Mifamurtide for the treatment of osteosarcoma

1 Appraisal Committee’s preliminary recommendations

1.1 Mifamurtide in combination with postoperative multi-agent chemotherapy is not recommended in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection.

2 The technology

2.1 Mifamurtide (Mepact, Takeda) is an immune macrophage stimulant. It has a marketing authorisation for use in ‘children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection’. The marketing authorisation further states that mifamurtide is used in combination with postoperative multi-agent chemotherapy, and that safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis.

2.2 The summary of product characteristics lists the following adverse events that may be associated with mifamurtide treatment: respiratory distress, neutropenia, inflammatory response, cardiovascular disorders, allergic reactions and gastrointestinal toxicity. The results of the clinical study also suggested that mifamurtide significantly increased the incidence of objective and subjective hearing loss. However, the manufacturer suggested that the likely cause was related to the use of cisplatin as part of multi-agent chemotherapy rather than mifamurtide. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 Mifamurtide is available as a powder for suspension for intravenous infusion, with each vial containing 4 mg of mifamurtide. The recommended dose of mifamurtide for all patients is 2 mg/m² body surface area. Mifamurtide should be administered as adjuvant therapy following resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 doses in 36 weeks.

2.4 The manufacturer’s submission states that the price for one mifamurtide dose is £2375 with a total cost of £114,000 for a full treatment course of 48 doses. The manufacturer has agreed a patient access scheme (PAS) with the Department of Health, in which mifamurtide for the treatment of osteosarcoma will be available at no charge to the NHS for the first 7 doses. The Department of Health considered that this PAS does not constitute an excessive administrative burden on the NHS.

3 The manufacturer’s submission

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

3.1 In the submission, the manufacturer compared mifamurtide as an add-on treatment to postoperative multi-agent adjuvant chemotherapy (three- or four-agent adjuvant chemotherapy using high-dose methotrexate, doxorubicin and cisplatin with or without ifosfamide) with postoperative multi-agent adjuvant chemotherapy (three- or four-agent) alone in patients with high-grade, resectable, non-metastatic osteosarcoma.

3.2 The evidence for the efficacy of mifamurtide in the manufacturer’s submission was obtained from one multicentre, open-label randomised controlled trial (RCT), the Intergroup study 0133 (INT-0133). Most of the patients were recruited in the USA. Patients in INT-0133 (n = 678) received 10 weeks of neoadjuvant induction therapy with either chemotherapy regimen A (methotrexate, doxorubicin and cisplatin) or chemotherapy regimen B (methotrexate, doxorubicin, cisplatin and ifosfamide) before surgical resection of their tumour. Surgical resection was performed during weeks 10–11, when patients were not receiving chemotherapy. Adjuvant therapy was scheduled to begin at week 12 when patients received one of four regimens: regimen A, regimen A+ (regimen A with the addition of mifamurtide), regimen B, or regimen B+ (regimen B with the addition of mifamurtide). Using a two by two factorial design, the study compared mifamurtide plus multi-agent chemotherapy (regimens A+ and B+) with multi-agent chemotherapy alone (regimens A and B). The primary endpoint was overall survival. However, the study was powered for the first planned analysis of the intermediate endpoint, that is, disease-free survival.

3.3 The patients in the study were under 30 years of age with a new diagnosis of malignant high-grade osteosarcoma. Exclusion criteria included metastatic disease or unresectable primary disease, low-grade osteosarcoma, parosteal or periosteal sarcoma, radiation-induced sarcoma or osteosarcoma arising in premalignant bony lesions, or previous chemo- or radiation therapy.

3.4 The manufacturer presented analyses based on three data sets. The initial clinical study report presented data collected up to June 2003 (2003 data set), and August 2006 (2006 data set); an addendum subsequently provided the updated findings based on data to March 2007 (2007 data set). Both the manufacturer and the ERG considered the 2007 data set to be the most up to date and comprehensive. Therefore, only the 2007 data set is referred to in this document. The overall survival data in the INT-0133 study showed that after a median follow-up of 7.9 years, adding mifamurtide to chemotherapy (regimens A+ and B+ combined) significantly improved overall survival compared with chemotherapy alone (regimens A and B combined) with an overall survival of 71% in the control arm and 78% in the mifamurtide arm. For the intention-to-treat (ITT) population, the hazard ratio for death was 0.72; 95% confidence interval [CI] 0.53 to 0.97. Adding mifamurtide to chemotherapy (regimens A+ and B+ combined) also increased disease-free survival compared with chemotherapy alone (regimens A and B combined), but this was not statistically significant. For the ITT population, the hazard ratio for disease free survival was 0.78; 95% CI 0.61 to 1.01.

3.5 The manufacturer presented a number of post hoc subgroup analyses for the data set combining regimens A and B. These analyses showed a consistent, but not always a statistically significant, increase in overall survival with mifamurtide plus chemotherapy compared with chemotherapy alone across a broad range of demographic factors (age, gender, ethnicity, study site and geographic location) and prognostic factors (tumour size, lactate dehydrogenase level, alkaline phosphatase level, cooperative study group and background chemotherapy). Only the subgroup of patients older than 16 years did not benefit (that is, the hazard ratio was greater than 1) from adding mifamurtide to chemotherapy.

