Health-economic review of zoledronic acid for the management of skeletal-related events in bonemetastatic

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1 Expert Review of Pharmacoeconomics & Outcomes Research ISSN: (Print) (Online) Journal homepage: Health-economic review of zoledronic acid for the management of skeletal-related events in bonemetastatic prostate cancer John A Carter & Marc F Botteman To cite this article: John A Carter & Marc F Botteman (2012) Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic prostate cancer, Expert Review of Pharmacoeconomics & Outcomes Research, 12:4, , DOI: / erp To link to this article: Published online: 09 Jan Submit your article to this journal Article views: 369 Citing articles: 8 View citing articles Full Terms & Conditions of access and use can be found at

2 For reprint orders, please contact Health-economic review of zoledronic acid for the management of skeletalrelated events in bonemetastatic prostate cancer Expert Rev. Pharmacoecon. Outcomes Res. 12(4), (2012) John A Carter & Marc F Botteman* Pharmerit North America LLC, 4350 East West Highway, Suite 430, Bethesda, MD 20814, USA *Author for correspondence: Tel.: mbotteman@pharmerit.com Zoledronic acid is the only bisphosphonate approved for the prevention or delay of skeletal-related events in patients with bone metastases secondary to prostate cancer. Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer. This article summarizes the cost effectiveness literature pertaining to these two agents when used in the prevention of skeletal-related events secondary to malignancy. Zoledronic acid (and denosumab in comparison with zoledronic acid) have been found to be cost effective and cost ineffective depending on the analytical perspective and model parameters. Keywords: bone metastases cost effectiveness denosumab prostate cancer skeletal-related events zoledronic acid An estimated 217,730 men in the USA were newly diagnosed with prostate cancer in 2010 [1]. Approximately 65 75% of those patients with advanced prostate cancer will develop bone metastases [2]. Without bisphosphonate treatment, approximately 50% of patients with prostate cancer metastatic to the bone will develop 1 skeletal-related event (SRE; e.g., radiotherapy or surgery to bone, pathological fracture or spinal cord compression) within 2 years [3]. These SREs are associated with increased treatment costs [4], decreased survival [5] and impaired quality of life [6,7]. Thus, the prevention or reduction of SREs in bone-metastatic prostate cancer is an important treatment goal. Patients with metastatic prostate cancer at risk of experiencing SREs often receive zoledronic acid, a third-generation intravenous bisphosphonate. Zoledronic acid is the only member of its class approved in this indication across the USA and Europe [8 10]. A Phase III clinical trial has shown that zoledronic acid (4 mg every 3 4 weeks) was superior to placebo in reducing SREs in hormonerefractory prostate cancer patients with bone metastases [11,12]. Significantly fewer zoledronic acid-treated patients experienced 1 SRE at 15 and 24 months (p < 0.05) amounting to a 53% overall reduction in SREs (RR: 0.47; p < 0.05) [11 13]. At 15 months, the median time to the first SRE was 321 days in the placebo group, but had not yet been reached in the zoledronic acid group. After the 24-month extension study, the median time to first SRE was approximately 6 months longer for zoledronic acid-treated versus placebo-treated patients (p = 0.011) [12]. In an exploratory analysis, zoledronic acid was associated with a significant reduction of SREs (-11%; p = 0.019) when excluding asymptomatic fractures [12]. Denosumab (a fully human monoclonal antibody administered via subcutaneous injection) was recently approved by the US FDA [14] and the EMA [15] for SRE prevention in patients with prostate cancer and bone metastases on the basis of a Phase III trial comparing it with zoledronic acid [16]. In the trial, patients with bone-metastatic prostate cancer were randomized to receive monthly denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously) until the first on-study SRE or death [16]. Denosumab demonstrated a primary end point of noninferiority to /ERP Expert Reviews Ltd ISSN

3 Carter & Botteman zoledronic acid for time to first SRE (HR: 0.82; 95% CI: ; p = ; p = for secondary end point, superiority). No significant differences in overall survival, disease progression and adverse event rates were observed. While denosumab is a step forward for SRE-preventative therapy in terms of clinical effectiveness, a number of oncologists have raised concerns that denosumab s clinical advantages and ease of administration may not justify its high incremental cost (e.g., approximately twice that of zoledronic acid in the USA) [17 19]. Regardless, denosumab and zoledronic acid are widely used therapies that have been recommended for SRE-prevention in bone-metastatic prostate cancer at the highest recommendation level by the European Association of Urology [20] and the National Comprehensive Cancer Network [21]. The purpose of the present article is therefore to assess and summarize the available evidence regarding the cost effectiveness of zoledronic acid and denosumab in bone-metastatic prostate cancer with the goal of informing clinicians and policy makers who have to make formulary and reimbursement decisions regarding these agents. Systematic literature review A systematic literature review was conducted to identify all relevant research articles and abstracts that assessed the cost effectiveness of zoledronic acid and/or denosumab for SREprevention in patients with bone metastases secondary to prostate cancer in which the outcome was the incremental cost per qualityadjusted life year (QALY) gained or incremental cost per SRE avoided. A primary search was conducted in PubMed/MEDLINE (years: January 2012) using the following search terms (cost effectiveness OR cost utility) AND (zoledronic OR denosumab) AND prostate. Expansion of terms traditionally associated with economic analyses (i.e., the inclusion of cost benefit, economic evaluation and value for money in the search