ***** **** Golimumab 50mg ***** **** ***** **** ***** **** ***** **** Golimumab 100mg ***** **** ***** **** ***** **** ***** **** Adalimumab ***** **** ***** **** ***** **** ***** **** Etanercept 25mg/50mg **** **** **** **** ***** **** ***** **** Infliximab ***** **** ***** **** ***** **** ***** **** Table 16. PASI 90 - Proportion of responders for the anti-tnfα naïve population, using the weight-based dosing criteria compared with ITT PASI 90 Response PASI 90 Response Treatment WEIGHT BASED ITT Week Week 24 Week Week 24 Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Ustekinumab 45mg ***** **** ***** **** ***** **** ***** **** Ustekinumab 90mg ***** **** ***** **** ***** **** ***** **** Golimumab 50mg ***** **** ***** **** ***** **** ***** **** Golimumab 100mg ***** **** ***** **** ***** **** ***** **** Adalimumab ***** **** ***** **** ***** **** **** **** Infliximab ***** **** ***** **** ***** **** ***** **** 65

66 Table 17. PsARC - Proportion of responders for the anti-tnfα naive population, using the weight based dosing criteria compared with ITT PsARC Response Treatment WEIGHT BASED ITT Week Week 24 Week Week 24 Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Ustekinumab 45mg **** **** ***** **** ***** **** ***** **** Ustekinumab 90mg ***** **** ***** **** ***** **** ***** **** Golimumab 50mg ***** **** ***** **** ***** **** ***** **** Golimumab 100mg ***** **** ***** **** ***** **** ***** **** Adalimumab ***** **** ***** **** ***** **** ***** **** Etanercept 25mg/50mg ***** **** ***** **** ***** **** **** **** Infliximab **** **** ***** **** ***** **** ***** **** In general the results are fairly similar across both the strict weight-based and full ITT populations, with only the 24 week PASI 75 in the ustekinumab 90mg arm showing some variation. The ustekinumab 90mg arm was most affected by the switch to ITT data, which is to be expected given that the weight based dosing criteria resulted in a large portion of subjects in that arm to be excluded. The ERG believe that it is important to be aware of the impact of these alternative analysis, but acknowledge that given the licence it is unlikely that patients <100kg will receive a 90mg dose in clinical practice so the use of the weight-based data for the 90mg arm is reasonable. However, the ERG clinical advisor suggested that it would be expected in practice that patients will be administered ustekinumab 45mg initially regardless of their weight making the full ITT analysis results (PsARC, PASI 75 and 90) for this arm more representative of clinical practice. The impact of using the ITT data for this population is assessed and discussed in Section In addition, the ERG requested that an analysis be undertaken pooling the 45mg and 90mg arms of the PSUMMIT trials. These results are presented in the manufacturer s points for clarification (A21, pg. 40). The pooling of doses does not appear to impact on the effectiveness of ustekinumab relative to its ranking in terms of probability of response. Overall the results of the NMA found that *********** **** had the lowest or one of the lowest response rates for PASI 75 and 90 and PsARC. For PASI 75 response, ********** was the most effective treatment, and for PASI 90 response ********** was the most effective treatment. Across both the weight-based and ITT analyses, ******* achieved the greatest proportion of PsARC responders, followed by *********** ***** *** **********and **********. 66

67 In the two previous submissions (TA199/TA220) a NMA of HAQ conditional on PsARC response was undertaken. For this submission the manufacturer did not undertake this analysis, rather they used the results from the previous TA220 submission to inform the estimates for the comparator drugs. They then utilised the PSUMMIT trial data to inform the ustekinumab estimates. In brief, the ERG opted to undertake a NMA of these data to appropriately incorporate the ustekinumab trials. Overall, despite the heterogeneity between trials the ERG believe that it was appropriate to undertake the network meta-analysis. The results obtained by the manufacturer were robust when compared with the results of the ERG analysis. The comparative results are presented in appendix Conclusions of the clinical effectiveness section While PSUMMIT trial data suggest that ustekinumab (45mg and 90mg) is a more effective treatment than conventional management over 24 weeks in terms of PASI and PsARC response among anti- TNFα naïve patients, the NMA suggests that ustekinumab 45mg has lower PASI and PsARC response rates than all currently available TNFa inhibitors for PsA. Pooling of 45mg and 90mg doses does not appear to impact on the effectiveness of ustekinumab relative to its ranking in terms of probability of response. The treatment effect of ustekinumab did not differ significantly between the anti-tnf naive and experienced patients. Evidence for the relative efficacy of ustekinumab and anti-tnfs in anti- TNF experienced patients is not available. Futhermore **** * **** ***** ****** ** ******** in the anti-tnf experienced subgroup of PSUMMIT could be considered having truly failed anti-tnf therapy (having tried > 3, ****) 67

68 5 Cost Effectiveness This section focuses on the economic evidence submitted by the manufacturer and the supplementary information provided post the ERG s points for clarification. The manufacturer s initial economic submission included: A systematic review of existing economic evaluations of therapies used in the treatment of psoriatic arthritis (MS, Section 7.1) with additional information presented in an appendix (, Appendix 10). A report on the de novo economic evaluation conducted by the manufacturer. The report described the technology; comparators and patient population (MS, Section 7.2); clinical parameters and variables (MS, Section 7.3); the assumptions and sources of evidence used to assess quality of life (MS, Section 7.4); the resource use and unit cost assumptions and sources (MS, Section 7.5); sensitivity analysis (MS, Section 7.6); and the base-case costeffectiveness results (MS, Section 7.7). An Excel-based model comprising the manufacturer s electronic economic model. The ERG has noted that the Excel-based model allows the user to produce the results of scenarios that are not presented or discussed within the main submission. In response to the request for clarification made by the ERG (see manufacturer s response to ERG s points for clarification, Section B), the manufacturer further submitted: An updated version of the previously submitted Excel-based model. Clarification around the resource use estimates, some of the scenario analyses, the natural history of the disease estimates, and the agreement to supply nurses free of charge to administer ustekinumab to patients. The components of the submission were subject to a critical review on the basis of the manufacturer s report and by direct examination of the electronic version of the economic model. A narrative review was undertaken to highlight key assumptions and possible limitations. Section 6 of this report presents additional work undertaken by the ERG to address and explore some remaining uncertainties. 5.1 Overview The manufacturer conducted a review of published cost-effectiveness studies of therapies used in the treatment of PsA. The review identified a number of previous economic models; although no other evaluations which included ustekinumab as a comparator were included. Most of the evaluations 68

69 identified were developed or based on those developed for NICE technology appraisals. 12, 23, 24 A critique of the identified studies was undertaken and presented. The majority of the models adopted the same structure, and the manufacturer chose a similar structure to model the cost-effectiveness of ustekinumab. In line with the NICE scope, ustekinumab was compared to adalimumab, etanercept, infliximab, golimumab and conventional care. The population considered in the economic model was adult patients with active PsA who had failed to achieve an adequate response to previous DMARD therapy. Within this group of patients two distinct populations were considered; these will be discussed in more detail in Section The economic model comprised two elements: an initial short-term decision tree, which evaluates a patient s initial response to the biologic treatment; followed by a longer-term Markov model, which captures the longer term costs and consequences of treatments. The time horizon of the model was 52 years (i.e. lifetime). The decision tree element of the model is structured around treatment response rules: patients achieving an initial PsARC response at 12 weeks for adalimumab, etanercept, infliximab and golimumab, and 24 weeks for ustekinumab were considered to be responders and continued on an active treatment. Based on these responses patients enter the Markov model which evaluates patients through four initial cycles of 12 weeks followed by annual cycles across the model states. Patients not achieving an initial PsARC response are considered non-responders and withdraw to conventional management. After initial response a constant annual withdrawal rate was applied to allow for long-term discontinuation of treatment due to adverse events or lack of efficacy. Full details of the model structure are discussed in Section Health states within the Markov model captured both the joint (PsARC) and skin (PASI) components of PsA, as both of these are related to quality-of-life and costs. PASI score changes were applied dependent on PASI 75 response and health assessment questionnaire (HAQ) scores were applied dependent on PsARC (see Sections and ). HAQ and PASI improvements (i.e. reductions) were estimated using clinical trial data and network meta-analyses. Health-related qualityof-life was measured using quality-adjusted life-years (QALYs). A previously published mapping algorithm was used to relate both HAQ and PASI scores to health-related quality-of-life (i.e. utilities). The mapping algorithm has been used in previous submissions and is discussed further in section Resource use assumptions were based on a previous publication (Rodgers et al., 2011) and the British Society for Rheumatology guidelines. 12 These data were then validated by experts at an advisory board meeting. In addition, health state costs were estimated as a function of HAQ and PASI through 69

70 the use of previously published work. List prices were taken from the BNF (2013) for all treatments. 25 Adverse event costs were not included in the model, as it was reported that adverse events related to treatment tend to be infrequent and minor. These issues are discussed fully in section A probabilistic analysis was undertaken and a number of scenario analyses were conducted to test the impact of uncertainty. Deterministic and probabilistic results were presented separately for two populations: anti-tnfα naïve patients and anti-tnfα experienced patients. A discussion of these results and their limitations are presented in section Table 18 presents a summary of the manufacturer s economic evaluation, with signposts to the relevant sections of the MS. Table 18: Summary of the manufacturer s economic evaluation (and signposts to MS) Approach Source/Justification Location in Population The population were adult patients with active PsA for whom response to previous DMARD therapy had been inadequate, which broadly matched the clinical trials. Two distinct sub-groups were considered (i) anti-tnfα naïve patients; (ii) anti-tnfα experienced patients. The adult patient with active PsA for whom response to previous DMARD therapy has been inadequate is based on the licensed indication for ustekinumab and the NICE scope. The two sub-groups were identified as relevant under the licensed indication; and for the anti-tnfα experienced patients a clear unmet need. Section 2.6; pg 16 Section 7.2; pg 96 Comparators The comparators for anti-tnfα naïve patients included: golimumab, infliximab, etanercept, adalimumab and conventional management. The comparator for anti-tnfα experienced patients was conventional management. For the for anti-tnfα naïve patients the selection was based on the product indications and the relevant NICE guidelines. The selection was also consistent with the scope. For the anti-tnfα experienced patients the use of conventional management as the sole comparator was based on a lack of available RCT evidence regarding secondline use of anti-tnfα therapies. Section 7.2.7; pg 103 to 104 Model, states and events A cost-effectiveness (cost-utility) analysis was undertaken using a combined decision tree and Markov model. An initial treatment response was applied in the decision tree and the resulting distribution of patients was used to populate an eight state Markov model. States included: No initial response (PsARC or PASI 75); Initial PASI 75 response only; Initial PsARC response only; Initial PsARC and PASI 75 response; conventional management; initial PsARC but withdrawn to conventional management; initial PsARC and PASI 75 but withdrawn to conventional management; and death. A similar model structure has been used in 12, 24 previous submission. It differs in the use of a longer decision rule to reflect the anticipated treatment rules associated with ustekinumab. Initial response is evaluated at 12 weeks for all of the comparators and the resulting decision to continue treatment or withdraw to conventional management; however for ustekinumab administration of the drug is likely to be less frequent and it is anticipated that patients will be assessed for response at 24 weeks rather than 12 weeks. Therefore, a decision rule of response at 24 weeks was used for ustekinumab (only). Section 7.2.2/3; pg 96 to

71 Natural history Natural history of the condition was based on an annual worsening of HAQ for those patients who are receiving conventional management. It was assumed that those patients responding to an anti-tnfα or ustekinumab did not experience disease progression. The assumption and data were derived Section 12, 24 from previous submission ; pg 100 Treatment effectiveness Effectiveness was measured as HAQ score change dependent on PsARC response, and PASI score change dependent on PASI 50, 75 and 90 responses. Data from 9 trials were utilised in the evidence synthesis model. 8, In addition, previous NMA results and the PSUMMIT trial results were used to inform these parameters. Section 7.3; pg 105 to 121 HRQoL QALYs are measured as a function of HAQ and PASI. In the base case, an algorithm estimating the utilities based on HAQ and PASI from Rodgers et al/ Yang et al. was used. 24, 34 In addition, an algorithm from Rowen et al was used to map SF-36 data from the two PSUMMIT trails to EQ-5D and OLS regressions were undertaken to estimate the relationship between EQ- 5D as the dependent variable and HAQ and PASI scores as explanatory variables. 35 The use of the algorithm and data from previous submissions was used in the base case to allow comparability. The additional mapping and OLS regressions were undertaken to explore some of the differences in the data. Section 7.4.3; pg 124 to 125 Section 10.20; Appendix 20. Adverse events Not included This was justified on the basis of the lack of consideration in earlier submissions. Section 7.4.8; pg. 128 Section 7.5.7; pg 142. Resource use and costs Resources use associated with active treatment were taken from Rodgers et al. 34 Those associated with conventional management were elicited from the experts attending the advisory board meeting. It is assumed that those treatments given by subcutaneous injection will be self-administered, with the exception of ustekinumab. For ustekinumab it is assumed that 70% of patients will have the injection administered by a nurse. However, the cost of the nurse will be covered by the company. Costs for hospital visits, monitoring tests, and follow-up care were taken from NHS reference costs. As outlined the experts at the advisory board meeting comprised one external clinical expert (a dermatologist) and four external health economic advisors. The assumption of self-administration and resource use were validated by the advisory board. These costs were originally derived from the Kobelt et al study. 36 Section 7.3.5; pg. 109 Section 7.5.5; pg. 137 to 142 Section 7.5.6; pg 141 Drug acquisition costs were taken from the BNF 65 (July 2013). 25 The on-going costs of managing PsA were estimated as a function of HAQ, which was taken from Yang et al. 24 Costs of psoriasis, as a function of PASI, were derived from Yang et al. 24 Discount rates 3.5% per annum for QALYs and costs NICE reference case Section 7.2.6; pg 71

72 103 Sensitivity analysis A number of alternative parameter scenarios were evaluated. These included: initial response criteria, HAQ rebound on withdrawal from treatment, cost assumptions, utility values, withdrawal rates, mortality and weightbased dosing. Probabilistic sensitivity analysis was also undertaken. Some justification was given on the choice of alternative parameter values and assumptions used in the sensitivity analysis. A number of parameters were not assigned distributions or were assigned incorrect distributions, no justification was provided for these omissions. Section 7.6.1; pg 143 Section 10.9; appendix ERG comment on manufacturer s review of cost-effectiveness evidence The MS described the search strategies used to identify cost-effectiveness studies and utilities relevant to this appraisal of Ustekinumab (Stelara) for treating active and progressive psoriatic arthritis. Search strategies were only briefly described in the main submission, however full details were provided on request. The electronic databases MEDLINE and MEDLINE In-Process (via Ovid), EMBASE (via Ovid), the Cochrane Library including CDSR, CENTRAL, HTA, DARE, Science Citation Index (SCI), Cinahl (via Ebsco) and Econ LIT were searched. In addition to the database searches, a further search was performed for relevant documentation from NICE technology appraisals (TAs) of interventions for PsA such. Database searches were performed in October 2012 and subsequently updated in July Search strategies for each database were documented in the MS Section 10.10, appendix 10. No language or date limits were applied to the search. Methodological search filters were included to identify economic studies and utilities in MEDLINE, EMBASE and Cinahl. The searches were appropriate and comprehensive, and included the use of both subject indexing terms and free text searching. Field searching, Boolean operators and truncation were used where required. All NICE required databases were searched though medical society and regulatory body websites were not. The review identified a number of previous economic models; although no other evaluations which included ustekinumab as a comparator were included. Most of the evaluations identified were developed or based on those developed for NICE technology appraisals. 12, 23, 24 A critique of the identified studies was undertaken and presented. The majority of the models adopted the same structure, and the manufacturer chose a similar structure to model the cost-effectiveness of ustekinumab. 72

73 5.3 ERG s summary and critique of manufacturer s submitted economic evaluation The analysis conducted by the manufacturer combines clinical and economic data to evaluate the costeffectiveness of ustekinumab for the treatment of patients with active and progressive PsA. The remainder of this section provides a summary and critique of the de novo model presented in the MS. A summary of the NICE reference checklist with the ERG s comments on whether the manufacturer s de-novo model has been judged to fulfil the NICE reference case is presented in Table 19. Table 19: NICE reference checklist Attribute Reference Case Included in MS Comment on whether de novo evaluation meets requirements of NICE reference case Comparator(s) Alternative therapies in the NHS, including those currently regarded as current best practice YES Meets the scope set by NICE, and includes alternative therapies recommended by NICE. However, sequencing of treatments was not fully addressed and for the evaluation of the anti-tnfα experienced sub-population it is clear that relevant comparators (i.e. second line anti-tnfα treatments) have not been included. Perspective costs NHS and PSS YES Perspective - benefits All health effects on individuals YES The utilities of patients were derived based on changes in both HAQ and PASI scores. Time horizon Sufficient to capture differences in costs and outcomes YES 52 year time horizon appears sufficient Synthesis of evidence on outcomes Systematic review YES Outcome measure QALYs YES Health states for QALY measurement Described using a standardised and validated instrument YES A published mapping algorithm was used to derive EQ-5D utility estimates. Additionally, patient level SF-36D data from the two PSUMMIT trails were mapped to EQ-5D and these were then used to derive an alternative algorithm estimating the relationship between HAQ, PASI and EQ-5D. Benefit valuation Time Trade Off or Standard Gamble YES Source of preference data Representative sample of the public YES Discount rate 3.5% on costs and health benefits YES Equity weighting No special weighting YES Sensitivity analysis Probabilistic sensitivity analysis YES The sensitivity analysis undertaken included probabilistic sensitivity analysis although a number of parameters were not assigned 73

74 distributions in the original submission Population The scope population for ustekinumab is people with active and progressive PsA whose disease has responded inadequately to previous DMARDs or anti-tnfα treatments. The inclusion criterion for all of the clinical trials is failure of two DMARDS. However, as discussed in Section 4.2.4, it is clear that this has not been strictly adhered to in either of the PSUMMIT trials, or the trials of the other biologics. The MS presented separate economic analyses for two distinct populations: Patients who are naïve to treatment with anti-tnfα (anti-tnfα naïve patients); Patients who are exposed to previous treatment with anti-tnfα (anti-tnfα experienced patients). Both populations are within the scope. The anti-tnfα naive population is in line with that used in previous submissions and is the licensed population for ustekinumab. 37, 38 However, the anti-tnfα experienced patients are a group of patients who have not been assessed in previous submissions for PsA. The MS described the unmet need of this group of patients, a group who have been exposed to, but achieved an inadequate response to anti-tnfα therapies. However no clear distinction is made between those who have failed the anti-tnfα class and therefore have a genuine unmet need; and those who have failed one or two anti-tnf treatments but have other options within the class still available to them. The baseline population characteristics for the anti-tnfα experienced population were based on a subgroup of patients from the PSUMMIT 2 trial (n=180). The populations have been fully discussed in Section 4.2.3, where the notable differences between the baseline characteristics have been presented Interventions and comparators This section discusses the use of ustekinumab for both the anti-tnfα naïve and anti-tnfα experienced populations as well as the comparators for each group Anti-TNFα naïve population 74

75 Ustekinumab is a subcutaneous injection available in a pre-filled syringe. For PsA, the recommended dose of ustekinumab is 45mg, with a 90mg dose being possible for patients weighing greater than 100kg. The comparators for the anti-tnfα naïve group include adalimumab, etanercept, golimumab, infliximab and conventional management strategies. Conventional management was not specifically defined, but reflects treatment with non-biologics. Table 20 provides the treatment dosing regimens for the biologic treatments considered in the model. Table 20: Treatment dosing regimens (adapted from Table 5, Section 4.1.1, pg. 20 in the MS) Mechanism of action Treatment Administration Dose/frequency TNFα inhibitors Adalimumab Subcutaneous 40mg every other week Etanercept Subcutaneous 25mg twice weekly or 50mg once weekly Golimumab Subcutaneous 50mg every month or 100mg every month for patients weighing >100kg who do not achieve adequate clinical response after 3 or 4 50mg doses. Infliximab Intravenous 5mg/kg over 1-2 hours, 5mg/kg every 8 weeks thereafter IL-12/IL-23 inhibitor Ustekinumab Subcutaneous 45mg dose at 2 week 0, 4, 16, then every 12 weeks thereafter. A 90mg dose may be used for patients >100kg. All of the comparator treatments were evaluated in RCTs, which were considered comparable to the ustekinumab trials for the anti-tnfα populations. These trials have been discussed in more detail in Section Anti-TNFα experienced population For the anti-tnfα experienced population, the only comparator included in the MS was conventional management strategies. As stated previously, conventional management was not specifically defined, but represents treatment with non-biologics. It is therefore implicitly assumed, within the model, that these experienced patients have exhausted anti-tnf treatment options and have no choice but to revert to non-biologic treatment options (i.e. DMARDs). 75

76 Currently NICE recommends that once patients meet the criteria for prescribing one of the anti-tnfα biologics (i.e. failure of two DMARD treatments), treatment with a biologic should commence. This population represents the anti-tnfα naïve population. Due to similarities in effectiveness NICE recommend that the prescriber commence treatment with the cheapest option first. Treatment should be discontinued if inadequate PsARC response is achieved at 12 weeks. Currently in UK routine practice, on failure of this first treatment, patients move onto a second anti-tnfα and response is judged in the same manner. This sequential approach to prescribing continues until the clinician judges that response is unlikely, the patient discontinues treatment due to an adverse event, or the best possible response for the patient has been achieved. The ERG s clinical expert confirmed that this sequential approach is reflective of the current situation in UK clinical practice. The ERG feels that to compare ustekinumab with only conventional management for the anti-tnfα experienced population is limited and potentially misleading. In only comparing ustekinumab to conventional management, the manufacturer s analysis represents the specific situation in which all possible anti-tnfα treatments have been exhausted, with ustekinumab being used as the final treatment option as an alternative to conventional management. In practice it is expected that up to three biologics are given to each patient; the data from the PSUMMIT 2 experienced population represents a mixed population - some of whom have failed only one anti-tnfα - unrepresentative of a population that have failed all anti-tnf options. The ERG feels that the analysis presented has severe limitations. To consider ustekinumab as a second or third treatment option, anti-tnfαs which have not been failed need to be considered as comparators. To consider ustekinumab as end of line treatment, all (or multiple) anti-tnf options need to have been trialled and failed. What little evidence there is on sequencing suggests that when anti-tnf treatments are used as a second-line treatment there is a degradation of efficacy, with this degradation likely to increase as a patient receives a 3 rd, a 4 th and so on, treatment. 1, There is no evidence to support that this same degradation of effect would not occur with ustekinumab. Thus derivation of efficacy data from a mixed population who are receiving ustekinumab 2 nd, 3 rd and 4 th line, is unlikely to provide appropriate estimates for the effectiveness of ustekinumab as an end of line treatment option. It should be noted that due to a lack of robust evidence and the inclusion of only treatment naïve patients, previous submissions did not include any sequencing of treatments within their base-case models. 23, 37, 38 However, Rodgers et al did attempt a secondary analysis where sequencing of treatment was permitted. 34 These issues will be discussed and explored further in Section