3.6 The ERG requested six additional post hoc analyses for both overall and disease-free survival comparing individual mifamurtide-containing regimens (regimen A+ or B+) with individual regimens not containing mifamurtide (regimen A or B). The analyses that compared mifamurtide plus three-agent chemotherapy (regimen A+) with the chemotherapy regimen most commonly used in UK clinical practice (regimen A) showed non-significant increases in overall survival (hazard ratio for death 0.75; 95% CI 0.49 to 1.16) and disease-free survival (hazard ratio for progression 0.96; 95% CI 0.67 to 1.38). For regimen B+ compared with four-agent chemotherapy regimen B, there was a non-significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05) and a significant improvement in disease-free survival (hazard ratio 0.63; 95% CI 0.44 to 0.91).

3.7 In the INT-0133 study, only severe adverse events (grade 3 or 4) were recorded. The study showed that with the exception of hearing loss, the number of adverse events was similar in patients receiving mifamurtide plus multi-agent chemotherapy (regimens A+ and B+ combined) compared with patients receiving multi-agent chemotherapy alone (regimens A and B combined). Adding mifamurtide to multi-agent chemotherapy significantly increased the incidence of objective hearing loss (11.5% with mifamurtide versus 7.1% without; p = 0.047) and subjective hearing loss (3.6% with mifamurtide versus 0.6% without; p = 0.007). The post hoc subgroup analyses by treatment regimen showed that the increased incidence of hearing problems occurred only in patients treated with three-agent chemotherapy plus mifamurtide (regimen A+) when compared with those treated with three-agent chemotherapy alone (regimen A).

3.8 Additional data from phase I and II studies of over 700 patients suggest that the most common adverse events in patients and healthy volunteers treated with mifamurtide alone were fever, chills, fatigue, headache, nausea/vomiting, myalgia and tachycardia, hypotension, hypertension and dyspnoea. Chills, fever and pyrexia were reported as mild to moderate.

3.9 In the INT-0133 study, the rates of discontinuation were higher in both mifamurtide groups (regimens A+ and B+) than in the groups without mifamurtide (regimens A and B). Statistical analyses comparing the rates of discontinuation between the treatment groups were not provided. The manufacturer stated that most of the withdrawals were not caused by adverse events that required significant intervention. The manufacturer also stated that the adverse events were not life threatening, and did not require mifamurtide to be stopped. The manufacturer assumed that many patients, or their parents, decided to withdraw from mifamurtide treatment because it was an investigational drug of unproven benefit and was uncomfortable or inconvenient (no further details were provided by the manufacturer) when added to existing multi-agent chemotherapy.

3.10 The manufacturer presented an economic model of the cost effectiveness of adding mifamurtide to three- and four-agent chemotherapy regimens combining cisplatin, doxorubicin and methotrexate with or without ifosfamide. The economic model had six health states. These were: disease free (start state), disease progression (optional start state), recurrence, disease free post recurrence, disease progression post recurrence, and death. The model had a cycle length of 6 months and a time horizon of 60 years. The manufacturer assumed that patients in the disease-free health state at 12.25 years had a mortality rate equivalent to the general population. Patients in the post-recurrence disease-free state were assumed to have a mortality rate dependent on the time to recurrence, which was derived from a study by Ferrari et al. (2003). For patients who had recurrence within 2 years, the 6-monthly mortality rate was 14.87% and for those who had recurrence after 2 years, the 6-monthly mortality rate was 4.98%.

3.11 The transition probabilities used in the deterministic base case were derived from the INT-0133 study for 604 patients who entered the adjuvant phase, and the post-recurrence estimates were mostly derived from the literature, except when death was recorded as an event post recurrence.

3.12 The default number of mifamurtide doses to be administered to each patient was assumed to be 38.4, which was the average number of mifamurtide doses administered in the INT-0133 study. The utility values used in the economic model were taken from a study using the EQ-5D in 22 survivors from the INT-0133 study (for the recurrence health state), and a review of utility values used in NICE technology appraisals undertaken by the manufacturer (for all other health states). This review included technology appraisals for treating colon, colorectal, renal cell, and prostate cancer, myeloid leukaemia and glioma. The utility values used in the model were as follows: 0.39 for disease progression, 0.85 for patients who were disease free, 0.61 for recurrence, 0.85 for patients who were disease free post recurrence, 0.39 for disease progression post recurrence, and 0.0 for death. The manufacturer’s submission only included adverse events associated with infusion in the base-case analyses. From the INT-0133 study, hearing loss was identified as the main adverse event for mifamurtide. A decrease in utility value associated with this adverse event was not included in the model because it was considered to be an anomaly of the data; hearing loss is associated with cisplatin and the number of additional cases observed in one of the mifamurtide arms was within the reported range of cisplatin-related hearing loss. An 18% decrease in utility value for hearing loss was explored in sensitivity analyses, based on data derived from one study found in the manufacturer’s Medline search on hearing loss in cancer patients.

3.13 The economic model included the following costs: adjuvant chemotherapy (cisplatin, doxorubicin, ifosfamide, methotrexate) with or without mifamurtide, treatment of adverse events during the maintenance phase, routine monitoring, diagnostics, surgery and second-line chemotherapy for disease progression (ifosfamide and etoposide). Costs and resource utilisation information were taken from the most recent NHS reference costs, that is 2007/08. Information on healthcare resource use was not collected in the study and the costs of these resources were therefore estimated from information provided by clinical specialists.

3.14 The manufacturer presented the following total costs and total quality-adjusted life years (QALYs) gained for the base case without the PAS.

