Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (part review of technology appraisal guidance 86)

Appraisal consultation document

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (part review of technology appraisal guidance 86) in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees.
It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• has all of the relevant evidence been taken into account?
• are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• the Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees
• at that meeting, the Committee will also consider comments made by people who are not consultees
• after considering these comments, the Committee will prepare the final appraisal determination (FAD)
• subject to any appeal by consultees, the FAD may be used as the basis for NICE's guidance on using imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours in the NHS in England and Wales.

For further details, see the 'Guide to the technology appraisal process' (available at www.nice.org.uk)
The key dates for this appraisal are:

Closing date for comments: 19 July 2010

Second Appraisal Committee meeting: 4 August 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1 Appraisal Committee’s preliminary recommendations

1.1 Imatinib at 600 or 800 mg/day is not recommended for the treatment of people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400 mg/day imatinib.

2 Clinical need and practice

2.1 Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract. Although GISTs can occur along the length of the gastrointestinal tract from the oesophagus to the anus, the majority (60-70%) arise in the stomach. Most GISTs are associated with the overexpression of the tyrosine kinase receptor KIT (CD117), which is thought to promote tumour growth or to inhibit tumour cell death through a signal transduction pathway involving stem cell factor.
2.2 Approximately one third of people with GISTs are asymptomatic during the early stages of the disease. Signs and symptoms can include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. People have more severe symptoms when tumours metastasise or when they become large, rupture and bleed or obstruct the gastrointestinal tract. In metastatic disease, systemic symptoms such as fever, night sweats and weight loss are common.
2.3 Approximately 900 new cases of GISTs are diagnosed in the UK each year. Although GISTs can occur at any age, the usual age of presentation is between 50 and 70 years. Diagnosis of GIST is confirmed by clinical presentation and tissue biopsy to determine the histological characteristics of the tumour, including expression of KIT/CD117 protein. Approximately 4% of GISTs have characteristic clinical and morphological features, but do not express the KIT/CD117 protein.
2.4 The size, growth rate and location of the tumour often influence prognosis. Without treatment GISTs progress and will eventually metastasise. Prognosis depends on whether the tumour can be resected, the primary treatment for GISTs. Only 50% of GISTs are resectable at presentation. Conventional cytotoxic chemotherapy and radiotherapy are ineffective in treating advanced or metastatic GISTs. Similarly, surgery to treat advanced or metastatic GISTs is not recommended unless there is an immediate clinical need, such as to remove an obstructing tumour.