strategy) did not result in additional analyses. This was supplemented with a secondary search (using keywords from the primary search) of relevant congresses (International Society for Pharmacoeconomics and Outcomes Research [ISPOR] [101] and the American Society of Clinical Oncology [ASCO] [102]; years: all). Additionally, the Database of Abstracts of Reviews of Effects, National Institute for Health Economic Evaluation Database, and the Health and Technology Assessment Database were searched via the Center for Reviews and Dissemination (years: 2000 to 20 January 2012) [103]. The authors personal files and references were also searched. Letters, editorials, correspondences and comments were excluded. All searches were performed without regard to language. Studies were systematically assessed by two reviewers and retained if they satisfied the above inclusion criteria. The literature search initially identified 64 studies (Figure 1). After inspection, 14 studies remained. Four studies reported in an abstract format corresponded to published, full analyses found in the PubMed primary search. These four studies were deemed duplicate analyses and removed. Following manual review of references and personal files, one study was added. During peer review, a cost effectiveness analysis of denosumab versus zoledronic acid from a USA managed care perspective was published, and was added to our review as well. Thus, 12 studies were retained in the final review (Tables 1 & 2). Outcomes were extracted systematically and presented in the currency and year in which they were originally reported (Tables 1 & 2). Of these 12 studies, five were fully published reports [22 26] and seven were congress presentations (four from ASCO [27 30]; two from ISPOR [31,32]; one from the European Cancer Organization [33]). Of the seven congress presentations, posters were available for four [29,31 33]. The remaining three [27,28,30] were presented as abstracts only. With the exception of studies of the cost effectiveness of denosumab versus zoledronic acid in The Netherlands [32], USA [25] and the UK [23], all studies included in this review received funding support from Novartis Pharmaceuticals; the maker of zoledronic acid. The Dutch analysis by Lothgren et al. (2011) [32], the USA analysis by Stopeck et al. (2012) [25] and the Amgen UK analysis presented by Ford et al. (2011; who also performed an independent [i.e., nonpharmaceutical industry funded] analysis based on the Amgen analysis presented in the same report) [23] were funded by Amgen Incorporated; the maker of denosumab. analysis by Ford et al. (2011) [23] was commissioned by the UK s health technology assessment program, and is thus the only analysis not to have been funded by a pharmaceutical company. Only one study (by Reed et al [24]) was prospectively designed and performed alongside a clinical trial. Reed et al. was also the only reviewed analysis to have been performed from a societal (i.e., nonpayer) perspective. Cost effectiveness of zoledronic acid & denosumab in metastatic prostate cancer The cost effectiveness of zoledronic acid versus placebo (i.e., no therapy) or pamidronate was assessed in six of the 12 studies retained for review and the cost effectiveness of denosumab versus zoledronic acid was also assessed in six of the 12 studies (Table 1). Zoledronic acid versus no therapy The seminal analysis (published in full) by Reed et al. [24] was a prospectively-designed evaluation from an international, societal perspective (but presented in US$) performed in parallel to the 15-month Phase III clinical trial of zoledronic acid versus placebo [11]. Resource utilization was collected alongside the trial and country-specific costs were drawn from local health economists in non-usa countries. USA costs were based on Medicare reimbursement rates and published average wholesale drug prices. Patients completed the EuroQol Group s EQ5-D (a descriptive system using five domains each with three levels that defines 245 mutually exclusive health states) to assess the effect of SREs on quality of life every 3 months. EQ-5D data were used to estimate the difference in quality of life between patients with and without SREs, and ultimately, to calculate the QALY difference between treatment groups. Reed et al. reported both the incremental cost per QALY gained and the incremental cost per SRE avoided as 426 Expert Rev. Pharmacoecon. Outcomes Res. 12(4), (2012)

4 Zoledronic acid for the management of skeletal-related events in prostate cancer measures of cost effectiveness (Table 1). Source n In their analysis, Reed et al. found that ASCO 33 the total medical cost (excluding study drug CRD 2 cost) was US$5689 per patient on placebo ISPOR 11 versus $5365 per patient on zoledronic NHS 9 Excluded if: acid (difference -$324; 95% CI: to PubMed 9 Not cost-effective analysis 1140; p = ). Including drug and Not zoledronic acid or denosumab administration costs of zoledronic acid, total Not SRE prevention Not bone metastases cost increased to $11,042 per patient on Not prostate cancer Source n zoledronic acid, resulting in a net increase of Not cost/qaly or cost/sre avoided ASCO 5 $5353 per patient relative to placebo-treated CRD 2 patients. The incremental costs per QALY ISPOR 3 gained and SRE-avoided were $159,200 NHS 1 (95% CI: 88, ,600) and $12,300 PubMed 3 Excluded: (95% CI: ,700), respectively [24]. One ASCO abstract (PubMed duplicate) Univariate sensitivity analysis indicated One ISPOR abstract (PubMed duplicate) that measures of cost effectiveness were Two CRD (both PubMed duplicates) most sensitive to drug acquisition cost Included studies n (i.e., an increase in zoledronic acid cost Research articles 4 Added: to its average wholesale price resulted in HTA report 1 One ECCO poster (from manual search) One research article (published during review) Congress abstracts/posters 7 $217,900/QALY and $16,900/SRE). The authors concluded that the cost effectiveness estimates of zoledronic acid versus placebo Figure 1. Study retrieval. exceeded typical thresholds for conferring ASCO: American Society of Clinical Oncology; CRD: Center for Reviews and Dissemination; ECCO: The European