• Regimen A and B combined: total costs £31,481; total QALYs 15.38.
• Regimen A+and B+ combined: total costs £123,852; total QALYs 16.72.
• Regimen A: total costs £29,709; total QALYs 16.10.
• Regimen A+: total costs £122,604; total QALYs 16.69.
• Regimen B: total costs £33,244; total QALYs 14.66.
• Regimen B+: total costs £125,121; total QALYs 16.71.

3.15 Under the PAS scheme there would be no charge to the NHS for the first 7 doses of mifamurtide. The manufacturer’s analyses produced the following incremental cost-effectiveness ratios (ICERs) including the PAS.

• Manufacturer’s base case (combined data set) was £56,683 per QALY gained.
• Manufacturer’s base case for regimen A+ compared with A was £130,814 per QALY gained.
• Manufacturer’s base case for regimen B+ compared with B was £36,913 per QALY gained.

3.16 The manufacturer conducted a series of one-way sensitivity analyses. The results showed that the model was mainly sensitive to the discount rates used for outcomes, and the health-related quality of life value for the disease-free health state.

3.17 The manufacturer’s economic submission also presented a scenario analysis evaluating the effect of the following model assumptions on its base case, including the PAS (using the combined data set).

• Incorporating amputation and limb salvage costs increased the ICER from £56,683 to £59,231 per QALY gained.
• Incorporating adverse events related to hearing loss increased the ICER from £56,683 to £71,065 per QALY gained.
• Allowing the post-recurrence mortality rate to equate to the general population mortality rate for patients who remain disease free after 5 years increased the ICER from £56,683 to £61,580 per QALY gained.
• Applying age-adjusted utility rates increased the ICER from £56,683 to £62,112 per QALY gained.

3.18 The manufacturer also carried out a scenario analysis which assessed applying all the assumptions described in section 3.18 simultaneously. This increased the base-case ICER from £56,683 to £91,442 per QALY gained. The manufacturer also carried out probabilistic sensitivity analyses, with analyses assuming a payment threshold of £50,000. The results showed that approximately 30% of the iterations were below this limit.

3.19 The ERG questioned whether pooling data from the INT-0133 study of the three- and four-agent chemotherapy regimens (that is combining regimens A+ and B+ and combining regimens A and B) was appropriate. The ERG noted that there were potentially significant differences in clinical effectiveness among the four groups, as demonstrated by the analyses that compared individual mifamurtide-containing regimens (A+ or B+) with regimens not containing mifamurtide (regimen A or B). The ERG highlighted the uncertainty about the effect of interaction between ifosfamide and mifamurtide on the results of the INT-0133 study. The ERG stated that if it was accepted that there was no such interaction, the results could be considered to represent two separate trials comparing the treatment of osteosarcoma. If considered in this way they would indicate a high degree of uncertainty in the true cost effectiveness of mifamurtide.

3.20 The ERG was concerned that a statistically significant difference between hearing loss rates reported in the INT-0133 study (15% for the mifamurtide regimens compared with 8% for the non-mifamurtide regimens) was omitted from the economic analysis.

3.21 The ERG noted that the base-case assumptions used by the manufacturer were favourable to mifamurtide and had concerns about the selection of the parameters entered into the model (for example, the most appropriate comparator, whether the effects of hearing loss should be incorporated, whether a general population mortality rate should be used if a patient went 5 years without recurrence, whether amputation or limb salvage costs should be used, whether age-related utilities should be used). The ERG stated that as a result, the ICER for regimen A+ and B+ compared with regimen A and B was likely to be substantially higher than the £56,683 per QALY gained reported in the manufacturer’s base case.

3.22 The ERG noted that the model lacked face validity because the modelled survival rates at 6 years (83% and 77% with and without mifamurtide respectively) were higher than the observed data in the clinical trial (80% and 73% with and without mifamurtide respectively). This represented increases in the range of 3–4 percentage points, and it was unclear what was driving the difference in survival. If, for example, it was simply the length of the time cycle in the Markov model, then a more appropriate time cycle should have been chosen in the model. The ERG stated that although this lack of face validity increases the uncertainty in the results, it is unclear what effect this would have on the ICER if the mortality rates observed in the INT-0133 study were accurately replicated in the model.

3.23 The ERG carried out a number of exploratory sensitivity analyses, including the following: use of data from regimen A+ compared with regimen A rather than pooled data, applying age-dependent utility values, mortality rates set to those of the age-matched general population if patients were disease free for 5 years, amputation and limb salvage costs. All increased the cost per QALY gained compared with the manufacturer’s base case. The ERG stated that the sensitivity analyses indicated that even including the PAS, it was very unlikely that the cost per QALY gained was below £50,000. The most plausible ICER, focusing on a comparison of regimens A+ with A as best reflecting UK clinical practice, would be higher than £100,000 per QALY gained. The ERG’s base-case analysis produced a deterministic ICER of £109,296 (probabilistic ICER of £103,494) per QALY gained.

3.24 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 mifamurtide for osteosarcoma, having considered evidence on the nature of osteosarcoma and the value placed on the benefits of mifamurtide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Management of high-grade resectable non-metastatic osteosarcoma in UK clinical practice

4.2 The Committee discussed the clinical needs of patients with high-grade resectable non-metastatic osteosarcoma. The patient experts stated that the diagnosis and treatment of osteosarcoma has a significant impact on patients and their families and friends. This included disruption of family life, strain on family relationships, additional stress at work and financial pressures. The Committee heard from the clinical specialists and patient experts that the main aim of treatment is to improve the cure rate (that is, the percentage of people who will subsequently have a normal lifespan, free of disease). The clinical specialists and patient experts stated that there had been no improvement in overall survival after treatment of osteosarcoma over the past 20 years. The patient experts stated that any improvement in overall survival from adding mifamurtide to standard chemotherapy was clinically significant and important.

