1 Appraisal Committee's preliminary recommendations

1.1 Ipilimumab is not recommended for the treatment of advanced (unresectable or metastatic) malignant melanoma in people who have received prior therapy.

2 The technology

2.1 Ipilimumab (Yervoy, Bristol-Myers Squibb Pharmaceuticals) is a fully human antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule expressed on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab has a UK marketing authorisation for 'the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy'. For further information see the summary of product characteristics (SPC).

2.2 Ipilimumab is most commonly associated with adverse events resulting from increased or excessive immune activity including diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. For full details of side effects and contraindications, see the SPC.

2.3 The recommended dose of ipilimumab is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks, with a total of four doses. The SPC states that all four doses should be administered ‘as tolerated, regardless of the appearance of new lesions or growth of existing lesions’. Ipilimumab costs £3750 for 10 ml and £15,000 for 40 ml (excluding VAT, MIMS September 2011), which is equivalent to an average cost of £19,565 per dose (excluding VAT, manufacturer’s estimate based on patient weights from the key clinical trial and compassionate use program). 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 ipilimumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The key evidence for the clinical effectiveness of ipilimumab came from one trial (MDX010-20), which assessed the efficacy and safety of ipilimumab in adults with advanced, unresectable stage III or stage IV malignant melanoma who had been previously treated with interleukin-2, dacarbazine, temozolomide or other chemotherapies. This evidence was supported by results from a dose-ranging trial (CA 184-022) and a safety and tolerability trial (CA 184-007).

3.2 The MDX010-20 trial was an international, multi-centre, double-blind, three-armed, randomised, controlled trial. A total of 676 adults with advanced malignant melanoma were randomised to receive ipilimumab 3 mg/kg in combination with an investigational gp100 peptide vaccine ('ipilimumab plus gp100'; n = 403), ipilimumab 3 mg/kg in combination with placebo ('ipilimumab alone'; n = 137), or gp100 in combination with placebo ('gp100 alone'; n = 136) every 3 weeks for four cycles. Approximately 38% of participants in the trial were from Europe, with 8% from the UK. The participants were all HLA-A*0201 (human leukocyte antigen serotype group) positive and were generally well-balanced for key baseline characteristics. At study entry, nearly all participants (98.2%) had stage IV disease.

3.3 The primary outcome of the MDX020-10 trial was overall survival for people treated with ipilimumab plus gp100 compared with gp100 alone. Secondary outcomes in the trial included overall survival in people treated with ipilimumab plus gp100 compared with ipilimumab alone, best objective response rate, disease control rate, duration of response, progression-free survival, time to progression and health-related quality of life.

3.4 Results from the MDX010-20 trial showed that ipilimumab plus gp100 led to a statistically significant gain in median overall survival of approximately 3.5 months compared with gp100 alone (hazard ratio [HR] = 0.68; 95% confidence interval [CI] 0.55 to 0.85; p = 0.0004). When ipilimumab alone was compared with gp100 alone, ipilimumab increased median overall survival by approximately 3.7 months (HR = 0.66; 95% CI 0.51 to 0.87; p = 0.0026). There was no statistically significant difference in median overall survival between people treated with ipilimumab plus gp100 compared with those treated with ipilimumab alone (HR = 1.04; 95% CI 0.83 to 1.30; p = 0.7575), which the manufacturer considered was evidence that gp100 did not influence the overall survival outcome with ipilimumab treatment. Approximately 65% of people treated with an ipilimumab-containing regimen received all four doses of ipilimumab in line with the licensed regimen, and in this subgroup, the median survival in both the gp100 and ipilimumab arms was greater than in those who received fewer than the full four doses. The difference in survival gain between the ipilimumab and gp100 arms was also more favourable in those treated with all four doses (results provided as academic in confidence). All response-related secondary outcomes (including best objective response rate and progression-free survival) showed positive results for people who received treatment with an ipilimumab-containing regimen compared with people who received gp100 alone.

3.5 The CA 184-022 trial was a double-blind, multicentre, dose-ranging, randomised, controlled trial that included 217 participants with previously treated, treatment-refractory or treatment-intolerant, unresectable stage III or stage IV melanoma. They were randomised to receive either ipilimumab 0.3 mg/kg, 3 mg/kg or 10 mg/kg every 3 weeks for four cycles followed by maintenance therapy every 3 months. The outcomes included estimated best objective response rate, progression-free survival at 24 weeks, median overall survival and duration of response. The CA 184-007 trial was a double-blind, multicentre, randomised, controlled trial. Participants (n = 115) with unresectable stage III or stage IV melanoma who were treatment-naive or who had been previously treated were randomised to receive open-label ipilimumab (10 mg/kg at weeks 1, 4, 7 and 10) with either concomitant oral budesonide or placebo. The outcomes included adverse events (specifically diarrhoea), best objective response rate, duration of response and overall survival.