77 Conventional management therapies The MS does not describe in detail what constitutes conventional management therapies, apart from that they can include DMARD therapy and will not include anti-tnfα therapy. The ERG s clinical expert confirmed that conventional management therapies usually consist of DMARD therapy, which would primarily include MTX, sulfasalazine and leflunomide Model structure The model structure presented in the MS is the same for both the anti-tnfα naïve and the anti-tnfα experienced patients. The economic model is composed of two elements. The model begins with an initial short-term decision tree. This can be seen in Figure 7. 77

78 Figure 7: Decision tree structure (Figure 20, Section 7.2.2, pg. 97 in the MS) Here a patient s initial response to the biologic treatment is assessed. Following on from this, patients then enter a longer-term Markov model. This can be seen in Figure 8. Figure 8: Markov model structure (Figure 31, Section 7.2.2, pg. 98 in the MS) 78

79 Patients initially enter the model within the decision tree where they are assigned to either receive a biologic treatment or conventional management, as can be seen in Figure 7. In the base case the initial response to treatment is assessed using PsARC: patients with an adequate PsARC response continue on biologic treatment and patients with an inadequate PsARC response withdraw to conventional management strategies. Other feasible response criteria are assessed in sensitivity analyses. These include additional scenarios where both PASI and PsARC are used to determine a patient s initial response and where either PASI or PsARC can be used to determine a patient s initial response (see section 5.3.9). The distribution of patients at the end nodes of the decision tree, that is the distribution of patients within the biologic treatment, conventional management strategies and dead health states, informs the initial distribution of patients within the longer term Markov model. A graphical depiction of the Markov model is presented in Figure 2. Within the Markov model, patients continue through the model by continuing to respond to treatment, withdrawing from treatment or until death. 79

80 The biologic treatments in the model affect the health of patients and cost to the health system through a reduction in patients PASI and HAQ scores and an increase or decrease in resources used. The model assumes that patients who remain on treatment do not experience disease progression. These issues are discussed in more detail in section Patients who withdraw to conventional management strategies experience natural progression of PsA in terms of gradually worsening HAQ scores. This assumption was stated as in line with previous submissions. Patients who remain on active treatment when they enter the Markov model are subject to an annual withdrawal risk to conventional management strategies (see Section ). The manufacturer augmented existing economic models, (Rodgers et al and Yang et al. 2012) that had a similar structure. 12, 24 The decision tree presented in the MS differs from previous submissions in that patients receiving ustekinumab are assessed for response to treatment at week 24 instead of week 12, which the manufacturer states is due to the fact that ustekinumab is administered less frequently than the other anti-tnfα treatments. The submission states that ustekinumab is anticipated to be assessed for response between the third and fourth injection, which translates to between week 16 and week 28. Therefore, with the model a 24 week decision rule was implemented for ustekinumab which was compared with a 12 week decision rule for the other comparators. The ERG s clinical advisor believed it was reasonable for response to be assessed at 24 weeks for patients receiving ustekinumab. The timing of decision rules was tested in sensitivity analysis. The manufacturer acknowledged that the assumption that patients withdraw from initial anti-tnfα treatment and move to conventional management is a simplifying assumption of the model and is not reflective of current UK practice. It is clear that in current clinical practice anti-tnfα treatments are delivered sequentially; however as highlighted by the manufacturer and in previous submission, the evidence base around sequencing is limited. The manufacturer also noted that this simplifying assumption has been included in all the previous economic evaluations identified in their literature review. These issues are investigated further by the ERG in section 6; however they are highlighted again here as these assumptions are crucial to the validity of the evaluations presented by the manufacturer Perspective, time horizon and discounting The economic evaluation was undertaken from the NHS and PSS perspective and both costs and utilities were discounted at an annual rate of 3.5%. These are both in line with the NHS reference case. The manufacturer assumed a lifetime horizon. A period of 52 years was selected on the basis that 99.9% of patients were assumed to have died by this time; however, it should be noted that this is 80

81 a longer time horizon than considered in previous submissions, the base-case time horizon for both the Rodgers MTA and the Yang STA was 40 years. 12, 24 This issue is explored as part of the ERG s additional analyses in section Treatment effectiveness and extrapolation Treatment effectiveness was modelled as an improvement in PASI and HAQ scores from baseline. The assumptions and methods applied for each are discussed below. The estimates used to population the model were derived from the manufacturers NMA (section 4.3), directly from the PSUMMIT trials or the NMA undertaken by the ERG for the golimumab STA. 24 The relative treatment effects were used in conjunction with the assumption that treatment halts disease progression, while patients receiving conventional management strategies were subject to the natural history of the disease. This enables the changes in HAQ and PASI score over time to be modelled appropriately PASI Score PASI score changes were applied dependent on PASI 75 response. Individuals on treatment who experienced PASI 75 response were assumed to experience a reduction (i.e. improvement) in their PASI score in week 12 (at the first cycle), whilst PASI 75 non-responders experienced a smaller reduction (i.e. improvement) in PASI score. While a patient continues on treatment the PASI score remains constant, however upon treatment discontinuation and withdrawal to conventional management, PASI scores were assumed to rebound back to the baseline PASI value. Due the nature of the skin element of the condition no natural history deterioration of PASI score was applied, so PASI scores in the conventional management arm remained constant at the baseline value. These assumptions are in line with previous submission and the ERG felt that they were appropriate. However, the ERG identified that there were errors in the calculation of the baseline PASI scores. The baseline PASI scores applied in the model are shown in Table 21. For the anti-tnfα naïve population, the majority of PASI scores for the included trials used to derive the estimate were >8, which was inconsistent with the manufacturer s baseline value (7.97). The ERG therefore recalculated the baseline PASI estimate, using a weighted mean calculation. For details of the ERG s calculations see appendix One study reported a median PASI instead of a mean value. 28 Since the median value is not an accurate assessment of an entire population s expected value, this value was excluded from the ERG s calculation. Including this study in the calculation did not significantly affect the baseline estimate (10.39 vs ). 81

82 The baseline PASI value used for the anti-tnfα experience population was similarly checked by the ERG. Although the point estimate was found to be correct, the standard error around the point estimate was not. The errors identified in the manufacturer s baseline PASI values were corrected for in the ERG s additional analysis (section 6). Table 21. Manufacturer and ERG baseline PASI scores Manufacturer s estimate ERG s estimate Anti-TNFα naïve population Baseline PASI 7.97 (SE: 4.44) (SE: 1.06) Source/method of estimation Pooled estimate of 9 trials. 7, 8, 26-32, 43 Weighted average of 8 trials (excluding Mease 2000 median value) Anti-TNFα experienced population Baseline PASI (SE:0.96) (SE:0.48) Source/method of estimation PSUMMIT 2 anti-tnfα experienced subgroup Weighted average of PSUMMIT 2 anti-tnfα experienced subgroup In line with previous submissions, the change in PASI score for PASI 75 responders and nonresponders was derived using data on baseline PASI and the proportion of PASI 50/75/90 responders. Four mutually exclusive outcomes were defined: 1. P(<PASI 50 <PASI 75) i.e. the probability of a change in PASI between 0 and 49% given that the improvement was less than 75%; 2. P(> PASI 50 < PASI 75); 3. P(<PASI 90 > PASI 75); and 4. P(>PASI 90 PASI 75). If PASI change was between 0 and 49% the manufacturer s made the conservative assumption that the improvement in PASI for those patients would be 0; if the change was between 50 and 74% a change of 50% was assumed; if the change was between 75% and 89% a change of 75% was assumed; and if the change was between 90 and 100% a change of 90% was assumed. The ERG believes that this approach was reasonable and is consistent with previous submissions. The sources used by the manufacturer to derive PASI response rates are shown in Table 22. For the anti-tnfα naïve population, the proportions of PASI 50/75/90 responders at week 12 and week 24 were derived from the manufacturer s NMA where possible, and using Yang et. al or Rodgers et. al. otherwise. 12, 24 The manufacturer s NMA is discussed fully and critiqued in section

83 Table 22. Sources used to derive PASI response rates in the MS Sources used to derive parameter Parameter Anti-TNFα naïve population Anti-TNFα experienced population PASI 50 Manufacturer s NMA PSUMMIT 2 PASI 75 Ustekinumab: PSUMMIT 1 and 2 Etanercept, infliximab, adalimumab: Rodgers et. al. 12 Golimumab: Yang et. al. 24 PASI 90 Etanercept: Rodgers et. al. 12 All others: Manufacturer s NMA PSUMMIT 2 PSUMMIT 2 For the anti-tnfα experienced subgroup, effectiveness estimates were derived from a weight-based analysis of the PSUMMIT 2 trial. The effect of this has been partially explored in section 6, however due to the limited data provided in the MS, a full ITT analysis has not been possible. A further issue concerns the effectiveness of the conventional management arm. The manufacturer assumed that PASI scores would remain constant for patients receiving conventional management. For PASI 75 response, in the manufacturer s NMA results, the placebo arm was associated with a ****PASI 75 response rate at week 12 and ****in week 24 for anti-tnfα naïve patients; and a ****PASI 90 response rate at week 12 and ****PASI 90 response rate at week 24. The ERGs clinical advisor stated that patients in the conventional management arm receiving treatments such as MTX might be expected to have fairly good PASI response scores, as skin conditions often respond well to DMARDs. It is not clear therefore that the manufacturer s assumption of constant PASI in the conventional management arm was appropriate. Nevertheless, since the rates of response in the conventional management arm appear to be relatively low, the ERG does not expect this assumption to be a key driver in the model PASI Score changes The PASI score changes for PASI 75 responders and non-responders for the anti-tnfα naïve and experienced populations are shown in Table 23 and Table 24. Table 23. PASI score change for PASI 75 responders and non-responders for the anti-tnfα naïve population (taken from the manufacturer s model, Inp_Efficacy!C247:D254 ) Ustekinumab 45mg Treatment PASI score change from baseline PASI 75 responders PASI 75 non-responders **** **** 83

84 Ustekinumab 90mg Golimumab 50mg Golimumab 100mg Adalimumab Etanercept 25mg and 50mg Infliximab **** **** **** **** **** **** **** **** **** **** **** **** Table 24. PASI score change for PASI 75 responders and non-responders for the anti-tnfα experienced subgroup analysis (taken from manufacturer s model, Inp_Efficacy! F247:D248 ) Ustekinumab 45mg Ustekinumab 90mg Treatment PASI score change from baseline PASI 75 responders PASI 75 non-responders ***** **** ***** **** In the main analysis *********** **** *** **** had the greatest effect in terms of the reduction in PASI scores for PASI 75 responders, followed by *********** *********** *********** *** ********** ********** had the greatest effect in terms of the reduction in PASI scores for PASI 75 non-responders, followed by *********** **** *** ***** *********** ********* ***** ********** *** ********* ***** HAQ Score HAQ score changes were applied dependent on PsARC response. The same assumptions regarding HAQ score changes were applied to both populations (anti-tnfα naïve and anti-tnfα experienced). As previously stated, it is assumed that treatment halts the natural progression of the disease; therefore all patients receiving treatment achieve some benefit. For those on treatment, individuals with a PsARC response (at week 12) were assumed to experience an initial reduction (i.e. improvement) in HAQ score from baseline, while PsARC non-responders experienced a smaller reduction in HAQ score. In the manufacturer s base case HAQ scores remain constant over time for those patients on treatment, and on discontinuation of treatment were assumed to rebound to the baseline HAQ and continue to deteriorate in line with the natural history of HAQ (i.e. a constant monthly rate of HAQ deterioration). 84

85 For the conventional management arm, initial HAQ score reductions for PsARC responders and PsARC non-responders were similarly applied in week 12, but all patients rebounded to the baseline HAQ score at week 24, and subsequently deteriorated in line with the natural history of HAQ. These assumptions are generally in line with previous submission and the ERG believes that they are reasonable. The baseline HAQ estimates used in the manufacturer s model are shown in Table 25. For the anti- TNFα naïve population, the majority of baseline HAQ scores from the included trials were >1.0, suggesting to the ERG that the estimate used was too low. The ERG recalculated the baseline HAQ score (using a weighted mean) and produced a value of 1.04 (see Appendix 10.2 for details of the ERG s calculation). Four of the included trials reported median HAQ values as opposed to mean values; removing these trials from the calculation reduced the estimate to , 8, 28, 29 In previous submissions, the manufacturer of golimumab used a value of 1.02 (method of calculation unclear), and Rodgers et al. used a value of 1.05 (weighted mean of a set of trials with median values excluded). Since the median is not a good estimate of the expected value for a given population, and in order to be consistent with the methods used in the previous MTA, the value excluding median scores (1.039) was applied in the model for all of the ERG s additional analyses in section 6. Table 25. Manufacturer and ERG baseline HAQ estimates Manufacturer s estimate ERG s estimate Anti-TNFα naïve population Baseline HAQ (se:0.31) 1.04 (SE: 0.02) Source/method of estimation Pooled estimate of 9 trials. 7, 8, 26-32, 43 Weighted average of 5 trials (excluding median 26, 27, 30, 31, 43 values) Anti-TNFα experienced population Baseline HAQ (se:0.05) 1.43 (SE:0.07) Source/method of estimation PSUMMIT 2 anti-tnfα experienced subgroup Weighted average of PSUMMIT 2 anti-tnfα experienced subgroup For the anti- TNFα experienced population the estimate was stated to have been derived from the PSUMMIT 2 trial (MS table 47, p118). Again the ERG checked this value by recalculating a weighted mean using the anti- TNFα experienced baseline HAQ scores reported in the manufacturer s response to the ERG s point of clarification (A.5, p14), and derived a value of (see Appendix 10.2 for details of this calculation). Although the PSUMMIT 2 trial baseline HAQ scores were given as median values, this was the only available evidence on which to derive a baseline HAQ estimate. This is therefore the value that was used in all of the ERG s additional analyses in section 6. 85

86 PsARC response rates Since the HAQ score changes are applied dependent on PsARC response, the effect of treatment on PsARC response is a key variable in the model. For the anti-tnfα naïve population, the proportion of patients with PsARC response and nonresponse at week 12 and 24 was derived from the manufacturer s de novo NMA analysis, which is discussed in section 4.3. In the anti-tnfα experienced subgroup analysis, the proportion of PsARC responders/non-responders was taken from the PSUMMIT 2 trial. The results are shown in Table 26. As for the PASI response rates (see section ), only data on participants meeting the weight based criteria for ustekinumab in PSUMMIT 2 were used to derive the PsARC response rates. Due to a lack of data reported in the MS, it is unclear how much data was lost by applying the weight based criteria. Restricting the analysis in the anti-tnfα naïve population to the weight-based dosing population resulted in a significant loss of data (see section 4.3); it is expected therefore that a similar loss of data has occurred in the anti-tnfα experienced population analysis. The potential impact of this assumption has been partially explored in section 6. Table 26. Proportion of Ustekinumab and conventional management PsARC responders for both populations Proportion of PsARC responders Treatment Mean (%) Week 12 Week 24 Upper/lower bound (%) Anti-TNFα naive population Mean (%) Upper/lower bound (%) Ustekinumab 45mg ***** **** ** **** ***** ***** ** **** Ustekinumab 90mg ***** **** ** **** ***** **** ** **** Conventional Management ***** **** ** **** ***** **** ** **** Anti-TNFα experienced population Ustekinumab 45mg ***** **** ** **** 52.5% to Ustekinumab 90mg ***** **** ** **** 41.7% to Conventional Management ***** ***** ** ***** 25.8% 15.8 to 37.3 As presented in table 17, section 4.3, in the anti-tnfα naive population *********** is associated with the **************** rate. There is an issue related to the effectiveness of the conventional management strategies. In the model initial HAQ score reductions for PsARC responders and PsARC non-responders in the conventional 86

87 management arm were applied in week 12, but all patients rebounded to the baseline HAQ score at week 24. The results in Table 26 suggest that PsARC response in the conventional management arm may be maintained between ****** in week 24. This effect is not accounted for in the model. The ERG believes that the assumption made is not unreasonable and any further short-term accrual of the small HAQ benefit to these patients would not greatly impact on the results achieved HAQ score change from baseline For all of the anti-tnfα treatments in the anti-tnfα naïve population analysis, both the HAQ score change from baseline for PsARC responders and HAQ score change from baseline for PsARC nonresponders were derived from a previously published NMA). 24 The manufacturer stated that, for the anti-tnfα treatments, insufficient data on HAQ score changes were identified in the systematic literature review of clinical evidence. The Yang NMA was conducted by the ERG for golimumab, and was based on evidence submitted by the manufacturer of golimumab and the previously conducted 12, 24 MTA (Rodgers et al.). The Yang NMA results were for the HAQ change from baseline for PsARC response/non-response at week In the manufacturer s model it was assumed that the HAQ change values for PsARC response/non-response for anti-tnfα s at week 24 would be the same as those reported in Yang for week This assumption is the consequence of a lack of evidence, and whilst it may be consistent with what other economic models have assumed the ERG note that it remains uncertain. For ustekinumab and conventional management, HAQ score changes were taken from the PSUMMIT 1 and 2 trials. For patients on conventional management, an initial HAQ score change was applied in week 12, however HAQ score changes were again assumed to rebound to the baseline score in week 24. To justify the combined use of the published NMA and the PSUMMIT data the manufacturer claimed that, because the HAQ score change for PsARC responders for the pooled placebo arms of the PSUMMIT 1 and 2 trials (-0.26) at week 24 were comparable to the placebo results in the Yang NMA (-0.27) at week 12, the value of the 24 week HAQ score change for PsARC responders and non-responders for ustekinumab and conventional management from the PSUMMIT trials could be used alongside the 12 week Yang NMA results for the anti-tnfα s. For the naïve population the ERG believes that there are limitations to utilising the data in this manner and present an alternative scenario in section 6.3, in which the two ustekinumab trials are included within the NMA and the results used to populate the decision model. For the anti-tnfα experienced subgroup analysis, the HAQ score change estimates for ustekinumab and the conventional management strategies were taken from PSUMMIT 2. 87

88 The value of HAQ score changes from baseline for PsARC responders/non responders used for the anti-tnfα naïve and anti-tnfα experienced populations are shown in Table 27 and Table 28. [Note: It was assumed that the alternative dosages of golimumab and etanercept would have equal efficacy.] Table 27. HAQ score change from baseline for PsARC responders and non-responders (naïve population) Responders Non-responders Treatment Mean (%) Week Week 24 Week Week 24 Standard Error Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Ustekinumab 45mg ****** ***** ****** ***** Ustekinumab 90mg ****** ***** ****** ***** Golimumab 50mg and 100mg Adalimumab Etanercept 25mg and 50mg Infliximab Conventional Management ****** ***** Table 28. HAQ score change from baseline for PsARC responders and non-responders (experienced population) Responders Non-responders Treatment Mean (%) Week Week 24 Week Week 24 Standard Error Mean (%) Standard Error Mean (%) Standard Error Mean (%) Standard Error Ustekinumab 45mg ****** **** ****** ***** Ustekinumab 90mg ****** **** ****** ***** Conventional Management For the anti-tnfα naïve population, for responders and non-responders, ********** had the greatest treatment effect on HAQ score change from baseline, followed by *********** *********** *********** **** *** ********** *********** **** was the least effective treatment (excluding conventional management) HAQ rebound and natural disease progression Upon treatment discontinuation, HAQ scores were assumed to rebound to the baseline HAQ value and subsequently deteriorated according to the natural history of HAQ (up to maximum HAQ score of 88

89 3). This was modelled as a increase in HAQ score every 28 days. This value was taken from 24, 44 Bojke et. al. 2011, and was used in the previous submission for golimumab. The value was derived from the Norfolk arthritis Register (NOAR), a register of patients with different types of inflammatory polyarthritis, including rheumatoid arthritis. The NOAR has been recruiting patients since For the purpose of the previous MTA the NOAR data was re-analysed by the ARC Epidemiology Unit at the University of Manchester to estimate HAQ change in patients who are uncontrolled (with three tender joints three swollen joints) and have previously tried two or more DMARDs. 12 The population was anti-tnfα naïve. Details of this analysis are reporting in TA The ERG feels that whilst the use of this data is consistent with previous submissions, it is based on the limited data that was available 4 years ago when the original MTA was undertaken. It is unclear why no attempt was made to update these data. Due to the time constraints of an STA the ERG were not in a position to undertake such an update. The ERG considers the manufacturer s assumption of an immediate rebound to baseline HAQ and PASI scores upon treatment discontinuation to be reasonable and consistent with scenarios presented in previous submissions. The ERG s clinical advisor suggested that, for withdrawals due to adverse events, it is likely that the rebound back to baseline HAQ and PASI scores would be rapid. For withdrawals due to waning efficacy it would be likely that skin and/or joint conditions would have been deteriorating for a period of time prior to treatment discontinuation, however this trajectory would be difficult to quantify, and in the absence of robust data the manufacturer s assumption is reasonable. Similarly the ERG s clinician confirmed that one would expect a steady decline in HAQ scores over time, as conventional management is not effective at halting joint damage; what you would expect in terms of the PASI score over time is more difficult to predict, and therefore use of a constant baseline PASI rate was assessed as being a reasonable assumption. The manufacturer also presented two scenario analyses to test the assumptions re HAQ rebound at the point of treatment withdrawal: 1. Patients rebound to the natural history of HAQ (presented in the model but not in the report) 2. Patients rebound to a HAQ score arbitrarily lower (i.e. better) than the baseline HAQ score. The value chosen was 1. In the response to the ERG s points of clarification (B9), the manufacturer clarified that the rebound to nature history scenario (1) was intended to model a patient s HAQ score rebounding to the point at which it would have reached had they never received treatment (and hence been progressing from their baseline score at the rate of per 12 weeks in line with the natural history of HAQ). The ERG considers this to represent a worst case scenario for the HAQ rebound. 89

90 The other scenario, HAQ rebounds to 1, lacked evidence to support its use. Further, whilst this analysis makes sense using the ERG s revised baseline HAQ of 1.03, under the manufacturer s baseline value of 0.8 this scenario actually results in HAQ scores rebounding to a score worse than the base case value). The ERG felt that it was more appropriate to recalculate the baseline HAQ using the relevant trial data and undertake further analysis, rather than placing too much weight on a scenario based on an arbitrary number Long term withdrawal Patients who remain on active treatment when they enter the Markov model are subject to an annual withdrawal risk to conventional management strategies. The manufacturer stated that due to a lack of long term RCT data for probabilities associated with response/non-response to PsARC/PASI75, a constant withdrawal rate from treatment was applied instead of transition probabilities. The long term withdrawal rate was assumed to capture withdrawals due to diminished efficacy and adverse effects. Two estimates of long term withdrawal were identified from the economic evaluations included in the manufacturer s systematic review. The more recent estimate of 16.5% per annum was used in the base case, which was taken from a meta-analysis of registry data from several countries used by the most recent evaluations. 12, 24 An alternative rate of 11.1% was used in a sensitivity analysis. 45 For the anti-tnfα naïve population, the ERG believe that the manufacturer s estimate of long term withdrawal is reasonable. Nevertheless the ERG believes that a wider range of values for long term withdrawal should have been considered. In response to the ERG s request, the manufacturer applied a probability distribution to the long term withdrawal parameter in the model, to reflect the uncertainty around this estimate. This alteration was used in all of the ERG s additional analyses (see Section 6.3). For the anti-tnfα experienced population, the long term withdrawal rate of 16.5% does not appear to be appropriate, since that value was derived from registry data which appears to have been derived from anti-tnfα naïve patients. A higher withdrawal rate for anti-tnfα experienced is discussed and calculated section Mortality All patients within the model were at a risk of death. All-cause mortality was taken from ONS life tables. 46 These life tables were adjusted for additional mortality associated with PsA. The PsA mortality multiplier for female patients was 1.59 and the PsA mortality multiplier for male patients was These were both derived from Wong et al (1997). 47 These mortality multipliers were also used in the model for anti-tnfα experienced patients. Given that these multipliers were derived some 90