4.3 The Committee heard from the clinical specialists that current UK clinical practice is neoadjuvant multi-agent chemotherapy and surgical resection, followed by postoperative adjuvant multi-agent chemotherapy. Standard adjuvant multi-agent chemotherapy regimens in the UK include doxorubicin, methotrexate and cisplatin and the 5-year overall survival rate for patients treated in the UK is approximately 55%. The clinical specialists highlighted that the use of ifosfamide is currently limited in the UK, and that ifosfamide is currently being investigated in an ongoing European and US osteosarcoma trial (EURAMOS 1) as part of an adjuvant regimen (with etoposide, cisplatin, doxorubicin and methotrexate) for patients with tumours showing a poor histological response to pre-operative chemotherapy. The clinical specialists stated that this study is due for completion in 2010, and may establish the place of ifosfamide in UK clinical practice. The Committee accepted that the current standard chemotherapy regimen in England and Wales is doxorubicin, methotrexate and cisplatin, but noted that a significant number of patients in the UK have been recruited into the EURAMOS 1 trial and some may therefore also be receiving ifosfamide.

4.4 The Committee noted evidence from the clinical specialists and patient experts that treatment with mifamurtide is safe and well tolerated. The Committee noted that standard neoadjuvant and adjuvant chemotherapy in the UK (regimen A) is completed in approximately 30 weeks, and that an additional 18 weeks of treatment with mifamurtide would be required to be consistent with the administration schedule in the INT-0133 trial. Patient experts stated that increased overall survival is so important that patients would accept the option of prolonged treatment with mifamurtide if it was shown to improve overall survival. The Committee heard from the clinical specialists that in the INT-0133 study a significant proportion of patients (22–30%) did not complete treatment with mifamurtide, and that based on evidence from the EURAMOS 1 study, this may be caused by patients not wanting to extend treatment beyond the duration of standard multi-agent chemotherapy. The Committee concluded that patients may show greater willingness to extend the treatment period if mifamurtide was offered as a routine treatment which they believed had benefits, than if it was offered only as part of an investigational clinical trial.

Clinical effectiveness

4.5 The Committee considered the evidence on the clinical effectiveness of mifamurtide as presented in the manufacturer’s submission and the ERG’s critique. It considered the evidence from the only relevant randomised clinical trial (INT-0133). The Committee noted that the study was relatively well conducted, but it agreed that there were substantial methodological issues identified by the ERG which led to uncertainty around the estimates of survival. These included delayed administration of mifamurtide (including non-administration of mifamurtide after randomisation), and imbalance in histological response to neoadjuvant therapy between treatment groups. This was particularly pronounced for those patients assigned to regimen A+, where a greater proportion of tumours showed a poor [greater than 5% remaining viable tumour] histological response. Furthermore, although the study was powered to demonstrate disease-free survival, a statistically significant reduction was not shown (p = 0.0586). The Committee concluded that these aspects of the study made interpretation more difficult, and that the effect of these factors on the results could not be reliably predicted.

4.6 The Committee noted that the manufacturer had presented a pooled analysis of the two mifamurtide-containing regimens (comparing chemotherapy plus mifamurtide [regimen A+ or B+] versus chemotherapy without mifamurtide [regimen A or B]) for overall survival and a number of post hoc efficacy analyses. The Committee discussed whether it was reasonable for the manufacturer to have pooled the data from the three- and four -agent chemotherapy arms (regimens A and B, and regimens A+ and B+). The Committee considered that the analysis had methodological flaws and the data should have been analysed as four separate and independent treatment regimens. However, the Committee was aware that the pooled analysis was the primary analysis of the trial and noted that this suggested a statistically significant improvement in overall survival from 71% in the control arm to 78% in the mifamurtide arm over a median follow-up period of 7.9 years. The study also demonstrated that although regimens of chemotherapy plus mifamurtide (regimens A+ and B+ combined) increased disease-free survival compared with chemotherapy alone (regimens A and B), this was not statistically significant. The Committee discussed the uncertainty around the pooled analysis and noted the ERG’s concerns that although the addition of mifamurtide to multi-agent chemotherapy (regimens A+ and B+ combined) increased overall survival compared with multi-agent chemotherapy alone (regimens A and B combined), the size of the treatment effect of mifamurtide was uncertain, partly related to the disparity of survival events in the subset of patients who did not enter the maintenance phase. The Committee noted that a greater proportion of patients assigned to regimen A+ had tumours showing a poor (greater than 5% remaining viable tumour) histological response to neoadjuvant pre-operative therapy. It accepted the view of the clinical specialists that there was evidence of a link between poor histological response to neoadjuvant therapy and prognosis, but concluded that it was not possible to establish whether, or to what extent, this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results. The Committee also noted the ERG’s concerns that there may have been interaction between treatments (that is, ifosfamide may be required to ensure activity of mifamurtide). However the Committee accepted that based on the 95% confidence intervals observed there was no strong evidence to suggest that there was interaction, and it accepted the clinical specialists’ views that there was no biologically plausible reason for such an effect.