3.6 The most common adverse events associated with ipilimumab treatment reported in the three trials included in the manufacturer’s submission resulted from increased or excessive immune activity. They included diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. These adverse events were considered to be generally medically manageable and usually reversible with topical and/or systemic immunosuppressants. Progressive disease was the most frequent reason for death in the MDX010-20 and CA 184-022 studies. There were 14 (2.2%) adverse events with an outcome of death in the MDX010-20 trial that related to the study treatments; eight deaths in the ipilimumab plus gp100 group, four in the ipilimumab alone group and two in the gp100 alone group. Seven of the deaths were associated with immune-related adverse events (including colitis, bowel perforation and organ failure); five in the ipilimumab plus gp100 group and two in the ipilimumab alone group.

3.7 The manufacturer undertook a systematic search and identified 10 economic evaluations in pre-treated or advanced melanoma. None of the studies evaluated ipilimumab. The manufacturer therefore submitted a de novo economic evaluation, based on a partitioned survival model, in which people treated with ipilimumab were compared with those who received best supportive care. Four mutually exclusive states were included in the model: baseline disease, non-progressive disease, progressive disease and death. All people were assumed to start in the baseline disease state (after chemotherapy), then at the end of each cycle they could move to the non-progressed health state or to the progressed health state, or they could die. The model used daily cycles for the first 5 years during the trial period, and weekly cycles thereafter for a lifetime (30 year) horizon. The perspective adopted in the economic evaluation was that of the NHS and Personal Social Services and costs and benefits were discounted at 3.5% per year.

3.8 The proportion of people in each health state was calculated using progression-free survival and overall survival data from the MDX010-20 trial. Because data on progression-free survival and overall survival for people receiving best supportive care were not available directly from the trial, data from the gp100 arm of the trial were assumed by the manufacturer to be a proxy for the course of disease in people receiving best supportive care. Adverse-event rates for ipilimumab and best supportive care were estimated from the MDX010-20 trial. The resource costs included in the model were drug acquisition and administration costs, and the cost of the disease, which included costs related to each health state and of treating adverse effects.

3.9 The manufacturer presented two approaches to parametric curve fitting for the survival modelling. The first strategy involved a single curve fit approach that showed that none of the curves fit the Kaplan-Meier data from MDX010-20 study. The second strategy involved using a two-part curve fit where the Kaplan-Meier estimates for overall survival and progression-free survival were used for the first 18 months and ‘best-fit’ parametric curves were used thereafter. The manufacturer concluded that the ‘best-fit’ curves were: exponential for progression-free survival in the ipilimumab arm, Gompertz for overall survival in the ipilimumab arm and exponential for overall survival in the best supportive care arm. Progression-free survival in the best supportive care arm was represented by the overall survival arm.

3.10 Health-related quality of life was measured in the MDX010-20 trial which used the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the short form 36 (SF-36) questionnaires. For the economic analysis, utilities were obtained from responses to the EORTC QLQ-C30 from 971 trial observations using a recently developed preference-based version of the instrument. The utility values assumed for the progression-free disease and progressive disease health states in the model were 0.80 (95% CI: 0.53 to 0.97) and 0.76 (95% CI 0.46 to 0.97) respectively. The manufacturer also conducted a systematic review to identify studies that included health-related quality of life data for people with metastatic melanoma. One study was identified that included 63 participants from the UK and 77 participants from Australia who valued 'vignettes' or descriptions of advanced melanoma health states developed by the researchers.

3.11 In the manufacturer's base case, ipilimumab treatment led to an undiscounted incremental gain in overall survival of 33.8 months compared with best supportive care. The incremental cost-effectiveness ratio (ICER) for ipilimumab compared with best supportive care was £60,737 per quality-adjusted life year (QALY) gained (incremental cost £83,351 and incremental benefit 1.37 QALYs). When it was assumed that all patients receive all four doses of ipilimumab in line with the marketing authorisation, the ICER increased to £70,163 per QALY gained.