Cancer Organisation; HTA: Health and Technology Assessment; cost effectiveness [24]. ISPOR: International Society for Pharmacoeconomics and Outcomes Research; In t heir f u lly published cost NHS: National Health Service; QALY: Quality-adjusted life year; SRE: Skeletal-related event;. effectiveness analysis of zoledronic acid versus no therapy, Carter et al. (2011) as low as in Portugal and as high as 46,327 in France [22] assessed the incremental costs per QALY gained from as a result of varying the cost per infusion of zoledronic acid. In payers perspectives in France, Germany, Portugal and The The Netherlands, nonvertebral fracture cost was the strongest Netherlands over 15 months, corresponding to the timeframe of cost-driver (i.e., a difference of 21,812 between the minimum the clinical trial reported by Saad et al. (2002) [11]. The authors [- 8476] and maximum [ 13,336] values). The cost per infusion found that zoledronic acid patients experienced an estimated of zoledronic acid ranked second. The analysis by Botteman et al. (2009) assessed the cost fewer SREs (0.831 and SREs in zoledronic acid and no-therapy cohorts, respectively) and gained an estimated effectiveness of zoledronic acid versus no therapy from a French QALYs versus placebo patients. The QALY gain was payer perspective over 15 months and was presented as an abstract estimated directly from the analysis by Reed et al. and SRE costs only [28]. Therefore details were limited. Botteman et al. (2009) (which ranged from 144 for vertebral fracture in Germany to employed the same global 15-month analysis as Carter et al. 16,829 for bone surgery in The Netherlands) were based on (2011) [22,31] but with French-specific drug, administration and literature estimates and country-specific reimbursement tariffs. SRE costs. The 15-month cumulative number of SREs was 0.83 Zoledronic acid was associated with reduced SRE-related for zoledronic acid patients and 1.66 for no therapy patients. Costs costs [net costs] ( [ 1,284] in France, [ 841] related to SRE management were 2659 lower in the zoledronic in Germany, [ 309] in Portugal and [ 87] in acid group than no therapy. The subsequent incremental The Netherlands). The incremental costs per QALY gained cost associated with zoledronic acid treatment was 266, and ranged from 2430 (The Netherlands) to 36,007 (France) [22]. incremental QALYs were (estimated from Reed et al. The authors concluded that the the cost effectiveness estimates [24]). The incremental cost per QALY gained with zoledronic fell below the standard 50,000/QALY threshold in non-uk versus no therapy was 7447, and it remained below 50,000 in European countries, and therefore, that zoledronic acid was a various sensitivity analyses for which details were not provided. cost-effective alternative to no treatment. El Ouagari et al. (2003) [33] estimated the cost effectiveness of Univariate sensitivity analysis indicated that the cost per zoledronic versus no therapy from a Canadian payer perspective, infusion of zoledronic acid was the most important determinant but used the 15-month clinical trial report originally reported by of the results in France, Germany and Portugal. That is, Saad et al. (2002) [11] and not the 24-month extension study [12]. variability in the cost per infusion (± 10% as per Reed et al. [24]) This is despite zoledronic acid not being indicated in Canada for was associated with the greatest subsequent variability in costs per bone-metastatic prostate cancer; although it may be routinely QALY gained; with the cost effectiveness estimates having been used. The analysis was presented as a poster at the 2003 European 427

5 Carter & Botteman Table 1. Cost effectiveness analyses of zoledronic acid versus no therapy or pamidronate in prostate cancer patients with bone metastases. Study (year) Country Horizon (months) ZOL vs NT Drug/ admin Cost diff. QALY SRE CE end point SRE Total diff. diff. Cost/ Cost/SRE QALY Botteman et al. (2009) France ,447 [28] Botteman et al. (2006) Canada 24 $7, $78,366 [27] Carter et al. (2011) France , ,007 [22] Carter et al. (2011) Germany ,582 [22] Carter et al. (2011) The Netherlands [22] Carter et al. (2011) Portugal [22] El Ouagari and Baladi (2011) Canada 15 $6910 -$432 $6, $32,378 [33] Reed et al. (2004) Global 15 $5353 $ $159,200 $12,300 [24] ZOL vs PAM Botteman et al. (2006) Canada 24 $ $18,343 $7950 [27] ZOL vs PAM/NT Carter et al. (2011) ,874 [31] Admin: Administration; CE: Cost effectiveness; Diff.: Difference; : Not reported; NT: No therapy; PAM: Pamidronate; QALY: Quality-adjusted life year; SRE: Skeletal-related event; ZOL: Zoledronic acid. Ref. Cancer Organization meeting. SRE costs were estimated based on consultation with a Novartis Oncology Advisory Board, which provided a clinically informed assessment of local treatment patterns. Canadian specialists provided information with which resource use patterns were adjusted and validated for Canadians [33]. However, SREs were assumed to incur cost only if they had required treatment and occurred no fewer than 6 days from the previous event in the clinical trial. Drug acquisition and administration costs were also Canadian-specific. The relevant outcome measure of cost effectiveness was the cost per SRE avoided. The authors found that patients treated with zoledronic acid incurred greater overall treatment costs (i.e., $6910 vs $0) but the average cost of treating SREs per patient were lower in the zoledronic acid group ($567 vs $999). Given that zoledronic acid reduced the total number of SREs by 43, the cost per SRE avoided was $32,378. Interestingly, El Ouagari also presented the cost per patient avoiding an SRE ($58,890 given an 11% reduction in patients experiencing an SRE) [33]. Scenario analysis indicated that cost effectiveness estimates were robust to varying SRE-related resource consumption costs ($53,963/QALY), excluding costs associated with bone surgery ($60,390/QALY), and taking healthcare support costs into consideration ($54,309/QALY) [33]. Given that SREs may cost in excess of $40,000, the authors concluded that zoledronic acid offers a reasonable value for money versus no therapy from a Canadian payer perspective [33]. Zoledronic acid versus pamidronate In some countries, nonapproved bisphosphonates (e.g., pamidronate) are used off-label in place of more effective but more expensive SRE-limiting agents, such as zoledronic acid. Thus, a number of analyses in this review estimated the cost effectiveness of zoledronic acid versus no therapy and/or pamidronate. In an analysis presented as a poster at ISPOR, Carter et al. (2011) [31] adapted the same decision-analytic model described previously [22] to calculate the incremental cost per QALY gained of zoledronic acid versus no therapy from a UK payer s perspective using UK-specific drug and administration costs and SRE-related costs. One important addition in this analysis was the inclusion of a cohort of patients treated with pamidronate (i.e., in addition to no therapy). The rationale for including pamidronate is its off-label use in 17% of patients in the UK despite its lack of efficacy relative to placebo [34]. Hence, in this analysis, it was assumed 17% of patients in the comparator group were treated with pamidronate (and incurred costs associated with pamidronate acquisition and administration) but without any reduction in SREs. Over 15 months (coinciding with the duration of the clinical trial) Carter et al. estimated zoledronic acid patients to have experienced fewer SREs (-0.831), more QALYs ( / patient, estimated from Reed et al. [23]) and fewer SRE-related costs (GBP 1639; 2004 vs 3643), but greater treatment and administration costs (+ 2419/patient; 2789 vs 370) and greater overall costs (+ 780/patient) [31]. Thus, the incremental cost per QALY gained was 21,874 [31]. Because 30,000 per QALY gained is a standard willingness-to-pay threshold in the UK, the authors concluded that zoledronic acid is a cost-effective treatment alternative to pamidronate or no therapy. In univariate sensitivity analysis, key variables (number of infusions, SRE cost, proportion on no therapy and QALY gained) were varied ±10%. In no scenario did the cost effectiveness exceed 30,000 per QALY 428 Expert Rev. Pharmacoecon. Outcomes Res. 12(4), (2012)

6 Zoledronic acid for the management of skeletal-related events in prostate cancer Table 2. Description of cost effectiveness analyses of zoledronic acid and denosumab in prostate cancer patients with bone metastases. Comparators Study (year) Country Horizon Population Efficacy assumption Drug/ admin Cost diff. QALY SRE CE end point Ref. diff. diff. SRE Total Cost/QALY Cost/SRE DMAB vs BSC Ford et al. (2011) [23] No-PAS Amgen SRE-N ,067 PAS Amgen SRE-N ,320 DMAB vs ZOL Lothgren et al. (2011) The Netherlands All $ , [32] Snedecor et al. (2011) The USA 27 months All $7314 -$1924 $ $1,248,051 [29] Stopeck et al. (2012) The USA All $15,431 -$8522 $ $ $8567 [25] Xie et al. (2011) The USA 12 months All $8270 -$488 $ $71,027 [26] Yu et al. (2011) The USA 12 months All $ $66,864 [30] Ford et al. (2011) [23] No-PAS Amgen SRE-E All SRE-N SRE-E All SRE-N SRE-E Nai Exp ,276 46,976 35, , ,237 93, ,575 PAS Amgen SRE-E All SRE-N SRE-E All SRE-N SRE-E Nai Exp Dom Dom Dom Dom Dom Dom Dom Specifically for Ford et al., results are stratified by model source (Amgen submission to NICE [i.e., Amgen] or Ford and colleagues adaptation for NICE []), patient group (SRE-E, SRE-N, or all), source of SRE hazard and risk ratios (i.e., pooled across all patients [], from SRE-E patients [Exp], or from SRE-N patients [Nai]), and whether the patient access scheme was (PAS) or was not (no-pas) used. Indicates that the analysis was supplemented with nontrial data drawn from an analysis comprised mostly of patients who were SRE-experienced. Admin: Administration; BSC: Best supportive care; CE: Cost effectiveness; Diff.: Difference; Dom: Dominated; DMAB: Denosumab; : NICE Assessment Group; : Not reported; PAS: Patient access scheme; QALY: Quality-adjusted life year; SRE: Skeletal-related event; SRE-E: SRE-experienced; SRE-N: SRE-naive; ZOL: Zoledronic acid

7 Carter & Botteman gained. Results were most sensitive to the number of (or cost per) infusions of zoledronic acid (i.e., the incremental costs per QALY gained varied by 13,568 from 15,090 to 28,658). Because the singular comparator cohort was comprised of patients receiving pamidronate or no therapy, the results apply to a comparison of zoledronic acid versus a treatment strategy involving a certain proportion receiving pamidronate or no therapy. Therefore, the analysis by Carter et al. did not establish, from a UK payer perspective, whether zoledronic is cost effective versus no therapy or pamidronate, individually [31]. An analysis by Botteman et al. (2006) [27] is the only analysis reviewed herein to have estimated the cost effectiveness of zoledronic acid versus no therapy and versus pamidronate using the 24-month extension study [12] of the 15-month Phase III trial [11]. As was done in the 2011 ISPOR analysis by Carter et al. [31], Botteman et al. (2006) incorporated pamidronate as a third treatment option (i.e., used costs associated with pamidronate acquisition/administration and efficacy from the placebo cohort to represent patients treated with pamidronate). However, unlike Carter et al. [31], Botteman et al. compared zoledronic acid to no therapy and to pamidronate separately, and did not create one comparator cohort comprised of both. It should also be noted that the QALY gain estimated by Botteman et al. was greater than that used by Reed et al. (and studies that incorporated Reed et al. s QALY gain estimate) because the time horizon in Botteman et al. was longer (i.e., 24 months as opposed to 15 months). The analysis by Botteman et al. was performed from a Canadian payer perspective. Again, zoledronic acid is not approved in Canada for SRE-prevention in bone-metastatic prostate cancer. Botteman et al. (2006) estimated the cumulative number of SREs to be 2.69 for pamidronate and no therapy patients and 1.76 for zoledronic acid-treated patients. Total costs were $11,918, $17,593 and $19,312 (+$7394 vs no therapy; +$1719 vs pamidronate) for no therapy, pamidronate and zoledronic acid patients, respectively. Zoledronic acid-treated patients gained QALYs compared with pamidronate or no therapy. Compared