3 The technology

3.1 Imatinib (Glivec, Novartis Pharmaceuticals UK) is a signal-transduction inhibitor designed to selectively inhibit tyrosine kinases, including the KIT (CD117) receptor that is expressed in GISTs. Imatinib binds to activated KIT (CD117) receptors and blocks the cell-signalling pathway to inhibit uncontrolled cell proliferation. Imatinib has a UK marketing authorisation for the treatment of adult patients with KIT (CD117)-positive unresectable and/or metastatic malignant GISTs.
3.2 The most commonly reported adverse events in trials of imatinib were oedema, fatigue, myalgia, muscle cramps, rash, abdominal pain, vomiting, diarrhoea and nausea. For full details of adverse effects and contraindications, see the summary of product characteristics.
3.3 Imatinib is administered orally. The summary of product characteristics recommends 400 mg/day imatinib for the treatment of unresectable and/or metastatic GISTs. It states that limited data exist on the effect of dose increases of imatinib from 400mg/day to 600 or 800 mg/day in patients whose disease has progressed at the lower imatinib dose.
3.4 Imatinib is available in doses of 100 mg (60-tablet pack) and 400 mg (30-tablet pack) at a cost of £802.04 and £1604.08 per pack respectively (excluding VAT; 'British national formulary' [BNF] edition 59). The annual acquisition costs for treatment with imatinib are approximately £19,500 (400 mg/day), £29,300 (600 mg/day) and £39,100 (800 mg/day). Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
4.1 Clinical effectiveness
4.1.1 The Assessment Group assessed the clinical effectiveness of increased doses of imatinib (600 or 800 mg/day) compared with sunitinib or best supportive care for the treatment of people with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day imatinib. Studies reporting the clinical effectiveness of comparator treatments (sunitinib plus best supportive care or best supportive care alone) were also identified.
4.1.2 The Assessment Group did not identify any randomised controlled trials or non-randomised comparative studies comparing the effectiveness of increased doses of imatinib (600 or 800 mg/day) with sunitinib or best supportive care. However, it identified six papers and ten abstracts reporting four separate clinical trials and one non-randomised retrospective cohort study that included a treatment arm of 400 mg/day imatinib and reported data separately for people who received an increased dose of imatinib on disease progression ("crossover groups"). Outcomes reported for the crossover groups informed the appraisal.
4.1.3 The EORTC-ISG-AGITG trial (n = 473) (Zalcberg et al. 2005; Debiec-Rychter et al. 2006) compared treatment with 800 mg/day imatinib with 400 mg/day imatinib in people with advanced GISTs. When disease progressed in people randomised to 400 mg/day imatinib, the dose was increased to 800 mg/day imatinib (n = 133). Interim response data was reported for 97 people from this trial. The S0033 trial (n = 345) (Blanke et al. 2008a) also compared treatment with a high dose of imatinib (800 mg/day) with a standard dose of imatinib (400 mg/day) in people with advanced GISTs. One hundred and seventeen people who received an increased dose of 800 mg/day imatinib after disease progression were assessed for response after cross-over. Interim response data was reported for 68 people from this trial. The B2222 trial (n = 73) (Blanke et al. 2008) compared 400 mg/day imatinib and 600 mg/day imatinib in people with advanced GISTs. A non-randomised retrospective cohort study (Park et al. 2009; n = 24) provided separate outcome data for people with metastatic or unresectable GISTs. People in this study received an initial dose of 400 mg/day imatinib that was increased to higher doses (600 or 800 mg/day) on disease progression. Seven abstracts were identified that provided interim results of an ongoing, non-comparative open-label trial on the effectiveness of sunitinib in people whose condition failed to respond to treatment with different doses of imatinib (including doses up to 400 mg/day). An abstract by Seddon et al. (2008; n = 1117) was considered the primary source for this trial.
4.1.4 Overall, 28.1% (EORTC-ISG-AGITG), 34.2% (S0033) and 58.9% (B2222) of people initially randomised to receive imatinib 400 mg/day had disease progression and were crossed over to a higher dose of imatinib (600 mg/day or 800 mg/day). All people in the retrospective cohort study received an increased dose of imatinib. In the sunitinib study, 31.4% of people received sunitinib following disease progression on 400mg/day imatinib.

Overall response
4.1.5 The results for people treated with an increased dose of 600 mg/day imatinib after disease progression on 400 mg/day imatinib were reported in the B2222 trial and the retrospective cohort study. In the B2222 trial, the median length of follow-up was 63 months (maximum 71 months), and after disease progression, and 11 out of 43 people (25.6%) either showed a partial response or had stable disease. The Assessment Group noted that some of the people who crossed over to increased doses would have had an initial response to 400 mg/day imatinib before disease progression. This was because only 11 people in the 400 mg/day imatinib arm showed a best overall tumour response (based on Southwest Oncology Group [SWOG] criteria) before disease progression. In the retrospective cohort study the median length of follow-up was 8 months (range 1.4-22.3 months). Of the 12 people who received an increased dose of 600 mg/day imatinib, 5 (41.7%) showed either a partial response or had stable disease after treatment.
4.1.6 The manufacturer of imatinib reported data from a confidential trial in their submission, which gave response to treatment in people who received increased doses of imatinib. However, the Assessment Group did not use these data in their review because there were differences between these data and the results from the same studies available as published articles in the numbers of people who achieved stable disease or had a partial response after increased doses of imatinib.
4.1.7 The results for people treated with an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day imatinib were reported in the S0033 trial, the EORTC-ITG-AGITG trial, and the retrospective cohort study. Of the crossover populations in the S0033 and EORTC-ITG-AGITG trials (117/345 and 133/473 people respectively), 3 people in each trial had a partial response to treatment, while 33 and 36 people respectively achieved stable disease as a best response. Overall, out of a total of 250 people in both studies, 75 (30%) met the criteria for a response to treatment after the dose of imatinib was increased from 400 to 800 mg/day. The retrospective cohort study reported that 4 of the 12 people (33.3%) who received an increased dose of imatinib (800 mg/day) after disease progression achieved either a partial response or had stable disease after treatment.
4.1.8 Interim data for the EORTC-ISG-AGITG trial reported that, of 97 people, 2 (2.1%) showed a partial response, 30 (30.9%) had stable disease, and 65 (67.0%) still had progressive disease after the dose of imatinib was increased from 400 to 800 mg/day. Interim data for the S0033 trial showed that, of 68 people, 5 (7.4%) had a partial response and 20 (29.4%) had stable disease when imatinib was increased from 400 to 800 mg/day. In addition, a secondary analysis of the EORTC-ISG-AGITG trial (Debiec-Rychter et al.) indicated (without stating the number of people involved) that response to treatment after crossover was significantly more likely to occur in people with wild-type GIST than with KIT exon 11 mutation (p = 0.0012). Response after crossover was also significantly more likely to occur in people with KIT exon 9 mutation compared with exon 11 mutation (p = 0.0017).
4.1.9 Response rates following 50 mg/day sunitinib after disease progression on 400 mg/day imatinib were not reported in the studies identified by the Assessment Group. A weighted average response rate from two studies (Demetri et al. [2002] and Prior et al. [2009]) was calculated, however the Assessment Group noted that the patient groups in these two studies were different. The Prior et al. study did not report the dose of prior imatinib treatment received by patients. In Demetri et al., most of the population had disease progression following 800 mg/day imatinib. The Assessment Group determined that there was no statistically significant difference in the response rates in these studies.