3.12 Probabilistic sensitivity analysis reported a 14% chance of ipilimumab being cost effective compared with best supportive care at £50,000 per QALY gained. Deterministic sensitivity analyses showed that the ICER was most sensitive to the utility values assumed for the progressive disease health state. An increase in this utility value reduced the ICER and conversely a reduction in utility increased the ICER. For example, using a lower utility (0.60) for progressive disease increased the base-case ICER to £73,854 per QALY gained. Structural sensitivity analysis showed that decreasing the discount rate to 0% reduced the ICER from £60,737 to £42,871 per QALY gained, as the long term benefits of ipilimumab in the base case were discounted to a large degree, while costs of treatment were only incurred within the first year of the model, and therefore were unaffected by discounting. Other variables that significantly affected the ICER were the curve type selected to fit the clinical data, the cost of ipilimumab and the patient’s starting age in the model. The manufacturer also conducted scenario analyses to explore the effect on the ICER of assumptions about the amount of each dose of ipilimumab needed per patient and the possibility of vial sharing. Results from these analyses showed that the dose of ipilimumab given per patient has a large impact on the ICER with the minimum dose given in the trial and compassionate use programme (3 x 50 mg) resulting in an ICER of £38,387 per QALY gained and the maximum dose (2 x 200 mg) given resulting in an ICER of £88,788 per QALY gained. In addition, the results showed that vial sharing has the potential to reduce the base-case ICER to £55,824 per QALY gained.

3.13 The ERG reviewed the clinical-effectiveness evidence for ipilimumab and noted that none of the studies included in the manufacturer’s submission compared ipilimumab with any of the comparators listed in the decision problem (best supportive care, carboplatin-based chemotherapy and dacarbazine). The ERG commented that the MDX010-20 study was well designed and that it was satisfied that the participants were representative of patients in UK clinical practice. The ERG expressed concern that the manufacturer considered gp100 clinically comparable to best supportive care because patient outcomes in the gp100 alone arm of the MDX010-20 study appeared less favourable than might be expected in untreated people.

3.14 The ERG commented that the clinical data provided by the manufacturer suggested that treatment with ipilimumab was associated with an overall survival benefit over gp100 for a small number of patients. However, they noted that to date no patient characteristics or biomarkers have been identified that can prospectively identify the people most likely to benefit from treatment with ipilimumab. The ERG noted that the European Medicines Agency considered a number of ancillary analyses carried out by the manufacturer in an attempt to identify possible subgroups of people who might (or might not) benefit from treatment with ipilimumab. However, the subgroups were small and the ERG determined that no conclusions could be drawn from this analysis.

3.15 The ERG considered that the manufacturer’s model was well constructed, but it proposed a number of minor corrections and modifications, which slightly reduced the base-case ICER to £54,462 per QALY gained. The ERG noted that the main weakness of the manufacturer’s model was the estimated mean overall survival. The ERG acknowledged that the natural history and prognosis for metastatic melanoma is not well understood and the manufacturer claimed a substantial improvement in mean survival on the basis of results from a single trial. The ERG cited a study published in 1999 involving a re-analysis of eight trials of interleukin-2 for people with metastatic melanoma. Of the participants, 80% died within 2 years but most of those surviving the 2‑year follow-up period survived for a further 9 years. The ERG noted that this response pattern was replicated in the MDX010-20 study and suggested that this was likely to be because survival rates for people with advanced metastatic melanoma vary substantially. In light of this, it is possible that the data available for analysis is weakest when enhanced survival is likely to generate the most added life years from the treatment. The ERG therefore noted that although the MDX010-20 trial used by the manufacturer showed a survival advantage for ipilimumab, it was unable to reliably quantify the long-term survival benefit beyond 2 years.

3.16 The ERG had concerns about the manufacturer’s interpretation of the MDX010-20 trial data. In particular, it noted that the fitted overall survival functions beyond 18-months follow-up generated mortality risks lower than those in the general (healthy) population at a comparable age, and as a consequence the model predicted significant numbers of people surviving to unreasonably advanced ages (beyond 100 years). To counter this anomaly, the manufacturer replaced the calculated model mortality risks with mortality risks experienced by the general population beyond 5‑year follow-up. The ERG noted that this approach implied that anyone surviving beyond 5 years of second-line systemic treatment was effectively cured; however, no evidence was submitted by the manufacturer to support this claim.