with no therapy, zoledronic acid resulted in an incremental cost per QALY gained of $78,366. Versus pamidronate, zoledronic acid resulted in $18,343 per QALY gained. The authors concluded that zoledronic acid was cost effective according to Canadian standards versus no therapy and pamidronate [27]. Specific details regarding the results of sensitivity and scenario analyses were not provided. Denosumab versus zoledronic acid The cost effectiveness of denosumab versus zoledronic acid was assessed in six analyses [23,25,26,29,30,32]. Each employed a Markov decision model based on a Phase III trial of denosumab versus zoledronic acid in patients with bone-metastatic prostate cancer described in the introduction [16]. Of these analyses, three were published in full [23,25,26], and the other three were presented at 2011 ASCO [29,30] or 2011 ISPOR [32] meetings. In the analysis reported by Xie et al. (2011) [26], a nine-state Markov decision-analytic model assessed the pharmacoeconomic value of denosumab versus zoledronic acid on the basis of cost per SRE avoided over 1- and 3-year time horizons from a US payer perspective. Xie et al. used the cost per SRE avoided as the measure of cost effectiveness. Only literature-derived direct medical costs (i.e., wholesale drug acquisition, creatinine monitoring, labor, SREs, adverse events, disease progression and terminal care) were considered. Health states were defined by SRE occurrence, SRE history, disease progression and death, and patients transited among the nine health states based on transition probabilities derived from the clinical trial [16] and supplemented with the literature estimates. Treatment-related adverse event resource utilization was estimated based on expert opinion. One-way and probabilistic sensitivity analyses were performed to test robustness of model parameters. Patients treated with denosumab experienced and estimated (0.49 vs 0.60) fewer SREs over the 1-year base-case scenario and (1.18 vs 1.46) over 3 years; consistent with the Phase III trial [16] in which denosumab was superior to zoledronic acid. Within the 1-year base-case time horizon, the estimated total costs per denosumab-treated patient were $35,341 ($19,230 and $16,111 for drug and nondrug costs, respectively) and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for zoledronic acid. The incremental total direct cost of denosumab was $7813 and $13,856 over 1 and 3 years, respectively [26]. The estimated incremental total direct costs per SRE avoided with the use of denosumab instead of zoledronic acid were $71,027 for 1 year and $51,319 for 3 years. In descending order of robustness, the following were the five most sensitive model parameters: median time to first on-study SRE for denosumab, median time to first on-study SRE for zoledronic acid, denosumab acquisition cost, zoledronic acid acquisition cost and relative risk of having an SRE associated with disease progression. Within the 1- and 3-year model horizons examined, costs per SRE avoided ranged from $27,318 to $161,680 and from $18,870 to $83,767, respectively. The probabilistic sensitivity analysis indicated that based on cost effectiveness thresholds of $70,000, $50,000 and $30,000 per SRE avoided, denosumab was cost effective in 49.5, 17.5 and 0.3% of the cases at 1 year, respectively. The proportions were 79.0, 49.8 and 4.1% in the 3-year scenario. The authors concluded that denosumab was not a cost-effective treatment alternative to zoledronic acid [26]. Similar to Xie et al., Yu et al. (2011) [30] assessed the cost effectiveness of denosumab versus zoledronic acid from the perspective of cost per SRE avoided in the USA. Yu et al. was presented as an abstract only and therefore details beyond the model structure, inputs and base-case results were limited. The authors employed a 1-year Markov model (number of states not defined) populated with transition probabilities drawn from the Phase III trial [16] and costs derived from the literature. Over 1 year, Yu et al. estimated a total incremental cost of $7355 associated with denosumab ($37,854 vs $30,499). The estimated number of SREs during the 1-year period was 0.56 for denosumab and 0.67 for ZA, where the denosumab patients had 0.11 fewer SREs. The incremental cost per SRE avoided with the use of denosumab was $66,864. Sensitivity analysis indicated that the cost per SRE avoided was driven by the differences in the drug 430 Expert Rev. Pharmacoecon. Outcomes Res. 12(4), (2012)

8 Zoledronic acid for the management of skeletal-related events in prostate cancer costs, risk of progression and risk of first SRE, but outcome values were not provided [30]. The analyses by Snedecor et al. (2011) [29] and Lothgren et al. (2011) [32] were presented at the annual meetings of ASCO and ISPOR, respectively. Both analyses were Markov decision analytic models that assessed the cost effectiveness of denosumab versus zoledronic acid using the incremental cost per QALY gained and/or incremental cost per SRE avoided and based on the Phase III trial reported by Fizazi et al. (2011) [16]. Snedecor et al. estimated that patients treated with denosumab in the USA experienced fewer SREs (-0.25; 1.04 vs 1.29), more QALYs ( ; vs ) and fewer SRE-related costs (-$1942; $7604 vs $9528). However, patients treated with denosumab also incurred greater drug, administration and monitoring costs (+$7314; $20,277 vs $12,963), and thus, greater overall costs (+$5390; $27,881 vs $22,491). Consequently, the incremental cost per QALY gained with denosumab was $1,248,051 [29]. This value increased to $1,375,378, $1,674,075 and $1,899,618 in scenario analyses assuming post-sre discounted therapy, average wholesale drug pricing, and therapy continuation until death, respectively. Univariate sensitivity analysis showed that cost effectiveness was most influenced by assumptions regarding the effect of radiation to bone on patient utility (range in cost per QALY gained: $666,284 to $4,582,138) and time to first SRE in the denosumab cohort (range in cost effectiveness per QALY: $318,968 to Dominated). Probabilistic sensitivity analysis indicated a low likelihood that denosumab is cost effective. That