1 Appraisal Committee's preliminary recommendations

1.1 Pixantrone is not recommended within its marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy.

1.2 People currently receiving pixantrone for relapsed or refractory aggressive non-Hodgkin’s lymphoma should be able to continue treatment until they and their clinician consider it appropriate to stop.

2 The technology

2.1 Pixantrone (Pixuvri, Cell Therapeutics) is an aza-anthracenedione analogue and inhibitor of topoisomerase II. The recommended dosage is pixantrone 50 mg/m² on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. It is administered intravenously. Pixantrone has a conditional UK marketing authorisation ‘as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy’ (that is, it is conditionally approved for patients who have received at least 2 previous lines of treatment). The European public assessment report noted pixantrone had a reduced benefit in patients pretreated with rituximab. The conditional marketing authorisation is linked to results being provided from the phase III PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have previously received a rituximab-containing regimen.

2.2 The summary of product characteristics states the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting, and diarrhoea were generally infrequent, mild, reversible, manageable, and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, it recommends monitoring left ventricular ejection fraction. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3 Pixantrone is priced at £553.50 per 20 ml vial containing 29 mg free base pixantrone, which is equivalent to 50 mg pixantrone dimaleate (excluding VAT; costs from manufacturer’s submission). The estimated cost of a course of treatment is £19,926.18 (costs calculated over 4 cycles using an average of 3 vials per dose based on the median length of treatment in the PIX301 trial). Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pixantrone and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1 The manufacturer's systematic review identified 1 randomised controlled trial, which was included in its submission. No other relevant randomised controlled trials or non-randomised controlled trials were identified. The manufacturer also included some supporting cardiotoxicity data from a randomised phase II study that did not meet the inclusion criteria of the literature review (because it evaluated pixantrone in combination with other drugs, not as monotherapy).

3.2 PIX301 is a randomised, controlled, open-label phase III study that was conducted in 66 centres, including the USA and Europe. Eligible patients were adults with aggressive de novo or transformed non-Hodgkin’s lymphoma that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that had lasted at least 24 weeks. Seventy patients were randomised to pixantrone and 70 patients to a physician’s choice of single-agent comparators. The full publication of the PIX301 trial described how 67 patients went on to receive vinorelbine (n=11), oxaliplatin (n=30), ifosfamide (n=12), etoposide (n=9), mitoxantrone (n=4) and gemcitabine (n=1). Pixantrone was administered at a dosage of 85 mg/m² on days 1, 8 and 15 of a 28-day cycle for up to 6 cycles. Comparators were administered at predefined standard dosages for up to 6 cycles. Follow-up was for 18 months after completing study treatment.

3.3 The primary outcome was complete and unconfirmed complete response, which was determined by a blinded independent assessment panel. Secondary outcomes were overall survival, response lasting at least 4 months and progression-free survival. Other predefined end points were overall response rate, time to response, time to complete response, duration of response and relative dose intensity. Health-related quality of life was not assessed. The primary analysis was the intention-to-treat population. Secondary analyses included a prespecified analysis of the response and survival end points for the histologically confirmed intention-to-treat population (that is, if the lymphoma had been classified according to retrospective independent central pathological assessment).

3.4 It was initially planned that 320 patients would be recruited to the PIX301 trial but study enrolment was closed early because of slow accrual. The manufacturer’s submission stated that, with a final enrolment of 140 patients, the study was considered to be sufficiently powered (about 80%) to detect a 15% difference in the complete or unconfirmed complete response rate, assuming a complete or unconfirmed complete response rate of at least 18% in the pixantrone arm. In contrast, the full publication of PIX301 reported that, according to the original sample size assumptions, a sample of 70 patients per group would have about 40% power. It further stated that to achieve 81% power with 70 patients per group, the true proportion of patients with a complete or unconfirmed complete response would have to have been 22% in the pixantrone group and 5% in the comparator group.

3.5 The manufacturer reported that baseline demographic and disease characteristics were similar in the 2 arms. Previous treatment for non-Hodgkin’s lymphoma, including median number and category of previous chemotherapy, was broadly similar for both groups. Aggressive histological features were identified onsite in all patients before treatment was given and confirmed by central independent pathological review in 54 (77%) of 70 patients in the pixantrone arm and 50 (71%) of 70 patients in the comparator arm receiving treatment of physician’s choice. Of the remaining 36 patients, reasons for non-confirmation included low-grade histology (n=13) and lack of consensus (n=10). Out of 140 patients, 36 patients completed 6 cycles of protocol treatment, and 104 patients discontinued early. The most common reason for early discontinuation in both groups was disease progression or relapse. After completing study treatment, 95 patients entered follow-up and 26 of these completed 18 months of follow-up.

3.6 The manufacturer's submission reported that at the end of treatment, confirmed and unconfirmed response rates for the intention-to-treat population (70 patients in each arm) were statistically significantly higher for the pixantrone group than the comparator group receiving treatment of physician’s choice (20% versus 5.7%; p=0.021). This was also the case at the end of study after 18 months of follow-up (24.3% versus 7.1%; p=0.009).

3.7 The manufacturer's submission described the results for progression-free and overall survival in the intention-to-treat population. Median progression-free survival was statistically significantly longer for the group receiving pixantrone than the comparator group receiving treatment of physician’s choice at 5.3 months versus 2.6 months (hazard ratio 0.60 and 95% confidence interval [CI] 0.42 to 0.82; p=0.005). However, there was no statistically significant difference in median overall survival between the 2 groups (10.2 months in the pixantrone arm compared with 7.6 months in the arm receiving treatment of physician’s choice, hazard ratio 0.79 [95% CI 0.53 to 1.18]; p=0.251).

3.8 The manufacturer's submission gave the results of the other prespecified end points for the intention-to-treat population. Overall response rate (patients with complete response, unconfirmed complete response or partial response) was statistically significantly higher in the pixantrone arm than the comparator arm at the end of treatment (37.1% versus 14.3%; p=0.003) and at end of study (40.0% versus 14.3%; p=0.001). There were no statistically significant between-group differences in time to overall response, time to complete response and duration of response. However, more patients in the pixantrone group than the comparator group had a response lasting at least 4 months (17.1% versus 8.6%). Median relative dose intensity was 90.6% in the pixantrone group and greater than 93% in the comparator group for all drugs except vinorelbine.

3.9 In addition to the results for the intention-to-treat population of the PIX301 trial, the manufacturer included clinical-effectiveness data for 6 post-hoc subgroups in its submission:

• Patients with aggressive B-cell lymphoma (classed as diffuse large B-cell lymphoma, transformed indolent lymphoma or follicular lymphoma [grade III]) confirmed by onsite pathological review.
• Patients with aggressive B-cell lymphoma confirmed by onsite pathological review who received pixantrone or a comparator as third- or fourth-line treatment.
• Patients with aggressive B-cell lymphoma whose disease had been histologically confirmed by central independent pathological review.
• Patients with diffuse large B-cell lymphoma confirmed by onsite pathological review.
• Patients with aggressive B-cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment.
• Patients with aggressive B-cell non-Hodgkin’s lymphoma confirmed by central independent pathological review who had previously received rituximab treatment.

3.10 The manufacturer considered the first of these groups, the post-hoc subgroup of patients with aggressive B-cell lymphoma confirmed by onsite pathological review, to be similar to the population eligible for treatment according to pixantrone’s UK marketing authorisation, and indicated that this formed the basis of population in the base case of its cost-effectiveness analysis (however, it should be noted that the manufacturer stated that its economic evaluation focused on those who had received 2 or 3 previous therapies; see section 3.19 for details). This subgroup excluded patients with peripheral T-cell lymphoma not otherwise characterised and other disease subtypes not included in pixantrone’s UK marketing authorisation. Compared with the group that received treatment of physician’s choice (n=62), complete or unconfirmed complete response rates at the end of the study in the pixantrone group (n=64) were statistically significantly higher (23.4% versus 8.1%; p=0.027). Overall response rates were also statistically significantly higher in the pixantrone group (40.6% versus 16.1%; p=0.003). Median progression-free survival was statistically significantly longer in patients who had received pixantrone than those who had received a comparator drug (5.7 months versus 2.5 months, hazard ratio 0.56 [95% CI 0.38 to 0.81]; p=0.002). The manufacturer advised that median overall survival was not included because the aggressive B-cell lymphoma analyses were exploratory.

