CLINICAL

The Value of Specialty Pharmaceuticals– A Systematic Review

Martin Zalesak, MD, PhD; Joyce S. Greenbaum, BA; Joshua T. Cohen, PhD; Fotios Kokkotos, PhD; Adam Lustig, MS; Peter J. Neumann, ScD; Daryl Pritchard, PhD; Jeffrey Stewart, BA; and Robert W. Dubois, MD, PhD

ovel specialty pharmaceuticals—typically biolog- ABSTRACT ical therapies which may cost tens of thousands Objectives of dollars for a course of treatment—hold great Novel specialty biopharmaceuticals hold promise for patients liv- N ing with complex and chronic conditions. However, high research promise for patients living with complex and chronic con- and development costs, special handling, and other necessary ditions.1 The improved efficacy and the potential to rede- enhancements to patient support programs all contribute to frequently higher prices for these products. This study sought to fine treatment modalities, however, are not without cost. assess the value of specialty pharmaceuticals through an exami- High research and development costs, special handling nation of the clinical, functional, and economic benefits of these and distribution networks, and necessary enhancements to treatments for the top 3 disease areas by pharmaceutical spend: rheumatoid arthritis (RA), multiple sclerosis (MS), and breast patient support programs all contribute to the high price cancer (BC). of specialty pharmaceuticals.2 Due in part to the high and Study Design often rising cost of these products, payers increasingly de- Systematic literature review. mand evidence of their value.3,4 It is predicted that by 2017 specialty pharmaceuticals© Managed willCare represent & more than half of Methods total pharmaceutical sales, intensifying the need to clearly A systematic review of market research and cost-effectiveness Healthcare Communications, LLC articles was conducted for each disease area to assess clinical, 5 understand their clinical and functional value. functional, and economic outcomes associated with specialty To holistically characterize the value of specialty pharma- medicine treatments versus the previous standard of care ceuticals, one must look beyond cost and take into account Results benefits. To this end, we systematically reviewed published All RA clinical (American College of Rheumatology) and functional studies involving specialty pharmaceuticals for the top 3 dis- (Health Assessment Questionnaire) outcome articles were classi- ease areas by pharmaceutical spending in the United States, fied as positive. The median cost-effectiveness ratio was $38,900 per quality-adjusted life year (QALY). All MS clinical outcome namely rheumatoid arthritis (RA), multiple sclerosis (MS), (relapse rate) articles were positive. The MS functional outcome and breast cancer (BC). For each disease area, we compared (Expanded Disability Status Scale) findings were less conclusive. The median cost-effectiveness ratio was $248,000 per QALY. The the clinical and functional efficacy of specialty pharmaceu- majority of BC articles yielded statistically inconclusive results for tical treatments with conventional therapies representing survival. All functional outcome (Quality of Life Questionnaire- Core 30) articles were positive. The median cost-effectiveness the previously available standard of care. To evaluate ther- ratio was $51,900 per QALY. apeutic benefits in an economic context, we also reviewed available cost-effectiveness findings for the specialty phar- Conclusions Novel specialty therapies hold promise for arresting disease maceuticals. This combined economic and clinical approach progression and improving quality of life for the 3 conditions as- allowed us to comprehensively assess the value of specialty sociated with the highest specialty pharmaceutical spend. These pharmaceuticals from both a patient and payer perspective. findings demonstrate a strong value proposition for specialty pharmaceuticals, and suggest even greater potential individual patient benefit with consideration of patient heterogeneity. Am J Manag Care. 2014;20(6):461-472 METHODS Definition of Specialty Pharmaceuticals A variety of definitions exist for “specialty pharmaceuti- cal.” We performed a literature search to identify a “specialty pharmaceutical” definition that was well accepted in the

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pharmaceuticals if they were: (1) marke­ Take-Away Points Specialty pharmaceuticals can offer significant benefits to patients living with complex ted in the United States; (2) identified as and chronic conditions compared with previously available therapies. a specialty pharmaceutical per our con- n In rheumatoid arthritis patients, the introduction of biologics cost-effectively im- structed definition; and (3) specified by proved clinical and functional outcomes compared with traditional disease-modifying antirheumatic drugs. guidelines for treatment in the disease n In multiple sclerosis patients, this review indicates biologic therapies are clinically area at time of publication. effective, as all studies reviewed reported a reduction in the relapse rate. Functional studies provided neutral findings. n In breast cancer patients, the majority of articles reviewed yielded statistically in- Selection of Metrics conclusive results for survival. With respect to the functional metric, the results were For each of the 3 disease areas, we strongly favorable, indicating that specialty pharmaceuticals improve quality of life. selected 1 clinical metric (eg, efficacy) and 1 functional metric (eg, quality of medical literature and would provide a reasonable frame- life). For the clinical metric, we first identified outcomes work for our review. mentioned in clinical trials catalogued in the US govern- Based on articles reviewed,1-4,6-9 we defined specialty ment’s clinical trials registry for the pertinent disease area. pharmaceuticals to be pharmaceutical treatments that: (1) We next searched PubMed (National Center for Biotech- are high cost (generally accepted as having prescription nology Information, US National Library of Medicine, price exceeding $600 per month); (2) require close moni- Bethesda, Maryland) for articles that used each metric toring, including personalized or frequent adjustment of and also mentioned both a specialty pharmaceutical in dosing; and (3) require special handling, such as careful that disease area and the disease area itself. We retained temperature control, or restrictions on where the medica- the clinical end point used in the greatest number articles tion can be administered, prepared, or distributed. as the end point for our literature review. We selected the functional metric using a similar process but the initial list Selection of Disease Areas of metrics was determined from review articles focused on We selected disease areas by first building a comprehen- functional outcomes in the disease area.10-17 Our economic sive list of specialty pharmaceuticals marketed in the United evaluation focused on analyses estimating cost-per-QALY States and identifying the corresponding disease area(s) for (quality-adjusted life year), a gold standard metric in the each therapy. A full list of specialty pharmaceuticals appears health economics literature.18 in eAppendix A (available at www.ajmc.com). We excluded orphan diseases because they typically lack a conventional Systematic Review therapy with which the specialty pharmaceutical can be We identified original clinical and functional outcome ar- compared. We excluded diseases for which specialty pharma- ticles for each disease area from review articles. We identified ceuticals provide only acute or supportive care because our review in PubMed using the search phrase: “(disease AND goal was to evaluate specialty pharmaceuticals in cases where metric)” and applying PubMed’s systematic review filter. To they incur the highest costs—namely when used chronically. this list, we added original articles published too recently Next, we reviewed market research reports and other ma- to appear in the reviews. We identified these articles from a terials to find the top 10 disease areas by specialty pharma- supplemental search of PubMed that omitted the systematic ceutical spend in the United States. We initially focused our review filter. We excluded original articles if they were: (1) analysis on the 4 top areas in this list but ultimately exclu­ published before January 1990; (2) not in English; (3) not an ded the disease area with the fourth-highest pharmaceutical original article; (4) not relevant (ie, did not provide original spend—human immunodeficiency virus (HIV)—because outcome data associated with the relevant drugs) based on we could find no studies comparing specialty therapies for the title or abstract; or (5) not available for electronic down- HIV with nonspecialty therapies. Since HIV therapies were load. Articles were likewise excluded if they: (6) did not re- not available prior to the introduction of specialty pharma- port quantitative results; or (7) did not compare the selected ceuticals to treat this disease, specialty pharmaceutical ben- specialty pharmaceuticals with nonspecialty treatments. efits to HIV patients have been substantial. Exclusion of We identified cost-effectiveness articles from the Tufts HIV left 3 disease areas: rheumatoid arthritis (RA), multiple Medical Center Cost-Effectiveness Analysis Registry,19 sclerosis (MS), and breast cancer (BC). which contains 3488 cost-utility analyses on a wide va- riety of diseases and treatments. For each disease area, Selection of Pharmaceuticals we searched the registry for articles evaluating pertinent For each of the 3 disease areas, we included specialty specialty pharmaceuticals. Articles that did not compare