91 years ago, it is very likely that the population were anti-tnfα naïve and therefore, these estimates may be unsuitable for anti-tnfα experienced patients Adverse events The adverse events experienced by patients in the PSUMMIT trials were presented in Table 40 and Table 41 (pg. 84 and 86) of the MS. The adverse events experienced by patients in the RCTs for the comparator biologics were also presented in appendix 15 of the MS. Within the economic model, adverse events were only considered in terms of their effect on withdrawal rates and the initial response to treatment rates, which were implicitly assumed to incorporate withdrawal due to adverse events. No dis-utility and no additional costs associated with adverse events were included in the economic model, which appears to be in line with previous submissions. Given the nature of the adverse events listed the ERG felt that this was reasonable Health related quality of life A systematic review was undertaken to identify studies relevant to the decision problem. This search identified 25 studies in PsA which reported HRQoL outcomes, with an additional four studies identified in the update of the systematic review. Only one UK specific study was identified, which did not report EQ-5D values and so this study was not used in the submission. The PSUMMIT 1 and PSUMMIT 2 trials collected the SF-36, a generic HRQL measure and the DLQI, a skin specific HRQL measure. In order to estimate utilities for the economic model, algorithms which estimate utilities based on a patient s HAQ and PASI scores were utilised. This is in line with previous submissions. The regression estimates were: Utility (EQ-5D) = *HAQ 0.004*PASI (SE) (0.006) (0.006) (0.0003) With this equation if a patient has no PsA scores, (i.e. their HAQ scores and PASI scores are zero), their utility estimate would be As a patient s HAQ score increases one point, the patient s utility will decrease by 0.298, and as their PASI scores increases by one point their utility will decrease by This utility equation was lifted directly from Bojke et al (2011) and is based on an ordinary least squares (OLS) regression of utility versus HAQ and PASI which were conducted using 91

92 data from three manufacturers submissions (adalimumab, etanercept, inflixamab). 44 The ERG believes that the use of the regression equation is appropriate. As a sensitivity analysis the manufacturer also presented utility estimates which were derived using the SF-36 data available from the two PSUMMIT trials. Within the sensitivity analysis, the SF-36 data from the PSUMMIT 1 and PSUMMIT 2 trials were mapped to EQ-5D using a published algorithm. 35 The regression estimates for this analysis were: Utility = **** *****HAQ *****PASI (SE) (0.006) (0.006) (0.0003) The MS described another available algorithm. 48 However the manufacturer stated that the Rowen et al algorithm was their preferred algorithm as this was now a published paper and had been peer reviewed; Gray et al was only published as part of a conference paper. The manufacturer submission did estimate utility values using the Gray et al algorithm and both algorithms have a high degree of correlation (R 2 =0.949). Within the sensitivity analysis, the utility estimates were also age-adjusted, using estimates from Ara and Brazier (2010). 49 The utility data for this population are lacking and the use of these published algorithms is common place across the published economic literature. The ERG feels that the manufacturer has used the best evidence available to them and appropriately explored the impact of the alternatives. However, the fact remains that there is limited evidence and the estimates obtained are uncertain Resources and costs The manufacturer conducted a systematic search to identify evidence on resource utilisation and valuation studies for the treatment of PsA in a UK setting. One study was identified which highlighted the relationship between increased age and HAQ scores, and the increased costs of the management of PsA. 50 This study only reported total average costs of different components of the management of PsA, and did not report the resource use data upon which cost calculations were based. The manufacturer therefore did not use the study to inform their resource or cost values, as it was not possible to accurately update the cost values from Poole et al. in order to make them relevant to current clinical practice. The ERG believes the exclusion of this study was justified, based on the lack of resource use data. In the model, costs were applied according to the following categories: drug acquisition, treatment administration, resource utilization (including routine initial and follow up appointments with 92

93 dermatologists and rheumatologists, and required tests), and health state-related (i.e. HAQ- and PASIrelated). These are discussed in detail below Drug acquisition costs Drug acquisition costs were applied for all anti-tnfα treatments and ustekinumab. No acquisition cost was applied to the conventional management arm (see section for further discussion). All drug acquisition costs were appropriately derived from the BNF 65, and dosage values were calculated based on EPAR Summary of Product Characteristics (SPC) data. 8, 25, Dosing for ustekinumab, golimumab and infliximab was based on patients weight: for ustekinumab patients weighing 100kg were assumed to receive the lower 45mg dose and patients weighing >100kg received the higher 90mg dose; for golimumab patients weighing 100kg were assumed to receive the lower 50mg dose and patients weighing >100kg received the higher 100mg dose; and for infliximab the dosing was 5 mg/kg. Based on data from the PSUMMIT trials, 75.8% of patients were assumed to weigh 100 kg, and the average patient was assumed to weigh 87.9 kg. Given that a vial of infliximab contains 100mg, the average dose of infliximab was assumed to require 5 vials. This assumes that there is no vial sharing permitted, which is in line with clinical practice. For the full dosage regimens for each treatment see Table 4, Section (Treatment dosing regimens). The drug acquisition costs applied in the model (based on the dosing regimens reported in Section ) are shown in Table 29. All drug costs were checked by the ERG and found to be correct. 93

94 Table 29. Unit costs used in the manufacturer's model (adapted from Table 55, pg. 139 of MS) Items Ustekinumab Golimumab Infliximab Etanercept Adalimumab Unit 45mg pre-filled 50 mg pre-filled pen 100 mg vial 25mg/50mg prefilled 40mg pre-filled pen syringe or syringe pen or syringe or syringe Technology unit cost (25mg) (50mg) Mean cost of technology treatment 45mg dose: Cycle 1: 4, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 8, Cycle 2-4: 4, Cycle 5+: 18, Administration cost N/A Home care service is provided free-of-charge to the NHS Total 45mg dose: Cycle 1: 4, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, N/A assumed 100% selfadministration 50mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, Based on average weight of 87.9 kg Cycle 1: 6, Cycle 2-4: 4, Cycle 5+: 13, Cycle 1: 1, Cycle 2-4: Cycle 5+: 2, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, N/A assumed 100% selfadministration Cycle 1: 7, mg dose: Cycle 2-4: 5, Cycle 1: 2, Cycle 5+: Cycle 2-4: 2, , Cycle 5+: 9, Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, N/A assumed 100% selfadministration Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 8, Cycle 2-4: 4, Cycle 5+: 18, Average (based on 75.8% weighing 100 kg): Cycle 1: 5, Cycle 2-4: 2, Cycle 5+: 11, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, Average(based on 75.8% weighing 100 kg): Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, mg dose: Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, Average (assuming equal use of both dosing regimen): Cycle 1: 2, Cycle 2-4: 2, Cycle 5+: 9, The model makes an assumption regarding the proportion of patients who would receive the higher dose of 90mg based on the population included in the PSUMMIT trials. Based on the limited evidence regarding weight in the trials of other biologics included in the NMA it would appear that this is a reasonable estimate to reflect the proportion in the wider PsA population, but the ERG have not been able to validate the estimate further Administration costs For anti-tnfα treatments administered by subcutaneous injection (golimumab, adalimumab and etanercept) no administration charge was applied, based on the assumption that all patients would self-administer treatment. For infliximab, which requires administration by intravenous infusion at a 94

95 hospital, it was assumed that a hospital day charge would be incurred. For ustekinumab, the manufacturer assumed (based on their advisory board s suggestions) that in 70% of cases subcutaneous injections of ustekinumab would be administered by a nurse at the patient s home, and 30% of patients would be self-administer. No administration cost was applied to ustekinumab in the model, since the manufacturer stated that they provide a homecare service whereby a nurse administers ustekinumab at the patient s home, free-of-charge to the NHS. In the points for clarification (B2) the manufacturer states that: The Stelara 'Homecare Service' is a personalised delivery and care service for people taking ustekinumab. The service delivers ustekinumab directly to a patient s home, or any other convenient location, if the patient and the clinician have agreed it is a suitable option. Home visits from fully qualified nurses can also be arranged so that they can inject ustekinumab to a patient, or train the patient to self-inject, depending on what the patient and the clinician have agreed. The Stelara 'Homecare Service' is delivered by Bupa Home Healthcare, a specialist homecare provider working in partnership with Janssen, and is free-of-charge to the NHS. The duration for which this free service will be available is unclear. In addition, it is unclear what proportion of patients may be expected to self-administer ustekinumab. This is clearly not an issue as long as the free Homecare Service is available. Further, based on the advice of the ERG s clinical expert, there is no clinical reason to suppose patients receiving ustekinumab would not be able to selfadminister in the same way as anti-tnfα patients, since anti-tnfα s require the same form of subcutaneous injection as ustekinumab Medical resource utilization The current clinical management of PsA requires patients to have regular face-to-face contact with both a dermatologist and a rheumatologist because the condition has both skin and joint involvement. The amount of medical resource use and associated costs were derived based on the assumptions used by Rodgers et al. in a previous submission, and the British Society for Rheumatology guidelines for anti-tnfα therapy in PsA (MS ref# 34, 55 ). The values for patients receiving conventional management were elicited from the experts at the manufacturer s advisory board meeting, as described in the MS, section The manufacturer assumed that the resource use requirements for patients on ustekinumab would be the same as the requirements for patients on anti-tnfα s, as per the advice their advisory board. Thus the same resource use costs were applied to all active treatment strategies. In weeks 0-12, the resource use cost applied to the conventional management arm was less than that applied to the active treatment arms, due to the assumption that conventional management patients would not receive a 95

96 chest radiograph, TB Heaf test, antinuclear antibodies test (ANA), or DNA binding. For weeks 13-24, and 25+, resource utilization for conventional management patients was assumed to be the same as that in the active treatment arms. These resource use assumptions were consistent with those in previous submission. The same resource use costs were applied in the anti- TNFα experienced subgroup analysis. Costs were applied to all resource use items using NHS Reference costs. The DRG codes used to cost each of the resource use items were listed in Table 53, pg. 132 of the MS. The ERG believes that the resource use and associated costs used in the manufacturer s model were consistent with previous submissions and are not aware of any more relevant sources for these data. Resource use and associated costs for patients on active treatment and conventional management are presented in the MS, Table 56, Section pg Health state costs (HAQ- and PASI-related costs) Health state costs were estimated as a function of HAQ and PASI scores for patients in each health state (as described in section 5.3.3). Costs as a function of HAQ score were derived from a previously published study. 36 The manufacturer stated that this was in line with the majority of previous economic evaluations identified in the manufacturer s literature review. The study began in 1987 and the cost component included 916 patients with Rheumatoid Arthritis (RA) with between 5 and 9 years of follow up. Direct health-care resources were collected prospectively for all patients for hospitalisations, surgical interventions and RA medications. Details of outpatient visits and community services were collected retrospectively in a subsample of 107 patients (details from Rodgers Appendix). The manufacturer s used the costs as reported in Yang et al, shown below: Cost = 1, *HAQ score The manufacturer stated that these costs were inflated to 2013 prices; however in the model the original 2010 Yang prices shown above were applied. In response to the ERGs request, the manufacturer updated the model values to reflect the inflated prices: Cost = 1, *HAQ score. The manufacturer assumed that patients receiving biologic treatments would incur 85% of HAQrelated costs, while those receiving conventional management strategies incur 100% of these costs. In response to the ERG s request for a justification regarding this assumption, the manufacturer stated that patients on biologic therapy were assumed to incur 85% of the HAQ-related costs because they are assumed not to be using DMARDs. This assumption was similarly applied in the STA for 96

97 golimumab. Thus, although no direct drug cost was applied to the conventional management arm, the cost of DMARDs was incorporated indirectly in this assumption. The MTA during which these analyses were first identified, selected and used was undertaken in Due to the time constraints when undertaking an STA the ERG were not in a position to be able to confirm that these remain the most appropriate data on which to assess the impact of changes in functional and disability as measured by the HAQ on costs. The ERG therefore considered that these estimates may be sufficient to give some indication regarding these costs in the model, but the use of these estimates to predict costs over the patients lifetime introduces further uncertainty into the model. An additional cost per PASI score increase was applied in the model, again using the same values as applied in the previous golimumab submission. 24 Two costs were included: one excluding phototherapy ( 53 per PASI point, used in the base case), and one including phototherapy ( 167 per PASI point, used in a sensitivity analysis). In response to the ERG s request for clarification (B4), the manufacturer stated that the 53 PASI-related cost accounted for resource use costs such as dermatology inpatient, consultant-led outpatient and nurse-led outpatient costs (stated to have been discussed in Cummins et. al. 2011). 56 The PASI related costs were stated to have been inflated to 2013 prices using the Hospital and Community Health Services (HCHS) index, to and including/excluding phototherapy. However in the model the original 2010 prices from Yang were applied. In response to the ERG s request, the manufacturer amended this mistake in the model. According to the ERG clinical advisor, phototherapy would be expected to be used in a small minority of cases; most PsA cases have mild to moderate skin disease and so phototherapy is unlikely to be required. The PASI-related cost used in the manufacturer s base case analysis therefore appears to be appropriate. The ERG felt that following the minor corrections and clarifications these cost estimates were reasonable Adverse event costs. No costs relating to adverse events were applied in the model. The manufacturer stated that the adverse events associated with treatments for PsA tend to be infrequent, minor and have similar prevalence across treatment arms; it was therefore assumed that adverse events influenced the initial response to treatment and the long-term withdrawal rate, and were implicitly accounted for within these rates. This assumption was stated to have been in line with previously conducted economic evaluations and the ERG believe that it is a reasonable assumption. 97

98 No miscellaneous costs were applied in the model Cost effectiveness results Within this section, the manufacturer s base case cost-effectiveness results, one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analyses are discussed. These are presented separately for anti-tnfα naïve and anti-tnfα experienced patients Cost-effectiveness results for the anti-tnfα naïve patients Base-case cost-effectiveness results The deterministic incremental cost-effectiveness results presented in the MS are presented in table 20. Table 30: Base-case deterministic results, anti-tnfα naïve patients (based on Table 64, Section 7.7.6, pg. 165 in the MS) Total costs ( ) Total QALYs Incremental costs ( ) Incremental QALYs ICER vs. baseline ( /QALYs) ICER incremental ( /QALYs) Conventional management strategies 28, Golimumab 58, , ,288 12,288 Adalimumab 60, , ,386 Dominated Ustekinumab 66, , ,550 Dominated Etanercept 68, , , ,913 Infliximab 131, , , ,706 Both adalimumab and ustekinumab were found to be dominated. That is, both of these treatments were more costly and less effective when compared with the next most costly alternative. The manufacturer appears to have undertaken a full incremental analysis, excluding dominated treatments; although small variations in the results were obtained by the ERG when checking ICERs the ERG has assumed that these differences are due to rounding errors. In response to the ERG s request for clarification (B4 and B7), the phototherapy costs were removed from the base-case cost and the PASI related costs were adjusted to appropriately account for inflation. These changes to the cost data altered the base-case deterministic results slightly. These altered results are presented in Table 31. Table 31: Amended base-case deterministic results, TNF naïve patients (pg. 50 in the manufacturer s response to clarification) Total costs ( ) Total QALYs Incremental costs ( ) Incremental QALYs ICER vs. baseline ICER incremental 98

99 Conventional management strategies 29, ( /QALYs) ( /QALYs) Golimumab 59, , ,235 12,235 Adalimumab 61, , ,332 Dominated Ustekinumab 67, , ,499 Dominated Etanercept 69, , , ,196 Infliximab 132, , , ,448 The ICERs for each of the pairwise comparisons with conventional management strategies ranged from 12,235 to 38,091 with the ICER for ustekinumab compared with conventional management strategies being 21,499. This ICER represents a situation wherein the only alternative to conventional management strategies for the naïve population is ustekinumab. In this unrealistic scenario the ICER is greater than 20,000. One-way sensitivity analysis The MS conducted several one-way sensitivity analyses. The parameters were varied by +/- 25% of the mean value. No justification was provided for this value, but the ERG feels that for this type of analysis this was a reasonable variation to assume. When compared with conventional management strategies, golimumab, etanercept, the analysis indicated that the most influential parameter on the results is the HAQ score natural history change per 28 days parameter. When compared with adalimumab, the proportion of PsARC responders at week 12 for adalimumab becomes the influential parameter on the results. When compared with infliximab, the unit cost of intravenous infusion is the most influential parameter. The economic model also allows these one-way sensitivity analyses to be undertaken when ustekinumab is compared with each of the other biologic treatments for TNF naïve patients. Probabilistic sensitivity analysis A probabilistic sensitivity analysis was undertaken by the manufacturer, using 10,000 iterations, with the following outputs: Mean cost and QALY estimates, incremental cost and QALY estimates, and ICERs compared with both conventional management strategies and the next most costly non-dominated alternative treatment; Cost-effectiveness scatter plot of the results for ustekinumab compared with each of the other comparators; 99

100 95% confidence ellipses for all treatments; Cost-effectiveness acceptability curve for ustekinumab compared with all treatments. Within this analysis, the probability distributions were specified for the majority of the parameters. However, the following adjustments were made to the manufacturer s model as requested by the ERG within the points of clarification (B6): Gamma distributions were assigned to all uncertain unit costs; The HAQ score change to Week 24 PsARC non-responders: ustekinumab 45mg was assigned a normal distribution; The HAQ score natural history change per 28 days parameter was assigned a gamma distribution; Beta distributions were assigned to the proportion of HAQ score costs applied to patients on treatment and proportion of HAQ score costs applied to patients on conventional management strategies parameters; and A normal distribution was assigned to the HAQ score rebound to between baseline and natural history parameter. When these adjustments were made to the model as well as the adjustments outlined earlier regarding some costs, the PSA results were as presented in Table 32. The results obtained are very similar to the deterministic results. Table 32: PSA results; mean of 10,000 simulations, anti-tnfα naïve patients (pg 50 in the manufacturer s response to clarification) Total costs ( ) Total QALYs Incremental costs ( ) Incremental QALYs ICER vs. baseline ( /QALYs) ICER Incremental ( /QALYs) Conventional management strategies 29, Golimumab 59, , ,134 13,134 Adalimumab 61, , ,478 Dominated Ustekinumab 67, , ,048 Dominated 100

101 Etanercept 69, , , ,629 Infliximab 132, , , ,

102 Scenario analysis Several scenario analyses addressing a number of uncertainties in the MS were undertaken. A summary of these analyses and the pairwise results for ustekinumab compared to conventional management are presented in Table 33. Table 33. Summary of scenario analyses and results (based MS. Tables 68-34, pg174-7) Technologies Total costs ( ) Total LYG Total QALYs Incremental costs ( ) Incremental QALYs ICER vs. baseline ( /QALYs) Scenario analysis 1: All treatments assessed for initial response at Week 12 Conv. mgmt 28, Ustekinumab 64, , ,157 Scenario analysis 2: All treatments assessed for initial response at Week 24 Conv. mgmt 27, Ustekinumab 66, , Dominated Scenario analysis 3: PsARC or PASI 75 responders continue treatment Conv. mgmt 28, Ustekinumab 76, , Dominated Scenario analysis 4: PsARC and PASI 75 responders continue treatment Conv. mgmt 28, Ustekinumab 45, , Dominated Scenario analysis 5: PASI score related costs exclude phototherapy Conv. mgmt 28, Ustekinumab 66, , Dominated Scenario analysis 6: Annual risk of withdrawal from treatment is 11.4% (Geborek et al., 2002) Conv. mgmt 28, Ustekinumab 73, , Dominated Scenario analysis 7: HAQ rebounds to a lower HAQ score than baseline (score = 1) on withdrawal from active treatment Conv. mgmt 29, Ustekinumab 66, , Dominated Scenario analysis 8: Baseline weight is 77.4 kg based on the general population (HSE, 2012) Conv. mgmt 28, Ustekinumab 66, , Dominated Scenario analysis 9: No excess mortality is associated with PsA; mortality based on general population all-cause mortality Conv. mgmt 31, Ustekinumab 68, , Dominated Scenario analysis 10: EQ-5D utilities from Bojke et al. used - with age-adjustment Conv. mgmt 28, Ustekinumab 66, , Dominated Scenario analysis 11: EQ-5D utilities from PSUMMIT used - with age-adjustment Conv. mgmt 28, Ustekinumab 66, , Dominated Scenario analysis 12: EQ-5D utilities from PSUMMIT used - no age-adjustment Conv. mgmt 28, Ustekinumab 66, , Dominated Scenario analysis 13: Efficacy for ustekinumab 45 mg and 90 mg based on full analysis set Conv. mgmt 28, Ustekinumab 66, , Dominated 102

103 Within the points of clarifications, the ERG requested the manufacturer to clarify several issues. These included: The assumptions being applied to the HAQ scores in Scenario 10 of the economic model; Provide the scenario analysis discussed in the submission where the whole ITT population from the PSUMMIT studies is used to assess the weight-based dosing on cost-effectiveness; Clarify that these scenario analysis generated probabilistic ICERs, and if this is not the case, provide the probabilistic results. Following these clarifications, the manufacturer presented the probabilistic results for these 13 scenarios. Ustekinumab was dominated by the next mostly costly alternative in all of these scenario analyses and generated the lowest QALYs in all but one scenario. The pairwise ICER (ustekinumab versus conventional management) was 23,048 in base case; throughout these scenario analyses it varied from 27,137 to 37, Cost-effectiveness results for the anti-tnfα experienced patients Base-case cost-effectiveness results The deterministic incremental cost-effectiveness results presented in the MS are presented in Table 35 below. Table 35: Base-case results, anti-tnfα experienced patients (based on Table 65, Section 7.7.6, pg. 165 in the MS) Conventional management strategies Total costs ( ) Total QALYs Incremental costs ( ) 34, Incremental QALYs ICER ( ) Ustekinumab 75, , ,751 The altered base-case results following the ERG s request for clarification are presented in Table 36 below. Again, the adjustments made to the base-case costs estimates did not have a major impact on the results. Table 36: Base-case results, anti-tnfα experienced patients (pg 54 in the manufacturer s response to clarification) Conventional management strategies Total costs ( ) Total QALYs Incremental costs ( ) 35, Incremental QALYs ICER ( ) Ustekinumab 76, , ,

