Cost-effectiveness analyses and cost analyses in castration-resistant prostate cancer: A systematic review.

BACKGROUND: Treatment of metastatic prostate cancer is associated with high personal and economic burden. Recently, new treatment options for castration-resistant prostate cancer became available with promising survival advantages. However, cost-effectiveness of those new treatment options is sometimes ambiguous or given only under certain circumstances. The aim of this study was to systematically review studies on the cost-effectiveness of treatments and costs of castration-resistant prostate cancer (CRPC) and metastasizing castration-resistant prostate cancer (mCRPC) on their methodological quality and the risk of bias. METHODS: A systematic literature search was performed in the databases PubMed, CINAHL Complete, the Cochrane Library and Web of Science Core Collection for costs-effectiveness analyses, model-based economic evaluations, cost-of-illness analyses and budget impact analyses. Reported costs were inflated to 2015 US$ purchasing power parities. Quality assessment and risk of bias assessment was performed using the Consolidated Health Economic Evaluation Reporting Standards checklist and the Bias in Economic Evaluations checklist, respectively. RESULTS: In total, 38 articles were identified by the systematic literature search. The methodological quality of the included studies varied widely, and there was considerable risk of bias. The cost-effectiveness treatments for CRPC and mCRPC was assessed with incremental cost-effectiveness ratios ranging from dominance for mitoxantrone to $562,328 per quality-adjusted life year gained for sipuleucel-T compared with prednisone alone. Annual costs for the treatment of castration-resistant prostate cancer ranged from $3,067 to $77,725. CONCLUSION: The cost-effectiveness of treatments of CRPC strongly depended on the willingness to pay per quality-adjusted life year gained/life-year saved throughout all included costs-effectiveness analyses and model-based economic evaluations. High-quality cost-effectiveness analyses based on randomized controlled trials are needed in order to make informed decisions on the management of castration-resistant prostate cancer and the resulting financial impact on the healthcare system.

Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. OBJECTIVE: To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. METHODS: A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. RESULTS: In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to enzalutamide drug cost, size of the chemotherapy-naïve mCRPC patient population, and enzalutamide adoption rate. CONCLUSIONS: Results indicate a modest 1-year budget impact of adopting enzalutamide for chemotherapy-naïve mCRPC patients, partly because of the cost offset of a moderate incidence of adverse events and lack of additional required monitoring.

Sipuleucel-T (Provenge(®))-Autopsy of an Innovative Paradigm Change in Cancer Treatment: Why a Single-Product Biotech Company Failed to Capitalize on its Breakthrough Invention.

Approved by the US Food and Drug Administration (FDA) in 2010, sipuleucel-T (Provenge(®)) was the first 'personalized' cancer vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA. Sipuleucel-T is prepared individually for each patient and infused in three sessions over a period of 1 month. However, in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. This opinion paper reviews the probable reasons this innovative product failed to achieve commercial success. PubMed and internet searches were performed focused on pricing, reimbursement, and market access. We found that sipuleucel-T's FDA approval was delayed by 3 years, reportedly because of the vaccine's new mechanism of action. Sipuleucel-T was cleared by the European Medicines Agency 2 years later, but other national agencies were not approached. It was priced at $US93,000 for a course of treatment, and this high price combined with the company's late securement of reimbursement for the vaccine by the US Centers for Medicare and Medicaid Services (CMS) resulted in another year's delay in accessing the market. Despite a positive recommendation by the National Comprehensive Cancer Network, sipuleucel-T's complex administration, high price, and uncertainty about the reimbursement status deterred doctors from prescribing the product. Furthermore, the vaccine's supply was limited during the first year of launch due to limited manufacturing capacity. In addition, two oral metastatic prostate cancer drugs with similar survival benefits reached the US market 1 and 2 years after sipuleucel-T. Also, even though Dendreon's market capitalization topped $US7.5 billion following the FDA's approval of sipuleucel-T, this value degraded gradually until the firm's bankruptcy 5 years later. We conclude that the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. Licensing sipuleucel-T to a pharmaceutical company more experienced in the market access pathway may have saved the company and the product.