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n Table 1. Top 10 Specialty Pharmaceutical Disease Areas by Estimated Spend on Specialty Pharmaceuticals in the United States Representative Estimated Specialty Pharmaceutical Disease Area Therapeutic Category Specialty Drugs/Regimen Spend in $B (year) Rheumatoid arthritis Antineoplastics, abatacept, infliximab, rituximab $6.0B (2011)24 immunological agents, antirheumatics Multiple sclerosis Immunological agents dimethyl fumarate, fingolimod, $5.5B (2011)25 interferon beta Breast cancer Antineoplastics, trastuzumab, everolimus, $5.2B (2011)26 immunological agents ixabepilone HIV Antiretrovirals efavirenz/tenofovir/emtricitabine, $5.1B (2010)27 elvitegravir/cobicistat/emtricita- bine/tenofovir disoproxil fuma- rate, enfuvirtide Colorectal cancer Antineoplastics, bevacizumab, capecitabine, $4.3B (2010)21 immunological agents irinotecan Lymphoma (non-Hodgkins) Antineoplastics, bendamustine, tositumomab, $3.9B (2009)20 immunological agents rituximab Pulmonary hypertension Antihypertensives ambrisentan, bosentan, $3.3B (2011)28 treprostinil Head and neck cancer Antineoplastics cetuximab, fluorouracil $3.2B (2011)29 Inflammatory bowel disease Immunological agents adalimumab, certolizumab pegol, $3.0B (2010)22 infliximab Psoriasis Immunological agents alefacept, etanercept, $2.3B (2010)23 ustekinumab HIV indicates human immunodeficiency virus. a pertinent specialty drug with a conventional treatment ratios reported by pertinent articles. Because each article were excluded. can report multiple ratios (eg, for different populations, or evaluating different doses of the specialty pharmaceutical), Evidence Assessment we reported both unweighted and weighted summary sta- Two reviewers independently examined each clinical and tistics. For the weighted results, we assigned each ratio a functional metric article to determine if its results were posi- weight of 1/n, where n is the number of ratios reported by tive (favorable), negative (unfavorable), or neutral. Results that article. Doing so equalizes the statistical contribution were deemed positive if they indicated that the specialty from each article regardless of how many ratios it reports. drug confers a statistically significant improvement relative to the alternative conventional treatment; negative if they indicated a statistically significant advantage for the conven- RESULTS tional treatment; or neutral if they did not achieve statistical Case Example Disease Areas significance, regardless of the direction of the finding. The literature review, along with an examination of Given the heterogenous nature of the studies reviewed, payer materials,2,8,9 yielded 266 specialty pharmaceuticals a qualitative, as opposed to quantitative, assessment of corresponding to 85 disease areas marketed in the United the literature was necessary. Patient populations, time States. Exclusion of 31 orphan diseases and 22 conditions frames, treatment administration, and methods of mea- for which specialty pharmaceuticals provide only acute or suring outcomes across studies were diverse, precluding supportive care yielded 32 diseases for inclusion. The spe- the use of meta-analytic techniques. However, the more cialty pharmaceuticals and disease areas we evaluated are standardized nature of the cost-effectiveness papers al- listed in eAppendix B. Table 1 reports the estimated spend lowed quantitative aggregation of results, and subsequent on specialty pharmaceuticals for the top 10 disease areas, reporting of summary statistics. as determined from various analyst and market research We summarized economic results by reporting the reports.20-29 The top 3 areas—RA, MS, and BC—were mean, median, minimum, and maximum cost-effectiveness identified as the targets for our analyses.

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n Table 2. Clinical, Functional, and Economic Metrics Chosen for Assessment consisting of a combined bio- of Specialty Pharmaceuticals in the 3 Selected Disease Areas logic and nonbiologic disease- Disease Area Metric Metric Type Rating Citation modifying antirheumatic drug Rheumatoid arthritis ACR Clinical Positive 47-110 (DMARD) with a purely non- HAQ Functional Positive 51, 54, 67, 69, 78, 82, 85, 87, biologic DMARD. The study 91, 95, 99, 102, 103, 105-108, populations included patients 110-113 who either had severe RA or Multiple sclerosis RRR Clinical Positive 114-127 who had previously failed treat- EDSS Functional Positive 115,117,120-122,125,126,128 ment with tumor necrosis factor Neutral 118,129-133 alpha (TNFα) inhibitors and Breast cancer OS Clinical Positive 134-142 were being considered for non- Neutral 143-153 anti–TNF biologics. QLQ-C30 Functional Positive 154-158 Cost-effectiveness ratios re- ACR indicates American College of Rheumatology score for RA; EDSS, Expanded Disability Status Scale; ported by these 15 studies (N = HAQ, Health Assessment Questionnaire; OS, overall survival; QLQ-C30, Quality of Life Questionnaire- Core 30; RRR, reduction in relapse rate. 45), all reported in 2012 US dol- lars, had a mean of $47,500, a Identified Pharmaceuticals median of $38,900, and a range of $5000 to $230,000 per We identified 10 specialty pharmaceuticals for treat- QALY. The results weighted so that each article makes the ment of RA: abatacept, adalimumab, anakinra, cer- same statistical contribution regardless of the number of tolizumab pegol, etanercept, golimumab, infliximab, ratios reported (not shown), and were comparable. rituximab, tocilizumab, and tofacitinib; 8 specialty phar- maceuticals for treatment of MS: dimethyl fumarate, fin- MS golimod, glatiramer acetate, interferon beta-1a, interferon We identified 14 articles for the MS clinical outcome beta-1b, mitoxantrone, natalizumab, and teriflunomide; (relapse rate) and 14 articles that reported the MS func- and 10 specialty pharmaceuticals for treatment of BC: bev- tional outcome (EDSS) (Figure, Panel B). We classified all acizumab, capecitabine, eribulin mesylate, everolimus, ixa- 14 relapse rate studies (8258 subjects) as positive, 8 of the bepilone, lapatinib, paclitaxel, pertuzumab, trastuzumab, 14 EDSS studies as positive (4429 subjects), and the re- and vinorelbine. maining 6 EDSS studies as neutral (4533 subjects). We identified 13 cost-per-QALY studies (eAppendix Metrics C). Identified cost-effectiveness studies typically compared We used the following clinical metrics: the American a specialty pharmaceutical treatment with either no treat- College of Rheumatology (ACR) score for RA, reduction ment or to best supportive care. The study populations in relapse for MS, and overall survival for BC. The func- were comprised of either patients with active relapsing- tional metrics used were the Health Assessment Ques- remitting or secondary progressive MS. tionnaire (HAQ) for RA, the Expanded Disability Status Cost-effectiveness ratios (N = 31), all reported in 2012 Scale (EDSS) for MS, and the Quality of Life Question- US dollars, had a mean of $642,000, a median of $248,000, naire-Core 30 (QLQ-C30) for BC. Table 2 lists the selected and a range of $13,600 to $3,730,000 per QALY. Weighted metrics for each disease area and identifies which articles results (not shown) did not differ substantially from these reported positive, negative, or neutral findings.eAppendix unweighted results. C lists all the cost-effectiveness ratios. BC Evidence Assessment We identified 20 original articles that reported BC RA clinical outcome (overall survival) and 5 articles that re- We identified 64 original articles for the RA clinical ported the QLQ-C30 functional outcome (Figure, Panel outcome (ACR score) and 21 for the RA functional out- C). We classified 9 of the 20 clinical outcome articles as come (HAQ) (Figure, Panel A). We classified all 64 ACR positive (15,421 subjects), and the other 11 as neutral studies (19,947 subjects) and all 21 HAQ studies (11,132 (8406 subjects). We classified all 5 articles reporting the subjects) as positive. QLQ-C30 functional outcome as positive (1794 subjects). We identified 15 cost-per-QALY studies (eAppendix We identified 15 cost-per-QALY studies. The majority C). Identified studies typically compared a treatment of articles (N = 13) (eAppendix C) compared trastuzumab