104 One-way sensitivity analysis The MS conducted the same one-way sensitivity analyses for the anti-tnfα experienced patients. Again no justification was provided for the variation of +/- 25% of the mean value; although the ERG believes that it is a reasonable range to vary over. Once again, it was found that the HAQ score natural history change per 28 days was the most influential parameter on the results, when ustekinumab is compared with conventional management strategies. Probabilistic sensitivity analysis The same PSA was run for the anti-tnfα experienced patients, using the same distributions and assumptions as detailed for the anti-tnfα naïve patients. These PSA results are presented in Table 37. Table 37: PSA results; mean of 10,000 simulations, anti-tnfα experienced patients (Table 67, Section 7.7.8, pg. 172 in the MS) Conventional management strategies Total costs ( ) Total QALYs Incremental costs ( ) 34, Incremental QALYs ICER ( ) Ustekinumab 75, , ,451 When the adjustments were made by the manufacturer, following the points for clarification, the PSA results altered slightly; these results presented in Table 37. Table 38: PSA results; mean of 10,000 simulations, anti-tnfα experienced patients (pg 54 of manufacturer s response to clarification) Conventional management strategies Total costs ( ) Total QALYs Incremental costs ( ) 35, Incremental QALYs ICER ( ) Ustekinumab 77, , ,132 Scenario analysis The same scenario analyses were undertaken for the anti-tnfα experienced population as were described for the anti-tnfα population. For the scenario analyses in the original MS, the ICERs achieved ranged from 26,273 to 37,960. The scenario where both PsARC and PASI responders continue treatment reduced the ICER to 26,273. Scenarios where the utilities estimates were derived 104

105 from the PSUMMIT trial data pushed the ICERs to 37,960. When both ustekinumab and conventional management strategies were assessed for response at week 24, this increased the ICER up to 36,740. These results are presented in Table 39. Table 39. Summary of scenario analyses and results (MS. Table 40, pg178) Technologies Total costs ( ) Total LYG Total QALYs Incremental costs ( ) Incremental QALYs ICER ( ) incremental (QALYs) Scenario analysis 1: All treatments assessed for initial response at Week 12 Conv. mgmt 34, Ustekinumab 68, , ,980 Scenario analysis 2: All treatments assessed for initial response at Week 24 Conv. mgmt 32, Ustekinumab 77, , ,740 Scenario analysis 3: PsARC or PASI 75 responders continue treatment Conv. mgmt 34, Ustekinumab 90, , ,006 Scenario analysis 4: PsARC and PASI 75 responders continue treatment Conv. mgmt 34, Ustekinumab 56, , ,273 Scenario analysis 5: PASI score related costs exclude phototherapy Conv. mgmt 34, Ustekinumab 75, , ,751 Scenario analysis 6: Annual risk of withdrawal from treatment is 11.4% (Geborek et al., 2002) Conv. mgmt 34, Ustekinumab 83, , ,419 Scenario analysis 7: HAQ rebounds to a lower HAQ score than baseline (score = 1) on withdrawal from active treatment Conv. mgmt 33, Ustekinumab 74, , ,235 Scenario analysis 8: Baseline weight is 77.4 kg based on the general population (HSE, 2012) Conv. mgmt 34, Ustekinumab 75, , ,751 Scenario analysis 9: No excess mortality is associated with PsA; mortality based on general population all-cause mortality Conv. mgmt 36, Ustekinumab 78, , ,137 Scenario analysis 10: EQ-5D utilities from Bojke et al. used - with age-adjustment Conv. mgmt 34, Ustekinumab 75, , ,751 Scenario analysis 11: EQ-5D utilities from PSUMMIT used - with age-adjustment Conv. mgmt 34, Ustekinumab 75, , ,960 Scenario analysis 12: EQ-5D utilities from PSUMMIT used - no age-adjustment Conv. mgmt 34, Ustekinumab 75, , ,960 Scenario analysis 13: Efficacy for ustekinumab 45 mg and 90 mg based on full analysis set Conv. mgmt 34, Ustekinumab 77, , ,783 For the scenario analyses which included the adjustments following points for clarification, the ICERs ranged from 27,606 to 40,019. The scenario where both PsARC and PASI responders continue treatment reduced the ICER to 27,606. Scenarios where the utilities estimates were derived from the 105

106 PSUMMIT trial data pushed the ICERs to 40,019 and 39,905, which was similar to the previous scenario analysis. None of the scenarios reduced the ICER below a threshold of 20,000. In the majority of scenarios the ICER was increased to > 30, Model validation and face validity check The manufacturer validated the model by comparing the total costs and QALYs gained by the anti- TNFα treatments within the model against the published results from similar models. In particular, emphasis was placed on comparing the results to those reported by Bojke et. al (2011), which reported the results for the Multiple Technology Assessment (MTA) conducted on etanercept, infliximab and adalimumab. 44 The manufacturer stated that, in general, the QALYs and costs obtained using their de novo economic model were similar to those reported by Bojke et. al. 44 However, costs and QALYs were consistently higher in the de novo model, with the exception of the cost of etanercept which was lower. These differences were considered to be a result of the different inputs which were used within the manufacturer s model, including the updated cost sources, the costs inflated to the 2013 level, and clinical efficacy inputs taken from NMA analyses which include ustekinumab. The manufacturer noted that their de novo model was restricted to the anti-tnfα naïve population, whereas Bojke et. al. did not restrict their analysis to this sub-population. 44 The ERG note that this is incorrect: the evaluation by Bojke et al. was restricted to the same naïve population. The manufacturer correctly noted that the analysis by Bojke et al. assumed a shorter time horizon of 40 years compared to the 52 years assumed by the manufacturer. The comparative cost-effectiveness results from the MS, TA220 and TA199 are presented in table 41. The results differ in the total costs and QALYs generated, however, if we were to rank treatments based on their cost-effectiveness to conventional management the ranking remains fairly consistent. The ERG do not advocate this as a method to inform decision making, rather as an aid to establishing the consistency of the model which have been undertaken and considered by NICE for treatments in this population. 106

107 Table 41: Results comparison: TA199; TA220 and Ustekinumab submission Technologies Total costs ( ) TA TA Ustekinumab ICER ( ) Total QALYs versus Con. Man Total costs ( ) Total QALYs ICER ( ) versus Con. Man Total costs ( ) ICER ( ) Total QALYs versus Con. Man Con. Man 42, , , Adalimumab 68, ,786 86, ,820 60, ,373 Etanercept 74, ,854 94, ,402 68, ,660 Infliximab 88, , , , , ,196 Golimumab , ,811 58, ,304 Ustekinumab , ,596 The manufacturer stated that their model was checked for logic and accuracy by an economist not involved with the construction of the model, and its structure and logic were reviewed by a senior economist not involved with the project. The ERG also checked the model for logic and accuracy. The small errors identified by the ERG were corrected at the points for clarification stage. As far as the ERG can tell the model is error free and works appropriately. Although some of the methods used vary from previous submissions, on the whole they appear justified. Those areas of uncertainty that warranted further exploration are discussed and explored by the ERG in section 6. A comparison of the manufacturer s decision model, TA199 and TA220 shown in Table 42. Table 42: Comparisons with previous submissions MS TA199 (Etanercept, infliximab and adalimumab MTA) TA220 (Golimumab STA) Model A short-term decision tree followed by a long-term Markov model A probabilistic decisionanalytic Markov model. Cohort model with common baseline HAQ and PASI (varied in sensitivity analysis). States and events Initial response determined using PsARC. HAQ and PASI tracked over time, accounting for withdrawals. Initial response determined using PsARC. HAQ and PASI tracked over time, accounting for withdrawals Initial response determined using PsARC. HAQ and PASI tracked over time, accounting for withdrawals. Adjustment for placebo effect There was no adjustment done The change in HAQ in patients using biologics is reduced by the mean change in HAQ across the placebo arms of the RCTs. A similar adjustment is made for the expected change in PASI in patients using biologic The placebo effect was adjusted for by subtracting the mean HAQ change in the placebo group (across PsARC responders and non-responders) from the HAD change of patients on biologic therapy. 107

108 therapy Time horizon 52 years 40 years 40 years Females at baseline TNF naïve: 44.2% TNF experienced: Average of RCTs 40% Age at baseline 48 years 47 years 47 years Mean weight at baseline TNF naïve: 87.9kg TNF experienced: 93.3kg Assumed to be between 60kg and 80kg this was based on the mean adult weight in the UK general population. 85.2kg Baseline HAQ score TNF naïve: 0.80 TNF experienced: , the mean of HAQ across the RCTs 1.02 Baseline PASI score TNF naïve: 7.95 TNF experienced: (this is assumed to be mild-to-moderate psoriasis) 9.9 Duration of PsA In PSUMMIT 2 trial: Anti-TNF naïve patients: mean 6.71 years Anti-TNF experienced patients: mean 8.91 years At least 7 years since diagnosis of PsA this was based on the average characteristics of participants on the RCTs Minimum duration of PsA 3 years Mortality Multipliers Female: 1.59 Male: 1.65 Female: 1.59 Male: 1.65 Multipliers estimated from Wong et al Treatment withdrawal decision rule PsARC response at 24 weeks for ustekinumab; PsARC response at 12 weeks for other comparators. PsARC response at 3 months PsARC non-responder Withdrawal rates TNF naïve: 16.5% TNF experienced: 16.5% (In the submission stated as 17% in year 1 and 16.5% thereafter, but the model has 16.5% for all years Natural history HAQ progression HAQ score change per 28 days: % Base-case: 16.5% Sensitivity analysis: 11.14% per year per year HAQ change for responders HAQ was assumed to remain constant following an initial improvement while patients remain on treatment. HAQ gain that corresponds to a drop in HAQ score. Initial gain is maintained while the patient continues with biologic therapy. Basecase: Continued up to 3 cycles Sensitivity analysis: No HAQ benefit beyond the first cycle HAQ change for non-responders HAQ score rebounds to baseline score HAQ rebounds less than initial gain (assumed to be 1) A slight HAQ gain is estimated in the initial (3- month) treatment assessment period, after which they will no longer receive biologics Base-case: Trial based HAQ benefit in cycle 1 SA: No HAQ benefit for non-responders 108

109 Health related quality of life Bojke et al algorithm was used. Algorithm using IPD data from PSUMMIT trials used in sensitivity analysis. Algorithm based on Rodgers et al was used. Base-case: Gray algorithm using IPD from GO-REVEAL Also used Brazier algorithm HAQ rebound when stopping therapy Rebound is equal to initial gain in the base case. SA: rebound less than initial gain and rebound equal to natural history. PASI score on withdrawal from therapy Mean PASI returns to its initial score at baseline (rebound equal to initial gain) PsA management cost of HAQ on TNF-α inhibitors 85% of costs for patients on palliative care 85% of costs for patients on palliative care Costs of treatment As the mean weight was 87.9kg for TNF naïve patients 5 vials were assumed to be necessary For infliximab assumes no vial sharing (four vials, 70-80kg weight in basecase). Three vials for a 60-kg patient considered in sensitivity analysis The base-case assumes no vial-sharing (four vials Subgroup analysis TNF naïve and TNF experienced groups Varying the baseline HAQ and PASI scores to reflect more or less psoriasis involvement A sub-group analysis was conducted exclusively on patients presumed to have predominantly rheumatic disease (and no psoriasis). A subgroup analysis only including psoriatic arthritis patients with significant psoriasis was also modelled. 5.4 Exploratory and sensitivity analyses undertaken by the ERG The ERG constructed a corrected model which adjusted for errors and omissions. Using this corrected model, additional sensitivity analyses were undertaken. An exploratory analysis on the sequencing of treatment was also undertaken as well as an exploratory analysis on the budget impact model. Full details of these analyses are presented in Section 6. Explanations of the exploratory analyses undertaken are presented in appendix xx. 5.5 Conclusions of the cost effectiveness section The economic submission presented by the manufacturer has been outlined and discussed by the ERG in Section 5. A number of potential limitations which impact on the validity of the manufacturer s results have been outlined and will be further explored by the ERG in section

110 Overall, the submission reflects the NICE scope and meets the reference case criteria. The manufacturer has presented two alternative population scenarios, one which positions ustekinumab as a first-line comparator alongside the four anti-αtnf treatments currently available to the eligible PsA population; the second which positions ustekinumab as the only treatment option for patients who have failed (all) anti-αtnf treatment. The ERG believes that the clinical trials and licence support ustekinumab as a potential first-line treatment option for the eligible PsA population. However, the manufacturer has presented limited evidence for an anti-tnfα experienced population. Whilst the ERG acknowledges that this lack of evidence is problematic, it feels that this is a weak justification for ignoring the issue of sequencing in an anti-tnfα population. This issue is explored further by the ERG in section 6. Overall, the de novo economic evaluation was reasonably well conducted and reported. The driver of the model is HAQ score change over 28 days. The evidence base to support this natural history change is limited and, whilst consistent with the value applied in previous submissions, it is an area that requires further research. Given the limited timeframe, this work could not be undertaken by the ERG. However it is important to note the limitations in the evidence base of this estimate

111 6 Impact on the ICER of additional clinical and economic analyses undertaken by the ERG 6.1 Overview The ERG ran additional analyses to explore uncertainty in model parameters and assumptions. The manufacturer undertook a number of sensitivity analyses (outlined in section 5.3.9), however the ERG felt that further investigation of several issues was warranted. All of the additional analyses were run using probabilistic analysis, in order to account for uncertainty around the parameter estimates. The additional analyses focus on 1) Treatment effect 2) HAQ rebound assumptions 3) PsARC response criteria 4) Costs 5) Sequencing In each of the following sections the probabilistic results are presented for the naïve population, and where appropriate the experience population. 6.2 ERG corrections and adjustments to the manufacturer s base case model To undertake the additional analyses the ERG constructed a corrected model, which consists of two stages of corrections applied to the manufacturer s original model: 1. Amendments for errors in the manufacturer s original cost estimates and distributions applied to costs and HAQ parameters, completed by the manufacturer in response to the ERG s request (as outlined in section 5.3.9); and 2. Re-calculated baseline HAQ and PASI scores, calculated by the ERG (as outlined in section and appendix 10.2). The ERG correct values were higher than those used in the manufacturer s model. The probabilistic results for the corrected model are given in Table 43 and Table 44. The manufacturer s original (non-amended) probabilistic base case ICERs have been given in the final column to aid comparison. Note that when undertaking a full incremental analysis, ICERs are derived by comparing each intervention with the next best (i.e. less costly) alternative after ruling out dominated interventions (i.e. those which cost more but achieve lower benefits), such that in Table 43 etanercept is compared to golimumab, not ustekinumab. 111

112 When comparing the results of the corrected model to the manufacturer s original probabilistic base case results (MS, Table 66 and 67, Section 7.7.8), it can be seen that the total costs have increased whilst the total QALYs have fallen for all the technologies. Increasing the baseline HAQ and PASI values results in higher HAQ and PASI values throughout the entirety of the model cycles, since the HAQ and PASI score changes for each PsARC responder and non-responder remain fixed. As the total cost is in part determined by the HAQ and PASI related costs, increasing these values also leads to increased costs (along with the use of the higher inflated HAQ- and PASI-related costs). Similarly overall QALYS are reduced since in the utility equation higher HAQ and PASI scores lead to lower utility values. Despite these changes, the results for ustekinumab are not significantly affected, with ustekinumab remaining dominated by golimumab in the anti-tnfα population (Table 43), and the ICER vs. conventional management only increasing marginally in the anti-tnfα experienced population ( Table 44). Table 43: Corrected model probabilistic results (MS corrections and ERG baseline HAQ and PASI estimates (anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies Costs QALYs Costs QALYs baseline ( /QALYs) Incremental ( /QALYs) Incremental ICER Conventional management 33, strategies(baseline) Golimumab 62, , ,335 13,335 13,227 Adalimumab 64, , ,716 Dominated Dominated Ustekinumab 70, , ,508 Dominated Dominated Etanercept 72, , , , ,741 Infliximab 134, , , , ,009 Table 44: Corrected model probabilistic results (MS corrections and ERG baseline HAQ and PASI estimates (anti-tnfα experienced population) Technologies Costs Total QALYs Incremental ICER Incremental ( /QALYs) Base case Incremental ICER Conventional management strategies 36, Ustekinumab 77, , ,843 29,

113 This corrected model was used as the basis for all the ERG s additional analyses presented in Section 6.3, and from this point forward is referred to as the base case model. As the ERG considers the probabilistic results to be the most informative, all additional ERG analyses have been presented as probabilistic results. 6.3 Additional ERG analyses The additional scenarios/sensitivity analyses conducted for the anti-tnfα naïve population are listed below, with results given in section to Use of weight based NMA results vs. ITT NMA results; 2. Use of ITT NMA results for all treatments excluding ustekinumab 90mg arm; 3. Worst case scenario for HAQ rebound (natural progression point); 4. HAQ score changes from updated Yang NMA including ustekinumab; 5. Alternative time horizons (5, 10, 20 and 40 years); 6. Week 24 vs. week 12 as the PsARC response assessment time point; 7. Inclusion of the cost of phototherapy in the PASI-related cost estimate; and Where possible and appropriate the additional analyses were also run for the anti-tnfα experienced population: these results are presented in section The ERG also conducted an exploratory sequencing analysis for the anti-tnfα experienced population, discussed in section Note that for each of the additional analysis conducted, the probabilistic ICER results for the base case model (discussed in section 6.2) have been provided in the final column of each table to allow comparison Weight based NMA vs. ITT NMA (naïve population) For the manufacturer s NMA a weight-based dosing criteria was applied to data taken from the PSUMMIT trials for ustekinumab (see section 4.3). Application of the weight-based dosing criteria has two major drawbacks: first, it results in a significant amount of data being lost from the analysis; and second, for the ustekinumab 45mg arm, it does not match how patients are expected to be treated in practice (since all patients, regardless of weight, are likely to commence treatment on the 45mg dose). The full ITT results for the manufacturer s NMA were provided by the manufacturer in response to the ERG s request (i.e. for PsARC, PASI 75 and PASI 90 response rates). The ERG conducted a sensitivity analysis using the ITT values provided. The results are presented in Table

114 Table 45. Probabilistic results for model using full ITT NMA results (anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies (baseline) Golimumab 54, , ,578 13,578 13,335 Adalimumab 64, , ,642 46,547 Dominated Ustekinumab 70, , ,480 Dominated Dominated Etanercept 72, , ,062 14, ,900 Infliximab 134, , , , ,032 Using ITT analysis appears to have greatest effect on the total costs and QALYs for golimumab, which are both reduced. The reduction in QALYs for golimumab leads to adalimumab no longer being dominated, and subsequently reduces the ICER for etanercept. The results for ustekinumab were not significantly affected by this analysis; ustekinumab remained dominated. The ICERs vs. conventional management were not significantly affected, with the value for ustekinumab marginally decreasing from 23,508 to 23,480 per additional QALY. The ERG conducted an alternative analysis was conducted using the manufacturer s ITT NMA results for all treatments, except ustekinumab 90mg, for which efficacy parameters were taken from the manufacturer s weight-based NMA results. The assumption underlying this analysis is that in practice all patients will start off on the ustekinumab 45mg arm, regardless of weight, whilst only patients weighing >100kg (and therefore meeting the weight based dosing criteria) will be eligible to receive the higher 90mg dose. The ITT NMA results are therefore appropriate for the 45mg arm, but the original weight-based dosing results are appropriate for the 90mg arm. The results of this analysis are presented in Table 46. Again this analysis leads to reduced total costs and QALYs for golimumab, resulting in adalimumab no longer being dominated and etanercept s ICER decreasing but with ustekinumab remaining dominated. Similarly the ICERs vs. conventional management were 114

115 unaffected, with the value for ustekinumab marginally increasing from 23,508 to 23,542 per QALY. Table 46. Probabilistic results for model with ITT NMA results used, excluding ustekinumab 90mg (anti- TNFα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies(baseline) Golimumab 54, , ,586 13,586 13,335 Adalimumab 64, , ,674 46,729 Dominated Ustekinumab 70, , ,542 Dominated Dominated Etanercept 72, , ,977 14, ,900 Infliximab 134, , , , , Alternative HAQ score rebound assumptions (naïve population) A key assumption in the model is that upon treatment discontinuation patients HAQ rebounds to the baseline level, and subsequently deteriorates in line with the natural progression of HAQ. The ERG believes there is significant structural uncertainty around this assumption which was not sufficiently explored in the MS. The manufacturer s model allowed for a sensitivity analysis in which HAQ was assumed to rebound to the point where patients would have been had they remained on conventional management i.e. the point on the natural progression line for patients who received no biologic treatment. This is considered by the ERG to be an important scenario, as it represents a worst case scenario for HAQ rebounding. Although the model allowed for this analysis, the results for this scenario were not reported in the MS. This analysis was therefore re-run by the ERG. The results are reported in Table

116 Table 47. Probabilistic results for model assuming HAQ rebounds to natural progression ("worst case scenario"; anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies(baseline) Golimumab 62, , ,266 24,266 13,335 Adalimumab 64, , ,610 Dominated Dominated Ustekinumab 70, , ,500 Dominated Dominated Etanercept 72, , ,937 74, ,900 Infliximab 135, , , , ,032 Assuming a worst case scenario for HAQ rebound resulted in a reduction in the total QALYs associated with each of the biologic treatments, including ustekinumab, by around 1 QALY. Costs were unaffected. The treatment rankings remained unchanged, with ustekinumab dominated by golimumab. Looking at the ICERs vs. conventional management, it can be seen that all of the ICERs increased, with ustekinumab s ICER increasing from 23,508 to 41,500/QALY. These results show that the assumption regarding the point of HAQ rebound has a significant effect on the results. It is important to highlight that as well as there being uncertainty around the value to which HAQ rebounds to at treatment withdrawal, there is additional uncertainty around the speed at which HAQ may be assumed to rebound to this level. The manufacturer assumed that HAQ would immediately rebound to the baseline score upon treatment discontinuation. It may be that HAQ scores would gradually worsen over a period of time prior to treatment withdrawal, especially in cases of withdrawal due to waning efficacy. Due to time limitations the ERG could not run additional analyses to consider alternative speeds of withdrawal. However, the ERG believes that this scenario would again increase the ICERs making all of the treatments less cost-effective options HAQ score changes from ERG NMA (naïve population) For the HAQ score changes from baseline per PsARC responder/non responder, the manufacturer derived values for the anti-tnfα treatments from a previous NMA conducted by Yang et al. 24, and assumed that results for conventional management and ustekinumab could be taken straight from the PSUMMIT 1 and 2 trial results. The ERG believes there are limitations with this assumption. The ERG therefore re-ran the Yang NMA, including data on HAQ change per PsARC responder/non- 116

117 responder for ustekinumab from the weight-based PSUMMIT trial results. These data were then used to run two additional analyses on the decision model: one using results from the updated NMA using 12 week data from the PSUMMIT trials, and one using 24 week trial data. The results of these analyses are presented in Table 48 and Table 49. In both analyses the overall costs and QALYs did not vary significantly for any of the treatments. The ICERs for etanercept and infliximab were reduced, but remained well above the 20,000-30,000 per QALY threshold. Ustekinumab remained dominated in both analyses, and the ICER for ustekinumab vs. conventional management did not alter significantly from the baseline value of 23,508/QALY. Table 48. Probabilistic results for model using HAQ score change results from updated Yang NMA using 12-week PSUMMIT trial data (anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies Golimumab 62, , ,351 13,351 13,335 Adalimumab 64, , ,616 Dominated Dominated Ustekinumab 70, , ,140 Dominated Dominated Etanercept 72, , , , ,900 Infliximab 134, , , , ,