Sipuleucel-T for the Treatment of Metastatic Hormone-Relapsed Prostate Cancer: A NICE Single Technology Appraisal; An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited Dendreon, the company manufacturing sipuleucel-T, to submit evidence for the clinical and cost effectiveness of sipuleucel-T for asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer patients in whom chemotherapy is not yet clinically indicated, as part of NICE's single technology appraisal process. The comparator was abiraterone acetate (AA) or best supportive care (BSC). The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper describes the company submission (CS), ERG review, and subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost-effectiveness evidence of sipuleucel-T based upon the CS. Clinical-effectiveness data relevant to the decision problem were taken from three randomised controlled trials (RCTs) of sipuleucel-T and a placebo (PBO) comparator of antigen-presenting cells (APC) being re-infused (APC-PBO) (D9901, D9902A and D9902B), and one RCT (COU-AA-302) of AA plus prednisone vs. PBO plus prednisone. Two trials reported a significant advantage for sipuleucel-T in median overall survival compared with APC-PBO: for trial D9901, an adjusted hazard ratio (HR) 0.47; (95 % confidence interval [CI] 0.29, 0.76) p < 0.002; for D9902B, adjusted HR 0.78 (95 % CI 0.61, 0.98) p = 0.03. There was no significant difference between groups in D9902A, unadjusted HR 0.79 (95 % CI 0.48, 1.28) p = 0.331. Sipuleucel-T and APC-PBO groups did not differ significantly in time to disease progression, in any of the three RCTs. Most adverse events developed within 1 day of the infusion, and resolved within 2 days. The CS included an indirect comparison of sipuleucel-T (D9902B) and AA plus prednisone (COU-AA-302). As trials differed in prior use of chemotherapy, an analysis of only chemotherapy-naïve patients was included, in which the overall survival for sipuleucel-T and AA was not significantly different, HR 0.94 (95 % CI 0.69, 1.28) p = 0.699. The ERG had several concerns regarding the data and assumptions incorporated within the company's cost-effectiveness analyses and conducted exploratory analyses to quantify the impact of making alternative assumptions or using alternative data inputs. The deterministic incremental cost-effectiveness ratio (ICER) for sipuleucel-T vs. BSC when using the ERG's preferred data and assumptions was £ 108,585 per quality-adjusted life-year (QALY) in the whole licensed population and £ 61,204/QALY in the subgroup with low prostate-specific antigen at baseline. The ERG also conducted an incremental analysis comparing sipuleucel-T with both AA and BSC in the chemotherapy-naïve subgroup. Sipuleucel-T had a deterministic ICER of £ 111,682/QALY in this subgroup, when using the ERG's preferred assumptions, and AA was extendedly dominated. The ERG also concluded that estimates of costs and benefits for AA should be interpreted with caution given the limitations of the indirect comparison. The AC noted that the ICER for sipuleucel-T was well above the range usually considered cost effective, and did not recommend sipuleucel-T for the treatment of asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer.

Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.

Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.

Economic evaluation of sipuleucel-T immunotherapy in castration-resistant prostate cancer.

The objective is to examine the cost-utility of sipuleucel-T immunotherapy in asymptomatic or minimally symptomatic castration-resistant prostate cancer patients. The addition of sipuleucel-T immunotherapy to standard treatment led to a gain of 0.37 quality-adjusted life-year (QALY) at an additional cost of US$104,536. The incremental cost-utility ratio was US$283,000 per QALY saved. Threshold sensitivity analyses indicated that a price reduction of at least 53%, or application in a group of patients resulting in the relative reduction in the mortality rate of at least 39%, ought to augment the economic value of this regimen. Sipuleucel-T immunotherapy treatment at the current price with 96.5% certainty is not cost-effective. The specific group of patients who will benefit more from the treatment should be revealed and treated, or the cost of the vaccine should be lowered significantly to increase its economic value. Accounting for crossover treatment in control patients improves sipuleucel-T's value (US$132,000 per QALY saved) although further investigation is necessary.

Pharmaco-economic aspects of sipuleucel-T.

Sipuleucel-T, a new autologous active cellular immunotherapy, is indicated for metastatic castration-resistant prostate cancer. This Commentary aims to highlight pharmaco-economic aspects relating to the clinical evidence, cost-effectiveness and reimbursement of sipuleucel-T. Today, there is still uncertainty surrounding the clinical benefit of sipuleucel-T and existing evidence relates to the efficacy of sipuleucel-T in a structured setting rather than to its effectiveness in a real-world setting. Due to the clinical uncertainty, there may be scope to introduce a 'coverage with evidence development' scheme, where sipuleucel-T is reimbursed subject to further evidence being generated about its (cost-)effectiveness. Given the high price for a modest effectiveness, sipuleucel-T is unlikely to be cost-effective. However, other societal considerations may matter such as the fact that sipuleucel-T is an end-of-life treatment. A case can be made to apply weights to quality-adjusted life years accrued in the later stages of terminal diseases, thereby improving the cost-effectiveness of sipuleucel-T. Also, risk-sharing arrangements could be considered where the manufacturer shares the risk with the third-party payer that the product may or may not be effective for a particular patient. However, the current absence of markers to identify eligible patients and to assess treatment response inhibits the implementation of a risk-sharing arrangement for sipuleucel-T.

Sipuleucel-T for the treatment of metastatic prostate cancer: promise and challenges.