Overall survival
4.1.10 The S0033 study reported the overall survival for people randomised to an initial dose of 400 mg/day imatinib which was increased to 800 mg/day after disease progression. At the time of the analysis (median follow-up 4.5 years), 76 of 118 people (64.4%) had died. The median overall survival was 19 months (95% confidence interval [CI] 13 to 23 months) from the point at which the dose of imatinib was increased ('crossover'). Interim data for the S0033 trial were also provided by Rankin et al. (2004), who reported that median overall survival after crossover was 19 months.
4.1.11 Two abstracts with different follow-up periods reported overall survival data for people receiving 50 mg/day sunitinib after treatment failure of imatinib at a dose of up to 400 mg/day. Reichardt et al. analysed data after a median of 24 weeks. They estimated median overall survival to be 93 weeks (95% CI 72 to 100 weeks) at which point 231 of 339 people (68.1%) were still alive. Seddon et al. analysed data after a median of 51 weeks (range 0.1-159 weeks). Median overall survival at that time was 90 weeks (95% CI 73 to 106 weeks) and 193 of 351 people (55.0%) were still alive. Interim data from this study suggested the median overall survival was 80.4 weeks (95% CI 60.3 to N/A weeks).

Progression-free survival
4.1.12 Progression-free survival data were not published for the B2222 trial for people receiving an initial dose of 400 mg/day imatinib which was increased to 600 mg/day after disease progression.
4.1.13 The S0033 and the EORTC-ISG-AGITG trials reported data on progression-free survival for people randomised to an initial dose of 400 mg/day imatinib, which was increased to 800 mg/day after disease progression. For the S0033 trial, at a median follow-up of 54 months, disease had progressed in 99 of 118 people (83.9%) in the treatment crossover group. Median progression-free survival was estimated to be 5 months (95% CI 2 to 10 months). Using interim data from this trial for 68 people, investigators estimated a median progression-free survival after crossover of 4 months. For the EORTC-ISG-AGITG trial, at a median follow-up of 25 months (maximum follow-up 35 months), disease had progressed in 108 of 133 people (81.2%) in the treatment crossover group. Median progression-free survival was 2.7 months.
4.1.14 The sunitinib trial reported no data describing disease progression in people randomised to an initial dose of imatinib of up to 400 mg/day, followed by 50 mg/day sunitinib after treatment failure.

Time to treatment failure
4.1.15 The retrospective cohort study reported data on the duration of response and time to treatment failure. Of the 12 people who received an increased dose of 600 mg/day imatinib after disease progression, 1 person died of a cause unrelated to both disease and treatment, while disease progressed in the remaining 11 people after a median of 1.7 months (range 0.7-24.9 months).
4.1.16 Data from the EORTC-ISG-AGITG trial showed that of the people who showed a partial response or had stable disease after treatment crossover (imatinib dose increased from 400 to 800 mg/day after disease progression), the median duration of stable disease was 153 days (range 37-574 days).
4.1.17 The sunitinib trial did not provide the specific median duration of treatment with sunitinib for people initially receiving a dose of imatinib of up to 400 mg/day, followed by 50 mg/day sunitinib after disease progression. However the median duration of treatment for the whole cohort was reported to be 126 days (range 1-618 days). Median treatment duration did not significantly differ between people who previously received 400 mg/day imatinib and those who received higher doses).

