Letter to the editor

Re: Stopeck A, Rader M, Henry D, et al. Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ 2012;15(4):712-23

Dear Editor,

Stopeck et al.1 recently published a cost-effectiveness analysis comparing denosumab vs zoledronic acid for the prevention of skeletal-related events (SREs) among patients with solid tumors, including castration-resistant prostate cancer (CRPC), breast cancer, non-small-cell lung cancer (NSCLC), and bone metastases. This study is of substantial interest; however, we believe the assumptions applied, particularly those regarding the model inputs with the greatest impact on results, could lead to erroneous conclusions.

Effectiveness

The study was funded by Amgen, Inc. However, the effectiveness outputs reported in this study were substantially different from the cost-effectiveness analysis submitted to the National Institute for Health and Clinical Excellence (NICE) by the same company. For example, the lifetime incremental quality-adjusted life years (QALYs) for denosumab vs zoledronic acid reported in the study by Stopeck et al.1 were 0.14 for CRPC, 0.17 for breast cancer, and 0.06 for NSCLC, which were considerably higher than the 0.006 for CRPC, 0.007 for breast cancer, and 0.004 for other solid tumors reported in the NICE single technology assessment submitted by Amgen, Inc.2. It is unclear why the two studies resulted in such pronounced differences in incremental QALYs, especially given that both analyses used utility estimates derived from the same abstract that used a time trade-off approach to assess a 2-year period with each SRE3.

As incremental QALYs are the denominator of the incremental cost effectiveness ratio (ICER), even a small difference in incremental QALYs could yield substantial difference in the ICER and thus different conclusions. Stopeck et al.1 reported ICERs as $49,405/QALY for CRPC, $78,915/QALY for breast cancer, and $67,931/QALY for NSCLC. However, using the same incremental costs reported by Stopeck et al. and the incremental QALYs reported in Amgen’s NICE submission would result in ICERs of $1,151,667/QALY for CRPC, $1,921,571/QALY for breast cancer, and $1,019,000/QALY for NSCLC1,2. These alternative results are up to 24-times higher than the ICERs in the published study, and denosumab can no longer be considered cost-effective compared to zoledronic acid in the three populations of interest under these ICERs.

SRE rates

The study also used substantially higher SRE rates compared to those reported in the phase 3 clinical trials comparing denosumab vs zoledronic acid4–6. For example, Stopeck et al.1,4 estimated annual SRE rates for denosumab and zoledronic acid of 0.98 and 1.267 for breast cancer compared to the rates of 0.45 and 0.58 reported in the trial. The substantially higher SRE rates in the study by Stopeck et al.1 resulted largely from the use of an SRE adjustment factor derived from the SRE rates reported for patients with at least one SRE7. This significantly inflated the SRE rate among the populations of interest because many patients will not experience SREs. A retrospective claims analysis of prostate cancer patients with bone metastases showed that only half experienced one or more SRE8. Although the authors intended to use the adjustment factor to estimate the real world rates, the results may be opposite. In fact, a chart review of breast cancer patients treated with pamidronate in the non-trial setting found that the SRE rates were considerably lower than observed in clinical trials9. Therefore, use of the adjustment factor to increase the SRE rate in the real world is unfounded.

There are two important impacts of inflating SRE rates compared to the ones reported in the pivotal trials4–6. First, it increased the difference in the number of SREs between denosumab and zoledronic acid-treated patients and this difference is the denominator when cost per SRE avoided was used as the ICER. Second, higher SRE rates lead to larger incremental medical costs among zoledronic acid-treated patients compared to denosumab-treated patients and smaller total incremental costs. Both resulted in under-estimated ICERs, regardless of whether cost per QALY or cost per SRE avoided is used as the outcome. In fact, the sensitivity analysis presented in the study by Stopeck et al. revealed such impacts. When the adjustment factor was decreased by 50% (with the adjustment factor changing to 2.01*50% = 1.005, which was comparable to the SRE rates observed in the clinical trials), the ICER more than doubled, from $49,405/QALY to $125,000/QALY for CRPC, from $78,915/QALY to $175,000/QALY for breast cancer, and from $67,931/QALY to $150,000/QALY for NSCLC1.

Cost inputs

SRE costs

The study over-estimated SRE costs by using costs of SREs treated in the inpatient setting reported in a study by Barlev et al.10, while in the real world patients are treated in both inpatient and outpatient settings. In addition, although cited as the source for all SRE cost inputs by Stopeck et al.1, the study by Barlev et al.10 did not report costs for radiation to the bone. Thus, it is unclear how the authors derived costs for radiation (ranging from $9027–$11,512 for different cancer types). These costs are significantly higher than costs for radiation reported in other published studies (e.g. $7476 inflated to 2011 US dollars based on the study by Lage et al.8). Since radiation to the bone constituted a substantial proportion of the SREs (59–79% of SREs depending on cancer type) and zoledronic acid-treated patients had higher SRE rates in the model, over-estimated radiation costs increase the medical cost differences between zoledronic acid and denosumab-treated patients, reduces the total incremental costs and thus leads to lower ICERs comparing denosumab vs zoledronic acid. Overall, over-estimated SRE costs used in the base case bias results in favor of denosumab.

