The Pharmacological Costs of Second-Line Treatments for Recurrent Ovarian Cancer.

INTRODUCTION: In ovarian cancer, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrence; therefore, it might be interesting to make a balance between the cost of the drugs administered and the difference in progression-free survival (PFS) and overall survival (OS). METHODS: The present evaluation was restricted to pivotal phase 3 randomized controlled trials. We calculated the pharmacological costs necessary to get the benefit in PFS and OS. The costs of drugs are at the pharmacy of our hospital and are expressed in Euros (&OV0556;). We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale. RESULTS: Our study evaluated 3 phase 3 randomized controlled trials, including 2004 patients. The most relevant increase of costs was associated with the combination chemotherapy including trabectedin, with the highest costs for month of PFS gained (15,836 &OV0556;) and for month of OS gained (7198 &OV0556;), but it substantially differs considering the data of partially platinum-sensitive populations (platinum-free interval of 6-12 months), with 3959 &OV0556; for month of OS gained. CONCLUSIONS: The addition of trabectedin to pegylated liposomal doxorubicin for the treatment of recurrent ovarian cancer can lead to an increase of pharmacological costs. Differently, considering OS in patients with platinum-free interval of 6 to 12 months, there is a halving of pharmacological costs with the addition of trabectedin to pegylated liposomal doxorubicin. These costs are in line with the spending suggested as sustainable (thresholds of <$61,500 per life-year gained).

Cost-effectiveness analysis of pazopanib in second-line treatment of advanced soft tissue sarcoma in Spain.

PURPOSE: To assess the efficiency of pazopanib compared with trabectedin in the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) after chemotherapy failure. METHODS: The progression of STS was modeled using a partitioned survival analysis model. Survival curves for pazopanib and trabectedin were modeled using data from PALETTE phase III clinical trial and based on unadjusted indirect comparison. Effectiveness was measured in quality-adjusted life years (QALY). The Spanish National Health System perspective was considered over a 10-year time horizon, including direct health care costs (, 2014). A discount rate of 3% was applied to both costs and outcomes. The robustness of the results was evaluated using univariate and probabilistic sensitivity analyses (PSA). RESULTS: Pazopanib was associated with better health outcomes than trabectedin (0.705 versus 0.686 QALY). Pazopanib also showed lower direct health care costs (21,861 versus 45,338), mainly due to lower cost of pharmacological treatment (13,762 versus 33,392), administration (57 versus 2,955) and AE management (658 versus 1,695) costs. PSA confirmed that pazopanib was a dominant option in 71% of the simulations performed. CONCLUSIONS: In this analysis, and from a health economics perspective, pazopanib was the option of choice versus trabectedin in the treatment of adult patients with advanced soft-tissue sarcoma after chemotherapy failure.

Trabectedin for the treatment of advanced metastatic soft tissue sarcoma: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of trabectedin (PharmaMar) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of advanced metastatic soft tissue sarcoma (aMSTS), as part of the Institute's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a review of the evidence for the clinical and cost effectiveness of the technology contained within the manufacturer's submission to NICE. The ERG also independently modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main evidence was derived from a single phase II randomized controlled trial (RCT) conducted in liposarcoma and leiomyosarcoma only, in which the licensed dose of trabectedin was compared with a different dose of trabectedin. Additional data were also presented from three uncontrolled phase II trials. Supplementary studies were used to represent best supportive care (BSC). The median overall survival (OS) was 13.9 months for the licensed dose of trabectedin in the main randomized controlled trial (RCT) and ranged from 9.2 months to 12.8 months in the other studies included. Supplementary studies supplied by the manufacturer, and assumed to represent BSC, had median OS of 5.9-6.6 months. The progression-free survival (PFS) rates at 6 months for trabectedin were 35.5 % in the main RCT and 24.4-29 % in the other studies included. The PFS rates at 6 months were 8-14 % for BSC. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratio (ICER) of trabectedin compared with BSC was approximately £44,000 per QALY gained. After amendment of errors identified by the ERG, the ICER reported by the manufacturer increased to approximately £61,000. The ERG concluded that, despite clarifications from the manufacturer and the revisions made to the model, there was still considerable uncertainty in the ICER. The NICE Appraisal Committee (AC) gave a negative initial recommendation, although indicated that trabectedin in aMSTS met the end-of-life criteria. Subsequently, the manufacturer submitted a patient access scheme (PAS) where any cycles beyond the fifth were provided at no cost by the manufacturer. This improved the ICER to approximately £34,000 per QALY gained. The AC gave a positive recommendation, subject to the implementation of the PAS.