3.17 In an exploratory analysis, the ERG adopted a pragmatic approach to model overall survival by calculating the area under the Kaplan-Meier curve to a common late time-point beyond which both the ipilimumab and best supportive care arms could be seen to be following long-term trend lines. It then projected further life expectancy based on calibrating a parametric function. The results from this method suggested mean life years of 11.2 months for gp100 and 27.5 months for the combined ipilimumab arms from the MDX010-20 trial, which equated to a mean gain in overall survival of 16.3 months. These results were noted to be less than half the value calculated in the base case of the manufacturer’s model (that is, a mean gain in overall survival of 33.8 months). Using the revised projections, the ERG noted that the base-case ICER substantially increased to £96,717 per QALY gained. The ERG stated that its exploratory analysis on overall survival cannot be considered definitive, as the volume and duration of patient data available from the MDX010-20 trial were inadequate to achieve survival projections that can be used as a basis for decision making. However, the ERG considered that the manufacturer’s model is likely to have substantially overestimated the extent of survival benefit associated with treatment with ipilimumab.

3.18 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 ipilimumab, having considered evidence on the nature of advanced (unresectable or metastatic) malignant melanoma and the value placed on the benefits of ipilimumab 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 heard from the clinical specialists that ipilimumab represents a step change in the treatment of advanced melanoma and is the first new treatment available in 30 years that may offer significant palliation and possible survival gain for people with advanced, unresectable disease that has progressed after first-line therapy. Other drugs are also in development but are not yet licensed. It heard that the optimal place for ipilimumab treatment in the clinical pathway for advanced (unresectable or metastatic) malignant melanoma was still being debated in the clinical community. But the Committee understood that most clinicians in the UK would use ipilimumab as a second-line treatment in line with its UK marketing authorisation. The Committee heard from the patient expert that unresectable melanoma substantially worsens quality of life, and without effective new therapies, the prognosis for advanced disease is very poor. The patient expert explained that the incidence of malignant melanoma is disproportionately high in young adults, and that treatment that prolongs survival could allow people to return to normal life and resume work and other activities. The Committee concluded that there was a significant unmet need for effective therapies in this patient population.

4.3 The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ipilimumab. It noted that the manufacturer derived efficacy data primarily from the MDX010-20 trial, which showed that treatment with ipilimumab led to a statistically significant median overall survival gain of approximately 3.7 months compared with gp100 for people with progressive disease after first-line therapy. The Committee heard from the clinical specialists that approximately 30% of people treated with ipilimumab will have improved survival, and about 10% of people may have long-term benefits. The clinical specialists indicated that melanoma may have an unpredictable clinical course and that late recurrences are well recognised. The Committee noted that a curative treatment would be expected to result in the disappearance of all visible disease (complete response), and fewer than 1% of patients in the ipilimumab arms of the MDX010-20 trial showed a complete disease response. In addition, although there was trial evidence of some people whose disease remained stable after being treated with ipilimumab, it was not clear how prolonged that response might be. The clinical specialists agreed that it is too early to regard this as a curative treatment. The Committee noted that no patient characteristics or biomarkers have been identified that can prospectively identify the minority of people most likely to benefit from receiving ipilimumab.

4.4 The Committee considered the adverse events associated with treatment with ipilimumab. The Committee understood from the clinical specialists and patient experts that people being treated with ipilimumab can have significant immune-related adverse effects, which have a substantial negative impact on their quality of life. The Committee noted that 12 deaths related to treatment with ipilimumab occurred in the MDX010-20 trial, but heard from the clinical specialists that subsequent trials of ipilimumab as first-line treatment have not reported any treatment-related deaths. The clinical specialists considered that this indicated that, as experience with ipilimumab grows, adverse events will be more quickly identified and treated. The Committee also heard from the patient experts that the possible survival benefits from adhering to treatment with ipilimumab outweighed the severe adverse effects. The Committee concluded that although the adverse effects and mortality associated with ipilimumab seen in the MDX010-20 trial were considerable, most adverse effects were manageable and would be managed more effectively as clinicians become familiar with ipilimumab’s toxicity profile. It also concluded that people may be willing to tolerate significant toxicity if there were potential survival benefits.

4.5 The Committee noted that the UK marketing authorisation for ipilimumab stipulates that people should receive all four doses of treatment, even if the disease appears to progress during treatment. The Committee heard from the clinical specialists that late responses to treatment have been reported. It heard that people should therefore continue to be treated unless their disease progresses to a degree that a response is very unlikely, or the side effects become intolerable. The Committee also understood from the clinical specialists that, although it was not possible to predict a patient’s response to ipilimumab, people who experienced a significant decrease in performance status while receiving treatment were likely to have rapidly progressive disease and would not benefit from continued use of ipilimumab. The Committee noted that approximately 65% of people treated with ipilimumab in the MDX010-20 trial received all four doses of treatment.