118 Table 49. Probabilistic results for model using HAQ score change results from updated Yang NMA using 24-week PSUMMIT trial data (anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies Golimumab 62, , ,352 13,352 13,335 Adalimumab 64, , ,652 Dominated Dominated Ustekinumab 70, , ,987 Dominated Dominated Etanercept 72, , ,889 98, ,900 Infliximab 134, , , , , Time horizon (naïve population) In previous submissions, a range of time horizons have been considered when conducting additional analyses. The 52 year time horizon adopted in the manufacturer s model is longer than that used in the previous submissions: both TA119 and TA220 adopted 40 year times horizons. In this section four different time horizons have been considered: 5, 10, 20 and 40 years. The ICER results are presented in Table 50, and the pair-wise comparisons with conventional management are presented in Table 51. Alternative time horizons, ICER vs. conventional management strategy results (anti-tnf naive population)full results for each of the analyses can be found in appendix Error! Reference source not found.. 118

119 In all analyses ustekinumab produced the fewest QALYs (excluding conventional management) and was dominated by golimumab. For ustekinumab the ICER vs. conventional management was highest when a 5 year time horizon was adopted (reaching over 55,000/QALY). This value reduced with each extended time horizon, with the ICER only falling below the 30,000/QALY threshold with a time horizon of 20 years or more. This is a result of the fact that, relative to conventional management, patients on ustekinumab incur greater costs in the short-term, and more QALYs in the long-run. Table 50. Alternative time horizons, ICER results (anti-tnfα naive population) Technologies Base case (52 year time horizon) ICER (cost per additional QALY, compared to next best non-dominated alternative) 5 year time horizon 10 year time horizon 20 year time horizon 40 year time horizon Golimumab 13,335 29,783 21,890 15,115 13,338 Adalimumab Dominated Dominated Dominated Dominated Dominated Ustekinumab Dominated Dominated Dominated Dominated Dominated Etanercept 109,900 63,590 75,599 96, ,400 Infliximab 321, , , , ,561 Table 51. Alternative time horizons, ICER vs. conventional management strategy results (anti-tnf naive population) Technologies Base case (52 year time horizon) 5 year time horizon ICER vs. conventional management strategies 10 year time horizon 20 year time horizon 40 year time horizon Golimumab 13,335 29,783 21,890 15,115 13,338 Adalimumab 17,716 38,505 28,637 20,007 17,728 Ustekinumab 23,508 55,029 38,685 26,545 23,509 Etanercept 16,942 34,173 26,393 18,978 16,942 Infliximab 40,597 58,238 45,921 36,418 38, Week 24 vs. 12 as the PsARC response assessment time point (naïve population) In previous submissions, response to treatment in terms of PsARC response has been assumed to occur at week 12. For ustekinumab, PsARC response was assumed to be assessed at week 24 (see section 5.3.3). The ERG s clinical advisor stated that it is plausible that all treatments would in fact be 119

120 assessed at 24 weeks. A scenario analysis was run applying a 24 week PsARC assessment time point for all treatments. It should be noted that 24 week PsARC response for all anti-tnfα treatments was assumed to be equal to week 12 results obtained from the manufacturer s NMA. This was due to the fact that there was insufficient evidence available to derive 24 week response results for the anti-tnfα s. Thus using a 24 week assessment time point does not actually change the proportion of patients kept on treatment for the anti-tnfα s, but rather only means that patients who would have been withdrawn to conventional management at week 12 stay on treatment for an additional cycle (and thus retain higher HAQ and PASI scores for one additional cycle). The results of this analysis are presented in Table 52. This alternative assumption has little effect on the ICER vs. the next best alternative for ustekinumab, which remains dominated by golimumab. Comparing the ICER vs. conventional management results to the base case results (table 43, section 6.2), it can be seen that the ICERs for all treatments have increased, with ustekinumab s increasing significantly from 23,508 to 30,495. Table 52. Probabilistic results for model using week 24 weeks as the PsARC assessment time point for all treatments (anti-tnfα naïve population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 31, strategies Golimumab 62, , ,666 15,666 13,335 Adalimumab 69, , ,687 Dominated Dominated Ustekinumab 70, , ,495 Dominated Dominated Etanercept 75, , ,746 51, ,900 Infliximab 132, , ,666 Dominated 321,032 Since the exact time point at which patients may be expected to be assessed for initial response appears to be subject to uncertainty, a further sensitivity analysis was conducted assuming that all patients on treatment would be assessed for response at 12 weeks. These results are reported in appendix Again this alternative assumption had little impact on the results Inclusion of the cost of phototherapy in the PASI-related cost estimate (naïve population) 120

121 A sensitivity analysis was run including the cost of phototherapy in the estimate for the PASI-related cost (see section for a discussion). It is expected that only a minority of patients would require phototherapy as part of their psoriasis treatment. This analysis therefore represents an upper bound for the expected PASI-related costs. The results are presented in Table 53. Including the cost of phototherapy in the analysis significantly increases the total costs for all treatments by around 22,000, with the total QALYs remaining unchanged. Since the increase in cost is fairly similar between the different treatments there is little change in the overall cost-effectiveness results; ustekinumab remains dominated. Table 53. Probabilistic results for model with cost of phototherapy included in the PASI-related cost estimate (anti-tnfα naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 57, strategies Golimumab 84, , ,196 12,196 13,335 Adalimumab 86, , ,476 Dominated Dominated Ustekinumab 92, , ,455 Dominated Dominated Etanercept 94, , , , ,900 Infliximab 155, , , , , The ERG s preferred base case for anti-tnf naïve population For the anti-tnfα naïve population, the ERG constructed a preferred base case. The preferred base case consisted of two changes applied to the manufacturer s corrected model: 1. The manufacturer s ITT NMA results were used instead of their weight based NMA results, for all treatments except ustekinumab 90mg (for which results were left as the weight based NMA results). The reasoning behind this choice of data was discussed in section

122 2. HAQ score changes per PsARC responder/non-responder were taken from the results from the updated Yang NMA for all treatments. The results of this analysis are presented in Table 54. The overall costs and QALYs associated with ustekinumab were only marginally affected. The greatest impact was on the total costs and QALYs for golimumab, which both decreased (from 62,794 to 54,534 and from 6.83 QALYs to 6.18 QALYs). This results in adalimumab no longer being dominated by golimumab, which subsequently reduces the incremental ICER for etanercept and infliximab. Ustekinumab remained dominated (but now by adalimumab as opposed to golimumab), and produced the least amount of QALYs of any of the biologics. The ICERs vs. conventional management were not significantly affected. Table 54. ERG's preferred base case (anti-tnf naive population) Total Incremental ICER vs. ICER Base case Technologies baseline Incremental Incremental Costs QALYs Costs QALYs ( /QALYs) ( /QALYs) ICER Conventional management 33, strategies Golimumab 54, , ,663 13,663 13,335 Adalimumab 64, , ,632 43,977 Dominated Ustekinumab 70, , ,246 Dominated Dominated Etanercept 72, , ,963 14, ,900 Infliximab 134, , , , , Anti-TNFα experienced population Where possible and appropriate the same analyses as considered for the anti-tnfα naïve population were run for the experienced population. However, the scenarios concerning data derived from NMA results are not applicable for the anti-tnfα experienced population, since all efficacy data for the anti-tnfα experienced population was derived from the PSUMMIT 2 trial. The following analyses were run for the experienced population: 122

123 1. Efficacy values derived from all available ITT trial results 2. Efficacy values derived from available ITT trial results for ustekinumab 45mg arm only 3. PsARC response assessed at 24 weeks for all 4. PsARC response assessed at 12 weeks for all 5. Including the cost of phototherapy 6. HAQ rebound to natural progression ( worst case scenario ) 7. Alternative time horizons (5, 10, 20, and 40 years) 8. Alternative assumptions regarding sequencing of treatment These analyses are summarized below. For the anti-tnfα experienced population, efficacy parameters were derived from the anti-tnfα experienced subgroup of the PSUMMIT 2 trial, with data restricted to the weight-based dosing population. The manufacturer reported partial results for the ITT PSUMMIT 2 trial results, with PsARC and PASI 75 response rates at week 24 reported in the MS (MS Table 59, section 7.7.1). Two sensitivity analyses were run incorporating this data: the first using all of the available ITT data, the second using only the ITT results for ustekinumab 45mg and leaving the 90mg results as the weightbased results. This second analysis was intended to reflect the assumption that ITT results are suitable for the 45mg arm since all patients, regardless of weight, will be started on this dose, whereas weightbased results are suitable for the 90mg arm, since only patients weighing >100kg will be applicable for this dose. Due to a lack of available variance data, the beta distributions applied to the alternative ITT trial results were left as those given for the weight-based results. In addition, scenarios were run to assess the impact of assuming a worst case scenario for HAQ rebound (i.e. rebound to natural progression); assuming all patients were assessed for response at 12 weeks or 24 weeks; and of including the cost of phototherapy. These results are summarized in Table 55. Full results can be found in Appendix Table 55: Probabilistic results for scenario analyses on the anti-tnfα experienced population Technologies Base case ICER (cost per additional QALY, compared to next best alternative) Model uses all available ITT trial results ITT results for ustekinumab 45mg arm only All PsARC response assessed at week 24 All PsARC response assessed at week 12 Cost of phototherapy included in the PASIrelated cost HAQ rebounds to natural progression Ustekinumab 29,843 29,797 29,889 39,362 32,162 28,670 52,408 Neither of the scenarios using available ITT trial results significantly altered the results. Similarly including the cost of phototherapy in the PASI-related cost estimate does not significantly change the 123

124 overall ICER, as this scenario leads to a similar increase in costs for both the ustekinumab and conventional management arms. Changing the point of assessment so that all are assessed at week 24 or week 12 leads to an increase in the ICER. Increasing the assessment time point for conventional management to 24 weeks leads to those patients receiving an additional cycle of reduced HAQ scores (before they rebound to the baseline score at the defined assessment week), which increases the QALYs associated with conventional management and thereby increases the ICER for ustekinumab. Decreasing the assessment time point for ustekinumab to 12 weeks, means that patients in that arm are more quickly removed to the conventional management arm and therefore the total QALYs for ustekinumab are reduced relative to conventional management. Assuming a worst case scenario for HAQ rebound had the greatest effect on the results, with the ICER increasing to over 50,000/QALY in this instance. Table 56 presents the alternative time horizons for the anti-tnfα experienced populations. Full results can be found in appendix For all of the reduced time horizons the ICER results for ustekinumab are higher than in the base case, with most falling above the 30,000 per QALY threshold. At the 40 year time horizon used in previous submissions the ICER was 29,846. Table 56: Alternative time horizons (anti-tnfα experienced population) Technologies Base case (corrected model, 52 year time horizon) ICER (cost per additional QALY, compared to next best alternative) 5 year time horizon 10 year time horizon 20 year time horizon 40 year time horizon Ustekinumab 29,843 69,139 46,578 32,539 29,846 For the anti-tnfα experienced population, a preferred base-case analysis was not undertaken. The ERG identified four key areas of uncertainty for this population: first, that model parameters were estimated from a small subgroup of trial participants, which was further restricted by the application of the weight based criteria; second, that the treatment effectiveness was derived from a mixed population receiving second-, third- and fourth-line treatments, so not all end of line; third, that the value for HAQ natural progression (which has been identified as a key driver of the model) was derived from an inappropriate population, and is therefore unlikely to be accurate; and finally, that the analysis failed to address the issue of sequencing. Due to time limitations and a lack of available data, the ERG could not fully address these issues. However, using a previous analysis conducted by Rodgers et. al., an exploratory analysis was conducted to highlight the potential impact of issues relating to the sequencing of treatments Sequencing of treatment 124

125 As previously discussed (Section 5.3), the ERG believes there are problems with the manufacturer s analysis of the anti-tnfα experienced population and the lack of consideration given to treatment sequencing. It is clear that the population evaluated as experienced are not all patients who have exhausted anti- TNFα treatments. There is evidence to suggest that after failure of an anti-tnfα agent, the effectiveness of a second anti- TNFα agent is reduced. 1, 2 It is also clear that in clinical practice anti-tnfα are used sequentially. The decision question that has not been addressed is where ustekinumab fits within that sequence. The two analyses presented consider ustekinumab as a first treatment option and a last treatment option. However, as discussed in section 4, there is no clinical evidence to support that the effectiveness of ustekinumab in the experienced population is any greater than the effectiveness of another, yet unused anti-tnfα agent. This section discusses an alternative analysis conducted by the ERG which aims to highlight the impact of this issue. Currently anti-tnfα treatments are given to patients in sequence based on cost (as they are generally assumed to be equally effective) as recommend by NICE. 37, 38 The ERG s clinical advisor suggests that in clinical practice it would not be unusual for patients to receive up to three anti-tnfα treatments. As previously mentioned in section , Rodgers et al 12 attempted a secondary analysis, where the cost-effectiveness analysis was extended to allow sequencing of treatments. An analysis was undertaken where the ICERs for second-line treatments were estimated. Several strategies were presented, where adalimumab, etanercept and infliximab were each assumed to be first-line treatment and the ICER for the two other treatments were estimated as being second-line treatments. These strategies were estimated by adjusting the second-line treatments response and withdrawal rates to account for decreased efficacy and increased risk of withdrawal of second line treatment. The secondary analysis considered two groups of patients: 1. Patients who failed their first-line treatment due to adverse events; and 2. Patients who failed their first-line treatment due to lack of efficacy. Based on clinical literature on the relative risk of failing a second biologic drug compared to failing a first-line drug, 12, 39 Rodgers et al estimated four sets of equations that adjusted the response rates and the withdrawal rates for anti-tnfα experienced patients. These are presented in Appendix Using these equations, Rodgers et al estimated costs and QALYs for adalimumab, etanercept and infliximab as second line treatments. 125

126 ERG sequencing analysis The ERG applied the equations discussed in the previous section to the data presented in the MS results to produce alternative estimates for initial PsARC response and withdrawal rates. These alternative estimates are presented in Appendix The ERG analysis then made several simplifying assumptions. These were: Although the anti-tnfα experienced population in PSUMMIT 2 are a combination of patients who have had 1, 2 or 3 or more previous anti-tnfα, the ERG assumes that they have all failed only 1 previous treatment. In reality, only a subset of the anti-tnfα experienced patients in the PSUMMIT 2 trial, those who have had only one previous anti-tnfα treatment, are suitable for this analysis. However, as the necessary data for this subset of the population were not available, this major simplifying assumption was made in order to undertake the analysis. The characteristics of the anti-tnfα experienced patients in the PSUMMIT 2 trial were the same for all the anti-tnfα experienced patients. Rodgers et al made no distinction between those who had a complete lack of response (an initial non-responder) and those who had a secondary loss of treatment efficacy (those captured in the annual withdrawal rate). This simplifying assumption was also assumed in the ERG s analysis. Rodgers et al assumed that the probabilities of a PASI 75 response in second line treatment would be the same as those for first line treatment. The justification for this was that in the base case model, patients are not withdrawn for failing to obtain a PASI 75 response. This assumption was similarly made in the ERG s analysis. Finally, due to a lack of the appropriate data, only deterministic results were presented Results of ERG sequencing analysis The ERG produced the following estimates for ICERs in second-line treatments, which are based on Table 39 pg 81 of Rodgers et al. 12 Three different scenarios are presented and these tables are presented in Appendix The cost-effectiveness of the treatments is discussed below, at various willingness to pay (WTP) thresholds. The tables present the scenarios where golimumab, adalimumab and etanercept are the only treatments available as first-line treatments. The ERG s clinical advisor confirmed that these treatments are expected to be the first choice of treatment for PsA patients. 126

127 In the first scenario, Scenario 1, the first biologic fails due to inefficacy. For this scenario, the manufacturer s data was used from PSUMMIT2 for ustekinumab and the ERG estimates were used for the other comparators. The cost-effectiveness of the different treatments is explored in Table 57. Table 57: Cost-effective treatments for various WTP thresholds for scenario 1 WTP threshold less than 20,000 WTP threshold less than 30,000 Golimumab was used first line Adalimumab was used first line Etanercept was used first line Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective ICER for Ustekinumab 37,738 37,738 32,818 These results show that the willingness to pay for biologic treatment for an experienced population would need to be greater than 30,000 for ustekinumab to be considered a cost-effective treatment in this population, for scenario 1. In the second scenario, Scenario 2, the first biologic fails due to adverse events. The costeffectiveness of the different treatments is explored in Table 58. Table 58: Cost-effective treatments for various WTP thresholds for scenario 2 WTP threshold less than 20,000 WTP threshold less than 30,000 Golimumab was used first line Adalimumab was used first line Etanercept was used first line Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective ICER for Ustekinumab Dominated Dominated Dominated These results show that ustekinumab is dominated by other treatments regardless of which treatment failed at first-line. The willingness to pay for biologic treatment for an experienced population would need to be greater than 80,000 for another biologic treatment to be considered a cost-effective treatment in this population, for scenario 2. In the third scenario, Scenario 3, the first biologic fails due to inefficacy. For this scenario, the ERG estimates were used for all treatments. The cost-effectiveness of the different treatments is explored in Table 59. Table 59: Cost-effective treatments for various WTP thresholds for scenario 3 127

128 WTP threshold less than 20,000 WTP threshold less than 30,000 Golimumab was used first line Adalimumab was used first line Etanercept was used first line Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective Etanercept is cost-effective Golimumab is cost-effective Golimumab is cost-effective ICER for Ustekinumab Dominated Dominated 54,630 These results show that once again ustekinumab is dominated by other treatments regardless of which treatment failed at first-line, except for the situation where etanercept was used as the first-line treatment. However, the WTP threshold would need to be more than 55,000 for ustekinumab to be deemed cost-effective. As can be seen from these tables, ustekinumab is always either dominated or not the most costeffective, regardless of the scenario and regardless of the first line treatment. However, as mentioned earlier, these analyses were conducted using some very strong assumptions, and the results are subject to significant uncertainty. Although the ERG analysis presented above is more reflective of current practice as the appropriate comparators have now been included, it still does not fully represent current UK practice. This analysis has some major limitations and is presented as a purely an exploratory type of analysis. Some of the issues with the sequencing analysis include: This exploratory analysis only explores second-line treatment and does not allow patients to continue on to a third or fourth line treatment, so is still not reflective of current UK practice. Data to facilitate this type of analysis was unavailable at the time of this report. The analysis makes a similar but opposite assumption to the MS. We assume that effectiveness derived from a mixed population reflects second-line effectiveness, the MS assumes that it reflects end of line effectiveness. Neither assumption is robust. The ERG s clinical advisor expected etanercept and adalimumab to be at the beginning of the sequence, followed by golimumab; infliximab would usually be at the end of the sequence, given the day case hospital costs required making it likely to be the most expensive option. This sequence of treatment was not explored. Given that only second line treatment is assessed, this analysis does not address where in the sequence ustekinumab would fit. This is a short-coming of both the MS and the ERG s exploratory analysis. The ERG s analysis would suggest that ustekinumab is not a costeffective option for second-line treatment however. There are more up-to-date clinical estimates for persistence in anti-tnfα treatments in naïve and experienced patients. For example, the MS describes two registries which have assessed 128

129 both response rates and treatment persistence in anti-tnfα- experienced patients. However, the ERG did not incorporate data from these two registries, due to time constraints. No changes have been made to any of the resource use estimates, which may not be appropriate. 6.4 Budget impact model In their budget impact model, the manufacturer assumed that ustekinumab s market share would be **** ** ***** **** ** ***** ** ** ***** **** ** **** *** ** ** ***** This resulted in a cumulative increase in costs from of ********. The results of the manufacturer s budget impact model are presented in Table 60. Table 60: Estimated budget impact (Table 86, pg 186 of MS) Current treatment pathway *********** *********** *********** *********** ********** Future treatment pathway *********** *********** *********** *********** *********** Budget impact (future current) ******* ******** ******** ******* ******* The ERG s clinical advisor felt that, whilst *** ***** ** ******** ********** ****** ***** ****** was appropriate, the individual market share values appeared to be potentially too low. The ERG therefore conducted a sensitivity analysis, assuming that ustekinumab would have the same market share as the current comparator with the lowest market share i.e. golimumab. This is likely to over-estimate the market share, and therefore represents an upper bound on the estimate of the budget impact. The results of this analysis are presented in Table 61. Table 61: Re-estimated budget impact, assuming ustekinumab has the projected market share of golimumab Current treatment pathway *********** *********** ************ ************ ************ Future treatment pathway *********** *********** ************ ************ ************ Budget impact (future current) ********** ********** ******** ******** ******** Using the ERG market share assumptions, the cumulative increase in costs from are estimated to be **********. This is 10 times the cumulative increase in costs estimated in the MS. 6.5 Conclusions from ERG analyses 129

130 For the anti-tnfα naïve population, none of the ERG s additional analyses resulted in ustekinumab being a cost-effective treatment alternative; ustekinumab was dominated in each analysis (being both more costly and less effective than one of the anti-tnfα treatments), and produced the fewest QALYs of all the biologic treatments. The analyses that had the greatest impact on the results for ustekinumab were: assuming that HAQ rebounds to natural progression, adopting a shorter time horizon; and assuming that treatment response for all arms would be assessed at either week 12 or week 24. In all of these analyses ustekinumab remained dominated, and the ICERs for ustekinumab vs. conventional management were significantly increased: assuming that HAQ rebounds to natural progression at treatment withdrawal increased the ICER from 23,508 to 41,500/QALY; adopting shorter time horizons increased the ICER to 55, 029/QALY using a 5 year time horizon and 38,685/QALY using a 10 year time horizon; and assuming that all treatment response would be assessed at either week 12 or week 24 increase the ICERs to between 26,000-30,000/QALY. The ERG presented a preferred base case for the anti-tnfα naïve population. This combined the use of ITT NMA efficacy results for all treatment arms excluding ustekinumab 90mg, and HAQ score changes derived from an updated version of the Yang NMA. This analysis did not have a significant impact on the results, with the total cost, QALYs and ICER results being generally similar to the base case results. Overall, for the anti-tnfα naïve population the ERG s additional analyses indicate that the manufacturer s base case incremental ICER results are robust, with ustekinumab producing the fewest QALYs of all biologics and remaining dominated in each of the additional analyses. For the anti-tnfα experienced population, three analyses had a significant impact on the results: assuming HAQ rebounds to natural progression, which increased the ICER for ustekinumab vs. conventional management from 28,843 to 52,408; reducing the time horizon to 5 or 10 years, which increased the ICER to 69,578 and 46,578 respectively; and assuming all patients are assessed for treatment response at week 24, which increased the ICER to 39,362. None of the additional analyses significantly reduced the ICER for ustekinumab vs. conventional management. However the ERG has highlighted the limitations in the effectiveness estimates underpinning this analysis. No ERG preferred base case was presented for the anti-tnfα experienced population, as due to time limitations and a lack of data the key uncertainties could not be fully addressed. An exploratory analysis was conducted to highlight issues around the sequencing of anti-tnfα treatment. It should be noted however that this analysis was subject to very strong assumptions, and 130