4.7 The Committee then discussed the post hoc analyses that compared regimen A with A+, and regimen B+ with B. The Committee noted that for regimen A+ compared with A, there was a non-significant improvement in overall survival (hazard ratio 0.75; 95% CI 0.49 to 1.16). For regimen B+ compared with B, there was a non-significant improvement in overall survival (hazard ratio 0.68; 95% CI 0.44 to 1.05). The Committee then discussed the post hoc analysis in the context of UK clinical practice and concluded that the most appropriate analysis would be the one that compared the individual mifamurtide containing regimen (A+) with a regimen reflecting UK clinical practice (regimen A). Given that ifosfamide is only administered in a clinical trial setting in the UK, the analysis of B+ versus B and the pooled analysis including A+ and B+ combined versus A and B combined were not considered to represent UK clinical practice. The Committee noted that although the overall survival data for the regimen A analysis were similar to the combined regimen A and B analysis, the hazard ratio for disease-free survival for the regimen A+ compared with regimen A analysis was less favourable than for the combined regimen A and B analysis. The Committee heard from the clinical specialists that the small treatment effect in the analysis of A+ compared with A could be the result of trial randomisation taking place before starting neoadjuvant chemotherapy, when histological response to the neoadjuvant treatment was unknown and could not be factored into randomisation. The clinical specialists explained that it was plausible that response to subsequent adjuvant chemotherapy (with or without mifamurtide) would vary depending on tumour response to the pre-operative neoadjuvant treatment. The Committee also heard that the clinical specialists considered that the treatment effect of mifamurtide could be greater than that seen in the clinical study. However the Committee was not persuaded there was sufficiently robust evidence to support this assumption. It concluded that there was uncertainty around the clinical effectiveness of mifamurtide compared with standard care in the NHS because of the inconsistent results between the three- and four-agent chemotherapy regimes. Therefore, the Committee agreed that it was currently unknown if the non-significant hazard ratios for death of 0.75 and for progression of 0.96 were the result of an imbalance caused by the timing of the randomisation, before neoadjuvant disease response was known, or whether they were an accurate reflection of the benefit of mifamurtide.

4.8 The Committee discussed the adverse effects of mifamurtide plus multi-agent chemotherapy and noted that the pooled analysis showed a significant increase in subjective and objective hearing loss in patients receiving mifamurtide regimens. The Committee was aware that in the post hoc subgroup analyses an increased incidence of hearing loss occurred only in patients treated with regimen A+. It noted that there was uncertainty about which agent in the regimen could be associated with hearing loss. The Committee accepted the clinical specialists’ views that cisplatin was used in all arms of the study and there is a known risk of hearing loss associated with its use (usually in the range 5–15%). Therefore the rate of hearing loss observed in INT-0133 was not unusual and could be an effect of cisplatin rather than mifamurtide. The Committee also accepted the clinical specialists’ view that measurable hearing loss after treatment may not be clinically significant or require the use of hearing aids and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.

4.9 The Committee concluded that mifamurtide plus postoperative multi-agent chemotherapy may be more clinically effective than postoperative multi-agent chemotherapy alone. However, there was uncertainty around the size of this effect, particularly when compared with the regimen used in the NHS.

Cost effectiveness

4.10 The Committee considered the manufacturer’s economic model and the critique and exploratory sensitivity analyses performed by the ERG. The Committee was aware that the efficacy data for the manufacturer’s base-case analyses were taken from the INT-0133 study for regimens A+ or B+ combined compared with regimens A or B combined. The Committee also noted that the manufacturer presented cost-effectiveness estimates for the post hoc analyses for regimen A+ compared with regimen A and regimen B+ compared with regimen B and that these analyses incorporated a PAS. The Committee noted that the PAS had been agreed by the Department of Health and that cost-effectiveness analyses should include no charge to the NHS for the first 7 doses of mifamurtide. The Committee noted that the ICERs presented by the manufacturer for the base case and for the post hoc analyses, all of which included the PAS, were significantly higher than £30,000 per QALY gained. The Committee discussed the following parameters in the manufacturer’s economic model, which were explored in a number of sensitivity analyses.

• Incorporating amputation and limb salvage costs.
• Incorporating the hearing loss adverse events.
• Returning post-recurrence mortality to the general population rate after 5 years’ disease-free survival.
• Applying age-adjusted utility values.
• Applying discount rates.

4.11 The Committee considered incorporating the costs associated with amputation and limb salvage. It noted that these costs were omitted from the base-case analysis and when these were included the manufacturer’s base-case ICER increased from £56,700 to £59,200 per QALY gained. The Committee agreed that it was appropriate to include amputation and limb salvage costs in the model.

4.12 The Committee noted that adverse events, other than those associated with infusion, were not included in the manufacturer’s base-case analysis. When hearing loss was included in the model the ICER increased from £56,700 to £71,000 per QALY gained. However, the Committee accepted the views of the clinical specialists that although hearing loss was the main adverse event associated with mifamurtide treatment, the rate of hearing loss observed in INT-0133 was not unusual in cisplatin-containing regimens and therefore its exclusion from the model was justified.

4.13 The Committee considered the mortality rates used by the manufacturer in its base-case analysis, in which patients in the post-recurrence disease-free state were assumed to have had a mortality rate dependent on the time to recurrence. Mortality rates were derived from a study by Ferrari et al. (2003). The Committee heard from the clinical specialists that 25% of patients with recurrent disease may be cured and the prognosis following recurrence was dependent on time to recurrence (that is, patients with a longer time to recurrence have a better prognosis). The Committee agreed that using the mortality rates of the general population after 5 years free of disease was reasonable.