is, 0.36% (18/5000) model replicates had a cost/qaly $100,000 [29]. The authors concluded that denosumab was not a cost-effective treatment alternative to zoledronic acid in this indication from a US payer perspective [29]. The cost effectiveness analysis by Lothgren et al. (2011) [32] was an assessment of denosumab versus zoledronic acid from a Dutch payer s perspective. Funded by Amgen, Lothgren et al. had access to patient level data from the Phase III trial reported by Fizazi et al. [16]. As such, Lothgren et al. calculated baseline patient health state utility based on patient reports on the EQ-5D, which was administered every 4 weeks. SRE-related health state utility values were also drawn directly from the trial. This is opposed to the aforementioned analysis by Snedecor et al. (2011) [29] wherein health state utilities were estimated from the literature. In Lothgren et al., denosumab and zoledronic acid treatmentrelated resource utilization data were also drawn directly from the trial and monetized with local cost data. The specificity of data with which SRE-related treatment costs were calculated was not defined. Costs and outcomes were discounted at 4 and 1.5%, respectively [32]. Over a lifetime model horizon, Lothgren et al. found that patients treated with denosumab experienced fewer SREs (-0.158; vs 1.708), more QALYs (+0.013; vs 1.368), but greater overall costs (+ 542; 11,912 vs 11,370). Thus, the incremental costs per QALY gained and SRE avoided were 42,933 and 3360, respectively. Results of one-way sensitivity analysis indicated that medication administration cost was the strongest driver of modeled outcomes, followed by the impacts of SREs on QALYs and overall treatment costs [32]. Minimal and maximal values were not provided. Given that an incremental 50,000 per QALY gained is the traditional threshold in non-uk European countries, the authors concluded that denosumab is a cost-effective treatment alternative to zoledronic acid in The Netherlands. No such threshold exists for the incremental cost per SRE avoided; however, the authors also state that denosumab represents good value for money from this perspective. Commissioned by NICE, Ford et al. (2011) [23] presented a partially redacted cost effectiveness analysis of denosumab versus zoledronic acid supplied to NICE by Amgen (hereto for referred to as Amgen s analysis). The authors also presented their own analysis based on Amgen s (hereto for referred to as ), but with additional or modified assumptions. These analyses were from a UK payer perspective using a lifetime-horizon Markov model wherein costs and QALYs were discounted 3.5% per annum. SRE-related costs were based on an unpublished, prospective, global study commissioned by Amgen (STARS costing study). Quality of life effects of SREs (i.e., disutility) were measured directly from the clinical trial with the EQ-5D. Drug and administration costs were estimated based on an unpublished microcosting study in the UK and using UK-specific costs. In Amgen s analysis for bone-metastatic prostate cancer, denosumab was compared with zoledronic acid on the basis of incremental cost per QALY gained in patients with 1 SRE prior to initiating therapy (i.e., SRE-experienced). Ford et al. note that Amgen s reasoning for not including a comparison in SRE-naive patients (who were treated with supportive care in the analysis) was due to how zoledronic acid is indicated in the UK for metastatic prostate cancer patients. In the UK, zoledronic acid is recommended by NICE for reimbursement in bone-metastatic prostate cancer only if there is uncontrolled pain. While there was no assessment of uncontrolled pain by Amgen, they noted in their NICE submission that 80% of SRE-experienced bone-metastatic prostate cancer patients (26% of trial participants) had bone pain at trial baseline [23]. Thus, in the Amgen analysis the designation of SREexperienced was used as a proxy for uncontrolled bone pain, and so the comparison of denosumab to zoledronic acid was carried out for SRE-experienced patients only. The results of the Amgen analysis showed that patients treated with denosumab compared with zoledronic acid experienced fewer SREs (-0.14; 1.98 vs 2.12) and more QALYs (0.006; vs 1.083), but greater overall costs ( 922). Unfortunately treatment-specific overall costs were redacted from the report. The resulting incremental cost per QALY gained was 157,276; cost ineffective at NICE s willingness-to-pay threshold of 30,000/ QALY. Alternatively, Amgen (and Ford et al.) conducted the analysis under a scenario wherein the price of denosumab is essentially lowered with a NICE-approved patient access scheme (PAS; details were redacted from the report). Used to help patients gain access to high-cost therapies and improve cost effectiveness, PAS is a predefined strategy of discounts and rebates offered by the drug manufacturer to the UK National Health Service. When including PAS, denosumab saved 281 and zoledronic acid was dominated. In non-pas scenarios, outcomes 431

9 Carter & Botteman were relatively sensitive to excluding the rule that SREs must be 21 days apart (resulting in a reduction to 89,000/QALY), basing SRE-related utilities on an alternate source [35] (resulting in an increase to 348,000 per QALY), and zoledronic acid dosing frequency (resulting in a decrease to 125,000 per QALY) [23]. Incidentally, in SRE-naive patients, the Amgen model estimated that denosumab was cost ineffective versus best supportive care with PAS ( 71,320) and without PAS ( 102,067). Ford et al. noted that, with regard to SREs, Amgen applied to their analysis of denosumab versus zoledronic acid in SREexperienced patients trial-based hazard ratios and relative risks pooled across SRE-experienced and SRE-naive patients. Ford et al. stated that the SRE-experienced subgroup-specific central estimates suggest a smaller treatment effect of denosumab compared with pooled estimates, and that this effect was particularly robust in the prostate cancer analysis [23]. Ford et al. also presented their own model based on the model submitted by Amgen, but which made the comparison across and within SRE-experienced and SRE-naive