131 the results are subject to significant uncertainty. The analysis indicated that for second-line treatment, ustekinumab would be either dominated or not the most cost-effective alternative, regardless of which anti-tnfα treatment is assumed to be given as first line treatment. Overall for the anti-tnfα experienced population there remains significant uncertainty around the manufacturer s base case result. Three additional areas of key uncertainty have not been able to be addressed: (1) the fact that model parameters were estimated from a small subgroup of trial participants, which was further restricted by the application of the weight based criteria; (2) the fact that the population used was not restricted to patients receiving end of line treatment; and (3) the fact that the value for HAQ natural progression (which has been identified as a key driver of the model) was derived from an inappropriate population, and is therefore unlikely to be accurate. The ERG was unable to explore these areas of uncertainty, and it is unclear what impact they may have on the results. The ERG conducted a sensitivity analysis on the manufacturer s budget impact model, assuming that ustekinumab would have the same market share as the current comparator with the lowest market share i.e. golimumab. This analysis suggests that the cumulative increase in costs from would be **********, a value 10 times the cumulative increase in costs estimated in the MS. Although this analysis is likely to represent an upper bound on the potential budget impact between , it highlights the sensitivity of the results to the initial assumption of the market share in End of life End of life criteria are not relevant to this evaluation of ustekinumab for PsA. 131

132 8 Overall conclusions 8.1 Anti-TNFα naïve population The short-term estimates of efficacy for all agents against placebo were derived from RCTs of adequate methodological quality and are likely to be reliable. The manufacturer s NMA was robust, with little variation in estimates from the ITT, weight-based, or combined-dose analyses. The decision model structure was appropriate and the modelling met the NICE reference case. Ustekinumab appears to be a more effective treatment than placebo (conventional management) over weeks in terms of both joint (ACR 20/50/70, PsARC) and skin (PASI 75/90) response, and these benefits are likely to persist for at least 52 weeks. However, **** ******** **** **** ********** *** ********** ******** ********** *** ************** *** ********* **** *********** *** *** ****** ** *** ** *** ****** ******** ***** *** **** ***** ** *** *** *** ****** *******. A full probabilistic incremental cost-effectiveness analysis in this same population found both adalimumab and ustekinumab to be dominated. That is, both of these treatments were more costly and less effective when compared with the next most costly alternative. Pairwise comparisons against conventional management found that golimumab, etanercept and adalimumab all had lower pairwise ICERs than ustekinumab. The ERG s clarifications, corrections and additional analyses did not substantially change these results. 8.2 Anti-TNFα experienced population The manufacturer suggested that that ustekinumab provides a novel treatment option when anti-tnfα treatment has failed, and so the relevant comparator in all anti-tnfα experienced patients would be conventional treatment without any biologic component. However their model used evidence derived from a trial population who had experienced anti-tnfα agents but who had not necessarily failed them as a class. Whilst observational evidence suggests diminishing response rates and treatment persistence associated with the sequential use of anti-tnfα agents, there is no robust evidence for the relative efficacy of ustekinumab and anti-tnfs when used as second or later-line therapy. *** *** ******* ******* **** **** ********* ****** *** **** *********** **** *********** ** *** ********* ***** *********** *** ** ******** ** ********* ** ******* **** *** ********** ********* ** ******** ** * ** * * ** * ** * ** **** ********* ****** ***** **** ***** *** ***** ** ******** ******** *** *********** ** ********* *********** ********. 132

133 The ERG tried to address this issue in an exploratory cost-effectiveness analysis incorporating sequential use of anti-tnfs, but this was based on a number of strong assumptions and suboptimal data. 8.3 Implications for research The ERG believes that some uncertainty still remains due to a lack of robust evidence on some key model parameters. Further research is needed into: The natural history of HAQ score change. Rebound to HAQ on withdrawal from treatment. Further evidence is required to identify which scenario is most likely to reflect clinical reality. HAQ and PASI related costs. The limitations of these data were fully discussed in the previous submission and no attempt has been made to address the limitations. A properly powered trial of ustekinumab versus TNFα inhibitor therapy is required. Any such trial should clearly distinguish between prior anti-tnfα experience and anti-tnfα class failure in its selection of participants. 133

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137 46. Office for National Statistics. Population Estimates for UK, England and Wales, Scotland and Northern Ireland, Mid-2011 and Mid [cited /10]. Available from: Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40: Gray A, Clarke P, Rivero O. Estimating the association between SF-36 responses and EQ-5D utility values by direct mapping. In: 1st Franco-British Meeting in Health Economics. CES - HESG Workshop; January 2004; Paris, France January Ara R, Brazier JE. Populating an economic model with health state utility values: moving toward better practice. Value Health 2010;13: Poole CD, Lebmeier M, Ara R, Rafia R, Currie CJ. Estimation of health care costs as a function of disease severity in people with psoriatic arthritis in the UK. Rheumatology (Oxford) 2010;49: AbbVie Limited. Adalimumab (Humira ) Pre-filled Pen, Pre-filled Syringe and Vial. Summary of Product Characteristics (SPC) [cited /10]. Available from: Pfizer Limited. Etanercept (Enbrel ) 25 mg powder and solvent for solution for injection. Summary of Product Characteristics (SPC) [cited /10]. Available from: ution+for+injection/ 53. Merck Sharp & Dohme Limited. Golimumab (Simponi ) 50 mg solution for injection. Summary of Product Charateristics (SPC) [cited Available from: Merck Sharp & Dohme Limited. Infliximab (Remicade ) 100mg powder for concentrate for solution for infusion. Summary of Product Characteristics (SPC) [cited /10]. Available from: or+solution+for+infusion/ 55. Kyle S, Chandler D, Griffiths CEM, Helliwell P, Lewis J, McInnes I, et al. Guideline for anti- TNF-α therapy in psoriatic arthritis. [Erratum appears in Rheumatology (Oxford) 2005;44:569] Rheumatology 2005;44: Available from: Cummins E, Asseburg C, Punekar YS, Shore E, Morris J, Briggs A, et al. Cost-effectiveness of infliximab for the treatment of active and progressive psoriatic arthritis. Value Health 2011;14: U.S. Food and Drug Administration (FDA). Stelara (Ustekinumab) Injection. Efficacy Supplement with Clinical Data to Support. Label.; Available from: 137

138 10 Appendices 10.1 PSUMMIT outcome data for dactylitis, DLQI and SF 36 (provided by manufacturer in points for clarification spreadsheet only) * 138

139 * 139

140 * 140

141 10.2 NMA trial baseline comparison as provided by the manufacturer (PFC, C3, Section 6.7) Table 62: Comparison of baseline characteristics NMA RCTs Study PSUMMIT 1 PSUMMIT 2 Treatment arm Ustekinumab 45 mg Ustekinumab 90 mg Placebo Ustekinumab 45 mg Ustekinumab 90 mg Placebo Age, mean years (SD) 47.1 (12.6) 46.8 (11.8) 47.4 (12.3) 48.0 (11.2) 48.2(12.4) 47.6 (11.2) Sex, % male Race, % Caucasian Weight, mean kg (SD) 87.8 (20.6) 89.8 (21.5) 87.5 (21.7) 89.5 (22.6) 90.2 (21.3) 91.2 (22.3) Duration of PsA, mean years (SD) 6.1 (6.8) 7.0 (7.6) 6.7 (7.5) 8.2 (8.6) 7.2 (7.5) 8.5 (8.5) Duration of PsO, mean years (SD) 14.9 (13.0) 15.5 (12.1) 15.9 (12.8) 15.4 (11.2) 14.8 (12.7) 15.2 (11.8) Treatment history, % use DMARD: 79.5; NSAID: 89.3 DMARD: 78.4; NSAID: 90.6 DMARD: 80.6; NSAID: 87.8 DMARD: 86.4; MTX: 83.5; NSAID: 84.3; corticosteroid: 40.2; immunosuppressive: 15.5; anti-tnf: 60 DMARD: 83.8; MTX: 80.0; NSAID: 81.7; corticosteroid: 29.1; immunosuppressive: 16.2; anti-tnf: 58 DMARD: 88.5; MTX: 86.5; NSAID: 88.5; corticosteroid: 41.3; immunosuppressive: 16.3; anti-tnf: 62 DAS28, mean (SD) 5.1 (0.9) 5.2 (0.9) 5.2 (1.1) 5.6 (1.1) 5.4 (1.0) 5.2 (1.0) PASI score, mean (SD) 11.5 (11.8)* 10.6 (8.5)* 11.7 (10.3)* 13.4 (13.0)* 12.1 (10.3)* 11.3 (9.3)* Swollen Joint Count, mean (SD) 12.5 (7.8) 12.9 (8.3) 15.0 (10.2) 15.0 (9.2) 14.0 (10.9) 13.5 (9.9) Tender Joint Count, mean (SD) 22.2 (13.9) 23.2 (13.7) 25.1 (15.0) 27.2 (15.4) 25.9 (15.5) 23.4 (14.9) Enthesitis, n (%) 142 (69.3) 154 (75.5) 145 (70.4) 72 (69.9) 76 (72.4) 73 (70.2) Dactylitis, n (%) 101 (49.3) 99 (48.5) 96 (46.6) 48 (46.6) 41 (39.0) 38 (36.5) CRP mg/l, mean (SD) 16.9 (17.8) 18.0 (18.0) 15.9 (19.1) 26.6 (35.4) 20.2 (30.6) 15.9 (19.7) Data are number of participants (%) or median (IQR) (COX2=cyclo-oxygenase 2. DIP=distal interphalangeal joint.) 141

142 Adalimumab Trials Etanercept Trials Study ADEPT Genovese et al Mease et al Mease et al Treatment arm Adalimumab Placebo Adalimumab Placebo Etanercept Placebo Etanercept Placebo Age, mean years (SD) 48.6 (12.5) 49.2 (11.1) 50.4 (11.0) 47.7 (11.3) Median 46 Median Sex, % male Race, % Caucasian Weight, mean kg (SD) 86.0 (20.6) 85.5 (16.5) 91.5 (22.5) 88.5 (21.1) Median 90.7 Median 81.4 NR Duration of PsA, mean years (SD) 9.8 (8.3) 9.2 (8.7) 7.5 (7.0) 7.2 (7.0) Median 9 Median Duration of PsO, mean years (SD) 17.2 (12.0) 17.1 (12.6) 18.0 (13.2) 13.8 (10.7) Median 19 Median Treatment history, % use Mean (SD) DMARD: 1.5 (1.2) Mean (SD) DMARD: 1.5 (1.2) DMARD: 100; MTX: 80.4; NSAID: 90.2; corticosteroid: 19.6 DMARD: 100; MTX: 79.6; NSAID: 98; corticosteroid: 30.6 NSAID: 100 NSAID: 100 NSAID: 100 NSAID: 100 DAS28, mean (SD) NR NR NR NR PASI score, mean (SD) 7.4 (6.0)* 8.3 (7.2)* NR SJC, mean (SD) 14.3 (12.2) 14.3 (11.1) 18.2 (10.9) 18.4 (12.1) median (range) 10.1 (2.3-30)* median (95%CI) 14.0 (8, 23) median (range) 6.0 ( )* NR median (95%CI) 14.7 (7, 24) NR TJC, mean (SD) 23.9 (17.3) 25.8 (18.0) 25.3 (18.3) 29.3 (18.1) median (95%CI) 22.5 (11, 32) median (95%CI) 19.0 (10, 39) NR mean sites (SD) 0.9 mean sites (SD) 1.0 Enthesitis, n (%) NR (1.2) (1.3) NR NR Dactylitis, n (%) NR mean score (SD) 2.9 (5.1) mean score (SD) 2.5 (4.3) NR NR CRP mg/l, mean (SD) mg/dl 1.4 (2.1) mg/dl 1.4 (1.7) mg/dl 1.0 (1.0) mg/dl 1.6 (1.7) median (95%CI) 14 (7, 28) median (95%CI) 12 (8, 22) NR 142

143 Adalimumab Trials Etanercept Trials Study ADEPT Genovese et al Mease et al Mease et al Treatment arm Adalimumab Placebo Adalimumab Placebo Etanercept Placebo Etanercept Placebo Age, mean years (SD) 48.6 (12.5) 49.2 (11.1) 50.4 (11.0) 47.7 (11.3) Median 46 Median Sex, % male Race, % Caucasian Weight, mean kg (SD) 86.0 (20.6) 85.5 (16.5) 91.5 (22.5) 88.5 (21.1) Median 90.7 Median 81.4 NR Duration of PsA, mean years (SD) 9.8 (8.3) 9.2 (8.7) 7.5 (7.0) 7.2 (7.0) Median 9 Median Duration of PsO, mean years (SD) 17.2 (12.0) 17.1 (12.6) 18.0 (13.2) 13.8 (10.7) Median 19 Median Treatment history, % use Mean (SD) DMARD: 1.5 (1.2) Mean (SD) DMARD: 1.5 (1.2) DMARD: 100; MTX: 80.4; NSAID: 90.2; corticosteroid: 19.6 DMARD: 100; MTX: 79.6; NSAID: 98; corticosteroid: 30.6 NSAID: 100 NSAID: 100 NSAID: 100 NSAID: 100 DAS28, mean (SD) NR NR NR NR PASI score, mean (SD) 7.4 (6.0)* 8.3 (7.2)* NR SJC, mean (SD) 14.3 (12.2) 14.3 (11.1) 18.2 (10.9) 18.4 (12.1) median (range) 10.1 (2.3-30)* median (95%CI) 14.0 (8, 23) median (range) 6.0 ( )* NR median (95%CI) 14.7 (7, 24) NR TJC, mean (SD) 23.9 (17.3) 25.8 (18.0) 25.3 (18.3) 29.3 (18.1) median (95%CI) 22.5 (11, 32) median (95%CI) 19.0 (10, 39) NR mean sites (SD) 0.9 mean sites (SD) 1.0 Enthesitis, n (%) NR (1.2) (1.3) NR NR Dactylitis, n (%) NR mean score (SD) 2.9 (5.1) mean score (SD) 2.5 (4.3) NR NR 143

144 CRP mg/l, mean (SD) mg/dl 1.4 (2.1) mg/dl 1.4 (1.7) mg/dl 1.0 (1.0) mg/dl 1.6 (1.7) median (95%CI) 14 (7, 28) median (95%CI) 12 (8, 22) NR Golimumab Trials Infliximab Trials Study GO-REVEAL IMPACT IMPACT 2 RESPOND* Treatment arm Golimumab 50 mg Golimumab 100 mg Placebo Infliximab Placebo Infliximab Placebo Infliximab + MTX MTX Age, mean years (SD) 45.7 (10.7) 48.2 (10.9) 47.0 (10.6) 45.7 (11.1) 45.2 (9.7) 47.1 (12.8) 46.5 (11.3) 40.1 (12.3) 42.3 (10.5) Sex, % male Race, % Caucasian NR NR Weight, mean kg (SD) NR NR NR BMI kg/m (5.1) BMI kg/m (5.3) Duration of PsA, mean years (SD) 7.2 (6.8) 7.7 (7.8) 7.6 (7.9) 11.7 (9.8) 11.0 (6.6) 8.4 (7.2) 7.5 (7.8) 2.8 (2.6) 3.7 (2.7) Duration of PsO, mean years (SD) NR 16.9 (10.9) 19.4 (11.6) NR NR Treatment history, % use DMARD / NSAID: 100 DMARD / NSAID: 100 DMARD / NSAID: 100 DMARD: 100 DMARD: 100 DMARD / NSAID: 100 DMARD / NSAID: 100 DMARD:22.8; NSAID: 68.4; corticosteroid: 15.8 DMARD: 15.5; NSAID: 58.8; corticosteroid: 15.5 DAS28, mean (SD) 4.4 (1.1) 4.3 (1.0) 4.3 (1.0) 5.5 ( (1.0) NR 5.2 (1.1) 5.1 (1.2) PASI score, mean (SD) 9.8 (8.6) 11.1 (9.5) 8.4 (7.4) 5.1 (5.9) 4.2 (5.8) 11.4 (12.7) 10.2 (9.0) 8.3 (10.2) 11.6 (12.5) SJC, mean (SD) 14.1 (11.4) 12.0 (8.4) 13.4 (9.8) 14.6 (7.5) 14.7 (8.2) 13.9 (7.9) 14.4 (8.9) 15.1 (10.1) 14.3 (9.5) TJC, mean (SD) 24.0 (17.1) 22.5 (15.7) 21.9 (14.7) 23.7 (13.7) 20.4 (12.1) 24.6 (14.1) 25.1 (13.3) 21.1 (13.3) 20.1 (11.2) Enthesitis, n (%) 109 (75.0) 115 (79.0) 88 (78.0) 13 (25.0) 13 (25.0) 42 (42.0) 35 (35.0) mean sites (SD) 2.4 (3.0) mean sites (SD) 2.7 (2.8) Dactylitis, n (%) 50 (34.0) 49 (34.0) 38 (34.0) 25 (48.0) 26 (50.0) 40 (40.0) 41 (41.0) mean digits (SD) 3.3 (4.2) mean digits (SD) 3.1 (4.2) CRP mg/l, mean (SD) mg/dl 1.3 (1.6) mg/dl 1.4 (1.8) mg/dl 1.3 (1.6) 21.7 (27.0) 31.1 (38.1) 19 (21) 23 (34) NR 144

145 *The infliximab RESPOND trial was not included in the mixed treatment comparison because the comparator was MTX. As all other trials used placebo, it was not possible to integrate these data. 145

146 10.3 ERG NMA compared with MS NMA The lack of head-to-head trials facilitates the need for indirect comparisons, but also hinders the ability to assess consistency of the results obtained PsARC response In an attempt to validate the model developed by the manufacturer the ERG utilised the Winbugs model previously developed by them for use in TA199. The ERG model was a common-effects metaanalysis, which incorporated the same 12 to 16 week outcome data utilised by the manufacturer. The model is not a perfect fit for the data and due to time limitations no attempts has been made to account for the correlation present in the three arm trials. However, despite the limitations the model allows us to assess the comparability of the results. If these had been found to be significantly different then further analysis may have been warranted. However, as demonstrated in table 63 the results obtained are reasonably consistent and the ERG felt no need to further develop this basis model. Table 63: MTC comparison manufacturer s data compared with ERG reanalysis for PsARC response Analyses Treatment PsARC response Mean (SD) Weight-based MS estimate ***** ****** Placebo ERG estimate ***** ****** MS estimate **** ****** Infliximab ERG estimate **** ****** MS estimate **** ****** Etanercept ERG estimate ***** ****** MS estimate Adalimumab **** ****** ERG estimate ***** ****** MS estimate Golimumab **** ****** ERG estimate **** ****** MS estimate Ustekinumab 45mg **** ****** ERG estimate **** ****** MS estimate ERG estimate Ustekinumab 90 mg **** ****** **** ****** The code for this model is available in Rodgers et al HAQ conditional on PsARC In addition to validating the NMA on PsARC response, previous modelling undertaken by the ERG allowed the estimation of HAQ conditional on PsARC using the same model as previous submission. In the MS base case they elected to use the estimates obtained from this model reported in Yang et al. 146

147 together with trial based estimates obtained from PSUMMIT 1 & 2. Using this model allowed the ERG to undertake sensitivity analysis around this estimate. Table 64: ERG HAQ PsARC response compared with MS estimate Analyses Treatment HAQ change from baseline PsARC responders Mean (SD) HAQ change from baseline PsARC non-responders Mean (SD) MS Yang (0.044) (0.029) Placebo ERG estimate ******* ******* * MS Yang Infliximab (0.709) (0.079) ERG estimate ******* ******* ******* ******* MS Yang Etanercept (0.091) (0.099) ERG estimate ******* ******* ******* ******* MS Yang Adalimumab (0.065) (0.068) ERG estimate ******* ******* ******* ******* MS Yang (0.085) (0.088) Golimumab ERG estimate ******* ******* ***** ******* MS PSUMMIT trials (0.05) (0.05) Ustekinumab 45mg ERG estimate ************* ****** ****** MS PSUMMIT trials ( (0.10) ERG estimate Ustekinumab 90 mg ******* ******* ****** ******* The code for this model is available in Rodgers et al. 147

148 10.4 ERG re-calculated baseline HAQ and PASI score Table 65 ERG baseline PASI estimate for anti-tnf naive population Study/ Trial ADEPT Genovese 2007 GO-Reveal IMPACT 1 Source used Treatment arm Baseline PASI (P) Mean Standard error Number of participants measured (N) Rodgers et al. Adalimumab Numbers of participants measured in each arm represent those 2011, p16 12 Placebo stated to be evaluable for PASI in Rodgers et al MS - NR No data reported. Kavanaugh et Placebo Number of participants measured taken from golimumab STA al Golimumab 50mg manufacturer's submission, table B6, p48. N*P Golimumab 100mg Rodgers et al. 2011, p16 12 Infliximab Numbers of participants measured in each arm represent those stated to be evaluable for PASI in Rodgers et al. Rodgers based their analysis on only those patients with a PASI Placebo score >2.5, as opposed to the values reported in the manufacturer's submission which were based on the whole trial population, which included patients with no psoriasis, and were therefore significantly lower than these reported values [infliximab 5.1, placebo 4.2]. Notes IMPACT 2 Mease 2000 Rodgers et al. Infliximab Numbers of participants measured in each arm represent those 2011, p16 12 stated to be evaluable for PASI in Rodgers et al Placebo Rodgers et al. 2011, p16 12 Etanercept 10.1 Range: Median PASI and range reported. Numbers of participants measured in each arm represent those stated to be evaluable for PASI in Rodgers et al Placebo 6 Range:

149 Study/ Trial Mease 2004 PSUMMIT 1 PSUMMIT 2 anti- TNFα naïve subgroup Source used Treatment arm Baseline PASI (P) Mean Standard error Number of participants measured (N) Rodgers et al. - NR No data reported. 2011, p16 12 MS Ustekinumab 45 mg Assumed number of participants measured in each arm was Ustekinumab 90 mg equal to the number of patients with psoriasis on 3% body surface area, given in manufacturer's submission, table 13, p39. Placebo MS response to points of clarification (2nd) p14. Ustekinumab 45 mg ***** ****** ** ****** Assumed number of participants measured in each arm was Ustekinumab 90 mg ***** ***** ** ***** equal to the number of patients with psoriasis on 3% body surface area, given in manufacturer s response to ERGs points Placebo ***** ***** ** ***** of clarification, p14. N*P Total ( N, N*P) Weighted Average ( N*P/ N) Weighted Average excluding Mease 2000 (median score) Value used in manufacturer's model Value used in golimumab STA (TA220, p122; methods unclear) 9.9 Value used in TA119 (Rodgers et al. Table 33, p65; clinical opinion) 7.5 Notes 149