464 n www.ajmc.com n JUNE 2014 The Value of Specialty Pharmaceuticals n Figure. Results for Clinical and Functional Metrics Across the 3 Disease Areas 100 0 0

8406 80 6 4533 11

60

% 64 19,947 21 11,132 14 8258 5 1794 40 15,421 8 4429 20 9

0 ACR ACR HAQ HAQ Relapse Relapse EDSS EDSS Overall Overall QLQ C30 QLQ C30 (N of (N of (N of (N of Rate Rate (N of (N of Survival Survival (N of (N of articles) subjects) articles) subjects) (N of (N of articles) subjects) (N of (N of articles) subjects) articles) subjects) articles) subjects) RA MS Breast Cancer Panel A Panel B Panel C

Statistically significant benefit of specialty therapeutics compared with non-specialty therapeutics

Benefit of specialty therapeutics not statistically significant

ACR indicates American College of Rheumatology score for RA; EDSS, Expanded Disability Status Scale; HAQ, Health Assessment Question- naire; MS, multiple sclerosis; QLQ-C30, Quality of Life Questionnaire-Core 30; RA, rheumatoid arthritis. adjuvant treatment with no trastuzumab adjuvant treat- score) and functional (HAQ) outcomes compared with ment. Study populations consisted primarily of patients traditional DMARDs. Our study further suggests that with human epidermal growth factor receptor 2 (HER this improvement is achieved cost-effectively. The aver- 2)-positive breast cancer. Cost-effectiveness ratios re- age cost-effectiveness ratio of $47,500 per QALY is sub- ported by these studies (N = 28), all reported in 2012 US stantially more favorable than the generally accepted dollars, had a mean of $64,100, a median of $51,900, and threshold of $100,000 per QALY.18 Recent evidence sug- a range of $1660 to $406,000 per QALY. gests that earlier treatment with biologics, when used with proper adherence and compliance, can further improve outcomes31,32; indeed, the latest guidelines recommend DISCUSSION earlier treatment.33 It would be useful to analyze how any Although specialty biopharmaceuticals have histori- additional incurred costs resulting from earlier treatment cally been associated with rare medical conditions, they might influence cost-effectiveness. are increasingly being developed and used for the treat- ment of a number of chronic conditions. Consequently, MS spending on these medicines is projected to grow to 50% Effective treatments for MS were not available until of the total pharmaceutical spend by 2017.5 To shed light 1993 when interferon beta-1b was shown to treat the on the value of specialty pharmaceuticals, this study com- relapsing-remitting form of the disease.34 Subsequent prehensively assessed their value for the top 3 diseases by trials demonstrated the efficacy of interferon beta-1a, US pharmaceutical spending level, namely RA, MS, and glatiramer acetate, and the successful treatment of sec- BC. Our assessment included clinical outcomes, functio­ ondary progression MS with interferon beta-1b. The nal outcomes, and cost effectiveness (Table 3). importance of early intervention treatments for MS was shown in the CHAMPS35 and ETOMS36 trials, demon- RA strating that the early adoption of interferon beta-1a RA was one of the first diseases to see widespread use delayed conversion from suggestive MS to clinically of biologic agents, starting in the late 1990s.30 Our analy- definite MS.34 sis indicates that the introduction of biologics substan- Our analysis indicates that biologic therapies for MS tially and statistically improved patient clinical (ACR are clinically effective, as all studies reviewed reported a

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n Table 3. Clinical, Functional, and Economic Metrics Chosen for Assessment of Specialty Pharmaceuticals in the 3 Selected Disease Areas Metrics and Corresponding Original Articles Clinical Functional Economic Disease Area Metric Articles Metric Articles Metric Articles Breast cancer OS 134-153 QLQ-C30 154-158 Cost per QALY 159-173 Multiple sclerosis RRR 114-127 EDSS 115, 117, 118, 120-122, Cost per QALY 174-186 125, 126, 128-133 Rheumatoid arthritis ACR 47-110 HAQ 51, 54, 67, 69, 78, 82, 85, Cost per QALY 187-201 87, 91, 95, 99, 102, 103, 105-108, 110-113 ACR indicates American College of Rheumatology; EDSS, Expanded Disability Status Scale; HAQ, Health Assessment Questionnaire; OS, overall survival; QALY, quality-adjusted life year; QLQ-C30, Quality of Life Questionnaire-Core30; RRR, reduction in relapse rate. reduction in the relapse rate. Functional findings were therapy regimens, however, conferred marked mortality less conclusive, as 6 of the 14 reviewed studies found no improvements.39 statistically significant improvement in the EDSS. These The majority of studies yielded statistically inconclusive neutral findings may be attributable to side effects that results for survival. On the other hand, the subset of stud- compromise quality of life and hence mitigate clinical and ies evaluating trastuzumab showed improved survival out- functional improvements. comes relative to the other studies reviewed. With respect to Cost-effectiveness for specialty therapies generally our functional metric, QLQ-C30, the results were favorable exceeded (was less favorable than) the conventional across all studies obtained, suggesting that specialty phar- $100,000 per QALY threshold. Cost-effectiveness results maceuticals improve quality of life among BC patients. might have been more favorable if nonresponsive patients The limited number of cost-effectiveness studies (N = discontinued therapy. However, the randomized clinical 15) we reviewed indicate that specialty pharmaceutical BC trials that comprise most of the literature do not allow for treatments are cost-effective, with a mean of $64,000 per discontinuation among nonresponders, so this possibility QALY. Limiting attention to evaluations of trastuzumab cannot generally be explored using existing data. (N = 13) yielded even more favorable cost-effectiveness re- Functional and cost-effectiveness findings may im- sults (mean of $51,000 per QALY). prove in the future with the introduction of new oral therapies, such as dimethyl fumarate, fingolimod, and Limitations teriflunomide, which have been shown to be superior Our investigation had several limitations. First, while to previously used specialty pharmaceutical interferons. we identified a large number of clinical efficacy studies, These new therapies have the potential to reduce costs fewer studies evaluated functional metrics. Furthermore, and improve patient clinical and functional outcomes. the functional studies were sometimes retrospective, rath- We expect that the cost-effectiveness of specialty phar- er than randomized clinical trials. maceutical treatments for MS might also be improved by Second, because of both space and scope limitations, we monitoring patients and discontinuing treatments among limited attention to one clinical and one functional metric nonresponders. Such a strategy could protect most of the per disease area. Our results are still informative because population’s clinical and functional gains while decreas- we chose those metrics most commonly used in the litera- ing aggregate costs. ture. Nonetheless, complete characterization of a therapy’s effectiveness should consider a composite of many metrics. BC Third, cost-effectiveness studies have not been con- The 1998 approval of trastuzumab, a medication ducted for all therapies included in our review. Cost-ef- specifically indicated for women with elevated HER 2 fectiveness is less likely to have been analyzed for more production, sparked one of the largest increases in the recently introduced therapies. To the extent that more use of personalized medicine to date.37 Previously, spe- recently developed specialty pharmaceutical therapies are cialty pharmaceutical chemotherapy formulations such more effective than older therapies, and assuming they as paclitaxel and capecitabine improved patient surviv- are comparably priced, our assessment could be biased to- al.38 The addition of personalized medicines to chemo- ward reporting less favorable cost-effectiveness findings.

