4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of trabectedin, having considered evidence on the nature of advanced soft tissue sarcoma and the value placed on the benefits of trabectedin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
4.2 The Committee considered the UK treatment pathway for patients with advanced soft tissue sarcoma and noted that trabectedin is licensed for patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. The Committee heard from the patient experts and the clinical specialist that there have been no major changes in the treatment of advanced soft tissue sarcoma in the past 20 years and that treatment with trabectedin represents an option for those patients who would otherwise have no licensed treatment options. The Committee heard from the clinical specialist that trabectedin treatment would be managed by specialists in sarcoma units and would usually be administered in an outpatient setting, within existing care structures.
4.3 The Committee noted the evidence of clinical effectiveness presented by the manufacturer from the STS-201 trial, which compared two dosing regimens for trabectedin and included no alternative treatment as a comparator. The Committee appreciated that because soft tissue sarcoma is a rare condition, the evidence for the comparative effectiveness of trabectedin was limited. The Committee noted that the European Medicines Agency (EMEA) had granted trabectedin marketing authorisation under 'exceptional circumstances' based on evidence from a randomised, uncontrolled phase II trial of trabectedin in patients with L−sarcomas. The Committee was aware that there were three uncontrolled phase II trials that included patients with other types of sarcomas. The Committee heard from the clinical specialist that response to treatment varies according to the type of sarcoma, with some sarcomas being more sensitive to treatment with trabectedin. The Committee was aware that as part of the regulatory process for trabectedin, the manufacturer is committed to exploring the subtypes of soft tissue sarcoma that may best respond to treatment.
4.4 The Committee then considered whether the evidence from the 'historical' trials represented patients receiving BSC. Although the Committee was aware of the limitations of historical control data, it noted the 'exceptional circumstances' of the marketing authorisation regarding the difficulties of conducting adequately powered randomised controlled trials against BSC in this patient group, and of exploring factors associated with response to treatment in a reasonable timeframe. The Committee also heard from the clinical specialist that the patients in the 'historical' trials of BSC had been recruited relatively recently, that the general management of advanced soft tissue sarcoma had not changed significantly, and that the duration of the 'historical' control studies was comparable with the trabectedin trial. The Committee therefore concluded that the use of historical controls was appropriate for this disease area but nevertheless needed to be considered with caution.
4.5 The Committee noted that there were differences among the patient populations in the randomised trabectedin trial (STS-201) and the 'historical' trials of BSC, mainly with regard to previously received treatment, sarcoma type and ECOG performance status. The clinical specialist informed the Committee that the three other uncontrolled phase II trials of trabectedin had included patients who were similar to the patients in the 'historical' trials. The Committee therefore accepted that the results could be cautiously generalised to the wider population of patients with advanced soft tissue sarcoma.
4.6 The Committee considered the clinical effectiveness data presented by the manufacturer, and noted the median overall survival for patients randomised to the licensed dosage of trabectedin exceeded that for patients receiving BSC. For progression-free survival, patients randomised to the licensed dosage of trabectedin did better than those patients randomised to an active regimen of BSC (see sections 3.4 and 3.9). The Committee noted that there was no evidence on the effectiveness of trabectedin for patients with contraindications for ifosfamide or anthracyclines. The Committee heard from the clinical specialist, however, that a heart or liver impairment that prevents a patient from receiving ifosfamide or anthracyclines would not prevent a patient from receiving trabectedin.
4.7 The Committee understood that most adverse effects associated with trabectedin were reversible and non-cumulative. It heard from the clinical specialist and patient experts that there were fewer, less severe and less frequent adverse reactions associated with trabectedin than with the other chemotherapy agents used to treat soft tissue sarcoma. It understood that the adverse effects associated with trabectedin were manageable, but nevertheless important, as with other chemotherapy agents used to treat soft tissue sarcoma. Based on the clinical effectiveness evidence and the testimony from the clinical specialist and patient experts, the Committee concluded that trabectedin is a clinically effective treatment for advanced soft tissue sarcoma for patients in whom both anthracyclines and ifosfamide have failed, or who are unsuited to receive these agents, allowing for reservations about the use of historical control trials.