4.14 The Committee considered the utility values used in the model and that the manufacturer’s model contained utility values from two different sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in survivors from the INT-0133 trial. The Committee noted that the technology appraisals included in the review were from very different populations and did not generally use NICE’s preferred method to derive the utility values. The Committee also noted that although the sample size for the study using the EQ-5D was small, it included the population of interest (that is, only people with osteosarcoma) and used a method to derive the utility values that met NICE’s reference case. The Committee was aware that a utility value of 0.85, derived from the review of NICE technology appraisals, had been applied to the disease-free state in the model and that this utility value was subsequently maintained throughout the length of the model. The Committee agreed that in the general population, utility value declines with age, and that therefore age-adjusted utility values should be used in the modelling. It noted that the ICER increased when age-adjusted utility values were used.

4.15 The Committee discussed the sensitivity of the manufacturer’s base-case ICER to the discount rate applied to outcomes. The Committee was aware of the policy relating to the NICE reference case and section 5.6.2 of the ‘Guide to the methods of technology appraisal’ which specifies that a discount rate of 3.5% should be used for both costs and outcomes. The Committee was advised by NICE that for consistency across all technology appraisals and with the methods guide, a 3.5% discount rate should be applied.

4.16 The Committee agreed that it was appropriate to include the following parameters in the cost-effectiveness analysis: age-dependent utility values, post-recurrence mortality rates set to those of the age-matched general population if patients were disease free for 5 years and amputation and limb salvage costs. The Committee noted that sensitivity analyses, which included all these parameters plus hearing loss as an adverse event, conducted by the manufacturer on the pooled regimens A+ and B+ compared with pooled regimens A and B indicated that the base-case ICER increased from £56,700 to £91,400 per QALY gained. The Committee had accepted that hearing loss need not be incorporated into the analysis, and therefore the most plausible ICER based on the Committee’s agreed assumptions would be less than £91,400 per QALY gained. The Committee concluded that based on the analysis of regimen A+ and B+ combined compared with A and B combined as presented by the manufacturer, the ICERs were substantially higher than those normally considered to be an acceptable use of NHS resources.

4.17 The Committee discussed the cost-effectiveness estimates requested by the ERG and produced by the manufacturer’s post hoc analysis of regimen A+ compared with A and regimen B+ compared with B. It was aware that the clinical specialists considered that regimen A reflected UK clinical practice. Furthermore, the Committee agreed that when considering the costs and QALYs for the four separate and independent treatment regimens, incremental cost-effectiveness estimates indicated that regimen A dominates regimen B (that is, regimen A is more effective [16.1 versus 14.66 QALYs gained] and less costly than regimen B [total costs £29,709 versus £33,244). Therefore the Committee concluded that it was most appropriate to consider the comparison of regimen A+ compared with A rather than regimen B+ compared with B. The Committee therefore considered the ICERs presented by the manufacturer and ERG for regimen A+ compared with A. It noted that the manufacturer’s analysis for regimen A+ compared with A did not include the parameters the Committee considered appropriate (see section 4.16). The Committee noted that incorporating these parameters as undertaken by the ERG in their exploratory analysis produced a probabilistic ICER of £103,500 per QALY gained (deterministic ICER £109,300 per QALY gained). The Committee concluded that for regimen A+ compared with A the most plausible ICER would be greater than £100,000 per QALY gained, and therefore considered that it would not be considered to be a cost-effective use of NHS resources.

4.18 The Committee considered whether there were issues related to equality to be taken into account in its considerations in light of its current and future duties under the equalities legislation. The Committee discussed comments made at the scoping stage. These included the observation that osteosarcoma predominantly affects children, teenagers and young adults, and that osteosarcoma is a rare disease with little development in treatment over the past 20 years. The Committee noted that the latter point was not related to obligations under the equality legislation. The Committee further noted that when an appraisal affects a particular age group it does not mean that a negative recommendation in that appraisal constitutes discrimination on the grounds of age. The Committee noted that no different recommendations were made for the patient population for which mifamurtide is licensed, that is, the recommendation is not based on and does not vary according to the age of the patient. There was no evidence to suggest that different recommendations on the basis of age would be necessary to meet patient needs or that a different recommendation for one or more patient groups within the overall patient population would be clinically and cost effective. The Committee was therefore satisfied that there were no equalities issues in relation to age in this appraisal and that the recommendation was consistent with NICE’s obligations under the equalities legislation and the requirement for fairness.

4.19 The Committee concluded that mifamurtide plus postoperative multi-agent chemotherapy for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection might represent a potentially valuable new therapy, but the evidence of its benefit relative to standard UK clinical practice was not conclusive. Furthermore, the Committee agreed that the ICER based on the evidence available was at least £50,000 per QALY gained, and possibly even above £100,000 per QALY gained, and was too high to allow the Committee to recommend mifamurtide. The Committee therefore concluded that mifamurtide was not recommended as a cost-effective use of NHS resources.