Trabectedin for the treatment of relapsed ovarian cancer.

The paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of relapsed platinum-sensitive ovarian cancer, based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submission addressed only part of the decision problem and did not provide evidence to compare trabectedin (Yondelis®, PharmaMar) and pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx®, Schering-Plough) with key comparators. The submission's direct comparison evidence came from one reasonable-quality randomised controlled trial (RCT) of trabectedin and PLDH versus PLDH alone (ET743-OVA-301). The results of the RCT were subdivided into the entire platinum-sensitive population (> 6-month relapse after initial platinum-based chemotherapy) and partially platinum-sensitive (≥ 6- to 12-month relapse) and fully platinum-sensitive (> 12-month relapse) populations. The outcomes included were overall survival, progression-free survival measured by three types of assessor, response rates, adverse effects of treatment, health-related quality of life and cost per quality-adjusted-life-year (QALY) gained. A mixed treatment comparison (MTC) meta-analysis comparing trabectedin and PLDH with single-agent PLDH within the entire platinum-sensitive population, with paclitaxel or with topotecan also formed part of the submission. The RCT data showed that trabectedin plus PLDH compared with PLDH monotherapy had a significant effect on overall survival only within the partially platinum-sensitive subgroup. PFS results reported by the independent radiologists showed significant effects in favour of the trabectedin and PLDH arm for the entire and partially platinum-sensitive populations only. Rates of grade 3 and 4 adverse events were mostly higher in the trabectedin and PLDH arm than in the PLDH alone arm. There were several issues regarding the undertaking of the MTC, and thus the data were not considered robust. Furthermore, the ERG did not believe the MTC to be necessary to answer the decision problem. The manufacturer submitted a de novo cost-effectiveness model. The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population, using results estimated from the MTC. Additional analyses were presented comparing trabectedin in combination with PLDH versus PLDH monotherapy using direct evidence from the OVA-301 trial for the fully, partially and entire platinum-sensitive populations. The cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was estimated to be £ 70,076 in the main analysis. In the additional analyses, the cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was £ 94,832, £ 43,996 and £ 31,092 for the entire, partially and fully platinum-sensitive populations, respectively. Additional work was undertaken by the ERG using patient-level data and amending some assumptions to provide a better statistical fit to the Kaplan-Meier data than the exponential distribution assumed by the manufacturer. The ERG base-case estimate of the cost per QALY of trabectedin in combination with PLDH ranged from £46,503 to £54,607 in the partially platinum-sensitive population. At the time of writing, trabectedin in combination with PLDH for the treatment of women with relapsed platinum-sensitive ovarian cancer is not recommended by NICE in the final appraisal determination.

Trabectedin in the treatment of metastatic soft tissue sarcoma: cost-effectiveness, cost-utility and value of information.

BACKGROUND: to assess the cost-effectiveness of trabectedin compared with end-stage treatment (EST) after failure with anthracycline and/or ifosfamide in metastatic soft tissue sarcoma (mSTS). DESIGN: analysis was carried out using a probabilistic Markov model with trabectedin → EST and EST arms, three health states (stable disease, progressive disease and death) and a lifetime perspective (3% annual discount rate). Finnish resources (drugs, mSTS, adverse events and travelling) and costs (year 2008) were used. Efficacy was based on an indirect comparison of the STS-201 and European Organisation for Research and Treatment of Cancer trials. QLQ-C30 scale scores were mapped to 15D, Short Form 6D and EuroQol 5D utilities. The outcome measures were the cost-effectiveness acceptability frontier, incremental cost per life year gained (LYG) and quality-adjusted life year (QALY) gained and the expected value of perfect information (EVPI). RESULTS: trabectedin → EST was associated with 14.0 (95% confidence interval 9.1-19.2) months longer survival, €36 778 higher costs (€32 816 using hospital price for trabectedin) and €31 590 (€28 192) incremental cost per LYG with an EVPI of €3008 (€3188) compared with EST. With a threshold of €50 000 per LYG, trabectedin → EST had 98.5% (98.2%) probability of being cost-effective. The incremental cost per QALY gained with trabectedin → EST was €42 633-47 735 (€37 992-42 819) compared with EST. The results were relatively insensitive to changes. CONCLUSION: trabectedin is a potentially cost-effective treatment of mSTS patients.

Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of advanced metastatic soft tissue sarcoma, in accordance with the licensed indication, based on the evidence submission from the manufacturer to NICE as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were overall survival (OS), progression-free survival (PFS), response rates, adverse effects of treatment, health-related quality of life, and cost per quality-adjusted life-year (QALY) gained. The clinical evidence was derived from one randomised controlled trial (RCT), in which the licensed dose of trabectedin was compared with a different dose of trabectedin, and three phase II studies. In the RCT, the median OS was 13.9 months for the licensed dose of trabectedin, which was not significantly different from that for the comparator dose of trabectedin, which was 11.8 months. From the phase II uncontrolled trials, median OS was reported as 9.2 or 12.8 months. The RCT reported significantly superior PFS for the licensed dose of trabectedin (median 3.3 months) over the comparator trabectedin dose (median 2.3 months). One phase II uncontrolled trial reported median PFS as 1.9 months in the licensed dose of trabectedin. The RCT reported PFS rates at 6 months were 35.5% for the licensed dose of trabectedin, and 27.5% for the comparator dose of trabectedin. From the phase II uncontrolled trials, PFS rates at 6 months were 24.4% or 29%. For the RCT, deaths attributed to trabectedin occurred in 3.1% of the licensed dose, and 2.3% of the comparator group. The most common severe adverse events were neutropenia, although with a low rate of febrile neutropenia, thrombocytopenia, and aspartate aminotransferase and alanine aminotransferase elevation, although these were reported to be non-cumulative and reversible. Following dialogue iterations with the ERG team, the manufacturer revised the model twice. However, despite revisions, errors/inconsistencies were found in the latest version of the model and were corrected by the ERG (only for the base case). In the latest manufacturer's submission, the cost per QALY gained of trabectedin compared with best supportive care (BSC) was estimated to be 56,985 pounds for the base case using effectiveness from the STS (Soft Tissue Sarcomas)-201 trial for trabectedin and a pool analysis of the European Organisation for Research and Treatment of Cancer data set for BSC. This analysis was constrained to patients with L-sarcomas only. When the joint uncertainty between parameters was considered, the cost-effectiveness acceptability curve showed that trabectedin has a very low probability of being cost-effective at a threshold of 30,000 pounds per QALY gained compared with BSC for any scenario. The guidance has yet to be issued by NICE.

Aquaculture of three phyla of marine invertebrates to yield bioactive metabolites: process developments and economics.

Large-scale, renewable supplies of chemical constituents derived from marine invertebrates have limited development of potential new natural product drugs. This paper describes the development of two in-sea aquaculture systems designed and engineered for production of large quantities of biomass for two species of marine invertebrates desired for their natural product chemical constituents. The two invertebrates and their products were: (1) the cosmopolitan, arborescent bryozoan Bugula neritina (Phylum Bryozoa) for its anticancer chemical constituent bryostatin 1; and (2) Ecteinascidia turbinate (Phylum Tunicata) the source of anticancer ecteinascidin 743. For the third invertebrate Phylum Porifera, and its representative sponge Acanthella cavernosa (desired for its anti-parasitic and anti-infective kalihinols) in-sea systems were not developed in favor of controlled environment tank aquaculture systems. For the bryozoan and tunicate, projected economics for commercial-scale in-sea production proved cost effective. This was in contrast to the controlled environment sponge culture tank system, which did not prove to be economical due to inherent slow growth and low natural product yields of the sponge in culture. A non-destructive method for "milking" natural product chemicals from sponges was tested and is described.