3.11 The manufacturer presented a further analysis of patients with aggressive B-cell lymphoma confirmed by onsite pathological review who received pixantrone (n=50) or a comparator (n=49) as third- or fourth-line treatment, which it stated was more closely aligned with pixantrone’s marketing authorisation. It is not clear from the manufacturer’s submission how this population differs from that in the base case of its cost-effectiveness analyses (see section 3.19 for details). The group receiving pixantrone had a statistically significantly higher complete response or unconfirmed complete response rate (28.0% versus 4.0%; p=0.002) and overall response rate (48.0% versus 12.2%; p<0.001), and statistically significantly longer progression-free survival (5.8 months versus 2.8 months, hazard ratio not stated; p=0.002). Median overall survival in this population was numerically higher in the pixantrone arm than the comparator arm (13.9 months versus 7.8 months, hazard ratio 0.76 [95% CI 0.47 to 1.24]; p=0.275). The manufacturer’s submission did not state if the results were for end of treatment or end of study.

3.12 The manufacturer provided results for the post-hoc subgroup of patients with aggressive B-cell lymphoma whose disease had been histologically confirmed by central independent pathological review (n=50 in the pixantrone group, n=47 in the comparator group). At the end of the study, there was no statistically significant difference in complete or unconfirmed complete response rates between the pixantrone and comparator groups (9 patients versus 4 patients; p=0.236). However, the overall response rate was statistically significantly higher in the pixantrone group (18 patients versus 8 patients; p=0.041). Median progression-free survival was statistically significantly longer in the pixantrone arm than the comparator arm (5.6 months versus 2.5 months, hazard ratio 0.51 [95% CI 0.33 to 0.78]; p-value not stated) but there was no statistical difference in median overall survival between the 2 groups (8.1 months versus 6.3 months, hazard ratio 0.72 [95% CI 0.45 to 1.13], p-value not stated).

3.13 The manufacturer presented an analysis of a subgroup of patients with aggressive B-cell lymphoma confirmed by central independent pathological review who were receiving pixantrone (n=39) or treatment of physician’s choice (n=39) as third- or fourth-line treatment. Compared with the group receiving treatment of physician’s choice, the pixantrone group had a statistically significantly higher complete or unconfirmed complete response rate (23.1% versus 5.1%; p=0.047) and overall response rate (43.6% versus 12.8%; p=0.005). Median progression-free survival was statistically significantly longer with pixantrone compared with treatment of physician’s choice (5.7 months versus 2.8 months, hazard ratio 0.44 [95% CI 0.27 to 0.71]) but there was no statistically significant difference in median overall survival between treatment groups (11.9 months with pixantrone versus 7.0 months with comparator, hazard ratio 0.67 [95% CI 0.40 to 1.12]).

3.14 The manufacturer provided results for the post-hoc subgroup of patients with diffuse large B-cell lymphoma confirmed by onsite pathological review. At the end of the study, complete or unconfirmed complete response rates were statistically significantly higher in patients who had received pixantrone than those who had received a treatment of physician’s choice (18.9% versus 3.9%; p=0.029). Overall response rate was also statistically significantly higher in the pixantrone group than the comparator group (34.0% versus 13.7%; p=0.021). Median progression-free survival was statistically significantly longer in patients who had received pixantrone than those who had received a treatment of physician’s choice (4.6 months versus 2.1 months, hazard ratio 0.47 [95% CI 0.30 to 0.71], p<0.001). The manufacturer explained that overall survival results for this subgroup were not provided because the aggressive B-cell lymphoma analyses were exploratory and did not include overall survival.

3.15 In addition to these histologically defined subgroups of the PIX301 trial population, the manufacturer also supplied subgroup analyses that showed the influence of previous rituximab treatment on pixantrone’s efficacy in the subgroup of patients who had aggressive B-cell non-Hodgkin’s lymphoma confirmed by central independent pathological review. There was no statistically significant difference between pixantrone (n=30) and the comparator arm (n=26) in the proportion of patients who had a complete or unconfirmed complete response at the end of treatment (16.7% versus 7.7%; p=0.431). Median progression-free survival was longer in the pixantrone group for this subgroup of patients but the difference did not reach statistical significance (3.5 months versus 2.3 months, hazard ratio 0.66 [95% CI 0.38 to 1.14]). Similarly, median overall survival was longer in the pixantrone group but the between-group difference was not statistically significant (6.0 months versus 4.6 months, hazard ratio 0.85 [95% CI 0.48 to 1.50]).

3.16 The manufacturer's submission described the adverse events in the PIX301 trial for 68 patients in the pixantrone group and 67 patients in the comparator group who received treatment of physician’s choice. One dose reduction was allowed for patients who had neutropenia during treatment, and reductions were similar in the pixantrone and comparator groups (18% versus 15%). Dose delay was more frequent with pixantrone (40% versus 22%).

3.17 A similar number of patients had an adverse event of any grade but there was a higher incidence of grade 3 and 4 adverse events in the pixantrone group than the comparator group (76.5% versus 52.2%). Neutropenia occurred more frequently in the pixantrone group and was the most common adverse event of any grade (50.0% versus 23.9%) and the most common grade 3 or 4 adverse event (41.2% versus 19.4%). Grade 3 or 4 febrile neutropenia was also more common in the pixantrone group than the comparator group (7.4% versus 3.0%), and more patients in the pixantrone group than the comparator group received an immunostimulant (51.5% versus 26.9%). The manufacturer reported that severity of neutropenia did not increase with increasing cycle number and that the overall rates of grade 3 and 4 infections were similar in the 2 groups. It further stated that the common adverse events were similar to those expected in a heavily pretreated patient population, which reflected pixantrone’s intended use in UK clinical practice (that is, third and subsequent lines of treatment).

3.18 Approximately 40% of patients in the 2 treatment arms presented with cardiac history at study enrolment, and cardiac risk factors were also similar in the 2 groups. The manufacturer stated that pixantrone is an innovative treatment because it has been specifically designed to reduce cardiotoxicity associated with anthracyclines without compromising efficacy. More cardiac adverse events occurred in the pixantrone group (24 patients [35.3%] than the comparator group that received treatment of physician’s choice (14 patients [20.9%]). Thirteen (19.1%) patients in the pixantrone group experienced decreased left ventricular ejection fraction compared with 7 patients in the comparator group. The manufacturer provided supporting cardiotoxicity data from the randomised open-label phase II PIX203 trial, which closed before enrolment completed. The study compared the combination of cyclophosphamide, pixantrone, vincristine, prednisone and rituximab with the standard of care (that is, rituximab in combination with a regimen of cyclophosphamide, doxorubicin, vincristine and prednisolone) as first-line treatment in patients with diffuse large B-cell lymphoma. The results of the PIX203 trial broadly supported those of PIX301.

Cost effectiveness

3.19 The manufacturer did not identify any published economic evaluations or costing studies that were relevant to the decision problem and submitted a de novo economic analysis that assessed the cost effectiveness of pixantrone compared with treatment of physician’s choice in treating multiply relapsed or refractory aggressive B-cell lymphoma. The manufacturer advised that the base-case model considered patients who had received 2 or 3 prior therapies and were sensitive to treatment with anthracyclines because this population was consistent with pixantrone’s UK marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma (the marketing authorisation notes that a treatment benefit has not been established when used as fifth-line or greater chemotherapy in patients who are refractory to their last treatment). The clinical data for this population were derived from the PIX301 trial. The analysis was conducted from an NHS and personal and social services perspective and a lifetime horizon of 23 years was used. Weekly cycles were chosen to capture the 4-week treatment cycles of pixantrone and 3-week treatment cycles of some of the comparator treatments and a half-cycle correction was applied. Costs and benefits were discounted at 3.5% per annum.

3.20 The manufacturer created a semi-Markov model that contained 3 health states: stable or no progression, progressive or relapsed disease, and death. The stable or no progression health state had 2 distinct subpopulations. The first of these was patients on initial third- or fourth-line treatment. The second was patients who had discontinued third- or fourth-line treatment (because of complete response, adverse event, completion of 6 months’ treatment or a non-clinical reason) but had not experienced progression. All patients entered the model in the on-treatment subpopulation within the stable or no progression health state. During each cycle, patients could remain in the on-treatment subpopulation of this health state, discontinue treatment and move into the other subpopulation in this health state, progress and move into the progressive disease health state, or die. Patients who discontinued treatment before progression remained at risk of progression or death. Following progression, patients were at risk of death and unable to return to the stable or no progression health state. It was assumed that the original treatment was stopped following disease progression and patients received further treatment or palliative care. Adverse events were captured as events within the model by applying a utility decrement (disutility).