Health-related quality of life
4.1.18 None of the included studies reported health-related quality of life data.

Adverse events
4.1.19 Adverse events were not reported for people receiving an increased dose of 600 mg/day imatinib after disease progression.
4.1.20 No specific information on adverse events in people receiving an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day were reported by Zalcberg et al. (EORTC-ISG-AGITG trial). The authors reported that the majority of people who stopped taking imatinib (88.4%) did so because of disease progression. The Assessment Group suggested that this may indicate that 11.6% (11 of 97) withdrew treatment because of adverse events. Interim data from this study also showed that 31% of people (absolute number not given) required the dose to be reduced from 800 mg/day imatinib. No information was provided on the dose given following dose reduction.
4.1.21 Interim data for the S0033 trial reported by Dileo et al. (2005) showed that of the 77 people who had crossed over from 400 to 800 mg/day imatinib, 18 (23.4%) had at least one dose delay, and 14 (18%) had at least one dose reduction because of oedema or rash. No information was provided on the reduced dose given.
4.1.22 No adverse event data were available for people in the sunitinib trial.

4.2 Cost effectiveness
4.2.1 The Assessment Group carried out a systematic review of the literature. The Assessment Group did not find any studies that included an economic evaluation of increased doses of imatinib (600 or 800 mg/day), sunitinib and best supportive care for people who were intolerant to or whose disease failed to respond to 400 mg/day imatinib.
4.2.2 Three studies were found which compared imatinib with best supportive care (Wilson et al. 2005, Mabasa et al. 2008; Huse et al. 2007). Two studies included sunitinib, increased doses of imatinib, and best supportive care or palliative care as comparators for their economic evaluations (Contreras-Hernandez et al. 2008; Teich et al. 2009). Because the results of the Teich et al. study were available in abstract form only, information on how the study defined best supportive care was not available. Studies by Chabot et al. (2008) and Paz-Ares et al. (2008) compared treatment with sunitinib and best supportive care for people with GISTs that were resistant or intolerant to imatinib.
4.2.3 The Contreras-Hernandez et al. study suggested that 800 mg/day imatinib would deliver cost savings compared with best supportive care when best supportive care includes treatment with imatinib at a lower dose. Wilson et al. used a modified version of the model submitted by the manufacturer for technology appraisal 86, which evaluated the cost effectiveness of increased doses of imatinib (to 600 mg/day) following disease progression at 400 mg/day, in people with unresectable and/or metastatic GISTs from a UK NHS perspective. They estimated that the incremental cost per QALY gained ranged from £51,515 to £98,889 at 2 years, and £27,331 to £44,236 at 5 years compared with best supportive care.
4.2.4 Over the 5-year treatment horizon, Contreras-Hernandez et al. found that people receiving sunitinib had a mean life year gain of 1.4, 1.31 and 1.08 for imatinib and best supportive care respectively. The study also suggested that taking 800 mg/day imatinib incurred the highest mean costs of treatment. Teich et al. reported that sunitinib had a life year gain of 0.30 and progression-free life year gain of 0.26, with an incremental cost of Brazil $86,756 (equivalent to US $61,968, Purchasing Power Parity 2005) compared with best supportive care. They found that sunitinib was more effective (showing a life year gain of 0.02 and a progression-free life year gain of 0.47) and less costly than 800 mg/day imatinib over 6 years.

Manufacturer's submission
4.2.5 The manufacturer did not submit a cost-effectiveness analysis of imatinib for this appraisal. The manufacturer stated that major limitations with the available clinical data prevented them from developing a sufficiently robust health economics model for the use of 800 mg/day imatinib, increased from 400 mg/day on disease progression.

Assessment Group economic assessment
4.2.6 The Assessment Group developed a Markov model to compare alternative treatments for people with KIT (CD117)-positive unresectable and/or metastatic GISTs whose disease had progressed on imatinib 400 mg/day or whose treatment with imatinib had failed because of resistance or intolerance. They specifically addressed the cost-effectiveness of imatinib at doses of 600 or 800 mg/day compared with best supportive care or sunitinib.
4.2.7 The model looked at the costs and outcomes for GIST treatments. A time horizon of 10 years and a cycle length of 1 month were used to reflect the natural history of the disease. The costs and outcomes were discounted at 3.5% in accordance with the NICE reference case.
4.2.8 The Assessment Group considered a range of treatment pathways for people whose disease had progressed on 400 mg/day imatinib. Based on advice from its clinical advisers, the Assessment Group decided on seven clinically plausible pathways on which to base the model:

• Pathway 1: people receive best supportive care plus 400 mg/day imatinib
• Pathway 2: people receive 600 mg/day imatinib, and on further disease progression they receive 800 mg/day imatinib. On disease progression people then receive 50 mg/day sunitinib, followed by best supportive care and 400 mg/day imatinib on further disease progression.
• Pathway 3: people receive 600 mg/day imatinib and on further disease progression, they receive 50 mg/day sunitinib. After disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.
• Pathway 4: people receive 600 mg/day imatinib, and on further disease progression, they receive best supportive care plus 400 mg/day imatinib.
• Pathway 5: people receive 800 mg/day imatinib, and on further disease progression, they receive 50 mg/day sunitinib. After disease progression on sunitinib, people receive best supportive care plus 400 mg/day imatinib.
• Pathway 6: people receive 800 mg/day imatinib, and on further disease progression, they receive best supportive care plus 400 mg/day imatinib.
• Pathway 7: people receive 50 mg/day sunitinib and on further disease progression, they receive best supportive care plus 400 mg/day imatinib.

4.2.9 The Assessment Group determined clinical effectiveness using results from the systematic review and other literature. The Assessment Group combined these estimates within the model with health state utility data to provide estimates of quality-adjusted life years (QALYs) for the different treatment pathways. As noted, no data were available to estimate the effectiveness of any of the treatment pathways compared with each other.
4.2.10 The Assessment Group took survival data for best supportive care (which includes treatment with 400 mg/day imatinib for all pathways) from two studies (McGrath et al. 1987; Pierie et al. 2001). Pooled weighted estimates from these studies suggested that 87.9% of people died during the observation period of 60 months. Survival data for 600 mg/day imatinib were obtained from the B2222 trial. Forty-five per cent (5 of 11) of people who crossed over to 600 mg/day imatinib died during the trial period of 60 months. Data for 800 mg/day imatinib were from the S0033 trial, and indicated that 64.4% (76 of 118) died in this group. The survival data for sunitinib came from the sunitinib study (Seddon et al.) and showed that 55.0% (193 of 351) of people receiving sunitinib were still alive after a median survival period of 11.8 months. The Assessment Group derived a monthly mortality rate from these survival rates and assumed exponential rates. The Assessment Group also assumed that the mortality rate for people receiving sunitinib did not depend on whether or not they had received previous treatment.
4.2.11 The Assessment Group took response rates for 600 mg/day imatinib from the B2222 trial. The trial reported that 25.5% (11 of 43) of people receiving 600 mg/day imatinib responded to treatment and remained stable during a median follow-up of 63 months. S0033 and EORTC-ISG-AGITG trial data were used to provide evidence of the response rate to 800 mg/day imatinib. They reported that 30% (75 of 250) of people receiving 800 mg/day imatinib showed a partial response or remained stable after a median follow-up of 54 months. For response rates to sunitinib, the Assessment Group took data from two studies (Demetri et al. 2002; Prior et al. 2009). A simple weighted mean was used to derive a pooled response rate of 70% (266 of 382) which did not take into account previous treatment. The Assessment Group converted data reflecting no response for each treatment into monthly transition probabilities by assuming an exponential rate.
4.2.12 The costs of 400, 600 and 800 mg/day imatinib and 50 mg/day sunitinib in the Assessment Group's model were calculated from costs listed in BNF 58. Because sunitinib treatment involves 4 weeks of treatment followed by no treatment for 2 weeks, the Assessment Group calculated the costs per year, and a proportional rate per month. The Assessment Group assumed that all people receiving best supportive care would also receive medication and that this would be equivalent to the cost of 400 mg/day imatinib.
4.2.13 The Assessment Group based resource costs for 600 and 800 mg/day imatinib on those reported by Wilson et al. (2005). The costs included GP visits, outpatient visits including tests, computed tomography scans and managing adverse events. For sunitinib and best supportive care, the Assessment Group based resource costs on the manufacturer's submission for 'sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). The Assessment Group adjusted the costs from 2008 to 2009 prices using the Hospital and Community Health Services Index.
4.2.14 The Assessment Group derived health state utility values from the EQ-5D and Chabot et al. in the absence of data from the available studies. The utility value for progression-free survival for people whose disease responded to imatinib (regardless of dose) was assumed to be 0.935. The utility value for people receiving best supportive care was assumed to be 0.577 (Chabot et al). In the absence of alternative data, the utility value for people whose disease responded to sunitinib was assumed to be the same as that for imatinib (that is, 0.935).
4.2.15 The base-case results show that pathway 4 (600 mg/day imatinib and best supportive care, plus 400 mg/day imatinib on further disease progression) has an incremental cost-effectiveness ratio (ICER) of £27,304 per QALY gained compared with pathway 7 (50 mg/day sunitinib then best supportive care plus 400 mg/day imatinib). For pathway 2 (treatment with 600 mg/day to 800 mg/day imatinib, then 50 mg/day sunitinib followed by best supportive care plus 400 mg/day imatinib) the ICER was £45,850 per QALY gained (compared with the next more costly option, pathway 4). For pathway 3 (treatment with 600mg/day imatinib, then 50mg/day sunitinib followed by best supportive care plus 400mg/day imatinib) the ICER was £71,723 per QALY gained (compared to the next more costly option, pathway 4). Both pathway 5 (800 mg/day imatinib, then 50 mg/day sunitinib, followed by best supportive care plus 400 mg/day imatinib on further disease progression) and pathway 6 (800 mg/day imatinib, then best supportive care plus 400 mg/day imatinib on further disease progression) were dominated (by pathway 4, that is they were more costly and less effective). The estimated survival benefit provided by 800 mg/day imatinib compared with best supportive care was 4.2 months.
4.2.16 The Assessment Group also performed sensitivity analyses to account for uncertainties in the model. The parameters varied included structure and methodological assumptions around distribution, transition probabilities of survival and response to treatment with 600 mg/day imatinib, utility values and the costs of imatinib and sunitinib.