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On the other hand, if more recently developed therapies cost-effectiveness is not always straightforward, but can are more expensive than older therapies, our results could instead require identifying the most effective agents and be biased in the other direction. the most appropriate patients. Development of nuanced Fourth, the cost-effectiveness analyses were not all con- strategies to take advantage of these possibilities holds ducted in the same country and may not all account for great promise for improved patient quality of life and the same types of costs (eg, patient out-of-pocket costs). good value for the healthcare system. This limitation is inherent to the use of published results. Nonetheless, the collective information in multiple cost- Author Affiliations: Trinity Partners, LLC, Waltham, MA (MZ, JSG, FK, JS); Center for the Evaluation of Value and Risk in Health at Tufts effectiveness analyses still provides useful insights and as Medical Center, Boston, MA (JTC, PJN); National Pharmaceutical a result, such reviews are not uncommon.40-45 Council (NPC), Washington, DC (AL, DP, RWD). Finally, pharmaceutical indications change as new Source of Funding: This study was funded by the NPC, an industry- funded health policy research group that is not involved in lobbying or efficacy and safety evidence becomes available. In some advocacy. cases, studies included in our analysis pertain to prod- Author Disclosures: Mr Zalesak, Ms Greenbaum, Dr Kokkotos, and ucts for which the indication has changed. For example, Mr Stewart report employment with Trinity Partners, LLC, which was contracted by the NPC to conduct research and analysis related to this in 2010, the FDA removed bevacizumab’s indication for study. Dr Cohen and Mr Neumann report receiving payment from the BC.46 As with any review, some aspects of the constituent NPC in relation to this study. Mr Lustig and Drs Pritchard and Dubois report employment with the NPC. data may be out of date. In any case, our results still pro- Authorship Information: Concept and design (MZ, JSG, JTC, AL, vide a general characterization of the value of specialty PJN, DP, JS, RWD); acquisition of data (JSG, JTC, PJN, JS); analysis and pharmaceuticals, even if the quantitative results may interpretation of data (MZ, JSG, JTC, AL, PJN, DP, RWD); drafting of the manuscript (MZ, JSG, JTC, PJN); critical revision of the manuscript for reflect an evolution of care, including some potentially important intellectual content (MZ, JSG, JTC, FK, AL, PJN, DP, RWD); obsolete treatment options, rather than the current state statistical analysis (JSG, FK); obtaining funding (PJN, DP, JS, RWD); ad- ministrative, technical, or logistic support (MZ, JSG, AL); supervision of the art. (MZ, RWD). Address correspondence to: Fotios Kokkotos, PhD, 230 Third Ave, Waltham, MA 02451. E-mail: [email protected]. 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Chilcott J, McCabe C, Tappenden P, et al. Modelling the cost effec- plus exemestane versus placebo plus exemestane in the phase 3, tiveness of interferon beta and glatiramer acetate in the management randomized, controlled, BOLERO-2 trial. Cancer. 2013. of multiple sclerosis. Commentary: evaluating disease modifying treat- 155. Kaufman B, Wu Y, Amonkar MM, et al. Impact of lapatinib ments in multiple sclerosis. BMJ. 2003;326(7388):522; discussion 522. monotherapy on QOL and pain symptoms in patients with HER2+ 176. Forbes RB, Lees A, Waugh N, Swingler RJ. Population based cost relapsed or refractory inflammatory breast cancer.Curr Med Res Opin. utility study of interferon beta-1b in secondary progressive multiple 2010;26(5):1065-1073. sclerosis. BMJ. 1999;319(7224):1529-1533.

VOL. 20, NO. 6 n THE AMERICAN JOURNAL OF MANAGED CARE n 471 CLINICAL

177. Gani R, Giovannoni G, Bates D, Kemball B, Hughes S, Kerrigan J. inhibitor in rheumatoid arthritis in the Finnish setting. Rheumatology. Cost-effectiveness analyses of natalizumab (Tysabri) compared with 2010;49(4):767-777. other disease-modifying therapies for people with highly active 192. Kobelt G, Eberhardt K, Geborek P. TNF inhibitors in the treatment relapsing-remitting multiple sclerosis in the UK. Pharmacoeconomics. of rheumatoid arthritis in clinical practice: costs and outcomes in a fol- 2008;26(7):617-627. low up study of patients with RA treated with etanercept or infliximab 178. Jankovic SM, Kostic M, Radosavljevic M, et al. Cost-effectiveness in southern Sweden. Ann Rheum Dis. 2004;63(1):4-10. of four immunomodulatory therapies for relapsing-remitting multiple 193. Kobelt G, Jonsson L, Young A, Eberhardt K. The cost-effectiveness sclerosis: a Markov model based on data in a Balkan country in socio- of infliximab (Remicade) in the treatment of rheumatoid arthritis in economic transition. Vojnosanit Pregl. 2009;66(7):556-562. Sweden and the United Kingdom based on the ATTRACT study. Rheu- 179. Kobelt G, Jonsson L, Fredrikson S. Cost-utility of interferon matology. 2003;42(2):326-335. beta1b in the treatment of patients with active relapsing-remitting or 194. Kobelt G, Lekander I, Lang A, Raffeiner B, Botsios C, Geborek P. secondary progressive multiple sclerosis. Eur J Health Econ. 2003;4(1): Cost-effectiveness of etanercept treatment in early active rheumatoid 50-59. arthritis followed by dose adjustment. Int J Technol Assess Health 180. Kobelt G, Jonsson L, Henriksson F, Fredrikson S, Jonsson B. Cost- Care. 2011;27(3):193-200. utility analysis of interferon beta-1b in secondary progressive multiple 195. Lekander I, Borgstrom F, Svarvar P, Ljung T, Carli C, van Vollen- sclerosis. Int J Technol Assess Health Care. 2000;16(3):768-780. hoven RF. Cost-effectiveness of real-world infliximab use in patients 181. Kobelt G, Jonsson L, Miltenburger C, Jonsson B. Cost-utility with rheumatoid arthritis in Sweden. Int J Technol Assess Health Care. analysis of interferon beta-1B in secondary progressive multiple scle- 2010;26(1):54-61. rosis using natural history disease data. Int J Technol Assess Health 196. Soini EJ, Hallinen TA, Puolakka K, Vihervaara V, Kauppi MJ. Cost- Care. 2002;18(1):127-138. effectiveness of adalimumab, etanercept, and tocilizumab as first-line 182. Nuijten MJ, Hutton J. Cost-effectiveness analysis of interferon beta treatments for moderate-to-severe rheumatoid arthritis. J Med Econ. in multiple sclerosis: a Markov process analysis. Value Health. 2002; 2012;15(2):340-351. 5(1):44-54. 197. Vera-Llonch M, Massarotti E, Wolfe F, et al. Cost-effectiveness of 183. Parkin D, Jacoby A, McNamee P, Miller P, Thomas S, Bates D. abatacept in patients with moderately to severely active rheumatoid Treatment of multiple sclerosis with interferon beta: an appraisal of arthritis and inadequate response to tumor necrosis factor-alpha cost-effectiveness and quality of life. J Neurol Neurosurg Psychiatry. antagonists. J Rheumatol. 2008;35(9):1745-1753. 2000;68(2):144-149. 198. Vera-Llonch M, Massarotti E, Wolfe F, et al. Cost-effectiveness of 184. Prosser LA, Kuntz KM, Bar-Or A, Weinstein MC. Cost-effectiveness abatacept in patients with moderately to severely active rheumatoid of interferon beta-1a, interferon beta-1b, and glatiramer acetate in arthritis and inadequate response to methotrexate. Rheumatology. newly diagnosed non-primary progressive multiple sclerosis. Value 2008;47(4):535-541. Health. 2004;7(5):554-568. 199. Virkki LM, Konttinen YT, Peltomaa R, et al. Cost-effectiveness of 185. Tappenden P, McCabe C, Chilcott J, et al. Cost-effectiveness of infliximab in the treatment of rheumatoid arthritis in clinical practice. disease-modifying therapies in the management of multiple sclerosis Clin Exp Rheumatol. 2008;26(6):1059-1066. for the Medicare population. Value Health. 2009;12(5):657-665. 200. Wong JB, Singh G, Kavanaugh A. Estimating the cost-effective- 186. Touchette DR, Durgin TL, Wanke LA, Goodkin DE. A cost-utility ness of 54 weeks of infliximab for rheumatoid arthritis.Am J Med. analysis of mitoxantrone hydrochloride and interferon beta-1b in 2002;113(5):400-408. the treatment of patients with secondary progressive or progressive 201. Yuan Y, Trivedi D, Maclean R, Rosenblatt L. Indirect cost-effective- relapsing multiple sclerosis. Clin Ther. 2003;25(2):611-634. ness analyses of abatacept and rituximab in patients with moderate- 187. Bansback NJ, Brennan A, Ghatnekar O. Cost effectiveness of to-severe rheumatoid arthritis in the United States. J Med Econ. 2010; adalimumab in the treatment of patients with moderate to severe 13(1):33-41. n rheumatoid arthritis in Sweden. Ann Rheum Dis. 2005;64(7):995-1002. 188. Barbieri M, Wong JB, Drummond M. The cost effectiveness of infliximab for severe treatment-resistant rheumatoid arthritis in the UK. Pharmacoeconomics. 2005;23(6):607-618. 189. Benucci M, Saviola G, Baiardi P, Manfredi M. Cost-effectiveness treatment with Rituximab in patients with rheumatoid arthritis in real life. Rheumatol Int. 2011;31(11):1465-1469. Web exclusive Follow-up editorial by 190. Davies A, Cifaldi MA, Segurado OG, Weisman MH. Cost-effective- Buxbaum, de Souza, ness of sequential therapy with tumor necrosis factor antagonists in and Fendrick early rheumatoid arthritis. J Rheumatol. 2009;36(1):16-26. 191. Hallinen TA, Soini EJ, Eklund K, Puolakka K. Cost-utility of differ- www.ajmc.com Full text and PDF ent treatment strategies after the failure of tumour necrosis factor Web exclusive eAppendices A-C