3.21 The manufacturer outlined how the transition between health states was calculated from the clinical data for any given weekly cycle. It noted that semi-Markov models allow the use of a partition approach, which has been used extensively in oncology because it is particularly suited to progressive conditions that have ongoing risks that may vary over time. The distribution of the patient cohort between the different health states defined by these curves was estimated by calculating the area under the survival curves at each cycle. The progression-free survival curve defined the stable or no progression state, while the progressed state was defined by subtracting those patients who remain progression free from all surviving patients.

3.22 Clinical parameters for progression-free survival and overall survival were incorporated into the base case of the manufacturer’s economic model by statistical analysis of patient-level data from the aggressive B-cell population of the PIX301 trial. Predictive equations for progression-free survival and overall survival were derived by fitting the patient-level data and extrapolating beyond the data from the PIX301 trial (around 2 years). A log-normal distribution was used in the base case for both progression-free survival and overall survival.

3.23 Further clinical parameters were incorporated into the base case of the manufacturer’s economic model. The cycle probability of treatment discontinuation distinguished between patients remaining on initial treatment and those who discontinued while stable. The frequency and duration of adverse events (grades 2–4) before progression while taking initial treatment were based on the PIX301 trial. Grade 3 and 4 adverse events occurring in at least 5% of the total patient population were considered to have cost and utility consequences. Some grade 2, and rarer grade 3 and 4, adverse events were included if considered important by clinical specialists in England. Other data from the PIX301 trial that were used to inform the model were mean dose for the comparator treatments plus sex, body surface area and mean time on treatment.

3.24 There were no patient-reported outcomes in the PIX301 trial and the manufacturer did not identify any utility data for any line of treatment in aggressive non-Hodgkin’s lymphoma in its systematic literature review for studies on health-related quality of life. Utility data were identified from published sources for similar patient populations, and for disease areas with similar expected survival, disease progression, nature of the disease and quality of life. These were diffuse large B-cell lymphoma, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, renal cell carcinoma and melanoma. The manufacturer considered the self-reported quality of life in elderly patients with aggressive diffuse large B-cell lymphoma to give the estimation closest to the PIX301 trial population and used these values (pre-progression 0.81, post-progression 0.60) in its base-case analysis. The manufacturer did not provide a rationale for this decision. Utility values were assumed to depend only on the health state and any adverse events experienced, but not the treatment arm. Based on expert clinical opinion, the manufacturer assumed no difference in baseline health-related quality of life between the 2 subpopulations in the stable or no progression health state. All stable/no progression patients were assumed to have similar quality of life (that is, there was no difference according to complete response, partial response or stable disease).

3.25 The manufacturer determined disutilities associated with each adverse event that was included the model from relevant literature from other oncology indications. If no utility decrements were available, the maximum value of the range identified was assumed by the manufacturer to keep the calculations conservative (that is, so that pixantrone was not favoured).

3.26 Adverse events were modelled by the manufacturer as events rather than as health states and were assumed to be time independent because adverse events are likely to be experienced at different stages of treatment. Any grade 1–4 adverse event that occurred in less than 5% of the trial population was assumed to have no impact on quality of life. After consulting some clinical specialists in England, the manufacturer included some rarer grade 3 and 4 adverse events and some grade 2 adverse events that the clinical specialists considered to be important. Because no disutility values were available specifically for grade 2 and grade 3 or 4 adverse events, they were assumed to be the same for each grade. Within a health state, disutilities relating to an adverse event were applied to the proportion of patients assumed to experience the adverse event as weighted average disutilities. For each treatment, the manufacturer calculated a weighted average of grade-specific disutilities that were weighted by the number of effects of that particular grade. The disutility for each adverse event was then applied for the duration of that specific type of effect. The manufacturer’s model limited the consideration of adverse events to patients on original treatment upon entering the model (pixantrone or treatment of physician’s choice).

3.27 Costs captured in the manufacturer’s model included drugs and their administration, plus those associated with health state and disease management, including adverse events. Drug and administration costs were calculated based on average dose per administration from the trial using the British National Formulary edition 62 (BNF) (published in September 2011) and the NHS reference costs. From the second attendance onwards, administration costs were £206 for each attendance for all drugs except etoposide 50 mg (£163). Drug costs per administration supplied in the manufacturer’s submission were: £1660 for pixantrone, £86 for vinorelbine, £546 for oxaliplatin, £223 for ifosfamide, £26 for etoposide 100 mg, £7 for etoposide 50 mg, £185 for mitoxantrone and £282 for gemcitabine. At clarification, the manufacturer corrected an error in the vial price, which had been mistakenly quoted as £343.80 (based on the vial size given in pixantrone base) instead of £553.50 (equivalent to 50 mg pixantrone dimaleate). It advised that this error had a minimal impact on the cost-effectiveness estimates (which increased by 0.3%) because the drug costs in the model had been calculated based on cost per administration. The total number of administrations varied according to the dosing schedule for each drug. Drug wastage was incorporated in the base case. Personal and social services were £476.42 per 28 days for stable health state on treatment, £119.10 for stable health state on palliative care and £1993.89 for progressive health state. Disease management costs (comprising healthcare professional contact, disease follow-up and hospital-related costs) were different for active treatment and palliative care. For active treatment, health professional contact was £788.96 on treatment and £220.38 after treatment (per 28 days), disease follow-up was £86.63 per 28 days and annual hospital-related costs were £2,357.28. For palliative care, health professional contacts were £990.74 per 28 days, disease follow-up was £18.44 per 28 days and annual hospital-related costs were £1,982.03. End of life care was excluded from the calculations because it affected only the last few weeks of life and estimates would be similar for pixantrone and its comparators. Within a health state, costs for managing an adverse event were applied to the proportion of patients assumed to experience the adverse event.

3.28 The manufacturer advised that the predicted median progression-free survival and predicted median overall survival were similar to the results reported in the PIX301 study. Compared with the clinical trial results, the manufacturer noted that the model slightly underestimates the median overall survival with pixantrone (13.1 months versus 13.8 months) while overestimating it for the comparator (9.2 months versus 7.6 months). It reported that, conversely, the model overestimates the median progression-free survival for the pixantrone arm (7.8 months versus 6.4 months) and slightly underestimates it for the comparator arm (3.2 months versus 3.5 months).

3.29 The manufacturer's base-case analyses for pixantrone compared with treatment of physician’s choice in patients with aggressive B-cell lymphoma confirmed by onsite pathological review (third- or fourth-line treatment) produced a deterministic incremental cost-effectiveness ratio (ICER) of £28,423 per quality-adjusted life year (QALY) gained. Incremental costs were £17,638 and incremental QALYs were 0.62. Using the correct vial price supplied at clarification increased the ICER to £28,503 per QALY gained.

3.30 The manufacturer undertook a probabilistic sensitivity analysis to explore uncertainty. This analysis showed that the probability of pixantrone being cost effective compared with treatment of physician’s choice in patients with aggressive B-cell lymphoma confirmed by onsite pathological review (third- or fourth-line treatment) is 43.8% at £20,000 per QALY gained, 53.0% at £30,000 per QALY gained and 78.2% at £50,000 per QALY gained.

3.31 The manufacturer tested the robustness of the model using one-way sensitivity analyses and reported that the key drivers of the cost-effectiveness estimates produced using its economic model were the parametric fitting methodology for progression-free survival and overall survival, the utility estimate for the stable or no progression health state, the time horizon and the cost of pixantrone. The manufacturer noted that when the effect of pixantrone relative to treatment of physician’s choice was overestimated using the 2.5% lower CI for progression-free survival, pixantrone dominated treatment of physician’s choice (that is, gave a greater benefit at lower cost). Conversely when the effect of pixantrone was underestimated using the 97.5% upper CI, the ICER increased to £90,914 per QALY gained.

3.32 The manufacturer provided alternative utility scenarios using data from published sources for similar patient populations, and for disease areas with similar characteristics. These were second-line treatment in patients with chronic myelogenous leukaemia, third-line treatment in patients with chronic lymphocytic leukaemia, first-line maintenance treatment in patients with follicular lymphoma, first-line treatment in patients with metastatic renal cell carcinoma, second-line treatment in patients with renal cell carcinoma and second-line treatment in patients with malignant melanoma. The results ranged from £28,056 per QALY gained to £35,248 per QALY gained.