4.3 Consideration of the evidence
4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib, having considered evidence on the nature of unresectable and/or metastatic GISTs and the value placed on the benefits of imatinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
4.3.2 The Committee discussed current clinical practice for the treatment of people with unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86, people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600 mg/day imatinib is rarely prescribed after disease progression on 400 mg/day. The clinical specialists explained to the Committee that clinicians often consider increasing the dose of imatinib before offering treatment with sunitinib because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib. They further noted that if a person's disease fails to respond to higher doses of imatinib, it is common practice to continue treatment with 400 mg/day imatinib (in approximately 50% of people) in addition to best supportive care if the person are tolerant to imatinib. The Committee heard from patient experts that the limited data available suggest that imatinib at higher doses may be effective in prolonging survival and improving quality of life. Clinical specialists and patient experts also highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after failure of 400 mg/day imatinib. The Committee acknowledged that despite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment, there is a perception among both patient experts and clinical specialists that treatment with 800 mg/day imatinib after failure of 400 mg/day imatinib may offer some benefit.
4.3.3 The Committee considered the evidence provided by the Assessment Group and the manufacturer on the clinical effectiveness of 600 and 800 mg/day imatinib after disease progression on 400 mg/day imatinib. The Committee heard from the Assessment Group that no randomised controlled trials were identified on the effectiveness of an increased dose of imatinib compared with sunitinib or best supportive care, the two comparator treatments identified in the scope to this appraisal. Uncontrolled observational data were available evaluating the effectiveness of increased doses of imatinib in people with unresectable and/or metastatic GISTs who had not received previous imatinib treatment. However, the Committee were concerned that the populations in these studies differed from the population covered by this appraisal (that is, people whose disease progressed on 400 mg/day imatinib), and that the studies did not explore the comparisons defined in the scope. The Committee further noted that the populations in the studies varied substantially and that combining results may introduce more heterogeneity. The Committee noted that this appraisal is a part review of 'imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours' (NICE technology appraisal guidance 86), and had been scoped only to review recommendation 1.4 of that appraisal, about increasing the dose of imatinib. The Committee noted that this review had been requested by consultees based on the belief that sufficient clinical trial evidence was available. The Committee heard from the manufacturer that no new evidence for increased doses of imatinib has emerged since NICE technology appraisal guidance 86 was published in 2004. The Committee heard from the patient experts that they were disappointed that the available studies did not provide clear evidence about the effectiveness of higher doses of imatinib. The Committee agreed with the manufacturer and the Assessment Group that there is a paucity of robust data available to demonstrate the effectiveness of increased doses of imatinib, and that the available evidence is associated with uncertainty and potential bias.
4.3.4 The Committee noted that the majority of the available data were for people who received an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day. Only one phase II study (B2222) described the experience of 43 people who received an increased dose of 600 mg/day imatinib. The Committee heard that data from the Gastrointestinal Stromal Tumor Meta-Analysis Group (metaGIST) had been recently published in March 2010. However, these data were not included in the Assessment Group's economic evaluation because the population was randomised to higher doses of imatinib at baseline and had not received treatment with 400 mg/day imatinib first. Therefore, the population in this study was not consistent with the population for this appraisal. The Committee discussed the possible biases in the evidence on increased doses of imatinib from the uncontrolled observational data. The Committee recognised that if people with a better prognosis preferentially received increased doses of imatinib, then any improvement in outcome might not directly relate to the higher doses. The Committee heard from the manufacturer that there are no on-going trials which might provide clarity to the decision problem in this appraisal. The Committee heard from the clinical specialists that a trial comparing high dose imatinib with sunitinib had been stopped after it failed to recruit a sufficient number of people. The Committee concluded that the Assessment Group had made a good effort to include all available data relevant to this appraisal in their report but was concerned about the paucity and nature of the evidence available.
4.3.5 The Committee considered the effectiveness of imatinib at slowing disease progression in unresectable and/or metastatic GISTs. The Committee heard from the clinical specialists that comparable measures of disease progression had been used in the different clinical trials. The Committee heard that the three studies in which the dose of imatinib was increased from 400 to 800 mg/day showed that approximately one third of people had either a partial response or had stable disease. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400 mg/day imatinib, however they were mindful that the current evidence supporting this conclusion was uncertain.
4.3.6 The Committee heard from patient experts that measuring plasma concentrations of imatinib could be a major advantage, because it might allow an individualised approach to dosing of imatinib. However, the clinical specialists noted that this does not occur in routine UK clinical practice, and the Committee noted that no data had been presented to demonstrate an association between plasma concentrations and outcomes. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit, it could not base any recommendations on this because of the lack of evidence and because it was not used in routine clinical practice.