4.6 The Committee discussed the cost-effectiveness estimates from the manufacturer’s economic model, the assumptions on which these were based, and the ERG’s critique and exploratory analyses. The Committee noted that the manufacturer assumed that the gp100 vaccine was clinically comparable to best supportive care and used the efficacy estimates from the gp100 arm in the MDX010-20 trial to inform model inputs. The Committee understood from the clinical specialists that although studies of vaccines, other than gp100, in people with advanced and metastatic melanoma have shown a survival disadvantage, there is no evidence that this occurs for people treated with gp100. The Committee agreed with the clinical specialists that gp100 was likely to be an acceptable proxy for best supportive care in the model.

4.7 The Committee noted that EORTC-QLQ and SF-36 utility data were collected in the MDX010-20 trial but considered there was not enough information included in the manufacturer’s submission about the time points at which the data were collected, the number of participants completing the questionnaires or how the utility data had been aggregated for use in the economic model. In addition, the summary of patient-reported outcome data from the SF‑36 and EORTC QLQ-C30 questionnaires had not been presented and the Committee was unable to determine how the quality of life of patients changed over time in the trial or whether there were any differences observed in quality-of-life profiles between the treatment groups that were influenced by the different treatment protocols or response rates. The Committee noted that there was little difference between the utilities assigned to the progression-free and the progressive disease health states. The Committee concluded that it was unable to reach a conclusion without further information on the underlying data and while there were still uncertainties about the collection and analysis of the data.

4.8 The Committee noted that the length of follow-up in the MDX010‑20 trial was too short to provide robust evidence of the overall survival gain beyond 2 years. It noted that as a result, the manufacturer had to extrapolate the data using parametric curves. The Committee noted the ERG’s concern that the manufacturer assumed that people who survived more than 5 years after treatment had the same mortality risk as the general population – that they are effectively cured of their disease. The Committee noted that the ERG’s alternative, pragmatic approach to estimating the long-term survival benefit from the trial data produced survival estimates that were approximately half those estimated by the manufacturer, but concluded that without more long-term data, neither the ERG's nor the manufacturer’s approach could wholly address the uncertainty around the true magnitude of the survival benefit from ipilimumab treatment.

4.9 The Committee noted that the manufacturer's base-case ICER for ipilimumab compared with best supportive care was £60,700 per QALY gained, and that this ICER was reduced to £54,500 per QALY gained when corrections suggested by the ERG were applied. When the cost of administering the full course (four doses) of ipilimumab in line with the UK marketing authorisation was included in the model, the manufacturer’s base-case ICER increased to £70,200 per QALY gained. The Committee heard from the ERG that the ICER was most sensitive to the overall survival benefit ascribed to ipilimumab and the utilities associated with each health state in the model, and that the most plausible ICER could be higher than £96,700 per QALY gained if the ERG’s revised projections of a smaller survival gain than had been modelled by the manufacturer are accepted. The Committee considered that the ICER was in the range of £54,500 to £70,200 per QALY gained only if the manufacturer's estimate of survival gain was accepted. It noted however, that because of the lack of data available on the long-term benefits of treatment, further analyses are unlikely to produce a more plausible estimate of the ICER.

4.10 The Committee discussed whether it would be appropriate to consider a sensitivity analysis on the effects of discounting based on the long-term survival benefit that a small number of patients may have from ipilimumab treatment. The Committee noted that the manufacturer’s sensitivity analysis which included no discounting of costs or benefits yielded a reduced ICER of £42,900 per QALY gained. The Committee noted the clarification to the 'Guide to the methods of technology appraisal' issued by the Board of NICE, which states: 'Where the Appraisal Committee has considered it appropriate to undertake sensitivity analysis on the effects of discounting because treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years), the Committee should apply a rate of 1.5% for health effects and 3.5% for costs'. The Committee questioned whether ipilimumab is a treatment with curative intent. It heard from the clinical specialists that unresectable malignant melanoma that has progressed on previous therapy is not considered to be curable. The Committee concluded that evidence that ipilimumab was a curative treatment was lacking, and it was unlikely to have substantial benefits beyond 30 years. The Committee therefore concluded that there was no case for differential discounting to be applied.