patients. When using pooled SRE-related hazard ratios and relative risks (as was done in Amgen s model), the authors found that, compared with zoledronic acid, denosumab s cost effectiveness was 46,976, 35,732 and 167,503/QALY in all patients, SREnaive and SRE-experienced, respectively (Table 2). Including PAS, denosumab was dominant in each patient group. Ford et al. conducted the same analysis using SRE-naive and SREexperienced-specific SRE effects. In this scenario, denosumab was cost ineffective at 113,237, 93,575 and 249,575/QALY in all patients, SRE-naive and SRE-experienced, respectively. Again, when including PAS, denosumab was cost-saving and dominated zoledronic acid. The costs per QALY were most sensitive to SRE-naive and SRE-experienced specific hazard ratios and relative risks [23]. None of the scenarios presented by Ford and colleagues took into account the effect of generic zoledronic acid in 2013 on modeled outcomes. Ford et al. indicated that an increase in the incremental cost of denosumab due to generic zoledronic acid will likely increase the increase the incremental cost per QALY gained with denosumab and that such considerations are imperative to health-economic comparisons of these agents. However, consistently across these analyses, denosumab was cost ineffective at its current price but dominant when including PAS (except when versus best supportive care in SRE-naive patients). Stopeck et al. (2012) [25] reported the only fully published analysis of denosumab versus zoledronic acid from a US payer perspective. The authors used a 28-day cycle, lifetime (i.e., 15-year) Markov model (based on the clinical trial report by Fizazi et al. [16]) wherein QALY decrements were estimated from nontrial based time trade-off studies and SRE costs were estimated from a US commercial claims database. Outcomes were discounted 3% per year. Interestingly, this was also the only analysis reviewed that incorporated real-world retrospective claims data [36] in order to adjust the trial-based cumulative number of SREs modeled over patients lifetimes. The cumulative number of SREs estimated to have been experienced by zoledronic acid-treated patients was based on a 2.01 upward adjustment of the trial-based SRE rate, from which the total number of SREs experienced in the denosumab cohort was calculated using the relative treatment effects reported in the clinical trial [25]. The authors justified this assumption with the explanation that SREs have been underreported in clinical trials, and therefore the adjustment ensured that the model better reflected a US managed care perspective [25]. It was estimated that, on average, denosumab-treated patients experienced 0.81 (3.23 vs 4.04) fewer SREs, gained 0.14 more QALYs (0.97 vs 0.83), and incurred $6910 greater total lifetime costs ($76,486 vs $69,577). The subsequent incremental costs per QALY gained and SRE avoided were $49,405 and $8567, respectively. One-way sensitivity analyses indicated that the most influential variables were denosumab drug cost (with outcomes ranging from approximately -$100,000/QALY to $200,000/QALY), zoledronic acid drug cost (with outcomes ranging from approximately -$40,000/QALY to $125,000/QALY), and the adjustment factor by which the total number of SREs was upwardly adjusted (with outcomes ranging from approximately $25,000/QALY to $120,000/QALY) [25]. The probabilistic sensitivity analysis estimated that the probabilities of denosumab being cost effective at $100,000, $150,000 and $200,000 per QALY thresholds were 0.83, 0.94 and 0.98, respectively [25]. The authors concluded that denosumab is a cost-effective treatment alternative to zoledronic acid from a US managed care perspective. Expert commentary Zoledronic acid and denosumab are SRE-limiting agents proven effective in patients with bone-metastatic prostate cancer. As was presented in this article, denosumab has been compared with zoledronic acid from USA, UK and Dutch payer perspectives, and zoledronic acid has been compared with pamidronate and no therapy across Europe and North America. Zoledronic acid was found to be cost effective across Europe and Canada but not in the USA, while denosumab was found to be cost effective in The Netherlands, the UK and the USA in certain analyses, but cost ineffective in other analyses in the UK and the USA. Across the reviewed analyses, by far the most robust driver of modeled outcomes was drug acquisition cost. It was also noteworthy that analyses based on the same clinical trial data estimated SRE-limiting agents to be cost effective in some settings but not in others despite having also employed very similar model structures. For example, while both were based on the Phase III clinical trial reported by Saad et al. (2002) [11], Carter et al. (2011) [22] found zoledronic acid to be a costeffective treatment alternative to placebo from a European payer perspective whereas Reed et al. [23] found it to be cost-ineffective from a US societal perspective. Likewise, Snedecor et al. [29] found denosumab to be cost ineffective versus zoledronic acid from a US payer perspective, while Lothgren et al. found denosumab to be cost effective from a Dutch payer perspective. Both analyses were populated with clinical data from the Phase III clinical trial reported by Fizazi et al. [16]. These seemingly discrepant findings among analyses cannot be ascribed to a single cause. Rather, 432 Expert Rev. Pharmacoecon. Outcomes Res. 12(4), (2012)