3.33 The manufacturer provided subgroup analyses for the cost effectiveness of pixantrone compared with treatment of physician’s choice in the intention-to-treat population, patients with diffuse large B-cell lymphoma and patients with aggressive B-cell non-Hodgkin’s lymphoma confirmed by central independent pathological review. In comparison with the base-case deterministic ICER of £28,423 per QALY gained (incremental costs £17,638; incremental QALYs 0.62) for the population with aggressive B-cell lymphoma confirmed by onsite pathological review receiving third- or fourth-line treatment, the deterministic ICERs were higher for the intention-to-treat population (£43,102 per QALY gained [incremental costs £19,809; incremental QALYs 0.46]) and aggressive B-cell non-Hodgkin’s lymphoma confirmed by central independent pathological review (£32,728 per QALY gained [incremental costs £14,809; incremental QALYs 0.45]) but lower for the population with diffuse large B-cell lymphoma confirmed by central independent pathological review (£23,699 per QALY gained [incremental costs £9841; incremental QALYs 0.42]).

Evidence Review Group's comments

3.34 The ERG considered the evidence included by the manufacturer to be relevant to the decision problem in its analysis. No additional relevant trials were identified and the ERG found the manufacturer’s systematic review followed standard practices.

3.35 The ERG had concerns about the generalisability of the PIX301 trial population to clinical practice in England and Wales. It noted that only 7 out of 140 patients in the trial were recruited from the UK. The remaining patients were recruited from North America (n=8), Western Europe (n=31) and the rest of the world (n=94). It further noted that patients from Western Europe were heavily pretreated and may have had more severe disease than patients typically eligible for treatment with pixantrone in the UK.

3.36 The ERG had concerns about the potential effect of previous rituximab treatment on the response to pixantrone in UK clinical practice because rituximab is given as part of standard first-line treatment in the UK. The largest proportion of patients in the PIX301 trial was enrolled from the rest of the world and only 37.2% of these patients had previously received rituximab because it was not available in all participating countries. The ERG noted that about 50% of patients had previously received treatment with a biological agent (for example, rituximab). The ERG considered the clinical benefit of pixantrone in patients who have previously been treated with rituximab to be a key area of uncertainty, given that there were no statistically significant differences between the pixantrone and comparator arms for complete or unconfirmed complete response, progression-free survival or overall survival in the subgroup of patients with aggressive B-cell lymphoma confirmed by central independent pathological review who had previously received rituximab.

3.37 The ERG considered whether the treatments of physician’s choice in the PIX301 trial represented UK clinical practice. Following input from its clinical specialists, the ERG noted that there is no consensus on which chemotherapy regimens should be used after second-line treatment fails and that there is a lack of comparative data on their clinical effectiveness. The ERG concluded that this meant the choice of treatment in the comparator arm of the PIX301 trial was unlikely to be a key issue. It also concluded that the small number of patients receiving each treatment meant that the choice of treatment in the comparator group could not be reliably analysed.

3.38 The ERG was concerned about the statistical power of PIX301 to detect a difference between treatment groups. According to the manufacturer’s revised power calculation, 81% power with 70 patients per group (the intention-to-treat population) would be achieved if the true proportion of patients with complete or unconfirmed complete response was 22% in the pixantrone group and 5% in the comparator group. However, the observed proportions of patients with a complete or unconfirmed complete response in the intention-to-treat population were 20.0% in the pixantrone group and 5.7% in the comparator group. The ERG noted that the difference between groups did not always reach statistical significance, and that results of the analyses in the subgroups confirmed by central independent pathological review should be interpreted with caution because they are likely to be underpowered to detect a difference between treatment groups. For these reasons, the ERG had reservations about whether pixantrone had been shown to have superior efficacy in the PIX301 trial.

3.39 The ERG was concerned about the reliability of the diagnosis of aggressive non-Hodgkin’s lymphoma at study entry. It noted that central independent pathological review by consensus was undertaken retrospectively (that is, after the trial), rather than at enrolment, and that aggressive disease was subsequently confirmed in only 104 of the 140 patients who were randomised. Consequently, it felt that results from the full trial population might not reflect the benefit of pixantrone in patients with aggressive B-cell lymphoma. The ERG acknowledged that the manufacturer said it had not been practical to confirm aggressive disease by central independent pathological review at enrolment, but considered it was important to evaluate data from the subgroup of patients with disease confirmed by central independent pathological review. The ERG it noted that, as a subgroup analysis, the statistical power of the PIX301 trial would be less than the intention-to-treat population.

3.40 The ERG considered the different patient populations in the subgroup analyses presented by the manufacturer. The ERG viewed the data from the post-hoc subgroup of patients with aggressive B-cell non-Hodgkin’s lymphoma that was histologically confirmed by central independent pathological review to be more relevant to the marketing authorisation and the decision problem in the NICE scope than the other 2 subgroups categorised according to type of lymphoma determined by onsite pathological review (patients with aggressive B-cell non-Hodgkin’s lymphoma and patients with diffuse large B-cell lymphoma). The ERG noted that retrospective central independent pathological review revealed 23% of patients receiving pixantrone and 29% of patients receiving a comparator in the intention-to-treat population had disease that was subsequently determined not to be aggressive. The ERG was aware that disease severity is an important factor in deciding treatment strategy because patients without aggressive disease are likely to have a more favourable response than those with aggressive disease.

3.41 The ERG considered the statistical robustness of the subgroup analyses. It observed that the comparative clinical effectiveness results for most of the subgroups were based on post-hoc subgroup analyses. It also noted that the number of patients in the analysis was generally small, increasing uncertainty around the results. For subgroups based on retrospective histological confirmation of aggressive disease and previous rituximab treatment, the ERG noted the potential for unbalanced groups because randomisation had not been stratified by these factors. The ERG concluded that the results of the subgroup analyses should be interpreted with caution.

3.42 The ERG considered the adverse events reported to occur more often in the pixantrone group than the comparator group receiving treatment of physician’s choice to be consistent with the common adverse events associated with pixantrone reported in the summary of product characteristics.

3.43 Overall, the ERG considered the manufacturer’s model to be in line with current best practice recommendations, was generally well constructed and largely transparent. The ERG considered that an important limitation of the manufacturer’s base-case analysis was that it used data from patients whose disease had not been histologically confirmed as aggressive. The ERG indicated that the subgroup of patients with aggressive B-cell non-Hodgkin’s lymphoma confirmed by central independent pathological review for all lines of treatment in the PIX301 trial was the most informative to the decision problem because it excluded patients who were later found to have disease that was irrelevant to the decision problem (for example, indolent disease). However, the ERG noted that the manufacturer’s estimate of cost-effectiveness in this patient population was highly uncertain because it used post-hoc subgroup data and because the subgroups were not powered to detect a difference in efficacy between treatment with pixantrone and the comparators.

3.44 The ERG considered the utility weights used by the manufacturer in its economic model to be potentially inappropriate. It noted that the utility values were from a population of patients receiving first-line treatment for aggressive non-Hodgkin’s lymphoma and were derived from a study that had initially been rejected by the manufacturer in its systematic review. It further noted that the manufacturer’s reported utility values are higher than those that have been derived for healthy elderly patients in the UK.

3.45 The ERG indicated that the manufacturer’s assessment of uncertainty was very detailed and that the probabilistic and one-way sensitivity analyses, including various scenario analyses, were satisfactorily reported. It noted that, with the exception of parameters used to inform progression-free survival and overall survival estimates, the manufacturer’s cost-effectiveness estimate was relatively insensitive to changes in individual parameters in the manufacturer’s base case (aggressive B-cell lymphoma confirmed by onsite pathological review [third- or fourth-line treatment]) and in the subgroup of patients with aggressive B-cell lymphoma confirmed by central independent pathological review. For the latter subgroup, which it considered to be more appropriate, the ERG noted that only 6 of 102 one-way sensitivity analyses produced a deterministic ICER greater than £35,000 per QALY gained.

3.46 The ERG noted that the results of the manufacturer’s economic model may potentially be biased towards pixantrone because of an overestimation of pixantrone’s relative progression-free survival benefit compared with treatment of physician’s choice for the populations with aggressive B-cell lymphoma (whether confirmed by onsite or central independent pathological review). Clinical specialist opinion received by the ERG expressed concern that the data used in the model may not be sufficient to reach reasonable conclusions about the clinical or cost effectiveness of pixantrone.