472 n www.ajmc.com n JUNE 2014 eAppendix A. Full List of Specialty Pharmaceuticals

Brand Name Molecular Name Actemra Tocilizumab Acthar Repository Corticotropin Injection Actimmune Interferon Gamma-1b Adagen Pegademase Bovine Adcirca Tadalafil Advate Antihemophilic Factor Afinitor Everolimus Aldurazyme Laronidase Alferon Interferon Alfa-N3 Alphanate Antihemophilic Factor Alphanine Coagulation Factor IX Amevive Alefacept Amifostine Amifostine Ampyra 4-Aminopyridine Apokyn Apomorphine Aralast Alpha-Proteinase Inhibitor Aranesp Darbepoetin Alfa Arcalyst Rilonacept Aredia Pamidronic Acid Arixtra Fondaparinux Armidex Anastrozole Aromasin Exemestane Aubagio Teriflunomide Avastin Bevacizumab Avonex Interferon Beta-1a Baraclude Entecavir Bebulin Factor IX Complex Benefix Coagulation Factor IX Benlysta Belimumab Berinert C1 Esterase Inhibitor Betaseron Interferon Beta-1b Bexxar Tositumomab Boniva Ibandronic Acid Bravelle Urofollitropin Campath Alemtuzumab Camptosar Irinotecan Carimune Immune Globulin Cayston Aztreonam Ceprotin Protein C Ceredase Alglucerase Cerezyme Imiglucerase Cetrotide Cetrorelix Chorionic Gonadotropin Chorionic Gonadotropin Cimzia Certolizumab Pegol Cinryze C1 Esterase Inhibitor Copaxone Glatiramer Acetate Injection Copegus Ribavirin Cystadane Powder Betaine Cytogam Cytomegalovirus Immune Globulin Intravenous Dacogen Decitabine Elaprase Idursulfase Eligard Leuprorelin Elitek Rasburicase Emcyt Estramustine Enbrel Etanercept Epivir Lamivudine Epogen Epoetin Alfa Epoprostenol Prostacyclin Erbitux Cetuximab Ethyol Amifostine Euflexxa Sodium Hyaluronate Exjade Deferasirox Extavia Interferon Beta-1b Fabrazyme Agalsidase Beta Feiba Anti-inhibitor Coagulant Complex Femara Letrozole Firazyr Icatibant Firmagon Degarelix Flebogamma Immune Globulin Flolan Epoprostenol Sodium Fluoroplex Fluorouracil Follistim Urofollitropin Forteo Teriparatide Fragmin Dalteparin Sodium Fusilev Levoleucovorin Fuzeon Enfuvirtide Gamastan Immune Globulin Gammagard Immune Globulin Gammaplex Immune Globulin Gammar Immune Globulin Gamunex Immune Globulin Ganirelix Ganirelix Acetate Ganite Gallium Nitrate Genarc Antihemophilic Factor Genotropin Somatropin Gilenya Fingolimod Gleevec Imatinib Gonal-F Follicle Stimulating Hormone Halaven Eribulin Helixate Antihemophilic Factor Hemofil Antihemophilic Factor Hepsera Adefovir Dipivoxil Herceptin Trastuzumab Hizentra Immune Globulin Humate Humic Acid Humatrope Somatropin Humira Adalimumab Hyalgan Sodium Hyaluronate Hycamtin Topotecan Hyperhep B Hepatitis B Immune Globulin Hyperrho Rho(D) Immune Globulin Ilaris Canakinumab Incivek Telaprevir Increlex Mecasermerin Infergen Interferon Alfacon-1 Innohep Tinazaparin Sodium Intron A Interferon Alfa-2b Iplex Insulin-like Growth Factor-1 Iressa Gefitinib Irinotecan Irinotecan Ixempra Ixabepilone Kalbitor Ecallantide Kepivance Palifermin Kineret Anakinra Koate Antihemophilic Factor Kogenate Antihemophilic Factor Kuvan Sapropterin Hydrochloride Letairis Ambrisentan Leukine Sargramostim Leupron Leuprorelin Lovenox Enoxaparin Sodium Lucentis Ranibizumab Lupron Leuprorelin Luveris Lutropin Alfa Macugen Pegatanib Makena Hydroxyprogesterone Caproate Menopur Menotropins Micrhogam Plus Rho(D) Immune Globulin Mitomycin Powder Mitomycin Powder Monarc Anitehemophilic Factor VIII Monoclate-P Antihemophilic Factor Mononine Coagulation Factor IX Mozobil Plerixafor Mylotarg Gemtuzumab Ozogamicin Myozyme Alglucosidase Alfa Nabi-hb Hepatitis B Immune Globulin Naglazyme Galsulfase Navelbine Vinorelbine Neulasta Pegfilgrastim Neumega Oprelvekin Neupogen Filgrastim Nexavar Sorafenib Nilandron Nilutamide Norditropin Somatropin Injection Novantrone Mitoxantrone Novarel Chorionic Gonadotropin Injection Novoseven Coagulation Factor VIIa Nplate Romiplostim Nutropin Somatropin Octagam Immune Globulin Octreotide Octreotide Omnitrope Somatropin Orencia Abatacept Orfadin Nitisinone Orthovisc Hyaluronan Ovidrel Choriogonadotropin Alfa Ozurdex Dexamethasone Pamidronate Pamidronic Acid Panglobulin Immune Globulin Pegasys Peginterferon Alfa-2a Pegintron Peginterferon Alfa-2b Pentam Pentamidine Pentamide Pentamidine Perjeta Pertuzumab Photofrin Porfimer Plenaxis Abarelix Pregnyl Chorionic Gonadotropin Prialt Ziconotide Privigen Immune Globulin Procrit Epoetin Alfa Profasi Protein Folding Aggregation Stimulator Profilnine Factor IX Complex Prolastin Alpha-Proteinase Inhibitor Proleukin Interleukin-2 Prolia Denosumab Promacta Eltrombopag Pulmozyme Dornase Alfa Raptiva Efalizumab Rebetol Ribavirin Rebif Interferon Beta-1a Reclast Zoledronic Acid Recombinate Antihemophilic Factor Refacto Antihemophilic Factor Refludan Lepirudin Remicade Infliximab Remodulin Treprostinil Repronex Menotropins Revatio Sildefanil Revlimid Lenalidomide Rhogam Rho(D) Immune Globulin Rhophylac Rho(D) Immune Globulin Riastap Fibrinogen Concentrate Ribapak Ribavirin Ribasphere Ribavirin Ribatab Ribavirin Rituxan Rituximab Roferon Interferon Alfa-2a Saizen Somatropin Sandostatin Octreotide Sensipar Cincacalcet Serostim Somatropin Simponi Golimumab Soliris Eculizumab Somatuline Lanreotide Somavert Pegvisomant Sprycel Dastinib Stelara Ustekinumab Supartz odium Hyaluronate Supprelin Histrelin Acetate Sutent Sunitinib Synagis Palivizumab Synarel Nafarelin Synvisc Hyaluronan Tarceva Erlotinib Tasigna Nilotinib Taxol Paclitaxel Tecfidera Dimethyl Fumarate Temodar Temozolomide Teslac Testolactone Tev-tropin Somatropin Thalomid Thalidomide Thiotepa Organophosphorous Thyrogen Thyrotropin Alfa Tobi Tobamycin Torisel Temsirolimus Tracleer Bosentan Treanda Bendamustine Trelstar Triptorelin TykerB Lapatinib Tysabri Natalizumab Tyvaso Treprostinil Tyzeka Telbivudine Uvadex Methoxsalen Vantas Histrolin Vectibix Panitumumab Velcade Borteozomib Venoglobulin Immune Globulin Ventavis Iloprost Vepesid Etoposide Viadur Leuprorelin Victrelis Boceprevir Vidaza Azacitidine Virazole Ribavirin Visudyne Verteporfin Vivaglobin Immune Globulin Vivitrol Naltrexone Votrient Pazopanib Vpriv Velaglucerase Alfa Winrho Rho(D) Immune Globulin Xalkori Crizotinib Xeljanz Tofacitinib Citrate Xeloda Capecitabine Xenazine Tetrabenazine Xolair Omalizumab Xyntha Antihemophilic Factor Xyrem Gamme-hydroxybutyric Acid Yervoy Ipilimumab Zavesca Miglustat Zelboraf Vemurafenib Zemaira Alpha 1-Proteinase Inhibitor Zemplar Paricalcitol Zevalin Ibritumomab Tiuxetan Zoladex Goserelin Zolinza Vorinostat Zometa Zoledronic Acid Zorbtive Recombinant Human Growth Hormone eAppendix B. List of Evaluated Disease Areas and Specialty Pharmaceuticals