Summary of the Appraisal Committee’s key conclusions relevant to the draft recommendation

TAXXX (STA)	Appraisal title: Mifamurtide for the treatment of osteosarcoma	ACD section
Key conclusion
Mifamurtide in combination with postoperative multi-agent chemotherapy is not recommended in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. The main reasons for this decision were that the evidence for the benefit of mifamurtide relative to standard UK clinical practice was not conclusive and that the ICERs based on the evidence available were too high.
Current practice
Clinical need of patients, including availability of alternative treatments	The main aim of treatment is to improve the cure rate (that is, the percentage of people who will subsequently have a normal lifespan, free of disease). The current standard chemotherapy regimen in England and Wales is doxorubicin, methotrexate and cisplatin, and the 5-year overall survival rate for patients treated in the UK is approximately 55%. The clinical specialists and patient experts stated that there had been no improvement in overall survival after treatment of osteosarcoma over the past 20 years. Ifosfamide is only used in the clinical trial setting and a significant number of patients in the UK have been recruited into the EURAMOS 1 trial.	4.2 4.2 & 4.3 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?	The patient experts stated that any improvement in overall survival from adding mifamurtide to standard chemotherapy was important for patients given that there has been no improvement in overall survival after treatment of osteosarcoma over the past 20 years.	4.2
What is the position of the treatment in the pathway of care for the condition?	Mifamurtide is aimed to be used after macroscopically complete surgical resection in combination with postoperative multi-agent chemotherapy consisting of	4.3 4.7
Adverse effects	The pivotal clinical study showed that with the exception of hearing loss, the number of adverse events was similar across treatment arms. However, hearing loss was considered usual for treatments containing cisplatin, and could therefore be an effect of cisplatin rather than mifamurtide. In addition, hearing loss after treatment may not be clinically significant or require the use of hearing aids. The Committee accepted the clinical specialists’ view that measurable hearing loss after treatment may not be clinically significant or require the use of hearing aids and that this risk should be considered in the context of a possible higher cure rate for osteosarcoma.	3.7, 4.8
Evidence for clinical effectiveness
Availability and nature of evidence	The Committee noted that the relevant randomised clinical trial (INT-0133) study was relatively well conducted, but it agreed that there were substantial methodological issues identified by the ERG, who requested six additional post hoc analyses for both overall and disease-free survival comparing individual mifamurtide-containing regimens (regimen A+ or B+) with individual regimens not containing mifamurtide (regimen A or B).	4.5
Quality of the evidence	The Committee noted that the study was relatively well conducted, but there were substantial methodological issues related to the timing of randomisation which led to uncertainty around the estimates of survival, particularly for regimen A+. The Committee concluded that these aspects of the study made interpretation more difficult, and that the effect of these factors on the results could not be reliably predicted.	4.5
Relevance to general clinical practice in the NHS	The Committee concluded that the most appropriate analysis compared the individual mifamurtide-containing regimen (A+) with a regimen reflecting UK clinical practice (regimen A). The Committee also concluded that given that ifosfamide is only administered in a clinical trial setting in the UK, the analysis of B+ versus B and the pooled analysis including A+ and B+ combined versus A and B combined were not considered to represent UK clinical practice.	4.7
Uncertainties generated by the evidence	There may have been interaction between ifosfamide and mifamurtide, but there was no strong evidence to suggest that there was interaction, and the Committee accepted the clinical specialists view that there was no biologically plausible reason for such an effect. A greater proportion of patients assigned to regimen A+ had tumours showing a poor histological response to neoadjuvant pre-operative therapy. The Committee accepted evidence from the clinical specialists that there is a link between poor histological response to neoadjuvant therapy and prognosis which may have been a result of randomisation taking place before neo-adjuvant treatment. However, it concluded that it was not possible to establish whether, or to what extent, this variation in histological response before adjuvant therapy in the different treatment groups might have affected the results.	4.6
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The clinical speclists considered that the treatment effect of mifamurtide in people receiving regimen A could be greater than that seen in the clinical study. However, the Committee was not persuaded that there was sufficiently robust evidence to support this assumption. The Committee were mindful that there was uncertainty around the clinical effectiveness of mifamurtide compared with standard care in the NHS because of the inconsistent results between the three- and four-agent chemotherapy regimes. The Committee agreed that is was currently unknown if the non-significant hazard ratios for death of 0.75 and for progression of 0.96 were the result of an imbalance caused by the timing of the randomisation, or whether they were could be an accurate reflection of the benefit of mifamurtide. The Committee concluded that mifamurtide might represent a potentially valuable new therapy, but the evidence of its benefit relative to standard UK clinical practice was not conclusive.	4.7 4.19
Are there any clinically relevant subgroups in whom there is evidence that effectiveness is different?	Apart from analyses by treatment regimen, no other subgroups were considered.	-
Evidence for cost effectiveness
Availability and nature of evidence	The manufacturer presented an economic model of the cost effectiveness of adding mifamurtide to three- and four-agent chemotherapy regimens combining cisplatin, doxorubicin and methotrexate with or without ifosfamide. The Committee was aware that efficacy data in the manufacturer’s base case analyses were taken from the INT-0133 study (for regimens A+ or B+ combined, compared with regimens A or B combined) and that post hoc analyses (for regimen A+ compared with regimen A, and regimen B+ compared with B) had been requested by the ERG.	3.10 & 4.10
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee agreed that the following assumptions explored in the manufacturer’s sensitivity analyses were appropriate: Incorporating amputation and limb salvage costs. Returning post-recurrence mortality to the general population rate after 5 years’ disease-free survival. Applying age-adjusted utility rates. Using the discount rates in the current methods guide. The Committee accepted that there was uncertainty about whether hearing loss should be incorporated into the economic modelling, but following the clinical specialists’ statements (see above) it concluded that hearing loss need not be incorporated.	4.11 to 4.16
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 considered that the manufacturer’s model contained utility values from two different main sources: a review of NICE technology appraisals for cancer treatments and a small study using the EQ-5D in survivors from the pivotal clinical study, the latter of which was considered to be from a relevant population. The Committee agreed that age-adjusted utility values should be used in the modelling, and noted that when this decline in utility value was incorporated, the ICER increased.. No health-related benefits were identified that were not included in the economic model.	4.14
Are there specific groups of people for whom the technology is particularly cost effective?	Apart from analyses by treatment regimen as described above, no other subgroups were considered.	-
What are the key drivers of cost effectiveness?	The Committee noted that the ICER was mainly dependent on whether the combined analyses (A+ and B+) or (A and B) or the subgroup analysis (A+ or A) was used, and on the discount rate applied. The Committee was aware that the clinical specialists considered the regimen A reflected UK clinical practice, and concluded that it was most appropriate to consider the comparison of A+ or A.	4.15 & 4.17
Most likely cost-effectiveness estimate (given as an ICER)	Using the preferred assumptions, the Committee concluded that the most plausible ICER for mifamurtide added to regimen A (that is, regimen A+) compared with the regimen A alone would be greater than £100,000 per QALY gained, and therefore considered that it would not be considered to be a cost-effective use of NHS resources.	4.18
Additional factors taken into account
Patient access schemes	The manufacturer’s cost-effectiveness estimates incorporated a patient access scheme, agreed with the Department of Health, in which there is no charge to the NHS for the first 7 doses of mifamurtide.	4.10
End-of-life considerations	Not applicable because the treatment is indicated for patients with a life expectancy of more than 24 months.	-
Equalities considerations, social value judgement	Comments made at the scoping stage, said to relate to equalities issues, included the observation that osteosarcoma predominantly affects children, teenagers and young adults, and that osteosarcoma is a rare disease with little development in treatment over the past 20 years. The latter point was not related to obligations under the equality legislation. The recommendation for mifamurtide is not based on age and does not vary according to the age of the patient. The Committee was therefore satisfied that no equalities issue about age arises in this appraisal.	4.19