Drug costs

Cost-effectiveness analyses should consider exogenous shocks causing payers to re-optimize their formulary decisions. The patent for zoledronic acid will expire on March 3, 2013. Upon patent expiry, drug costs for zoledronic acid are expected to decrease substantially. By applying 2011 drug costs to a 15-year time horizon, the study estimated ICERs unrealistically in favor of denosumab. A recently published study of denosumab vs zoledronic acid in patients with breast cancer used a 60-month time horizon and a reduced price of zoledronic acid (accounting for the anticipated availability of generics), resulting in an ICER of $447,390/QALY11, which is almost 6-times larger than the $78,915/QALY estimated in Stopeck et al.1. The results were consistent with the univariate sensitivity analysis in the study by Stopeck et al.1, which showed that ICERs were more than doubled compared to the base case values when zoledronic acid cost was decreased by 50%. Therefore, failing to account for the price reduction due to generic availability of zoledronic acid could not accurately estimate the cost-effectiveness from a US payer’s perspective. In addition, US payers are interested in cost-effectiveness based upon a shorter time horizon (e.g. 1–3 years), which was not reported in the study12.

In summary, this cost-effectiveness analysis of denosumab vs zoledronic acid used inappropriate assumptions and unclearly derived inputs, which lead to significant under-estimation of ICERs comparing denosumab vs zoledronic acid. The conclusion that denosumab is a cost-effective option compared to zoledronic acid is highly questionable, at best.

Sincerely,

Jipan Xie

Melissa Diener

Rachael Sorg

Analysis Group, Inc., New York, NY, USA

Eric Q. Wu

Analysis Group, Inc., Boston, MA, USA

Madhav Namjoshi

Novartis Pharmaceuticals Corporation

East Hanover, NJ, USA

References

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Authors’ response to letter to the editor

Alison Stopeck

David Henry

Roger Dansey

Yi Qian

Ze Cong

Jorge Arellano

Dear Editors,

In their Letter to the Editor, Xie et al. inquire why the published denosumab (XGEVA; Amgen, Thousand Oaks, CA) cost-effectiveness model differs from the one submitted to NICE in the UK. The present paper describes a US-based cost-effectiveness model with parameters reflecting real-world clinical practice in the US; the cost-effectiveness model submitted to NICE follows the relevant guidance to manufacturers issued by NICE for submissions in England and Wales. What Xie et al. do not adequately explain is that well-documented processes are put into place by nearly every national health system requiring pharmaceutical companies to adhere to unique national requirements for submission. These requirements generally differ between countries, with differences particularly notable between the US and UK healthcare systems. The availability of real-world treatment data and adherence to published preferences for time trade-off utility estimates largely explain the differences by national healthcare systems in cost-per-QALY estimates obtained in the models. Substantial differences in inpatient and outpatient costs in each system also lead to greater value of cost offsets in the US from SRE prevention. These differences are further explained below and we feel are justified given the national healthcare system context for each analysis.

Regarding SRE rates, we agree with Xie et al. that the Hatoum et al.1 study does not represent all patients treated with bone-modifying agents as it only includes patients with at least one SRE. Our study accounted for this limitation by using an adjustment factor to adjust the SRE rate for the probability of patients not experiencing an SRE. Therefore, we feel our approach was appropriate to accurately estimate the SRE rate.

Furthermore, it would not be accurate to use the SRE rates reported in the Lage et al.2 study cited by Xie et al., as the study was designed to estimate costs, not to assess the incidence of SREs. Similarly, the Trinkaus et al.3 study is not considered to reflect the real-world SRE rates of patients treated with zoledronic acid (Zometa; Novartis Pharmaceuticals Corp. Princeton, NJ) in the US as it evaluated the SRE rates among patients treated with pamidronate in Canada.

We agree with Xie et al. that SRE rates will impact significantly on the model results. As SRE rates from the real-world setting are more relevant from a reimbursement perspective than rates derived from clinical trials, in which patients are carefully selected and excluded based on specific eligibility criteria, accurately estimating real-world SRE rates for cost model inputs becomes increasingly important. As the SRE rates in our paper have been appropriately adjusted, we feel the consequences noted by Xie et al. do not apply.

The claim by Xie et al. that our study over-estimates SRE costs by using only inpatient costs was clearly a misreading of our publication. In our paper, we state that the SRE costs ‘… were estimated using the reimbursed amount from a large representative US commercial claims database, weighting the inpatient and outpatient costs …’ (Stopeck et al., J Med Econ 2012;15:712--23, page 716). Additionally, it would not be appropriate to use 1-year cumulative costs associated with SREs published by Lage et al.2 which was suggested by Xie et al., as our study applies a Markov-event cost-effectiveness analysis model, for which episode-based costs are applicable.4 Thus, the critique that our study over-estimates SRE costs is not valid.

This analysis was conducted to assess the cost-effectiveness of denosumab vs zoledronic acid using 2011 drug costs, as these were the two approved agents available in the US at the time of this analysis. Furthermore, the publication included sensitivity analysis of all relevant parameters including drug cost per administration. Therefore, our analysis accurately assessed the US-specific cost-effectiveness of denosumab, a therapy with demonstrated superior efficacy over the previous standard of care, and helps to inform medical decisions of physicians and patients when choosing bone-targeting agents.

Sincerely,

Alison Stopeck

University of Arizona Cancer Center

Tucson, AZ, USA

David Henry

Joan Karnell Cancer Center, Philadelphia, PA, USA

Roger Dansey

Amgen Inc., Thousand Oaks, CA, USA

and Gilead, Fremont, CA, USA

Yi Qian

Ze Cong

Jorge Arellano

Amgen Inc., Thousand Oaks, CA, USA

Acknowledgements

Editing assistance was provided by Vidya S. Beckman, who is an employee of Amgen Inc.