Category Disease Group Acute Genital Warts Acute Hepatitis A/Measles/Varicella/Rubella Acute Multiple Actinic Solar Keratoses Acute Pneumonia Acute Rescue After High-Hose Methotrexate Acute Respiratory Syncytial Virus Acute Thyroidectomy Treatment Included Addiction Included Ankylosing Spondylitis Included B-Cell Leukemia Included Breast Cancer Included Chronic Lymphocytic Leukemia Included Chronic Myeloid Leukemia Included Colorectal Cancer Included Deep Vein Thrombosis Included Esophogeal Cancer Included Head and Neck Included Hepatitis B Included Hepatitis C Included HIV Included Hodgkins Lymphoma Included Infertility Included Irritable Bowel Disease Included Lupus Included Macular Degeneration Included Melanoma Included Multiple Myeloma Included Multiple Sclerosis Included Myelodysplastic Disease Included Non-hodgkins Lymphoma Included Osteoporosis Included Pancreatic Cancer Included Prostate Cancer Included Psoriasis Included Pulmonary Hypertension Included Renal Cancer Included Rheumatoid Arthritis Included Stomach Cancer Included Testicular Cancer Orphan Acromegaly Orphan Angioedema Orphan Barrett's Syndrome Orphan Chronic Inflammatory Demyelinating Polyneuropathy Orphan Chronic Iron Overload Orphan Congenital Fibrinogen Deficiency Orphan Cryoprin Associated Periodic Syndrome Orphan Cystic Fibrosis Orphan Dermatofibrosarcoma Orphan Excessive Leukemic Myeloid Blasts Orphan Fabry Disease Orphan Familial Cold Urticaria Orphan Gaucher Disease Orphan Growth Hormone Deficiency Orphan Hemophilia Orphan Homocystinuria Orphan Hunter Syndrome Orphan Huntington's Disease Orphan Idiopathic Short Stature Orphan Maroteaux-Lamy Syndrome Orphan Muckle Wells Syndrome Orphan Mucopolysacchariodosis Orphan Narcolepsy Orphan Paget's Disease Orphan Pompe Disease Orphan Prader-Willi Syndrome Orphan Precocious Puberty Orphan Primary Immunodeficiency Orphan Thrombocytopenic Purpura Orphan Tuberous Sclerosis Orphan Turner Syndrome Supportive Anemia Supportive Anticoagulent Supportive Emphysema (AAT Deficiency) Supportive Heparin Associated Thrombocytopenia Supportive HIV Associated Wasting Supportive Hypercalcemia Supportive Hyperparathyroidism in Patients with CKD Supportive Neutropenia Associated Infections Supportive Osteoarthritis Pain Supportive Pallliative Care Supportive Plasmic Uric Acid Supportive Prophylaxis of Cytomegalovirus Disease Associated with Transplant Supportive Renal Toxicity in Patients with Ovarian Cancer Supportive Thrombocytopenia in Pateints with Chronic Immune Thrombocytopenia Supportive Xerostomia eAppendix C. Full List of Cost Per QALY Results

Disease Article Ratio Description Cost Per

Area QALY

RA 200 Methotrexate and infliximab versus methotrexate and $13,000 placebo in patients with active, refractory rheumatoid arthritis 193 Treatment with infliximab plus methotrexate for two $19,000 years versus treatment with methotrexate alone for two years in Swedish patients with advanced rheumatoid arthritis Treatment with infliximab plus methotrexate for one $4000 year versus treatment with methotrexate alone for one year in Swedish patients with advanced rheumatoid arthritis 187 Infliximab and methotrexate (MTX) versus traditional $56,000 disease modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis

Adalimumab monotherapy versus traditional disease $48,000 modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis

Etanercept monotherapy versus traditional disease $43,000 modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis

Etanercept and methotrexate (MTX) versus traditional $42,000 disease modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis

Adalimumab and methotrexate (MTX) DE009 and $41,000 DE019 versus traditional disease modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis Adalimumab and methotrexate (MTX) DE009 versus $40,000 traditional disease modifying antirheumatic drugs (DMARD) in Swedish patients with moderate to severe rheumatoid arthritis

192 Tumor necrosis factor inhibitor (etanercept) versus no $52,000 treatment in patients with rheumatoid arthritis in southern Sweden

Tumor necrosis factor inhibitor (infliximab) versus no $52,000 treatment in patients with rheumatoid arthritis in southern Sweden

188 Infliximab and methotrexate (MTX) versus placebo $48,000 and MTX in patients with severe treatment-resistant rheumatoid arthritis

198 Methotrexate + abatacept, 10 year duration versus $55,000 Methotrexate, 10 year duration IN US women aged 55- 64 years with moderate to severe rheumatoid arthritis

Methotrexate + abatacept, lifetime duration versus $49,000 Methotrexate, lifetime duration IN US women aged 55- 64 years with moderate to severe rheumatoid arthritis