10 Zoledronic acid for the management of skeletal-related events in prostate cancer differences in outcomes were likely due to factors such as but not limited to: the use of country-specific drug acquisition and SREtreatment costs, the assumed distribution of subsequent SREtypes, and study-specific assumptions related to the magnitude of effect of SREs on quality of life. These are inputs not typically presented in published clinical trial reports and so will vary among cost effectiveness analyses. Therefore, when assessing multiple cost effectiveness analyses that compare the same agents, one should pay particular attention to the inputs and assumptions specific to each analysis. Similarly, in reviewing the cost effectiveness of SRE-limiting agents in bone-metastatic solid tumors, it is important to emphasize that the choice of economic end points (i.e., incremental costs per QALY gained or SRE avoided) is integral to how one might interpret the analyses and findings. Rader et al. [37] criticized Xie et al. s [26] choice of incremental cost per SRE avoided as the end point on the basis that it did not consider the effect of SREs on patients quality of life within the context of decreasing time remaining in patients lives. Cost per SRE avoided measures incremental effectiveness in only two dimensions (i.e., considering the total costs in the numerator and the number of SREs avoided in the denominator), and thus fails to consider both the timing of SREs and duration of their effect. Conversely, the incremental cost per QALY gained provides a better indication of therapeutic value by considering costs and benefits across at least two additional dimensions: time and severity. Specifically, QALYs integrate SRE-related effects on quality of life and duration of life and the number and timing of SREs in relation to both treatment initiation and time of death. Because of these differences, two treatments with the same cost per SRE avoided could be seen as either cost effective or cost ineffective from an incremental cost per QALY gained perspective. The following example illustrates this point. Assume a US-based pharmacoeconomic comparison of hypothetical SRElimiting Therapy A (which costs $20,000/year) versus B (which costs $10,000/year), within a time-horizon of 2 years, and with a given average SRE cost of $12,000. Over 2 years, patients treated with Therapy A experienced 0.15 fewer SREs and 0.10 more QALYs than patients treated with Therapy B. However, assume that Therapy A did not prevent SREs until the end of the time-horizon (i.e., the incremental benefit of Therapy A over B was not apparent until after nearly 2 years of treatment). In this scenario, the incremental costs per SRE avoided and QALY gained with Therapy A are $121,333 and $182,000, respectively. One would conclude that Therapy A is cost ineffective using both cost effectiveness end points. Now assume a similar scenario in which Therapy A prevented SREs earlier in the time-horizon (i.e., its incremental benefit over Therapy B was evidenced at the beginning of treatment) such that patients treated with Therapy A still experienced 0.15 fewer SREs, but 0.20 more QALYs (rather than 0.10 in the aforementioned scenario) than Therapy B. For the purpose of this example, it is assumed that the QALY increased from 0.10 to 0.20 due to an increase in remaining lifetime and due to the value of preventing SREs in patients who are not as close to death (i.e., model termination). In this scenario, the incremental cost per SRE avoided with Therapy A is unchanged ($121,333) but the cost per QALY decreases to $91,000. Here, one would conclude that Therapy A is cost effective from the perspective of incremental cost per QALY gained. Thus, despite identical results in terms of incremental cost per SRE avoided, one reaches different conclusions based on cost per QALY gained. These examples illustrate that different conclusions regarding the economic value of a therapy can be reached when one considers the incremental cost per QALY gained versus the incremental cost per SRE avoided metric. It also shows that the direction of the disagreement may not be predictable and depends on many factors. Since the cost per QALY metric is a more sensitive and more meaningful measure, in addition to being a universal measure of cost effectiveness that can be compared across therapies and indications, it should be the preferred outcome in health-economic evaluations of SRE-limiting agents. The analyses reviewed herein were populated with clinical data drawn from either a 15-month Phase III trial of zoledronic acid versus placebo (or its 24-month extension study) [11,12] or from the 27-month trial of denosumab versus zoledronic acid [16]. That these models, which sought to determine the cost effectiveness of two treatments routinely used in real-world practice, were populated with clinical trial data, which may not reflect realworld practice, is worth exploration. In both clinical trials, patients underwent skeletal surveys and radiographic assessments approximately every 12 weeks [11,16]. Frequent clinical trial skeletal surveillance (especially with regard to asymptomatic vertebral fractures) may lead to overestimation of the number of SREs relative to what would be seen in a nonexperimental, real-world treatment setting and thus an overestimation of the effects of denosumab and zoledronic acid. In some of these analyses SREs that would not normally be brought to clinical attention, that require conservative therapy and are only identified by routine skeletal surveillance in clinical trials are accorded the same weight (via modeled economic and quality of life impacts) as those that require costly treatment and that have a marked impact on patients quality of life. Furthermore, the rates of asymptomatic skeletal events identified in clinical trials, with the exception of Saad et al. (2004) [12] where overall rates of symptomatic SRE rates were reported but not stratified by type, have not been reported. Therefore, there is the risk of overestimation of SRE burden and thus an overestimation of the value of SRE-limiting therapies in the existing cost effectiveness literature. Such concerns have been voiced previously [38]. In a research highlight of the Phase III denosumab trial reported by Fizazi et al. (2011), Sartor et al. postulated that possible over-identification of asymptomatic vertebral fractures in the Fizazi et al. and Saad et al. trials would overestimate the value of SRE-limiting agents that largely reduce asymptomatic events in patients with advanced disease [38]. By extension, it is possible that because these trials may have overestimated the real-world incidence of SREs and because all the reviewed cost effectiveness analyses were based on these trials, the estimated cost effectiveness values of SRE-limiting agents may be optimistically low. Interestingly, 433