In the past 18 mo, three new life-prolonging therapies have been approved by the US. Food and Drug Administration for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including sipuleucel-T, the first therapeutic vaccine approved for this disease. With very low toxicity and a demonstrable overall survival benefit, sipuleucel-T offers a promising new therapy and validates further investigation into other immunotherapy approaches for prostate cancer patients. However, questions about its mechanism of action, concerns about its cost, and its optimal sequencing in the prostate cancer treatment landscape may be limiting the adoption of sipuleucel-T. This review summarizes the state-of-the-science with respect to immunotherapy approaches for men with prostate cancer, provides information about the clinical development as well as the strengths and concerns associated with sipuleucel-T, and offers initial insights about where this promising treatment may best fit in the therapeutic landscape.

Sipuleucel-T (Provenge®) for castration-resistant prostate cancer.

UNLABELLED: Sipuleucel-T is known to be very well tolerated and to prolong overall survival, but not progression-free survival, measured according to prostate-specific antigen variations and radiographic progression. Its exact mechanism is unknown. Although the article does not present new data, a new way of assessing immunotherapy efficacy is proposed. This involves measuring 'consecutive' times to progression, in an attempt to capture the delayed effects of immunotherapy. OBJECTIVE: To propose a new way of assessing immunotherapy efficacy. Since 2010, the therapeutic armamentarium for prostate cancer has expanded to include the potent taxane agent cabazitaxel, the CYP17A1 inhibitor abiraterone and the novel immunotherapy agent sipuleucel-T (Provenge®. Demdreon, Seattle, WA, USA). Sipuleucel-T is an antigen-specific active immunotherapy agent, which is not designed to be directly toxic to tumour cells, but to help the immune system to selectively attack cancerous cells. We aimed to provide a comprehensive review of available safety and efficacy data about Sipuleucel-T. METHODS: A systematic analysis of the literature was conducted using the terms 'Sipuleucel-T' and 'Provenge'. PUBMED was the main search engine, but abstracts published by the American Society of Clinical Oncology and the European Society of Medical Oncology, as well as press releases and product monographs, were also considered for inclusion. Reference lists of key articles were searched for further leads. Articles providing safety and efficacy data were included in this review. RESULTS: Sipuleucel-T is based on autologous dendritic cells, which are collected by leukapheresis of peripheral blood, co-cultured with a modified PAP protein, and then re-injected intravenously. It is the first agent of its kind to obtain Food and Drug Administration approval for any kind of malignant tumour. Its approval was determined by the results of a placebocontrolled, randomized trial (the IMPACT trial), conducted in 512 asymptomatic or minimally symptomatic mean with metastatic castration-resistant prostate cancer. Although no difference in time to progression or PSA response rate was reported, a statistically meaningful 4.1-month improvement in median survival was achieved in the active arm with respect to the placebo arm (25.8 months vs 21.7 months). After Food and Drug Administration approval in April 2010, in view of the high economic cost of sipuleucel-T and the not completely flawless study design of the IMPACT trial, a national coverage analysis of sipuleucel-T was conducted by the Centers for Medicare and Medicaid Services. Such analysis has recently concluded that sipuleucel-T is a 'necessary and reasonable' treatment. CONCLUSION: Sipuleucel-T is an effective treatment for prostate cancer, although its widespread use is uncertain for complex social and economic reasons.

Recent advances in the therapy of castration-resistant prostate cancer: the price of progress.

Within the past two years, three agents have garnered approval from the US FDA for the specific treatment of metastatic castration resistant prostate cancer (mCRPC) - (1) abiraterone, (2) cabazitaxel and (3) sipuleucel-T. In separate phase III studies, each agent led to an improvement in overall survival (OS) of 2-4 months over a suitable comparator. With these costly therapies all having potential application in the patient with mCRPC, multiple entities (industry, government, and the general public) must strategize to determine how the cost burden of these agents can be balanced with the potential gains for the individual patient. Herein, we provide a framework with which to approach this dilemma.

Provenge: revolutionary technology or ethical bust?

Sipuleucel-T (known by the trade name, "Provenge") is the first prostate cancer vaccine approved by the Food and Drug Administration (FDA), and represents a new type of cancer therapy termed, Autologous Cellular Immunotherapy (ACT). This therapy has been described as a revolution in technology by clinicians and researchers alike. However, policy-makers and health economists question the efficacy of such treatment given its costs, while mainstream media often bemoan Provenge as yet another example of a healthcare system gone awry. This paper examines the debate for and against Provenge, and discusses why Medicare adoption of payment protocols for the vaccine may violate the egalitarian and feminist principles of distributive justice theory. The paper also acknowledges the larger context of the Provenge debate within the bioethical community; that is, how much should society be willing to invest to prevent death? The paper concludes by arguing for a more thorough ethical review of such new technologies by policy-makers prior to the adoption of funding protocols.