199 Infliximab in addition to disease modifying $220,000 antirheumatic drugs therapy versus disease modifying antirheumatic drugs therapy in patients with rheumatoid arthritis

Infliximab in addition to disease modifying $160,000 antirheumatic drugs therapy versus disease modifying antirheumatic drugs therapy in patients with mild to moderate rheumatoid arthritis (HAQ score <1)

Infliximab in addition to disease modifying $72,000 antirheumatic drugs therapy versus disease modifying antirheumatic drugs therapy IN Patients with moderate to severe rheumatoid arthritis (HAQ score >1 but <2)

Infliximab in addition to disease modifying $55,000 antirheumatic drugs therapy VERSUS disease modifying antirheumatic drugs therapy IN patients with severe to very severe rheumatoid arthritis (HAQ score >2)

197 Abatacept plus oral disease modifying antirheumatic $58,000 drugs versus oral disease modifying antirheumatic drugs in US women aged 55-64 years with moderate to severely active rheumatoid arthritis and inadequate response to anti-TNF (tumor necrosis factor) drugs; 10- year horizon

Abatacept plus oral disease modifying antirheumatic $52,000 drugs versus oral disease modifying antirheumatic drugs in US women aged 55-64 years with moderate to severely active rheumatoid arthritis and inadequate response to anti-TNF (tumor necrosis factor) drugs; lifetime horizon

190 Regimented Treatments: 1) adalimumab + $26,000 methotrexate --> 2) methotrexate + hydroxychloroquine -->3) leflunomide --> 4) gold --> 5) Palliative Care Versus Regimented Treatment: 1) methotrexate --> 2) methotrexate + hydroxychloroquine --> 3) Leflunomide --> 4) Gold -- > 5) Palliative care IN patients diagnosed with rheumatoid arthritis within the US healthcare system

Regimented Treatments:1) adalimumab + methotrexate $22,000 --> 2) etanercept + hydroxychloroquine -->3) methotrexate + hydroxychloroquine --> 4) Leflunomide --> 5) Palliative Care Versus Regimented Treatment: 1) methotrexate --> 2) methotrexate + hydroxychloroquine --> 3) Leflunomide --> 4) Gold -- > 5) Palliative Care IN Patients diagnosed with Rheumatoid Arthritis within the US healthcare system

201 Rituximab in combination with methotrexate versus $61,000 methotrexate alone in women aged 55-64 years with active rheumatoid arthritis and inadequate response to a tumor necrosis factor (TNF)-alpha therapy

Abatacept in combination with methotrexate versus $52,000 methotrexate alone in women aged 55-64 years with active rheumatoid arthritis and inadequate response to a tumor necross factor (TNF)-alpha therapy

191 Etanercept versus best supportive care in Finnish $79,000 patients with rheumatoid arthritis who failed tumor necrosis factor inhibitor (TNF-inhibitor) therapy

Infliximab versus best supportive care in Finnish $57,000 patients with rheumatoid arthritis who failed tumor necrosis factor inhibitor (TNF-inhibitor) therapy

Rituximab versus best supportive care in Finnish $47,000 patients with rheumatoid arthritis who failed tumor necrosis factor inhibitor (TNF-inhibitor) therapy

195 Infliximab versus natural progression in Swedish $35,000 patients who have been diagnosed with rheumatoid arthritis

189 Single infusion of rituximab 1000 mg given on days 1 $37,000 and 15 of each month for 1 year versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis for whom at least 1 anti-TNF (tumor necrosis factor) blocking agent had failed

Single infusion of rituximab 1000 mg given on days 1 $37,000 and 15 of each month for 1 year versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis for whom at least 1 anti-TNF (tumor necrosis factor) blocking agent had failed

Single infusion of rituximab 1000 mg given on days 1 $24,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis for whom at least 1 anti- TNF(tumor necrosis factor) blocking agent had failed for inefficiency

Single infusion of rituximab 1000 mg given on days 1 $24,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis for whom at least 1 anti- TNF(tumor necrosis factor) blocking agent had failed for inefficiency

Single infusion of rituximab 1000 mg given on days 1 $23,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 1 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (rituximab as second line)

Single infusion of rituximab 1000 mg given on days 1 $23,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 1 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (rituximab as second line)

Single infusion of rituximab 1000 mg given on days 1 $22,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 2 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (rituximab as third line)

Single infusion of rituximab 1000 mg given on days 1 $22,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 2 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (rituximab as third line)

Single infusion of rituximab 1000 mg given on days 1 $13,000 and 15 of each month for 6 months versus no biologic treatment IN Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 3 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (rituximab as fourth line)

Single infusion of Rituximab 1000 mg given on days 1 $13,000 and 15 of each month for 6 months versus no biologic treatment in Italian patients with moderate to severe rheumatoid arthritis with inadequate response to 3 anti- TNF (tumor necrosis factor) blocking agent had failed for inefficiency (Rituximab as fourth line)

194 Etanercept (ETA) plus methotrexate and half dose of $21,000 etanercept if remission occurs versus methotraxate in patients with early active rheumatoid arthritis in Sweden

196 Adalimumab plus methotrexate versus methotrexate $30,000 alone in patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: healthcare perspective

Adalimumab plus methotrexate versus methotrexate $30,000 alone in patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: societal perspective

Etanercept plus methotrexate versus Methotrexate $30,000 alone in patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: societal perspective

Etanercept plus methotrexate versus methotrexate $29,000 alone in patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: healthcare perspective

Tocilizumab plus methotrexate versus methotrexate $26,000 alone in patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: healthcare perspective

Tocilizumab plus methotrexate versus methotrexate $26,000 alone in Patients with moderate-to-severe rheumatoid arthritis with inadequate response to DMARDs: societal perspective

MS 176 Interferon beta-1b versus best practice without $2,400,000 interferon in ambulatory patients with secondary progressive multiple sclerosis

Interferon beta-1b versus best practice without $2,600,000 interferon in ambulatory patients with secondary progressive multiple sclerosis and attending neurology services

180 Interferon beta-1b versus no treatment in patients with $55,000 secondary progressive multiple sclerosis

183 Interferon beta-1b versus standard management in $1,900,000 patients with relapsing-remitting multiple sclerosis (RRMS)

Interferon beta-1b versus standard management in $770,000 patients with relapsing-remitting multiple sclerosis

Interferon beta-1b versus standard management in $530,000 patients with relapsing-remitting multiple sclerosis

181 Treatment with interferon beta-1b versus placebo (no $38,000 treatment) in patients from a Canadian epidemiological dataset (versus a comparator clinical trial dataset) who converted from relapsing-remitting to secondary progressive multiple sclerosis in the model

182 Preventive treatment with interferon beta versus usual $120,000 care in Hypothetical cohort of UK women with initial RRMS - aged 30 years

179 Interferon beta-1b therapy for 54 months versus no $57,000 treatment in patients with active relapsing-remitting or secondary progressive multiple sclerosis

Interferon beta-1b therapy for 36 months versus no $11,000 treatment in patients with active relapsing-remitting or secondary progressive multiple sclerosis

186 Treatment with interferon beta-1b plus routine $330,000 supportive care versus routine supportive care only in patients with secondary progressive or progressive relapsing multiple sclerosis

175 Glatiramer acetate 20 mg/wk (copaxone) versus $310,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting multiple sclerosis - aged 30 years

Interferon beta-1a - 44 µg/wk (Rebif) versus $230,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting multiple sclerosis - aged 30 years

Interferon beta-1a, 22 µg/wk (Rebif) versus $200,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting multiple sclerosis - aged 30 years

Interferon beta-1b, 8 MIU/wk (Betaferon) versus $160,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting multiple sclerosis - aged 30 years

Interferon beta 1b 8 MIU/wk (Betaferon) versus $150,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting and secondary progressive multiple sclerosis - aged 30 years