3.47 The ERG identified other areas of inaccuracy or uncertainty in the assumptions and parameter estimates used in the manufacturer’s model and indicated the most significant of these were structural assumptions made about treatment discontinuation, disutility, and the cost parameters used:

• The potential double-counting of treatment discontinuation because of disease progression.
• Excluding adverse event disutilities for patients on further lines of treatment.
• Discrepancies between the manufacturer’s and ERG’s interpretation of the literature on disutilities for adverse events.
• Using weighted average adverse event rates to inform costs and disutilities associated with adverse events for patients on original treatment.
• Missing data from data used to inform average adverse event costs.
• Excluding costs associated with treating leukopenia and thrombocytopenia.
• Using costs from BNF 62 (published September 2009) rather than BNF 64 (published September 2012).

ERG's exploratory analyses

3.48 The ERG confirmed the deterministic ICER for the manufacturer’s base case (the population with aggressive B-cell lymphoma) using the correct drug costs supplied by the manufacturer at clarification. This resulted in an ICER of £28,503 per QALY gained (incremental costs £17,688; incremental QALYs 0.62). This value was close to the ICER derived from the incorrect drug costs that was presented in the manufacturer’s submission (£28,423 per QALY gained).

3.49 The ERG stated that the manufacturer’s base-case cost-effectiveness results were generated deterministically rather than probabilistically (that is, mean values rather than distributions were used to inform the value of each parameter). However, the ERG noted that probabilistic cost-effectiveness results could be assessed using the manufacturer’s model. It noted that the mean probabilistic ICER of £28,846 per QALY gained (incremental costs £17,900; incremental QALYs 0.62) was highly consistent with the manufacturer’s deterministic ICER of £28,423 per QALY gained (incremental costs £17,638; incremental QALYs 0.62). Nevertheless, the ERG considered the wide 95% confidence interval, which ranged from pixantrone dominating treatment of physician’s choice (that is, it was more effective and less costly) to £308,681 per QALY gained, to show substantial uncertainty in the manufacturer’s cost-effectiveness results. The ERG also noted that pixantrone was less effective than treatment of physician’s choice in approximately 9% of the 5000 simulations, and pixantrone was dominated in 0.22% of simulations (that is, it was less effective and more expensive).

3.50 The ERG carried out exploratory sensitivity analyses to investigate the impact of alternative assumptions or parameters on the manufacturer’s cost-effectiveness results. The ERG judged the population with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of treatment in the PIX301 trial to be the most relevant to the decision problem (because it excluded patients who were later found to have disease that was not relevant to the decision problem [for example, indolent disease]) and used it in all its exploratory analyses.

3.51 Because it had concluded that the utility values used by the manufacturer may have been inappropriate, the ERG investigated how alternative utility values affected the manufacturer’s base case, using utility data from chronic lymphocytic leukaemia patients receiving third-line treatment to inform the utility of progression-free survival and progressive disease. In the population of patients with aggressive B-cell lymphoma confirmed by retrospective central independent pathology review, using the alternative utility data markedly increased the ICER for pixantrone compared with treatment of physician’s choice to £60,129 per QALY gained (incremental costs £14,855; incremental QALYs 0.247).

In further exploratory sensitivity analyses, the ERG varied other parameters where it perceived inaccuracy or uncertainty. Adding alternative estimates of disutility for selected adverse events and using costs from BNF 64 resulted in a cumulative base-case ICER of £60,154 per QALY gained (incremental costs £14,857; incremental QALYs 0.247) for pixantrone compared with treatment of physician’s choice in the population of patients with aggressive B-cell lymphoma confirmed by retrospective central independent pathology review. The ERG’s scenario analyses, which included costs for leukopenia and thrombocytopenia and excluded missing data, resulted in a cumulative ICER of £62,465 per QALY gained.

3.52 The ERG also commented on the anticipated effect on the base-case ICER of varying the other parameters when it had identified inaccuracy or uncertainty in the assumptions and parameter estimates used in the manufacturer’s model, but that it was not able to assess. These were: assessing treatment effectiveness in a patient population that had previously received rituximab; removing double-counting of treatment discontinuation as a result of disease progression; including adverse event disutilities for patients on further lines of treatment; using overall survival data from combination treatment rather than monotherapy; using accurate timing for each adverse event during the course of original treatment; adjusting the utility data for age. The ERG considered the ICER for patients previously treated with rituximab (in line with UK clinical practice) to be likely to increase substantially compared with the base-case ICER because the benefit of pixantrone was expected to be lower in this patient population. It anticipated that varying the other parameters would have a minimal or small impact on the ICER.

3.53 The ERG undertook probabilistic sensitivity analyses in the population of patients with aggressive B-cell lymphoma confirmed by retrospective central independent pathological review and found that the mean probabilistic ICER was £62,000 per QALY gained. It noted that the ICER had a 95% chance of falling between pixantrone dominating treatment of physician’s choice and £373,454 per QALY gained. The ERG observed that the wide confidence interval associated with the probabilistic ICER reflected the uncertainty about the data used in the manufacturer’s economic evaluation. The ERG also noted that these analyses do not account for treatment potentially being less effective in patients previously treated with rituximab.

3.54 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pixantrone, having considered evidence on the nature of relapsed or refractory non-Hodgkin’s lymphoma and the value placed on the benefits of pixantrone 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 discussed the treatment pathway for multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma. It heard from the clinical specialists that rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (also known as R-CHOP) was the standard first-line treatment in England and Wales, and that most patients would also receive a rituximab-containing regimen second line, unless their disease relapsed within 6 months of first-line treatment. It also heard that patients who developed relapsed or refractory disease after rituximab treatment were less likely to respond to any subsequent treatment. The Committee heard that a platinum-based regimen was offered as second-line treatment if the disease relapsed or became refractory to treatment but that there was no consensus on third- or fourth-line monotherapy treatment for relapsed or refractory disease. The Committee heard from the clinical specialists and patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life. The clinical specialists highlighted that the evidence base in this specific population was limited and the Committee heard that treatment options for patients ranged from participating in clinical trials (depending on eligibility and willingness to participate) to receiving palliative care.

4.3 The Committee heard from the patient expert about the impact of multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma on daily life and that the symptoms of the disease can reduce quality of life. It heard that patients are normally told at the start of their treatment that they are being treated with curative intent and that experiencing multiple relapses can be devastating; consequently, they would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma can place on patients and accepted that it was important to lessen these demands.

Clinical effectiveness

4.4 The Committee reviewed the suitability of the clinical trial evidence submitted by the manufacturer and expressed several concerns about the trial’s design. It considered the PIX301 trial to be underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee heard from the clinical specialists that although this end point would have been acceptable when the trial began in 2004, positron emission tomography (PET) scans have made unconfirmed complete response obsolete. The Committee also heard from the clinical specialists that they considered studies that were powered to detect a difference in overall survival to be more useful for clinical decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.

4.5 The Committee discussed the relationship between the UK marketing authorisation and the PIX301 trial population. The Committee noted that, although the UK marketing authorisation is for multiply relapsed or refractory disease and states that the benefit of pixantrone treatment in fifth-line or later treatment has not been demonstrated, this did not necessarily restrict use of pixantrone to third- and fourth-line treatment. It was aware that the intention-to-treat population included patients whose tumour histology would make them ineligible for treatment with pixantrone according to the terms of the UK marketing authorisation, and that these ineligible patients accounted for around 10% of the total trial population. The Committee concluded that, although the PIX301 study included a high proportion of patients eligible for treatment under the terms of the UK marketing authorisation, the intention-to-treat population of PIX301 was not appropriate for evaluation and decision-making.

4.6 The Committee discussed how the tumour histologies were diagnosed in the PIX301 trial population and if this was generalisable to clinical practice in England and Wales. It was already aware that the intention-to-treat population included disease histological subtypes that were not covered by the UK marketing authorisation (see section 4.5) and that the intention-to-treat population of PIX301 had been diagnosed by onsite review by a single pathologist. The Committee heard from the clinical specialists that this was not representative of UK clinical practice, in which multidisciplinary team review is routine and specimens are examined by 2 or 3 pathologists. It noted that the Evidence Review Group (ERG) had also been advised by clinical specialists that a population with disease confirmed by central independent pathological review was more relevant to UK clinical practice. It also noted that a considerable proportion of patients were excluded after the central independent pathological review (for example, if indolent disease had been confirmed). The Committee concluded that, when assessing the results from PIX301, it would be more appropriate to consider the population with tumour histology confirmed by retrospective central independent pathological review by consensus than the population with tumour histology diagnosed by onsite review by a single pathologist.