4.8 The Committee considered evidence on the cost effectiveness of trabectedin for the treatment of advanced soft tissue sarcoma. The Committee noted that overall survival, the acquisition cost of the drug and the utility estimates were the key factors driving the economic model. It heard from the ERG that, given the limited evidence available, the methods used by the manufacturer appeared robust and appropriate. It heard that the administration costs of trabectedin did not greatly affect the outcome of the model. The Committee also heard from the clinical specialist that the scenario submitted by the manufacturer which assumed no benefits of alternative chemotherapy was not clinically plausible. Clinical advice noted that 10% of patients might derive some benefit.
4.9 The Committee discussed the estimates of utility used in the model. It accepted the ERG's comment that the model was inappropriate in its assignment of different utility values to the initial health state of patients depending on the treatment to be received (trabectedin or BSC). The Committee heard from the ERG that the scenario analysis presented by the manufacturer was more appropriate, in which the progressive disease health state in the BSC arm was assigned an initial utility value identical to that of the progression-free health state and then declined linearly over the first four cycles of the model (see sections 3.18 and 3.23). The Committee agreed that this scenario represented the most plausible base-case estimation of the ICER.
4.10 The Committee next considered the appropriateness of the use of utilities associated with non-small-cell lung cancer as proxies for those associated with advanced soft tissue sarcoma, given that no utility values exist for advanced soft tissue sarcoma. The Committee heard from the clinical specialist and patient experts that it is not uncommon for patients with advanced soft tissue sarcoma to maintain a quality of life relatively undiminished by the disease for some time, experiencing a rapid decline of quality of life in the final weeks of life, rather than experiencing continued gradual decline over an extended period of time, as often occurs with non-small-cell lung cancer. It heard from the clinical specialist that it may be reasonable to assume that for some proportion of time, patients with advanced soft tissue sarcoma may therefore experience a higher quality of life than patients with non-small-cell lung cancer at a comparable stage of disease. The Committee accepted that these differences could be associated with a different utility profile for patients with advanced soft tissue sarcoma than for those with non-small-cell lung cancer.
4.11 The Committee understood from the ERG's exploratory analyses (see section 3.19) that the way in which utility was modelled influenced the ICER. The Committee had reservations about the use of utility data derived from patients with conditions other than advanced soft tissue sarcoma. The Committee considered that it was very unlikely that the progressive disease and progression-free health states would have the same utility value, and that it was more reasonable to assume a higher utility value for the progression-free state than for the progressive disease state. In the absence of compelling evidence to indicate otherwise, the Committee concluded that the manufacturer's base-case utility values for progression-free (0.653) and progressive disease (0.473) represented the best estimates available.
4.12 The Committee accepted that the patient access scheme for trabectedin was implemented correctly by the manufacturer in the updated economic model. The Committee noted that the patient access scheme involved capping the maximum acquisition cost of trabectedin per patient at five cycles. The Committee heard from the ERG that ICERs incorporating the patient access scheme were insensitive to changes in the operational costs of the scheme. The Committee concluded that the relevant and most appropriate ICER for trabectedin versus BSC on which to base a decision was approximately £34,500 per QALY gained (incorporating the manufacturer's base-case utility values, whereby the utility value in the progression-free health state in the BSC arm followed a linear decline to reach the utility value for progressive disease, and the patient access scheme, see section 3.23).
4.13 The Committee then considered the supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
4.14 The Committee discussed whether the benefit provided by trabectedin for the treatment of advanced soft tissue sarcoma fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that the total number of people with advanced soft tissue sarcoma in England and Wales was approximately 500–600, and that the number eligible for treatment with trabectedin may be as low as approximately 110 per year. Noting the limitations of analyses based on data from historical control trials, the Committee considered that life expectancy with BSC alone was likely to be approximately 6 months. The Committee considered the evidence from the trabectedin trial (STS-201) and noted the median overall survival for the licensed dosage was 13.9 months, although the Committee was not convinced that this value had not been overestimated. The Committee did, however, agree that trabectedin provided an improvement in the treatment of advanced soft tissue sarcoma and that it was likely that trabectedin would increase overall survival by more than 3 months. The Committee took the view that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust to conclude that trabectedin meets the criteria for being a life-extending, end-of-life treatment.
4.15 The Committee considered the best available estimate of the base-case ICER to be approximately £34,500 per QALY gained (see section 4.12). The Committee considered this ICER in light of the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits for the ICER to fall within the current threshold range was acceptable. The Committee concluded that, with the patient access scheme, trabectedin should be recommended as a treatment option for people with advanced soft tissue sarcoma in whom treatment with anthracyclines and ifosfamide has failed, or for those who are intolerant to or have contraindications for anthracyclines and ifosfamide.