4.11 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.
• There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
• The treatment is licensed or otherwise indicated for small patient populations.

In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.

4.12 The Committee discussed whether ipilimumab met the criteria set out for consideration as an end of life treatment. The Committee agreed that the life expectancy for people with advanced melanoma, particularly for those with distant metastases, as reflected in the trial population, was less than 24 months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The Committee heard from the clinical specialists that there are approximately 400–500 people with advanced melanoma that has progressed on second-line treatment each year in the UK, which represents a small patient population. Therefore the Committee was satisfied that ipilimumab met the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

4.13 The Committee noted that the best-case ICER (£54,500 to £70,000 per QALY gained) was higher than is normally considered an effective use of NHS resources and that the NICE 'Guide to the methods of technology appraisal' states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE 'Guide to methods of technology appraisal' states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:

• any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured
• whether the innovative nature of the technology may not have been adequately captured in the QALY measure.

The Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from a patient expert that the successfully treated people, although in the minority, could lead an active and fulfilling life and were able to contribute to society. The Committee accepted that ipilimumab may represent a potentially valuable new therapy and that the mechanism of action was novel. It acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need. Despite the combined value of these factors, and the fact that it is alife-extending, end­-of-­life treatment, the Committee considered that the magnitude of additional weight that would need to be assigned to the QALY gains for people with advanced melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources. Therefore, the Committee was unable to recommend ipilimumab for the treatment of advanced (unresectable or metastatic) malignant melanoma for people who had received prior therapy.

Summary of Appraisal Committee's key conclusions

5 Implementation

5.1 The Secretary of State and the Welsh Government Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually 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. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

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 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

• Referral guidelines for suspected cancer. NICE clinical guideline 27 (2005). Available from www.nice.org.uk/guidance/CG27
• Improving supportive and palliative care for adults with cancer. NICE cancer service guidance, (2004). Available from www.nice.org.uk/guidance/CSGSP
• Improving outcomes for people with skin tumours including melanoma. NICE cancer service guidance (2006). Available from www.nice.org.uk/guidance/CSGSTIM.

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Ipilimumab in combination with dacarbazine for previously untreated unresectable stage III or IV malignant melanoma (publication date to be confirmed).
• Skin cancer: how the NHS and local authorities can help prevent skin cancer using public information, sun protection resources and by making changes to the environment (publication date to be confirmed).

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 February 2015. 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.

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 Iain Squire (Vice-Chair)
Consultant Physician, University Hospitals of Leicester

Dr Jeremy Braybrooke
Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

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

Mr Adrian Griffin
Vice President, HTA & International Policy, Johnson & Johnson

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

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

Dr Anne McCune
Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Ms Pamela Rees
Lay Member

Dr Ann Richardson
Lay Member

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Dr Eldon Spackman
Research Fellow, Centre for Health Economics, University of York

Mr David Thomson
Lay Member

Mr William Turner
Consultant Urologist, Addenbrooke's Hospital

Dr Luke Twelves
General Practitioner, Ramsey Health Centre, Cambridgeshire

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

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

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.

Richard Diaz
Technical Lead

Fiona Rinaldi
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 Liverpool Reviews and Implementation Group (LRiG):

• Dickson R, Boland A, Bagust A et al. Ipilimumab for previously treated unresectable malignant melanoma: A Single Technology Appraisal. Liverpool Review and Implementation Group, The University of Liverpool (August 2011)

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:

• Bristol Myers-Squibb Pharmaceuticals

II Professional/specialist and patient/carer groups:

• British Association of Dermatologists
• Factor 50
• Macmillan Cancer Support
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• Skin Care Campaign

III Other consultees:

• Department of Health
• Welsh Government

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

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Health Care Improvement Scotland
• LRiG, The University of Liverpool
• National Collaborating Centre for Cancer
• National Institute for Health Research Health Technology Assessment Programme

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 ipilimumab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Paul Lorigan, Consultant Medical Oncologist, nominated by organisation representing Skin Care Campaign, Factor 50, and Bristol-Myers Squibb – clinical specialist
• Dr Paul Nathan, Consultant Medical Oncologist, nominated by organisation representing Skin Care Campaign, and Factor 50 – clinical specialist
• Mr Richard Jackson, nominated by organisation representing Skin Care Campaign – patient expert
• Ms Gillian Nuttall, CEO & Founder of Factor 50, nominated by organisation representing Factor 50 – 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.

• Bristol Myers-Squibb Pharmaceuticals