4.7 The Committee discussed whether the previous treatments received by the PIX301 trial population were generalisable to clinical practice in England and Wales. It noted that the trial had enrolled few patients from the UK and that patients from Western Europe tended to be more heavily pretreated than the anticipated population in England and Wales. The Committee was concerned that only just over half of patients in the PIX301 trial with aggressive B-cell lymphoma confirmed by central independent pathological review had previously received rituximab, because it heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and is also often used in second-line treatment. The Committee concluded that differences in previous treatment between the PIX301 trial population and UK clinical practice meant there was considerable uncertainty in determining the pixantrone’s likely clinical effectiveness in UK clinical practice.

4.8 The Committee then discussed more specifically the impact of previous rituximab treatment on response to any subsequent treatment. It again noted the clinical specialists’ opinion that patients with relapsed or refractory non-Hodgkin’s lymphoma who have previously received rituximab are less likely to respond to later lines of treatment than those who have not. The Committee noted the results of the manufacturer’s subgroup analyses, which showed a reduced benefit in patients who had previously received rituximab. It was also aware of the specific obligation to the European Medicines Agency in pixantrone’s UK marketing authorisation, which stipulated that an additional trial was required to confirm the clinical benefit in patients who have previously received rituximab. The Committee concluded that there was considerable doubt over the clinical benefit of pixantrone in patients who had previously received rituximab, and that this applied to virtually all patients with relapsed or refractory aggressive B-cell lymphoma in England and Wales.

4.9 The Committee discussed whether the comparator arm (treatment of physician’s choice) in the PIX301 trial was relevant to clinical practice in England and Wales. It heard from clinical specialists that apart from the PIX301 trial, there was no evidence base for selecting a third- or fourth-line treatment for multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma and that there was wide variation in UK clinical practice. The Committee noted that 45% of patients in the comparator arm of PIX301 had received oxaliplatin but heard from the clinical specialists that oxaliplatin was rarely used in this setting in the UK and was aware that the cost of oxaliplatin would be overestimated by the British National Formulary (BNF). The Committee further heard that gemcitabine was now routinely used in this setting in the UK but that only 1 patient in PIX301 had received it. Nevertheless, the Committee concluded that although there was some uncertainty in the proportions, all of the comparators used in the treatment of physician’s choice arm in the PIX301 trial were clinically relevant, and the comparator arm was therefore acceptable for decision-making.

4.10 The Committee discussed the adverse events associated with pixantrone. It noted the manufacturer’s assertion that pixantrone had less cardiotoxicity than anthracyclines. The Committee recalled that the decision problem specified in the NICE scope did not include any anthracyclines as comparators and that mitoxantrone was the only anthracenedione out of the 6 comparators. It heard from clinical specialists that doxorubicin (an anthracycline) was used as first-line treatment, and that none of the comparators for third- or fourth line treatment were associated with a similarly raised cardiovascular risk that is associated with anthracyclines. The Committee was aware that there were more cardiac adverse events in the pixantrone group than the comparator group, which received treatment of physician’s choice (35% versus 21%). However, it heard from the clinical specialists that efficacy is considered key in this patient population and that, because of its cardiovascular safety profile compared with anthracyclines, pixantrone offered an opportunity for response in patients who had previously shown sensitivity to anthracyclines but who could not receive further lines of anthracycline treatment after relapse because they had reached the maximum lifetime dose. It concluded that pixantrone had an acceptable adverse-effect profile although it was associated with more cardiotoxicity than treatments routinely used in this population in UK clinical practice.

4.11 The Committee discussed the subgroups in the manufacturer’s submission to identify the most appropriate population for evaluation. It noted that the manufacturer had identified various subgroups with aggressive B-cell lymphoma because these were more closely aligned with the UK marketing authorisation than the intention-to-treat population. However, the Committee noted that these were post-hoc subgroups and was aware that the ERG said that these should be considered with caution because of the lack of statistical power. The Committee recalled the clinical specialists’ and ERG’s opinion that the central independent pathological review mirrored clinical practice in the UK more closely than onsite pathological review. It noted that the retrospective central independent pathological review had excluded a sizeable proportion of patients originally included in the trial but later found not to have aggressive disease. In light of the breadth of the UK marketing authorisation (see section 2.1), it agreed that that it was more appropriate to evaluate all lines of treatment in the PIX301 trial and not restrict the assessment to third- and fourth-line treatment. Taking all of these factors into account, the Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of treatment in the PIX301 trial was the most appropriate for decision-making. However, it concluded that the results from this subgroup should be viewed with caution because of the lack of statistical power to detect a difference between treatment groups.

4.12 The Committee assessed the clinical effectiveness results of the PIX301 trial. It considered the PIX301 trial to be inadequately powered to detect a difference between treatment groups because it had had accrued less than half of the planned 320 patients. It noted that the difference between treatment groups did not always reach statistical significance in the intention-to-treat population and the post-hoc subgroups, and that there was no statistically significant difference in overall survival between treatment arms for all groups presented by the manufacturer. The Committee considered it was likely that the results of the analyses in the post-hoc subgroups confirmed by central independent pathological review were underpowered to detect a difference between treatment groups. This includes the post-hoc group that Committee considered to most accurately represent the likely population that would be treated with pixantrone in clinical practice (patients with aggressive B-cell lymphoma confirmed by central independent pathological review). The Committee noted that these statistical issues had led the ERG to conclude that it had reservations about whether superior efficacy of pixantrone had been shown. Taking all these issues into consideration, the Committee concluded that there was insufficient evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice for the population specified in the decision problem (adults with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma).

Cost effectiveness

4.13 The Committee discussed the manufacturer’s general approach to developing its economic model. It noted that the ERG considered the manufacturer’s approach to follow current best practice and was largely transparent. The Committee concluded that the outlined structure of the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.

4.14 The Committee reviewed the manufacturer’s approach to modelling mortality. It wished to explore the ERG’s concerns that the model may not accurately predict progression-free survival or overall survival, given that median progression-free survival with pixantrone had been overestimated compared with the results from the PIX301 trial. It heard from the manufacturer that although the results from the economic model overestimated the median progression-free survival with pixantrone, the area under the curve using the manufacturer’s model was similar to that observed in the PIX301 trial, and that uncertainty around the median using the model was because of steep drops in the survival curve in the clinical trial around that point. The Committee noted that the ERG accepted this was a plausible explanation for the uncertainty around median progression-free survival with pixantrone and that it was more relevant to look at the overall area under the curve to determine the accuracy of the predicted survival results using the manufacturer’s economic model. The Committee concluded that the manufacturer’s economic model produced estimates for progression-free survival and overall survival that were acceptable for evaluating pixantrone’s cost effectiveness.

4.15 The Committee considered the most appropriate population for evaluating cost effectiveness. The Committee noted that in the base case of its economic model, the manufacturer had used the subgroup with aggressive B-cell lymphoma confirmed by onsite pathological review (third and fourth lines of treatment). However, it was also aware that the ERG considered the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review across all lines of treatment to be more appropriate and had included this in its exploratory analyses. As described in section 4.11, the Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of treatment in the PIX301 trial was the most appropriate for decision-making and that therefore this population should inform the cost-effectiveness analyses.

4.16 The Committee discussed how quality of life had been incorporated into the manufacturer’s model. It heard from the clinical specialists that patients with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma (who are generally aged over 60 years) would have reduced quality of life compared with people of a similar age who were otherwise healthy. The Committee then heard from the ERG that the manufacturer’s utility values for patients receiving first-line treatment for aggressive non-Hodgkin’s lymphoma were higher than those for healthy older adults in the UK. The Committee then reviewed the utility values selected by the ERG for its exploratory analyses, which were for patients receiving third-line treatment for chronic lymphocytic leukaemia. The Committee heard from the clinical specialists that although these patients might have a similar quality of life to those receiving third- or fourth-line treatment for aggressive non-Hodgkin’s lymphoma, there were differences between the 2 conditions (such as increased infections with chronic lymphocytic leukaemia) that could mean these utility values were too low. The Committee agreed that the manufacturer’s utility values were likely to overestimate the quality of life for patients receiving third- or fourth-line treatment for relapsed or refractory aggressive non-Hodgkin’s lymphoma. Conversely, it decided that the ERG’s utility values were likely to underestimate the quality of life for this population. The Committee therefore concluded that, because of the utility values used, the manufacturer’s cost-effectiveness estimates for any given population would be too low and the ERG’s too high, and that the true cost effectiveness estimate would lie somewhere in the range between the two.