150 Table 66. Standard error and standard deviations for ERG baseline PASI estimates (anti-tnfα naive population) Excluding medians from the weighted mean Including medians in the weighted mean Standard deviation: Standard error: Table 67. ERG baseline PASI estimate for the anti-tnfα experienced population Study/ Trial Source used Treatment arm PSUMMIT 2 anti-tnfα experienced subgroup MS response to points of clarification (2nd) p14. Baseline PASI (P) Mean Standard error Number of participants measured (N) N*P Notes Ustekinumab 45 mg Ustekinumab 90 mg ***** **** ****** ****** ** ** ****** ***** Assumed number of participants measured in each arm was equal to the number of patients with psoriasis on 3% body surface area, given in manufacturer s response to ERGs points of clarification, p14. Placebo ***** ***** ** ***** Total ( N, N*P) Weighted Average ( N*P/ N) Value used manufacturer's model

151 Table 68. Standard deviation and standard error for ERG baseline PASI estimate (anti-tnfα experienced population) Standard deviation: Standard error: Table 694: ERG baseline HAQ estimate for the anti-tnfα naive population Study/ Trial Source used Treatment arm Baseline HAQ (H) Mean Standard error Number of participants measured (N) H*P ADEPT Rodgers et al. 2011, p16 12 Adalimumab Placebo Genovese 2007 Rodgers et al. 2011, p16 12 Adalimumab Placebo GO-Reveal Kavanaugh et al. Placebo Golimumab 50mg Golimumab 100mg

152 Study/ Trial Source used Treatment arm Baseline HAQ (H) Mean Standard error Number of participants measured (N) ADEPT Rodgers et al. 2011, p16 12 Adalimumab H*P Placebo Genovese 2007 Rodgers et al. 2011, p16 12 Adalimumab Placebo GO-Reveal Kavanaugh et al Placebo Golimumab 50mg Golimumab 100mg IMPACT 1 Rodgers et al. 2011, p16 12 Infliximab Placebo IMPACT 2 Rodgers et al. 2011, p16 12 Infliximab Placebo

153 Study/ Trial Source used Treatment arm Baseline HAQ (H) Mean Standard error Mease 2000* Rodgers et al. 2011, p16 12 Etanercept th, 75th percentile 0.9, 1.6 Placebo th, 75th percentile 0.8, 1.6 Number of participants measured (N) H*P Mease 2004* Rodgers et al. 2011, p16 12 Etanercept 1.1 NR Placebo 1.1 NR PSUMMIT 1* Manufacturer's submission Ustekinumab 45 mg 1.25 IQR: 0.75 to Ustekinumab 90 mg 1.25 IQR: 0.75 to Placebo 1.25 IQR: 0.75 to PSUMMIT 2 anti-tnfα naïve subgroup* MS response to ERGs points of clarification, p14 Ustekinumab 45 mg **** **** **** ** **** ** ***** Ustekinumab 90 mg **** **** **** ** **** ** ***** Placebo **** **** **** ** *** ** ***** Total ( N, N*P) Weighted Average ( N*P/ N) Weighted Average ( N*P/ N) excluding median values (Mease 2000 & 2004, PSUMMIT 1 and 2) Value used in manufacturer's model 0.84 Value used in golimumab STA (TA220, Table B21, p122; methods unclear)

154 Value used in TA119 (Rodgers et al. Table 33, p65; mean of RCTS, excluding median values)

155 Table 70. Standard deviation and standard error for ERG baseline HAQ estimates (anti-tnfα naive population) Excluding medians from the weighted mean Including medians in the weighted mean Standard deviation: Standard error: Table 71. ERG baseline HAQ score for anti-tnf experienced population Study/ Trial Source used Treatment arm Baseline HAQ (H) Median Inter-quartile range Number of participants measured (N) H*P PSUMMIT 2 anti- TNFα experienced subgroup Manufacturer's response to ERGs points of clarification, p14 Ustekinumab 45 mg **** **** ** **** ** **** Ustekinumab 90 mg **** **** ** **** ** ***** Placebo **** **** ** **** ** ***** Nb: numbers in each arm taken from denominators in table 20, p53 of manufacturer's submission Total ( N, N*P) Weighted Average ( N*P/ N) Value used in manufacturer's model

156 Table 72. Standard deviation and standard error for ERG baseline HAQ estimate (anti-tnfα experienced population) Standard deviation: Standard error:

157 10.5 ERG additional analyses Efficacy results derived from ITT trial data where possible (anti-tnfα experienced population) Table 73. Probabilistic results for model using all available ITT trial results (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 36, Ustekinumab 77, , ,797 29,843 Table 74. Probabilistic results for model using all ITT trial results for ustekinumab 45mg only (anti- TNFα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 35, Ustekinumab 77, , ,889 29, HAQ rebound to natural progression (anti-tnfα experienced population) Table 75. Probabilistic results for model assuming HAQ rebounds to natural progression ("worst case scenario"; anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 36, Ustekinumab 77, , ,408 29,

158 Alternative time horizons Table 76. Probabilistic results for model using 5 year time horizon (anti-tnfα naive population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS ICER vs. next best alternative Base case ICER Conventional management 9, strategies Golimumab 28, , ,783 29,783 13,335 Adalimumab 29, , ,505 Dominated Dominated Ustekinumab 34, , ,173 Dominated Dominated Etanercept 35, ,029 63, ,900 Infliximab 58, , , , ,032 Table 77. Probabilistic results for model using 5 year time horizon (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 9, Ustekinumab 38, , ,139 29,

159 Table 78. Probabilistic results for model using 10 year time horizon (anti-tnfα naive population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS ICER vs. next best alternative Base case ICER Conventional management 15, strategies Golimumab 41, , ,890 21,890 13,335 Adalimumab 43, , ,637 Dominated Dominated Ustekinumab 49, , ,685 Dominated Dominated Etanercept 50, , ,393 75, ,900 Infliximab 82, , , , ,032 Table 79. Probabilistic results for model using 10 year time horizon (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 16, Ustekinumab 53, , ,578 29,843 Table 80. Probabilistic results for model using 20 year time horizon (anti-tnfα naïve population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS ICER vs. next best alternative Base case ICER Conventional management 24, strategies Golimumab 54, , ,115 15,115 13,335 Adalimumab 55, , ,007 Dominated Dominated Ustekinumab 61, , ,545 Dominated Dominated Etanercept 63, , ,978 96, ,900 Infliximab 105, , , , ,

160 Table 81. Probabilistic results for model using 20 year time horizon (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 26, Ustekinumab 67, , ,539 29,843 Table 82. Probabilistic results for model using 40 year time horizon (anti-tnfα naive population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS ICER vs. next best alternative Base case ICER Conventional management 32, strategies Golimumab 62, , ,338 13,338 13,335 Adalimumab 63, , ,728 Dominated Dominated Ustekinumab 69, , ,509 Dominated Dominated Etanercept 71, , , , ,900 Infliximab 128, , , , ,032 Table 83. Probabilistic results for model using a 40 year time horizon (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 35, Ustekinumab 76, , ,846 29,

161 Week 12 vs. 24 PsARC assessment time point Table 84. Probabilistic results for model using week 12 weeks as the PsARC assessment time point for all treatments (anti-tnfα naïve population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS ICER vs. next best alternative Base case ICER Conventional management 33, strategies Golimumab 62, , ,360 13,360 13,335 Adalimumab 64, , ,750 Dominated Dominated Ustekinumab 68, , ,427 Dominated Dominated Etanercept 72, , , , ,900 Infliximab 134, , , , ,032 Table 85. Probabilistic results for model using week 12 weeks as the PsARC assessment time point for all treatments (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 35, Ustekinumab 70, , ,162 29,843 Table 86. Probabilistic results for model using week 24 weeks as the PsARC assessment time point for all treatments (anti-tnfα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 34, Ustekinumab 77, , ,362 29,

162 Including the cost of phototherapy Table 87. Probabilistic results for model including the cost of phototherapy in the PASI-related cost (anti- TNFα experienced population) Technologies Total Incremental Costs QALYs Costs QALYs ICER vs. CMS Base case ICER Conventional management strategies 64, Ustekinumab 103, , ,670 29,

163 10.6 Natural history of patients with psoriatic arthritis eligible for biologic therapy (Rogders et al Appendix 14) This appendix has been copied from a previous MTA submission to aid understanding re the derivation of 28 day HAQ score change a major driver of the model. The ERG feel that this parameter is uncertain and further research is required to reduce this uncertainty Introduction The decision model estimates long-term outcomes in terms of HAQ and PASI for patients with and without biologic therapy. As NICE would not recommend a placebo, the comparator is NH, a counterfactual state where no biologic therapy is available. Previous decision models of PsA have estimated what the change in HAQ would have been if no biologic therapy had been offered. Bansback et al.177 used data from a long-term, open-label follow-up of 35 patients who had originally been entered in a clinical trial comparing MTX with and without ciclosporin in the Leeds Musculoskeletal Unit. These patients had previously not been controlled on MTX alone. In total, 24 responses were received to a postal questionnaire. At the end of the trial, their mean HAQ was After some 4.2 years follow-up (it is not stated if this is the maximum, minimum, mean or median), mean HAQ was 1.4, a mean annual change of 0.07 (SD 0.03). Possible limitations of this analysis for the purposes of the current decision modelling are: Small sample size. Possibility of selection bias among responders to the postal questionnaire. Patients have failed one DMARD (MTX), rather than two as required by NICE guidelines. It is not stated in the paper if patients met the current guideline criteria for initiating biologics in PsA (three tender and three swollen joints). No other published estimates were found of long-term outcomes in patients who had been uncontrolled on DMARDs. Morgan et al.231 investigated outcomes in patients enrolled in NOAR between 1990 and 1994, with and without psoriasis. The median HAQ score for n = 79 patients with inflammatory polyarthritis plus psoriasis at baseline was [interquartile range (IQR) 0.25 to 1.375] and was 0.75 (IQR to 1.75) at 5 years, indicating a very small annual change in HAQ (0.025 per year). However, these data are not in patients who are necessarily uncontrolled with DMARD. The NOAR data was reanalysed by the ARC Epidemiology Unit at the University of Manchester to estimate HAQ change in patients who are uncontrolled (with three tender joints three swollen joints) and have previously tried two or more DMARDs. This paper describes how HAQ progression was estimated and used in the decision model. 163

164 Methods The NOAR database is a primary care-based cohort of patients with inflammatory polyarthritis. NOAR has been recruiting patients since Not all variables were assessed and recorded at follow-ups for the cohort registered between 1995 and 2000 and so this cohort was excluded from the analyses. HAQ and other outcomes are recorded at annual follow-ups. Baseline is the visit when the patient was first seen by the research nurse to be included into the NOAR register. NOAR did not record a diagnosis of PsA. As patients with inflammatory polyarthritis plus psoriasis are thought to have similar prognosis to those who are seronegative without psoriasis, patients who were RFnegative at baseline were selected from the NOAR register. At each time point (baseline, year 1, year 2, year 3 and year 5) we evaluated whether patients fulfilled the following criteria: three tender joints (TJC) and three swollen joints (SJC) using the 51-joint count previous use of two or more DMARDs, implemented as all patients who had used two DMARDs or were still using two DMARDs for at least 30 days. These criteria are intended to select patients who would be eligible for use of biologics. The BSR recommend that the 78 TJC and 76 SJC is used, 149 but this was not available in NOAR. The annual change in HAQ over the following 2 years was estimated from the time when a patient first fulfilled the criteria. The total score is based on the inclusion of all patients who fulfilled the criteria at different time points and their change in HAQ score since that time point. For example, from the data in Table 67, there were 216 patients in total: 24 patients at baseline, + 50 patients at year 1, + 46 patients at year 2, and + 52 patients at year 3 and + 44 patients at year 5. It is therefore possible that some patients are accounted for multiple times in the total score Results The results are shown in Table 67. For all patients regardless of when they first became eligible for biologics, the data suggests that there was little change in HAQ over 2 years (mean annual change 0.00, SD 0.228) (n = 216). For patients who met the eligibility criteria at baseline, their mean HAQ score at baseline was 1.55 (SD 0.84), and the mean change in HAQ over 2 years was per year (SD 0.279) (n = 24). These patients had a median of 2.72 years from first onset of symptoms of disease until entry to NOAR. As a higher HAQ score represents worse disability, a negative change is an improvement. For patients who met the eligibility criteria 3 years after entry to NOAR, the mean change in HAQ over 2 years was per year (0.228) (n = 52), i.e. a worsening of disability. These patients had a 164

165 median of 3.9 years from first onset of symptoms of disease until meeting the eligibility criteria for biologics. The following sensitivity analyses were carried out: Patients who (had) used a DMARD/DMARDs for > 90 days at time of assessment were included in the analyses. In addition, patients who had used two or more DMARDs for at least 30 days were also included in the analyses. All patients who had used a DMARD/DMARDs or were still using a DMARD/DMARDs, irrespective of duration and number of DMARDs, were eligible at that time point. Tender and swollen joints assessed using the 28-joint count (DAS28). Patients with a nurse assessment of psoriasis as baseline. The same trends observed in the primary analysis were also found in the sensitivity analyses. Change in HAQ for all patients who had used two DMARD(s) or were still using two DMARDs for at least 30 days Years from baseline until patient first fulfils criteria Median symptom duration at baseline Mean (SD) HAQscore at baseline Number of patients fulfilling criteria with one year follow-up HAQ-score data available Mean (SD) annual change in HAQ-score measured over subsequent year Number of patients fulfilling criteria with two year follow-up HAQ-score data available Mean (SD) annual change in HAQ-score measured over subsequent two years Baseline (0.84) (0.513) (0.279) One year (0.72) (0.427) (0.236) Two years (0.73) (0.352) (0.214) Three years (0.73) (0.389) (0.228) Five years (0.74) NA (0.180) Total score (0.408) (0.228) Note 1. HAQ was not recorded 6 years after baseline, therefore the change from year 5 to year 6 could not be estimated 165

166 Discussion This paper has estimated the change in HAQ from the time at which RF-negative patients with IP would have been eligible for biologics under current BSR guidelines. It finds that overall there is little or no change in HAQ over one or two years. For patients with symptoms for less than about 3 years before they became eligible for biologics, the data suggest that HAQ tends to improve over the following one or two years. For patients who have had symptoms of IP for more than about 3 years before they became eligible for biologics, the data suggests that HAQ tends to worsen over the following one or two years. These analyses have several limitations: The dataset cannot identify patients with a consultant diagnosis of PsA Biologics were licensed around the year Patients whose arthritis was not considered adequately controlled after this date would probably have been assessed against the criteria for anti-tnfs. In this study, we excluded patients who used a biologic agent at any time. Therefore the patients who did not use biologics are likely to be those whose disability was less severe or progressed more slowly. The criteria for commencement of anti-tnfs require patients to satisfy 3 tender and 3 swollen joints twice at least a month apart, and in these data we only have a single measure The criteria of 3 TJC and 3 SJC in some cases will be only moderate disease, and the patient and clinician might not consider that a failure. Patients in NOAR who satisfy the 3 TJC and 3 SJC criteria might go on to try other options such as increasing the dose of DMARDs, combination therapy or steroid injections. Patients in NOAR seem to satisfy the 3 TJC and 3 SJC criteria having been treated with 2 DMARDs for starting biologic therapy much earlier than patients in RCTs. This may be because RCTs tended to recruit patients who may have worse disease than the minimum entry criteria in the license Conclusion The York decision model will use as its base-case the mean progression of HAQ for patients not using anti-tnfs estimated in the NOAR data in patients with long-standing disease (about 3 years since onset of symptoms), that is, per year (SE = 0.228/sqrt(52) = 0.032). This value is very similar to 166

167 that estimated by Bansback et al } 57 (mean change per year 0.07). Sensitivity analyses will estimate model results at the upper and lower confidence interval of this parameter Sequencing analysis This section provides the details of the methods undertaken to conduct the sequencing analysis Formulas used by Rodgers et al The four parameters estimated in Rodgers et al were: 1. Initial PsARC response given patient discontinued first course because of a lack of efficacy It was estimated that the odds of achieving a PsARC response in the first three months on the second agent was reduced on average 2.7 fold. Therefore, the odds of a PsARC response at 3 months in drug j used as a second biologic given the first was discontinued for lack of efficacy are: o.psarcj 2 (first inefficacy) = o.psarc j1 / Initial PsARC response given patient discontinued first course because of an adverse event The probability of an initial PsARC response for the second agent, given the first was discontinued for an adverse event is unchanged. 3. Withdrawal after 3 months given patient discontinued first course because of a lack of efficacy Using the HRs from Hyrich et al - Rodgers et al estimated the following: 0.21 p.long 2 (first inefficacy) = p.long 1 x 0.36 x p.long 1 x p.long 1 x 4. Withdrawal after 3 months given patient discontinue first course because of an adverse event Again using the HRs from Hyrich et al Rodgers et al estimated the following: p.long 2 (first adverse event) = p.long 1 x p.long 1 x 0.43 x p.long 1 x 0.21 where: o.psarcj is the odds of a PsARC response at 3 months for drug j. p.long 1 is the rate of withdrawal from the first biologic agent for any reason. 167

168 ERG estimates based on the formulas from Rodgers et al The ERG applied the equations discussed in the previous section to the data presented in the manufacturer s submission results to produce the estimates presented in the following tables. Table 88: Initial PsARC response given patient discontinued first course because of a lack of efficacy (manufacturer s data derived from model: Cells Inp_Efficacy!C22:C39 ) Treatment % responders used in the manufacturer s model for firstline treatment % responders for second-line treatment based on the ERG s estimates Ustekinumab 45mg - Week 12 ********* *********** Ustekinumab 90mg - Week 12 ********* *********** Ustekinumab 45mg - Week 24 ********* *********** Ustekinumab 90mg - Week 24 ********* *********** Golimumab 50mg - Week 12 ********* *********** Golimumab 100mg - Week 12 ********* *********** Golimumab 50mg - Week 24 ********* *********** Golimumab 100mg - Week 24 ******* *********** Adalimumab - Week 12 ********* ********** Adalimumab - Week 24 ********* *********** Etanercept 25mg - Week 12 ********* *********** Etanercept 50mg - Week 12 ********* *********** Etanercept 25mg - Week 24 ******** *********** Etanercept 50mg - Week 24 ******** *********** Infliximab - Week 12 ******** ********** Infliximab - Week 24 ********* *********** Conventional management strategies - Week 12 ********* *********** Conventional management strategies - Week 24 ********* ********** Table 89: Withdrawal rates after three months, given patient discontinued first course of treatment because of lack of efficacy( manufacturer s estimates derived from model: Cells Inp_Outomes!C16:D20 ) Treatment Estimates from the manufacturer s submission for first-line treatment ERG estimates for second-line treatment Annual risk of withdrawal year 1 Annual risk of withdrawal year 1 Annual risk of withdrawal year 1 Ustekinumab 16.5% 16.5% 26.6% 26.6% Golimumab 16.5% 16.5% 26.6% 26.6% Annual risk of withdrawal year 1 168

169 Adalimumab 16.5% 16.5% 26.6% 26.6% Etanercept 16.5% 16.5% 26.6% 26.6% Infliximab 16.5% 16.5% 26.6% 26.6% Table 90: Withdrawal rates after three months, given patient discontinued first course of treatment because of an adverse event (manufacturer s estimates derived from model: Cells Inp_Outomes!C16:D20 ) Treatment Estimates from the manufacturer s submission for first-line treatment ERG estimates for second-line treatment Annual risk of withdrawal year 1 Annual risk of withdrawal year 1 Annual risk of withdrawal year 1 Ustekinumab 16.5% 16.5% 25.72% 25.72% Golimumab 16.5% 16.5% 25.72% 25.72% Adalimumab 16.5% 16.5% 25.72% 25.72% Etanercept 16.5% 16.5% 25.72% 25.72% Infliximab 16.5% 16.5% 25.72% 25.72% Annual risk of withdrawal year Full results of the Sequencing analysis Table 91: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to inefficacy (the manufacturer s data was used from PSUMMIT2 for ustekinumab and the ERG estimates were used for the other comparators) Cost ( ) QALY Golimumab was used first line Adalimumab was used first line Etanercept was used first line Ustekinumab was used first line Infliximab was used first line Conventional Management strategies 35, Golimumab 43, NA 12,168 12,168 12,168 12,168 Adalimumab 45, ED NA Dominated Dominated Dominated Etanercept 47, ,543 ED NA 14,543 14,543 Ustekinumab 67, ,738 37,738 32,818 NA 37,738 Infliximab 108, Dominated Dominated Dominated 1,019,550 NA Table 92: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to adverse events Cost ( ) QALY Golimumab was used first line Adalimumab was used first line Etanercept was used first line Ustekinumab was used first line Infliximab was used first line 169

170 Conventional Management strategies 35, Golimumab 53, NA 10,858 10,858 10,858 10,858 Adalimumab 58, ED NA Dominated Dominated Dominated Etanercept 64, ,734 ED NA 14,734 14,734 Ustekinumab 67, Dominated Dominated Dominated NA Dominated Infliximab 122, ,901 80,901 80, ,660 NA Table 93: Costs and QALYs of biologics used as second-line therapy if first biologic fails due to inefficacy (ERG estimates were used for all comparators) Cost ( ) QALY Golimumab was used first line Adalimumab was used first line Etanercept was used first line Ustekinumab was used first line Infliximab was used first line Conventional Management strategies 35, Golimumab 43, NA 12,163 12,163 12,163 12,163 Adalimumab 45, ED NA Dominated Dominated Dominated Etanercept 47, , ,000 NA 14,338 14,338 Ustekinumab 52, Dominated Dominated 54,630 NA Dominated Infliximab 108, , , ,985 1,054,707 NA 170

171 10.8 Model changes (Naïve model) Changes made for corrected model, corresponding to Table 43: Probabilistic results for the model, using ERG baseline HAQ and PASI estimates (anti-tnfα naïve population) (Section6.2) i) Within the Model Controls tab select all comparators from the available drop down list ii) Cell MC_Patient Characteristics!E35 = iii) Cell MC_Patient Characteristics!E39 = iv) Cell Parameters!G24 = v) Cell Parameters!G25 = Note that this model was used as the base case from which all further additional analyses were run for the naïve population. Therefore changes (i) to (v) were implemented for all of analyses 1 to 10 listed below, prior to any of the listed changes. 1. Changes corresponding to Table 45. Probabilistic results for model using full ITT NMA results (anti-tnf naïve population) (Section 6.3.1) (i) Cells Inp_Efficacy!C22:C39 changed to match the ITT results for PsARC response given in B8 (p55) of the manufacturer s response to the ERG s points of clarification i.e.: Treatment % responders Ustekinumab 45mg - Week 12 ********** Ustekinumab 90mg - Week 12 ********** Ustekinumab 45mg - Week 24 ********** Ustekinumab 90mg - Week 24 ********** Golimumab 50mg - Week 12 ********** Golimumab 100mg - Week 12 ********** Golimumab 50mg - Week 24 ********** Golimumab 100mg - Week 24 ********** Adalimumab - Week 12 ********** Adalimumab - Week 24 ********** Etanercept 25mg - Week 12 ********** Etanercept 50mg - Week 12 ********** Etanercept 25mg - Week 24 ********** Etanercept 50mg - Week 24 ********** Infliximab - Week 12 ********** Infliximab - Week 24 ********** Conventional management strategies - Week 12 ********** Conventional management strategies - Week 24 ********** 171