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 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 report and costing template to estimate the 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

• Improving outcomes for people with sarcoma. NICE cancer service guidance (2006).

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 in November 2013. 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.

Jane Adam
Chair, Appraisal Committee
April 2010

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.

Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital

Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of Bristol

Elizabeth Brain
Lay Member

Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Dr Paul Ewings
Statistician, Taunton and Somerset NHS Trust, Taunton

John Goulston
Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust

Adrian Griffin
VP Strategic Affairs, LifeScan, Johnson & Johnson

Dr Ann Richardson
Lay Member

Angela Schofield
Chairman, Bournemouth and Poole Teaching PCT

David Thomson
Lay Member

William Turner
Consultant Urologist, Addenbrooke's Hospital

Professor Karl Claxton
Professor of Health Economics, University of York

Dr David Newsham
Lecturer (Orthoptics), University of Liverpool

Professor Iain Squire
Consultant Physician, University Hospitals of Leicester

Dr James Moon
Consultant Cardiologist and Senior Lecturer, University College London Hospital (UCLH) and UCL

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Christopher Earl
Surgical Care Practitioner, Renal Transplant Unit, Manchester Royal Infirmary

Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine/Chemical Pathology, Guy’s and St Thomas’ Hospitals NHS Trust

Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London

Dr John Watkins
Clinical Senior Lecturer/Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

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), a technical adviser and a project manager.

Fay McCracken
Technical Lead

Nicola Hay
Technical Adviser

Bijal Joshi
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the School of Health and Related Research (ScHARR), The University of Sheffield:

• Pandor A et al. Mifamurtide for Osteosarcoma, January 2009
• Stevenson M, Mifamurtide for osteosarcoma: addendum critiquing the revised submitted economic model incorporating a patient access scheme, February 2010

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:

• Takeda UK (mifamurtide)

II Professional/specialist and patient/carer groups:

• Adam Dealey Foundation for Ewing Sarcoma
• Bone Cancer Research Trust
• Rarer Cancers Forum
• Royal College of Nursing
• Royal College of Paediatric and Child Health
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• Royal College of Radiologists
• Sarcoma UK

III Other consultees:

• Department of Health
• Welsh Assembly Government

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

• Department of Health, Social Services and Public Safety for Northern Ireland
• National Collaborating Centre for Cancer
• National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA Programme)
• NHS Quality Improvement Scotland
• School of Health and Related Research (ScHARR), The University of Sheffield

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on mifamurtide by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor Tim Eden, Professor of Teenage and Young Adult Cancer, nominated by the Bone Cancer Research Trust – clinical specialist
• Professor Anthony Freemont, Professor of Bone and Joint Pathology, nominated by the Royal College of Pathologists – clinical specialist
• Dr Maria Michelagnoli, Consultant paediatric and adolescent oncologist, nominated by the Bone Cancer Research Trust – clinical specialist
• Ms Sally Hurst, nominated by the Bone Cancer Research Trust – patient expert
• Mr Michael Francis, nominated by the Bone Cancer Research Trust – patient expert
• Hannah Millington, nominated by the Bone Cancer Research Trust – patient expert

D 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.

• Takeda UK