4.17 The Committee discussed how the uncertainty associated with the manufacturer’s model had been explored. The Committee noted the ERG’s opinion that the structural uncertainty associated with the model had been adequately explored. The Committee understood that the ERG’s exploratory probabilistic incremental cost-effectiveness ratios (ICERs) using the population in the manufacturer’s base case were highly uncertain, as indicated by the wide 95% confidence intervals (from pixantrone being less expensive and more effective than treatment of physician’s choice to £308,700 per quality-adjusted life year [QALY] gained). The Committee also noted the ERG’s view that the ICERs would be likely to increase substantially in a patient population that had been previously treated with rituximab because of a reduced treatment benefit compared with patients in the PIX301 trial population who had not all previously received rituximab. The Committee acknowledged, however, that the ERG had not performed this analysis and that the results for the population that had previous received rituximab were from post-hoc analyses on small patient numbers. The Committee concluded that the structural uncertainty associated with the manufacturer’s economic model had been satisfactorily explored but that there was still considerable uncertainty about the cost-effectiveness estimates for pixantrone in patients previously treated with rituximab, who would be the main population when treating multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma in England and Wales.

4.18 The Committee deliberated over the most plausible ICERs and considered those presented by the manufacturer and the ERG. It considered the intention-to-treat population of PIX301 not to represent the population that would be treated in UK clinical practice because it contained histological subtypes that were not covered by the UK marketing authorisation. When considering the post-hoc subgroups, the Committee agreed that it was more appropriate to evaluate a population that had disease confirmed by central independent pathological evaluation than onsite pathological evaluation. The Committee was mindful that the ICER would be likely to increase substantially in a population that had previously received rituximab (as in UK clinical practice) because of a reduced clinical benefit but acknowledged that these cost-effectiveness estimates for that population were not available for this appraisal. The Committee therefore agreed that, based on currently available evidence, the most plausible ICER would be for pixantrone compared with treatment of physician’s choice in people who had aggressive B-cell lymphoma confirmed by central independent pathological review. Having agreed this, it decided that the population should not be restricted to third- or fourth-line treatment, in line with the UK marketing authorisation. It noted that the manufacturer’s deterministic ICER for this population was £32,700 per QALY gained and that the ERG’s deterministic base-case ICER for this population, which used alternative utility values, was £60,200 per QALY gained. It concluded that the most plausible cost-effectiveness estimate, based on available evidence, would lie within the range between these 2 values and began to explore its further considerations based on this assumption. However, the Committee noted that this range was based on the data from the PIX301 trial, in which a sizeable proportion of patients had not previously received rituximab. The Committee concluded that the ICER could be much higher for the current UK patient group, for whom rituximab is given as part of standard first-line care for aggressive B-cell non-Hodgkin’s lymphoma.

4.19 The Committee was aware that the ongoing PIX306 study is scheduled to report in 2015. It noted that this larger randomised phase III study (n=350) will compare the effectiveness of pixantrone plus rituximab with gemcitabine plus rituximab in patients with relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have already received a rituximab-containing regimen. Given the relevance of the patient population (all of whom will have previously received rituximab) and the comparator (gemcitabine), the Committee recommended that pixantrone’s use for treating relapsed or refractory aggressive non-Hodgkin’s lymphoma should be considered for review by NICE once the PIX306 results are available in 2015.

4.20 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a 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 and
• 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 and
• 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 of the economic modelling are plausible, objective and robust.

The Committee noted the low median and mean overall survival for the various groups in the PIX301 trial and heard from the clinical specialists that life expectancy for patients with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma would typically be less than 2 years. The Committee agreed with the manufacturer’s and ERG’s calculations that the population eligible for treatment with pixantrone is considered small. However, the Committee considered the evidence insufficient to show that pixantrone offered an extension to life of an additional 3 months, compared with current NHS treatment. This was because none of the populations presented in the manufacturer’s submission showed a statistically significant difference between treatment groups. In addition, the Committee noted that the median survival advantage in the subgroup with aggressive B-cell lymphoma confirmed by central pathological review was 1.8 months and that there was uncertainty over the treatment benefit in patients who had previously received rituximab. Consequently, the Committee was not persuaded that the estimates of the extension to life were robust. The Committee concluded that pixantrone did not fulfil the criteria to be considered as a life-extending, end-of-life treatment.

4.21 The Committee discussed whether pixantrone was innovative in its potential to make a significant and substantial impact on health-related benefits. It considered pixantrone to have a new mechanism of action that is associated with lower cardiotoxicity compared with anthracyclines. It also observed that pixantrone is the first drug tested in a randomised phase III trial in patients with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma. However, the Committee heard from the clinical specialists that it was uncertain if pixantrone yielded outcomes that could be considered a step change in treatment. The Committee examined whether pixantrone had the potential to make a significant and substantial impact on heath-related benefits. On the basis of currently available evidence, the Committee did not consider pixantrone to be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.