172 (ii) Cells Inp_Efficacy!C136:C151 changed to match the ITT results for PASI 75 response given in B8 (p55-6) of the manufacturer s response to the ERG s points of clarification i.e.: Treatment % responders Ustekinumab 45mg - Week 12 ********** Ustekinumab 90mg - Week 12 ********** Ustekinumab 45mg - Week 24 ********** Ustekinumab 90mg - Week 24 ********** Golimumab 50mg - Week 12 ********** Golimumab 100mg - Week 12 ********** Golimumab 50mg - Week 24 ********** Golimumab 100mg - Week 24 ********** Adalimumab - Week 12 ********** Adalimumab - Week 24 ********** Etanercept 25mg - Week 12 ********** Etanercept 50mg - Week 12 ********** Etanercept 25mg - Week 24 ********** Etanercept 50mg - Week 24 ********** Infliximab - Week 12 ********** Infliximab - Week 24 ********** 172

173 (iii) Cells Inp_Efficacy!C177:C187 and Cells Inp_Efficacy!C192:193 changed to match the ITT results for PASI 90 response given in B8 (p56) the manufacturer s response to the ERG s points of clarification i.e.: Treatment % responders Ustekinumab 45mg - Week 12 ********** Ustekinumab 90mg - Week 12 ********** Ustekinumab 45mg - Week 24 ********** Ustekinumab 90mg - Week 24 ********** Golimumab 50mg - Week 12 ********** Golimumab 100mg - Week 12 ********** Golimumab 50mg - Week 24 ********** Golimumab 100mg - Week 24 ********** Adalimumab - Week 12 ********** Adalimumab - Week 24 ********** Infliximab - Week 12 ********** Infliximab - Week 24 ********** 173

174 (iv) Cells Parameters!G340:I357 changed to match the SE, alpha and beta ITT values for PsARC response given in B8 (p55) of the manufacturer s response to the ERG s points of clarification i.e.: Outcome SE Alpha Beta Proportion of PsARC responders at week 12 ustekinumab 45mg Proportion of PsARC responders at week 12 ustekinumab 90mg Proportion of PsARC responders at week 24 ustekinumab 45mg Proportion of PsARC responders at week 24 ustekinumab 90mg Proportion of PsARC responders at week 12 golimumab 50mg Proportion of PsARC responders at week 12 golimumab 100mg Proportion of PsARC responders at week 24 golimumab 50mg Proportion of PsARC responders at week 24 golimumab 100mg Proportion of PsARC responders at week 12 adalimumab Proportion of PsARC responders at week 24 adalimumab Proportion of PsARC responders at week 12 etanercept 25mg Proportion of PsARC responders at week 12 etanercept 50mg Proportion of PsARC responders at week 24 etanercept 25mg Proportion of PsARC responders at week 24 etanercept 50mg Proportion of PsARC responders at week 12 infliximab Proportion of PsARC responders at week 24 infliximab Proportion of PsARC responders at week 12 Conventional management strategies Proportion of PsARC responders at week 24 Conventional management strategies ********** *********** *********** ********** *********** *********** ********** *********** *********** ********** *********** *********** ********** *********** *********** ********** *********** ********** ********** *********** ********** ********** *********** ********** ********** *********** *********** ********** *********** *********** ********** *********** *********** ********** *********** *********** ********** *********** ********** ********** *********** ********** ********** *********** *********** ********** *********** *********** ********** ************ ************ ********** *********** ************ 174

175 (v) Cells Parameters!G413:I438 changed to match the SE, alpha and beta ITT values for PASI 75 and PASI 90 response given in B8 (p55-6) of the manufacturer s response to the ERG s points of clarification i.e.: Outcome SE Alpha Beta Proportion of PASI 75 responders at week 12 ustekinumab 45mg Proportion of PASI 75 responders at week 12 ustekinumab 90mg Proportion of PASI 75 responders at week 24 ustekinumab 45mg Proportion of PASI 75 responders at week 24 ustekinumab 90mg Proportion of PASI 75 responders at week 12 golimumab 50mg Proportion of PASI 75 responders at week 12 golimumab 100mg Proportion of PASI 75 responders at week 24 golimumab 50mg Proportion of PASI 75 responders at week 24 golimumab 100mg Proportion of PASI 75 responders at week 12 adalimumab Proportion of PASI 75 responders at week 24 adalimumab Proportion of PASI 75 responders at week 12 etanercept 25mg Proportion of PASI 75 responders at week 12 etanercept 50mg Proportion of PASI 75 responders at week 24 etanercept 25mg Proportion of PASI 75 responders at week 24 etanercept 50mg Proportion of PASI 75 responders at week 12 infliximab Proportion of PASI 75 responders at week 24 infliximab Proportion of PASI 90 responders at week 12 ustekinumab 45mg Proportion of PASI 90 responders at week 12 ustekinumab 90mg Proportion of PASI 90 responders at week 24 ustekinumab 45mg Proportion of PASI 90 responders at week 24 ustekinumab 90mg Proportion of PASI 90 responders at week 12 golimumab 50mg ********** ********** *********** ********** ********** ********** ********** ********** *********** ********** ********** *********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** *********** ********** ********** *********** ********** ********** ********** ********** ********** ********** ********** ********** ********** Proportion of PASI 90 responders at week 12 ********** ********** ********** 175

176 golimumab 100mg Proportion of PASI 90 responders at week 24 golimumab 50mg Proportion of PASI 90 responders at week 24 golimumab 100mg Proportion of PASI 90 responders at week 12 adalimumab Proportion of PASI 90 responders at week 24 adalimumab Proportion of PASI 90 responders at week 12 infliximab Proportion of PASI 90 responders at week 24 infliximab ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** ********** 2. Changes corresponding to Table 46. Probabilistic results for model with ITT NMA results used, excluding ustekinumab 90mg (anti-tnfα naive population) (Section 6.3.1) (i) Make the same changes as described in point 2.(i)-(iv) but ignore any changes for the ustekinumab 90mg arm i.e. do not make any changes in cells Parameters!G341:I341, Parameters!G343:I343, Parameters!G414:I414, Parameters!G416:I416, Parameters!G430:I430, or Parameters!G432:I Changes corresponding to Table 47. Probabilistic results for model assuming HAQ rebounds to natural progression ("worst case scenario"; anti-tnfα naive population) (Section 6.3.2) (i) Within Inp_Outcomes select the Rebound to natural progression option from the rebound assumption drop down list. 4. Changes corresponding to Table 48. Probabilistic results for model using HAQ score change results from updated Yang NMA using 12-week PSUMMIT trial data (anti-tnfα experienced population) (Section 6.3.3) (i) Change cells Inp_Efficacy!C93:D110 to match the following table: Treatment HAQ score change baseline to Initial assessment of response PsARC responders PsARC nonresponders Ustekinumab 45mg - Week 12 ******** ******** Ustekinumab 90mg - Week 12 ******** ******** Ustekinumab 45mg - Week 24 ******** ******** Ustekinumab 90mg - Week 24 ******** ******** Golimumab 50mg - Week 12 ******** ******** 176

177 Golimumab 100mg - Week 12 ******** ******** Golimumab 50mg - Week 24 ******** ******** Golimumab 100mg - Week 24 ******** ******** Adalimumab - Week 12 ******** ******** Adalimumab - Week 24 ******** ******** Etanercept 25mg - Week 12 ******** ******** Etanercept 50mg - Week 12 ******** ******** Etanercept 25mg - Week 24 ******** ******** Etanercept 50mg - Week 24 ******** ******** Infliximab - Week 12 ******** ******** Infliximab - Week 24 ******** ******** Conventional management strategies - Week 12 ******** ******* Conventional management strategies - Week 24 ******** ******* (ii) Change cells Parameters!G376:G411 to match the following table: Outcome SE HAQ score change to Week 12 PsARC responders: ustekinumab 45mg HAQ score change to Week 12 PsARC responders: ustekinumab 90mg HAQ score change to Week 24 PsARC responders: ustekinumab 45mg HAQ score change to Week 24 PsARC responders: ustekinumab 90mg HAQ score change to Week 12 PsARC responders: golimumab 50mg HAQ score change to Week 12 PsARC responders: golimumab 100mg HAQ score change to Week 24 PsARC responders: golimumab 50mg HAQ score change to Week 24 PsARC responders: golimumab 100mg HAQ score change to Week 12 PsARC responders: adalimumab HAQ score change to Week 24 PsARC responders: adalimumab HAQ score change to Week 12 PsARC responders: etanercept 25mg HAQ score change to Week 12 PsARC responders: etanercept 50mg HAQ score change to Week 24 PsARC responders: etanercept 25mg ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** 177

178 HAQ score change to Week 24 PsARC responders: etanercept 50mg HAQ score change to Week 12 PsARC responders: infliximab HAQ score change to Week 24 PsARC responders: infliximab HAQ score change to Week 12 PsARC responders: Conventional management strategies HAQ score change to Week 24 PsARC responders: Conventional management strategies HAQ score change to Week 12 PsARC non-responders: ustekinumab 45mg HAQ score change to Week 12 PsARC non-responders: ustekinumab 90mg HAQ score change to Week 24 PsARC non-responders: ustekinumab 45mg HAQ score change to Week 24 PsARC non-responders: ustekinumab 90mg HAQ score change to Week 12 PsARC non-responders: golimumab 50mg HAQ score change to Week 12 PsARC non-responders: golimumab 100mg HAQ score change to Week 24 PsARC non-responders: golimumab 50mg HAQ score change to Week 24 PsARC non-responders: golimumab 100mg HAQ score change to Week 12 PsARC non-responders: adalimumab HAQ score change to Week 24 PsARC non-responders: adalimumab HAQ score change to Week 12 PsARC non-responders: etanercept 25mg HAQ score change to Week 12 PsARC non-responders: etanercept 50mg HAQ score change to Week 24 PsARC non-responders: etanercept 25mg HAQ score change to Week 24 PsARC non-responders: etanercept 50mg HAQ score change to Week 12 PsARC non-responders: infliximab HAQ score change to Week 24 PsARC non-responders: infliximab HAQ score change to Week 12 PsARC non-responders: Conventional management strategies HAQ score change to Week 24 PsARC non-responders: Conventional management strategies ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** ****** 178

179 5. Changes corresponding to Table 49. Probabilistic results for model using HAQ score change results from updated Yang NMA using 24-week PSUMMIT trial data (anti-tnfα experienced population) (Section 6.3.3) (i) Change cells Inp_Efficacy!C93:D110 to match the following table: Treatment HAQ score change baseline to Initial assessment of response PsARC responders PsARC non-responders Ustekinumab 45mg - Week 12 ***** ***** Ustekinumab 90mg - Week 12 ***** **** Ustekinumab 45mg - Week 24 ***** ***** Ustekinumab 90mg - Week 24 ***** **** Golimumab 50mg - Week 12 ***** ***** Golimumab 100mg - Week 12 ***** ***** Golimumab 50mg - Week 24 ***** ***** Golimumab 100mg - Week 24 ***** ***** Adalimumab - Week 12 ***** ***** Adalimumab - Week 24 ***** ***** Etanercept 25mg - Week 12 ***** ***** Etanercept 50mg - Week 12 ***** ***** Etanercept 25mg - Week 24 ***** ***** Etanercept 50mg - Week 24 ***** ***** Infliximab - Week 12 ***** ***** Infliximab - Week 24 ***** ***** Conventional management strategies - Week 12 ***** **** Conventional management strategies - Week 24 ***** **** (ii) Outcome Change cells Parameters!G376:G411 to match the following table: HAQ score change to Week 12 PsARC responders: ustekinumab 45mg ****** HAQ score change to Week 12 PsARC responders: ustekinumab 90mg ****** HAQ score change to Week 24 PsARC responders: ustekinumab 45mg ****** HAQ score change to Week 24 PsARC responders: ustekinumab 90mg ****** HAQ score change to Week 12 PsARC responders: golimumab 50mg ****** SE 179

180 HAQ score change to Week 12 PsARC responders: golimumab 100mg ****** HAQ score change to Week 24 PsARC responders: golimumab 50mg ****** HAQ score change to Week 24 PsARC responders: golimumab 100mg ****** HAQ score change to Week 12 PsARC responders: adalimumab ****** HAQ score change to Week 24 PsARC responders: adalimumab ****** HAQ score change to Week 12 PsARC responders: etanercept 25mg ****** HAQ score change to Week 12 PsARC responders: etanercept 50mg ****** HAQ score change to Week 24 PsARC responders: etanercept 25mg ****** HAQ score change to Week 24 PsARC responders: etanercept 50mg ****** HAQ score change to Week 12 PsARC responders: infliximab ****** HAQ score change to Week 24 PsARC responders: infliximab ****** HAQ score change to Week 12 PsARC responders: Conventional management strategies ****** HAQ score change to Week 24 PsARC responders: Conventional management strategies ****** HAQ score change to Week 12 PsARC non-responders: ustekinumab 45mg ****** HAQ score change to Week 12 PsARC non-responders: ustekinumab 90mg ****** HAQ score change to Week 24 PsARC non-responders: ustekinumab 45mg ****** HAQ score change to Week 24 PsARC non-responders: ustekinumab 90mg ****** HAQ score change to Week 12 PsARC non-responders: golimumab 50mg ****** HAQ score change to Week 12 PsARC non-responders: golimumab 100mg ****** HAQ score change to Week 24 PsARC non-responders: golimumab 50mg ****** HAQ score change to Week 24 PsARC non-responders: golimumab 100mg ****** HAQ score change to Week 12 PsARC non-responders: adalimumab ****** HAQ score change to Week 24 PsARC non-responders: adalimumab ****** HAQ score change to Week 12 PsARC non-responders: etanercept 25mg ****** 180

181 HAQ score change to Week 12 PsARC non-responders: etanercept 50mg ****** HAQ score change to Week 24 PsARC non-responders: etanercept 25mg ****** HAQ score change to Week 24 PsARC non-responders: etanercept 50mg ****** HAQ score change to Week 12 PsARC non-responders: infliximab ****** HAQ score change to Week 24 PsARC non-responders: infliximab ****** HAQ score change to Week 12 PsARC non-responders: Conventional management strategies ****** HAQ score change to Week 24 PsARC non-responders: Conventional management strategies ****** 6. Changes corresponding to Table 50. Alternative time horizons, ICER results (anti-tnfα naive population) and Table 51. Alternative time horizons, ICER vs. conventional management strategy results (anti-tnf naive population) (Section 6.3.4) (i) Change cell Model Controls!E57 to 8 for 5 year time horizon; 13 for 10 year time horizon; 23 for 20 year time horizon; and 43 for 40 year time horizon. 7. Changes corresponding to Table 52. Probabilistic results for model using week 24 weeks as the PsARC assessment time point for all treatments (anti-tnfα naïve population) (i) In cells Model Controls!D45:D49 select 24 weeks from the drop down list. 8. Changes corresponding to Table 22. Probabilistic results for model using week 12 as the PsARC assessment time point for all treatments (anti-tnfα naïve population) in Appendix (i) In cells Model Controls!D45:D49 select 24 weeks from the drop down list. 9. Changes corresponding to Table 53. Probabilistic results for model with cost of phototherapy included in the PASI-related cost estimate (anti-tnfα naive population) (Section 6.3.6) (i) In cell Inp_Costs:E69 select the Include option from the drop down list 10. Changes corresponding to Table 54. ERG s preferred base case (Section 6.3.6) (i) Implement the changes detailed in points 3 and 5 (i.e. ITT NMA results and HAQ change from updated Yang NMA) 181

182 Experienced model 11. Changes made for corrected model, corresponding to Table 33: Probabilistic results for the model using ERG baseline HAQ and PASI estimates (anti-tnfα experienced population) (i) Within the Model Controls tab select just conventional management strategies from the available drop down list (ii) Within the Model Controls tab select the Anti-TNFα experienced subgroup from the drop down subgroup list (iii) Change cell MC_Patient Characteristics!E35 = (iv) Change cell Parameters!G24 = (v) Change cell Parameters!G25 = Note that this model was used as the base case from which all further additional analyses were run for the experienced population. Therefore changes (i) to (v) were implemented for all of analyses 12 to 18 listed below, prior to any of the listed changes. 12. Changes made for the model using all available ITT trial results (table 55, Section 6.3.8) (i) Change cell Inp_Efficacy!C24 to **** (ii) Change cell Inp_Efficacy!C25 to **** (iii) Change cell Inp_Efficacy!C138 to **** (iv) Change cell Inp_Efficacy!C139 to **** 13. Changes made for the model using available ITT trial results for (4 rd column in table 55, Section 6.3.8) (v) Change cell Inp_Efficacy!C24 to **** (vi) Change cell Inp_Efficacy!C138 to **** 12. Changes made for the model assuming all PsARC response assessed at week 24 (table 55, Section 6.3.8) (i) In cell Model Controls!D49 select 24 weeks from the drop down list. 14. Changes made for the model assuming all PsARC response assessed at week 12 (table 55, Section 6.3.8) (i) In cell Model Controls!D44 select 12 weeks from the drop down list. 182

183 15. Changes made for the model including the cost of phototherapy (table 55, Section 6.3.8) (i) In cell Inp_Costs:E69 select the Include option from the drop down list 16. Changes made for the model assuming HAQ rebounds to natural progression (table 55, Section 6.3.8) (i) Within Inp_Outcomes select the Rebound to natural progression option from the rebound assumption drop down list. 17. Changes made for the model assuming alternative time horizons (table 56, Section 6.3.8) (i) Change cell Model Controls!E57 to 8 for 5 year time horizon; 13 for 10 year time horizon; 23 for 20 year time horizon; and 43 for 40 year time horizon. Sequencing analysis for experienced population 1. Changes made for the model for experienced patients characteristics (ii) Change cell MC_Patient Characteristics tab!e13 to 48 (iii) Change cell MC_Patient Characteristics tab!e17 to % (iv) Change cell MC_Patient Characteristics tab!e25 to (v) Change cell MC_Patient Characteristics tab!e27 to % (vi) Change cell MC_Patient Characteristics tab!e29 to % (vii) Change cell MC_Patient Characteristics tab!e35 to (viii) Change cell MC_Patient Characteristics tab!e39 to (ix) Change cell MC_Patient Characteristics tab!e43 to 7.68 (x) Change Inp_Efficacy!C22:C39 to match the following table: Treatment % responders Ustekinumab 45mg - Week 12 ****** Ustekinumab 90mg - Week 12 ****** Ustekinumab 45mg - Week 24 ****** Ustekinumab 90mg - Week 24 ****** Conventional management strategies - Week 12 ***** Conventional management strategies - Week 24 ***** (xi) Change Inp_Efficacy!C44:C61 to match the following table: Treatment % responders Ustekinumab 45mg - Week 12 ***** Ustekinumab 90mg - Week 12 ***** 183

184 Ustekinumab 45mg - Week 24 ***** Ustekinumab 90mg - Week 24 ***** Conventional management strategies - Week 12 ***** Conventional management strategies - Week 24 ***** (xii) Change Inp_Efficacy!C93:D110 to match the following table: Treatment HAQ score change baseline to Initial assessment of response PsARC responders PsARC non-responders Ustekinumab 45mg - Week 12 ***** ***** Ustekinumab 90mg - Week 12 ***** ***** Ustekinumab 45mg - Week 24 ***** **** Ustekinumab 90mg - Week 24 ***** **** Conventional management strategies - Week 12 ***** **** Conventional management strategies - Week 24 ***** **** (xiii) Change Inp_Efficacy!C136:C139 to match the following table: Treatment % responders Ustekinumab 45mg - Week 12 ***** Ustekinumab 90mg - Week 12 ***** Ustekinumab 45mg - Week 24 ****** Ustekinumab 90mg - Week 24 ****** (xiv) Change Inp_Efficacy!C178:C181 to match the following table: Treatment % responders Ustekinumab 45mg - Week 12 ***** Ustekinumab 90mg - Week 12 ***** Ustekinumab 45mg - Week 24 ****** Ustekinumab 90mg - Week 24 ****** (xv) Change Inp_Efficacy!C200:C203 to match the following table: Treatment % responders Ustekinumab 45mg - Week 12 ***** Ustekinumab 90mg - Week 12 ***** Ustekinumab 45mg - Week 24 ****** Ustekinumab 90mg - Week 24 ****** Note that this model, outlined in 1. was used as the base case from which the following three scenario analyses were run. Therefore changes (i) to (xv) were implemented for all of the analyses 2. to 4. below, prior to any of the listed changes. 184

185 2. Changes made for Scenario 1: (i) Change Inp_Efficacy!C26:C39 to match the following table: Treatment % responders for second-line treatment based on the ERG s estimates Golimumab 50mg - Week 12 *********** Golimumab 100mg - Week 12 *********** Golimumab 50mg - Week 24 *********** Golimumab 100mg - Week 24 *********** Adalimumab - Week 12 ********** Adalimumab - Week 24 *********** Etanercept 25mg - Week 12 *********** Etanercept 50mg - Week 12 *********** Etanercept 25mg - Week 24 *********** Etanercept 50mg - Week 24 *********** Infliximab - Week 12 ********** Infliximab - Week 24 *********** Conventional management strategies - Week 12 *********** Conventional management strategies - Week 24 ********** (ii) Treatment Change Inp_Outcomes!C16:D20 to match the following table: ERG estimates for second-line treatment Annual risk of withdrawal year 1 Ustekinumab 26.6% 26.6% Golimumab 26.6% 26.6% Adalimumab 26.6% 26.6% Etanercept 26.6% 26.6% Infliximab 26.6% 26.6% Annual risk of withdrawal year 1 3. Changes made for Scenario 2 (i) Treatment Change Inp_ Outcomes!C16:D20 to match the following table: ERG estimates for second-line treatment Annual risk of withdrawal year 1 Ustekinumab 25.72% 25.72% Golimumab 25.72% 25.72% Adalimumab 25.72% 25.72% Etanercept 25.72% 25.72% Infliximab 25.72% 25.72% Annual risk of withdrawal year 1 185

186 4. Changes made for Scenario 3 (i) Change Inp_Efficacy!C22:C39 to match the following table: Treatment % responders for second-line treatment based on the ERG s estimates Ustekinumab 45mg - Week 12 *********** Ustekinumab 90mg - Week 12 *********** Ustekinumab 45mg - Week 24 *********** Ustekinumab 90mg - Week 24 *********** Golimumab 50mg - Week 12 *********** Golimumab 100mg - Week 12 *********** Golimumab 50mg - Week 24 *********** Golimumab 100mg - Week 24 *********** Adalimumab - Week 12 ********** Adalimumab - Week 24 *********** Etanercept 25mg - Week 12 *********** Etanercept 50mg - Week 12 *********** Etanercept 25mg - Week 24 *********** Etanercept 50mg - Week 24 *********** Infliximab - Week 12 ********** Infliximab - Week 24 *********** Conventional management strategies - Week 12 *********** Conventional management strategies - Week 24 ********** (ii) Treatment Change Inp_Outcomes!C16:D20 to match the following table: ERG estimates for second-line treatment Annual risk of withdrawal year 1 Ustekinumab 25.72% 25.72% Golimumab 25.72% 25.72% Adalimumab 25.72% 25.72% Etanercept 25.72% 25.72% Infliximab 25.72% 25.72% Annual risk of withdrawal year 1 186

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