Interferon beta-1a, 6 MIU/wk (Avonex) versus $140,000 conventional multiple sclerosis treatment - symptom control, physiotherapy, psychiatric support, social support, disability aids in patients with untreated relapsing remitting multiple sclerosis - aged 30 years

184 Interferon beta-1a versus no treatment in hypothetical $3,100,000 cohorts of men and women with newly diagnosed non- primary progressive multiple sclerosis

174 Subcutaneous Interferon Beta-1alpha versus symptom $490,000 management in RRMS patients (United States)

Intramuscular Interferon Beta-1alpha versus symptom $400,000 management in RRMS patients (United States) Subcutaneous Interferon Beta-1beta versus symptom $370,000 management in RRMS patients (United States)

Subcutaneous glatiramer acetate versus symptom $300,000 management in RRMS patients (United States)

177 Natalizumab therapy (300mg), diesese modifying $17,000 therapy (DMTs) versus best supportive care in UK patients with highly active relapsing-remitting multiple sclerosis (HARRMS) similar to patients from the placebo arm of the AFFIRM study

Interferon beta (INFbeta)-1b 8 MIU versus best $370,000 supportive care in patients with relapsing-remitting secondary progressive multiple sclerosis

Glatiramer acetate (GA) versus best supportive care in $360,000 patients with relapsing-remitting and secondary progressive multiple sclerosis

Interferon beta (INFbeta)-1a 22 micro g versus best $220,000 supportive care in patients with relapsing-remitting and secondary progressive multiple sclerosis

Interferon beta (INFbeta)-1b 8 MIU versus best $190,000 supportive care in patients with relapsing-remitting multiple sclerosis

Interferon beta (INFbeta)-1a 44 micro g versus best $150,000 supportive care in patients with relapsing-remitting and secondary progressive multiple sclerosis

Physician-administered Interferon beta (INFbeta)-1a 6 $130,000 MIU versus best supportive care in patients with relapsing-remitting and secondary progressive multiple sclerosis

Self-administered Interferon beta (INFbeta)-1a 6 MIU $120,000 versus best supportive care in patients with relapsing- remitting and secondary progressive multiple sclerosis

178 Symptom management alone in combination with $170,000 subcutaneous glatiramer acetate versus symptomatic management therapy in patients diagnosed with relapsing remitting multiple sclerosis, (MS); Serbian perspective.

BC 164 Combination therapy with vinorelbine plus mitomycin $32,000 C versus mitomycin plus vinblastine (standard 2nd-line chemotherapy) in female patient (aged 18-70) histologically diagnosed with metastatic breast cancer and progressive disease after 1st-line chemotherapy

159 Doxorubicin and cyclophosphamide chemotherapy $32,000 with adjuvant trastuzumab monotherapy versus doxorubicin and cyclophosphamide chemotherapy alone followed by paclitaxel in 50-year-old US women with early stage HER2-Positive breast cancer

168 Adjuvant chemotherapy with trastuzumab, 52 week $20,000 course versus usual care IN 50-year-old patients with human epidermal growth factor receptor 2 protein (HER2)-positive breast cancer

Adjuvant chemotherapy with trastuzumab, 9 week $1500 course versus usual care in 50-year-old patients with human epidermal growth factor receptor 2 protein (HER2)-positive breast cancer

FEC100 regimen, six cycles, 3-weekly basis, followed $54,000 by trastuzumab 3-weekly, 17 cycles. Versus FEC100 regimen, six cycles, 3-weekly basis in patients with early breast cancer patients that overexpress HER2

163 Nonanthracycline-based adjuvant trastuzumab therapy $68,000 ( NAT) versus nontrastuzumab (NT) therapy in 49- year-old women with HER2/neu-positive early-stage breast cancer

Anthracycline-based adjuvant trastuzumab therapy $47,000 (AAT) versus nontrastuzumab (NT) therapy IN 49- year-old women with HER2/neu-positive early-stage breast cancer

165 Adjuvant chemotherapy plus trastuzumab versus $22,000 Chemotherapy alone in patients with HER2-positive early breast cancer, from the United States healthcare system

Adjuvant chemotherapy plus trastuzumab versus $17,000 chemotherapy alone in patients with HER2-positive early breast cancer, from Italian healthcare system

166 Immunohistochemical (IHC) test: 1-year adjuvant $79,000 trastuzumab for IHC +2 and +3 patients; standard care for all other patients versus standard care in early breast cancer patients

FISH test: 1-year adjuvant trastuzumab for FISH+ $61,000 patients; standard care for all other patients versus immunohistochemical (IHC) test, FISH confirmation for IHC +2 and +3 patients: 1-year adjuvant trastuzumab for FISH+ patients; standard care for all other patients in 55-year-old female with early breast cancer completely excised and after 4 cycles of chemotherapy

Immunohistochemical (IHC) test: 1-year adjuvant $56,000 trastuzumab for IHC +3 patients; standard care for all other patients versus standard care in 55-year-old female with early breast cancer completely excised and after 4 cycles of chemotherapy

Immunohistochemical (IHC) test, FISH confirmation $53,000 for IHC +2 and +3 patients: 1-year adjuvant trastuzumab for FISH+ patients; standard care for all other patients versus standard care for all patients IN 55-year-old female with early breast cancer completely excised and after 4 cycles of chemotherapy

167 FISH test, with trastuzumab and chemotherapy for $89,000 FISH+ patients; chemotherapy alone for all other patients versus IHC test, with FISH confirmation for 2+ and 3+ patients, trastuzumab and chemotherapy for FISH+ patients; chemotherapy alone for all other patients in 65-year-old Swedish metastatic breast cancer patients

IHC test, with FISH confirmation for 2+ and 3+ $77,000 patients, trastuzumab and chemotherapy for FISH+ patients; chemotherapy alone for all other patients versus chemotherapy alone for all patients in 65-year- old Swedish metastatic breast cancer patients

172 Adjuvant Trastuzumab treatment (5-year) after $73,000 chemotherapy treatment for breast-cancer versus usual care, observation alone after chemotherapy IN US women with Her2/Neu-Positive Breast Cancer

173 Trastuzumab adjuvant therapy versus no trastuzumab $140,000 adjuvant therapy in women (>80 years) with metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer

Trastuzumab adjuvant therapy versus no trastuzumab $37,000 adjuvant therapy in women (70-79 years) with metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer

Trastuzumab adjuvant therapy versus no trastuzumab $18,000 adjuvant therapy in women (60-69 years) with metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer

Trastuzumab adjuvant therapy versus no trastuzumab $12,000 adjuvant therapy in women (50-59 years) with metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer

Trastuzumab adjuvant therapy versus no trastuzumab $9500 adjuvant therapy in women

171 Ixabepilone plus capecitabine: 40 mg/m2 on day 1 plus $380,000 capecitabine 2,000mg/m2 per day for the first 14 days of each 21-day cycle versus capecitabine alone: 2,500 mg/m2 per day for the first 14 days of each 21-day cycle in metastatic breast cancer patients previously determined to be taxane-resistant and previously treated with or resistant to an anthracycline

160 Treatment with trastuzumab versus treatment without $120,000 trastuzumab in US patients with HER-2 positive metastatic breast cancer

Treatment with trastuzumab versus treatment without $50,000 trastuzumab in US patients with HER-2 positive early and metastatic breast cancer

Treatment with trastuzumab versus treatment without $37,000 trastuzumab in US patients with HER-2 positive early breast cancer

170 9 week trastuzumab treatment versus treatment without $19,000 trastuzumab in Finnish women with HER2 positive early breast cancer

161 Trastuzumab versus none in British women with HER- $51,000 2 positive early breast cancer

162 12-month adjuvant trastuzumab versus standard $13,000 chemotherapy in women aged 50 years with early HER-2/neu-positive breast cancer and surgical resection of disease