4.22 The Committee considered whether NICE’s duties under the equalities legislation required it to alter or to add to its recommendations. It noted that no potential equalities issues had been raised during scoping, in any of the consultees’ submissions or during the Committee meeting. The Committee concluded that its decision on the use of pixantrone would not have a particular impact on any group with a protected characteristic and that there was no need to alter or add to its preliminary recommendations.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Pixantrone monotherapy for treating relapsed or refractory aggressive non-Hodgkin's lymphoma		Section
Key conclusion
Pixantrone is not recommended within its marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. Because of the inadequate statistical power of the PIX301 trial, the lack of statistically significant difference in overall survival between treatment arms, and the fact that the differences between treatment groups were not always statistically significant, the Committee concluded that there was insufficient evidence to show a greater clinical effectiveness for pixantrone compared with treatments currently used in clinical practice for the population specified in the decision problem (adults with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma). The Committee agreed that the most plausible incremental cost-effectiveness ratio (ICER) was for the comparison of pixantrone with treatment of physician’s choice in people who had aggressive B-cell lymphoma confirmed by central independent pathological review and considered that the population should not be restricted to third- or fourth-line treatment, in line with the UK marketing authorisation. It noted that the manufacturer’s deterministic ICER for this population was £32,700 per QALY gained and that the Evidence Review Group’s (ERG) deterministic base-case ICER for this population, which used alternative utility values, was £60,200 per quality-adjusted life year (QALY) gained. It concluded that the most plausible cost-effectiveness estimate, based on available evidence, would lie within the range between these 2 values. However, Committee noted that this range was based on the data from the PIX301trial, where a sizeable proportion had not previously received rituximab. The Committee concluded that the ICER could be much higher for the current UK patient group, for whom rituximab is given as part of standard first-line care for aggressive B-cell non Hodgkin’s lymphoma.			1.1, 4.12, 4.18
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life. The clinical specialists highlighted that the evidence base in this specific population was limited and Committee heard that treatment options for patients ranged from participating in clinical trials (depending on eligibility and willingness to participate) to receiving palliative care. The Committee heard from the patient expert that patients would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma can place on patients and accepted that it was important to lessen these demands.	4.2, 4.3
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		Pixantrone (Pixuvri, Cell Therapeutics) is an aza-anthracenedione analogue and inhibitor of topoisomerase with a new mechanism of action that is associated with lower cardiotoxicity compared with anthracyclines. The Committee concluded that there was insufficient evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice to treat multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. The Committee examined whether pixantrone had the potential to make a significant and substantial impact on heath-related benefits. On the basis of currently available evidence, the Committee concluded that using pixantrone would not be a step change in the management of multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma and that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.	2.1, 4.12, 4.21
What is the position of the treatment in the pathway of care for the condition?		Pixantrone has a conditional UK marketing authorisation ‘as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy’ (meaning that is conditionally approved for patients who have received at least 2 previous lines of treatment). In light of the breadth of the UK marketing authorisation, the Committee considered that it was more appropriate to evaluate all lines of therapy in the PIX301 trial and not restrict the assessment to third- and fourth-line treatment. The Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of therapy in the PIX301 trial was the most appropriate for decision-making.	2.1, 4.11
Adverse reactions		The summary of product characteristics states the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting, and diarrhoea were generally infrequent, mild, reversible, manageable, and expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, it recommends monitoring left ventricular ejection fraction. The Committee concluded that pixantrone had an acceptable adverse-event profile although it was associated with more cardiotoxicity than treatments routinely used in this population in UK clinical practice.	2.2, 4.10
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee considered that the PIX301 trial was underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee considered that although the PIX301 study had included a high proportion of patients who would be eligible for treatment under the terms of the UK marketing authorisation, the intention-to-treat population of PIX301 was not appropriate for evaluation and decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there would be considerable uncertainty in the validity and robustness of its results.	4.4, 4.5
Relevance to general clinical practice in the NHS		Because tumour specimens would be examined by 2 or 3 pathologists in clinical practice in the UK, the Committee concluded that it would be more appropriate to consider results from the PIX301 trial using a population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.	4.6
Uncertainties generated by the evidence		The Committee noted that patients from Western Europe in the PIX301 trial tended to be more heavily pretreated than the anticipated population in England and Wales. It was aware that only just over half of patients in the PIX301 trial had previously received rituximab; however, it heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and also often used in second-line therapy. The Committee concluded that differences in previous treatment between the PIX301 trial population and UK clinical practice meant there was considerable uncertainty in determining the clinical effectiveness in a population that was relevant to UK clinical practice. It was also aware of the specific obligation to the European Medicines Agency in pixantrone’s UK marketing authorisation, which stipulated that an additional trial was required to confirm the clinical benefit in patients who have previously received rituximab. The Committee further concluded that there was considerable doubt over the clinical benefit of pixantrone in patients who had previously received rituximab, and that this applied to virtually all patients with relapsed or refractory aggressive B-cell lymphoma in England and Wales.	4.7, 4.8
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted that the manufacturer had identified various post-hoc subgroups with aggressive B-cell lymphoma because these were more closely aligned with the UK marketing authorisation than the intention-to-treat population. The Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of therapy in the PIX301 trial was the most appropriate for decision-making but that the results from this subgroup should be viewed with caution because of the lack of statistical power to detect a difference between treatment groups.	4.11
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that there was insufficient evidence to show pixantrone was more clinical effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma.	4.12
Evidence for cost effectiveness
Availability and nature of evidence		The Committee concluded that the outlined structure of the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.	4.13
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that in the base case of its economic model, the manufacturer had used the subgroup with aggressive B-cell lymphoma confirmed by onsite pathological review (third and fourth lines of therapy). The Committee concluded that the subgroup with aggressive B-cell lymphoma confirmed by central independent pathological review for all lines of treatment in the PIX301 trial was the most appropriate for decision-making and that therefore this population should inform the cost-effectiveness analyses.	4.15
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee was aware that utility values used by the manufacturer were higher than values for healthy older adults in the UK and considered these would likely overestimate the quality of life for patients receiving third- or fourth-line treatment for relapsed or refractory aggressive non-Hodgkin’s lymphoma. The Committee considered that the ERG’s alternative utility values (for patients receiving third-line treatment for chronic lymphocytic leukaemia) were likely to underestimate the quality of life for this population. The Committee concluded that, for any given population, the true cost effectiveness estimate would lie somewhere in the range between the manufacturer’s and the ERG’s. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations and concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.	4.16, 4.21
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable. (See section 4.18 which outlines the subgroups considered by the Committee when determining the most plausible ICER.)
What are the key drivers of cost effectiveness?		The Committee concluded that the structural uncertainty associated with the manufacturer’s economic model had been satisfactorily explored but that that was still considerable uncertainty regarding the cost-effectiveness estimates for pixantrone in patients previously treated with rituximab, who would be the main population when treating multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma in England and Wales.	4.17
Most likely cost-effectiveness estimate (given as an ICER)		The Committee agreed that the most plausible ICER was for the comparison of pixantrone with treatment of physician’s choice in people who had aggressive B-cell lymphoma confirmed by central independent pathological review and considered that the population should not be restricted to third- or fourth-line treatment, in line with the UK marketing authorisation. It noted that the manufacturer’s deterministic ICER for this population was £32,700 per QALY gained and that the ERG’s deterministic base-case ICER for this population, which used alternative utility values, was £60,200 per QALY gained. It concluded that the most plausible cost-effectiveness estimate, based on available evidence, would lie within the range between these 2 values. However, Committee noted that this range was based on the data from the PIX301trial, where a sizeable proportion had not previously received rituximab. The Committee concluded that the ICER could be much higher for the current UK patient group, where rituximab is given as part of standard first-line care for aggressive B-cell non-Hodgkin’s lymphoma.	4.18
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable
End-of-life considerations		The Committee agreed that life expectancy for patients with multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma would typically be less than 2 years. The Committee agreed with the manufacturer’s and ERG’s calculations that the population eligible for treatment with pixantrone is considered small. However, the Committee considered that there was insufficient evidence demonstrating that pixantrone offered an extension to life of an additional 3 months, compared with current NHS treatment and was not persuaded that the estimates of the extension to life were robust. The Committee concluded that pixantrone did not fulfil the criteria to be considered as a life-extending, end-of-life treatment.	4.20
Equalities considerations and social value judgements		The Committee concluded that its decision on the use of pixantrone would not have a particular impact on any group with a protected characteristic and that there was no need to alter or add to its preliminary recommendations.	4.22

5 Implementation

5.1 The National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 require clinical commissioning groups, the NHS Commissioning Board and, with respect to their public health functions, local authorities to comply with NICE technology appraisal recommendations that recommend that the relevant health service body provide funding within the period specified. Where NICE recommends that a treatment be funded by the NHS, the Regulations require that the period within which health service body must comply will be stated in the recommendation as 3 months, except where particular barriers to implementation within that period are identified.

5.2 The technology in this appraisal may not be the only treatment for multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma. If a NICE technology appraisal recommends use of a technology, it is as an option for the treatment of a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes and the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Rituximab for aggressive non-Hodgkin's lymphoma. NICE technology appraisal guidance 65 (2003). Available from www.nice.org.uk/guidance/TA65
• Haemato-oncology: Improving outcomes in haemato-oncology cancer. Cancer Service Guidance CSGHO (2003). Available from www.nice.org.uk/guidance/CSGHO

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive when the PIX306 trial results are available and at the latest in August 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Gary McVeigh
Vice-Chair, Appraisal Committee

Andrew Stevens
Chair, Appraisal Committee

April 2013

Appendix A: Appraisal Committee members, and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Gary McVeigh
Vice Chair of Appraisal Committee C, Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Daniele Bryden
Consultant in Intensive Care Medicine and Anaesthesia, Sheffield Teaching Hospitals NHS Trust

Dr Andrew Burnett
Director for Health Improvement and Medical Director, NHS Barnet, London

David Chandler
Lay Member

Professor Peter Crome
Honorary Professor, Dept of Primary Care and Population Health, University College London

Dr Maria Dyban
General Practitioner, Kings Road Surgery, Glasgow

Professor Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Greg Fell
Consultant in Public Health, Bradford and Airedale Primary Care Trust

Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School

Professor Cathy Jackson
Professor of Primary Care Medicine, University of St Andrews

Dr Janice Kohler
Senior Lecturer and Consultant in Paediatric Oncology, Southampton University Hospital Trust

Emily Lam
Lay Member

Dr Grant Maclaine
Director, Health Economics & Outcomes Research, BD, Oxford

Henry Marsh
Consultant Neurosurgeon, St George's Hospital, London

Professor Eugene Milne
Deputy Regional Director of Public Health, North East Strategic Health Authority, Newcastle upon Tyne

Professor Stephen O’Brien
Professor of Haematology, Newcastle University

Dr Anna O’Neill
Deputy Head of Nursing & Healthcare School/Senior Clinical University Teacher, University of Glasgow

Alan Rigby
Academic Reader, University of Hull

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Professor Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle
Lay Member

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), and a project manager.

Linda Landells
Technical Lead

Lori Farrar
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by BMJ Technology Assessment Group:

• Edwards SJ, Barton S, Nherera L, Trevor N, Krause T, Thurgar EJ. Pixantrone monotherapy for the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma: A Single Technology Appraisal. BMJ-TAG, London, 2013

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Cell Therapeutics

II Professional/specialist and patient/carer groups:

• Leukaemia CARE
• Lymphoma Association
• British Society for Haematology
• Cancer Research UK
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III Other consultees:

• Department of Health
• Greater Manchester (PCT Cluster)
• South Essex (PCT Cluster)
• Welsh Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Bristol-Myers Squibb Pharmaceuticals
• Lilly UK
• Pfizer
• MRC Clinical Trials Unit
• BMJ Group
• National Institute for Health Research Health Technology Assessment Programme
• National Collaborating Centre for Cancer

The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on Pixantrone monotherapy for the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Andrew McMillan, Consultant Haematologist, nominated by the Royal College of Physicians – clinical specialist
• Dr Ruth Pettengell, Reader in Haemato-Oncology, nominated by the Royal College of Physicians – clinical specialist
• Jacky Wilson, Medical Writer, nominated by Lymphoma Association - patient expert

C Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Cell Therapeutics