4.3.7 The Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800 mg/day imatinib. In addition the clinical specialists explained that, although outside the current marketing authorisation, clinicians might choose to offer treatment with imatinib at 800 mg/day without having tried lower doses in people with confirmed exon 9 mutations. However, they explained that the clinical evidence supporting this practice is based on the experience of only a few people. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, for clinical decision making about increasing imatinib doses.
4.3.8 The Committee considered the data reported by the Assessment Group for the comparator treatment sunitinib. The Committee noted that this evidence was mainly from an 'expanded access programme', in which regulators allow investigational drugs to be used to treat people with serious or immediately life-threatening diseases who cannot participate in clinical trials and who have no alternative therapy. The Committee was aware that people in this study were treated with sunitinib after higher (600 or 800 mg/day) rather than lower (400 mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal, that is, people whose disease progresses on 400 mg/day imatinib.
4.3.9 The Committee discussed when treatment with imatinib should be stopped following non-response to imatinib. The Committee heard from the clinical specialists that the criteria in NICE technology appraisal guidance 86 remained valid, that is, continuing imatinib therapy is recommended only if a response to initial treatment is achieved within 12 weeks.
4.3.10 The Committee discussed the cost effectiveness of imatinib 600 and 800 mg/day after disease progression on 400 mg/day imatinib. The Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib. The Committee also noted that the manufacturer did not submit an economic model because of the lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.
4.3.11 The Committee then considered the monthly mortality rates used in the Assessment Group's economic evaluation and noted that they were key drivers of the outcomes in the model. The Committee noted that a higher monthly mortality rate for people receiving sunitinib treatment was used in the Assessment Group's model than for people receiving best supportive care, which was considered implausible. The Committee heard from the Assessment Group that the limited evidence available reported that the mortality rate following 600 mg/day imatinib was lower than the rate following 800 mg/day imatinib, and that treatment with 800 mg/day imatinib generated fewer life years and fewer QALYs than treatment with 600 mg/day imatinib. The Committee considered this assumption implausible and agreed that this difference was unlikely to reflect the true effect of 600 and 800 mg/day imatinib, but that this highlighted the limitations in the clinical evidence for the two doses. The Committee also noted that the monthly mortality rate applied for best supportive care appeared to be very low, and was aware that these data had been pooled from two studies that had been carried out before imatinib was introduced into clinical practice. The Committee also considered that when the studies were carried out, advanced diagnostic methods for GISTs did not exist, and that people may have had other tumours (for example, leiomyosarcoma) which were associated with a different mortality rate than for GISTs. The Committee was also aware that best supportive care was likely to have improved since the studies were carried out, leading to better outcomes including mortality. The Committee was reminded by the clinical specialists that the current practice of best supportive care in people previously treated with imatinib includes continuing 400 mg/day imatinib in approximately 50% of people. The Committee concluded that taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib and therefore should be interpreted with caution.
4.3.12 The Committee discussed the options for collecting alternative data to establish the treatment pathway for people receiving increased doses of imatinib or one of the comparator treatments defined in the scope. The Committee noted that despite the research recommendation in NICE technology appraisal guidance 86 suggesting that a national register for people receiving imatinib treatment for GISTs should be maintained, such a register had not been established. The Committee heard from the manufacturer that it is currently discussing the feasibility of setting up a register. The Committee heard from the clinical specialists that a small register has been set up in Scotland to collect long-term treatment outcomes for people diagnosed with GISTs, and that observational data from specialist cancer centres in the USA may also be available. The Committee concluded that it is important that registers collect data on outcomes specific to unresectable and metastatic GISTs.
4.3.13 The Committee discussed the health-related quality of life of people with unresectable and/or metastatic GISTs. It noted that the Assessment Group did not identify any data that specifically measured the quality of life of people with GISTs who received imatinib treatment to use in its economic model. The Committee heard from patient experts that the health measures defined in the NICE reference case, such as the EQ-5D, might not fully capture the benefits that people gain from imatinib treatment. The Committee considered the plausibility of the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee thought that this value was implausibly high and noted that this value had been derived from 3 out of 9 clinicians who responded to a questionnaire. The Committee also noted that this utility value was higher than that used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Despite sensitivity analyses performed by the Assessment Group that varied the utility value, the Committee was not convinced that the most plausible value had been used and thought that this added further uncertainty to the model. The Committee considered that using a more appropriate utility value would probably worsen the cost effectiveness. Therefore, the Committee concluded that collecting utility data is important for any future informed decision making for this population.
4.3.14 The Committee explored whether it was possible to estimate a most plausible ICER. It noted that the lowest calculated ICER was £27,300 per QALY gained for 600 mg/day imatinib compared with sunitinib but, in the light of the inconsistencies in the model inputs and in the results recognised that this value was associated with considerable uncertainty. The Committee considered whether any changes to the major assumptions made by the Assessment Group or further modelling may decrease the uncertainty in the cost-effectiveness estimates for high doses of imatinib. The Committee noted that any further modelling would require estimates of disease progression and mortality rates to be comparable across different treatment arms and would require the following changes to the assumptions:

• decreasing the utility value for imatinib and sunitinib from 0.935 to a more plausible value
• assuming that only 50%, rather than 100% of people receive 400 mg/day imatinib in addition to best supportive care following progression of disease at higher doses
• using a shorter time horizon of 6 years rather than 10 years in line with NICE technology appraisal guidance179
• using more up-to-date estimates on the effectiveness of best supportive care
• accounting for utility values for additional adverse events associated with higher doses of imatinib
• using a more realistic effectiveness rate for sunitinib treatment.

The Committee noted that it was likely that these changes to the assumptions would further increase the ICERs of higher doses of imatinib presented in the current economic modelling (that is, these changes would worsen rather than improve the cost-effectiveness). In light of this, the Committee concluded that it could not justify a recommendation for 600 or 800 mg/day of imatinib as a cost-effective use of NHS resources.
4.3.15 The Committee considered data for people with exon 9 mutations and discussed whether 600 or 800 mg/day imatinib could be a cost-effective treatment option for unresectable and/or metastatic GISTs in this population. The Committee noted that the main source of evidence came from a post-hoc publication on a subgroup of people with known exon mutations who were treated with an increased dose of 800 mg/day imatinib since the start of the study. Furthermore, the Committee noted that economic modelling for this subgroup would not be considered more robust than for the entire population. Therefore, the Committee concluded that it could not make separate recommendations for the subgroup of people with exon 9 mutations.
4.3.16 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 the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
4.3.17 The Committee was aware that the number of people diagnosed with GISTs in England and Wales ranges from approximately 200 to 2000 per year. It noted that imatinib has a marketing authorisation for a number of other indications in addition to treatment of unresectable and/or metastatic GISTs. The Committee noted that for people with unresectable GISTs, prognosis is poor with survival generally less than 2 years without further treatment. The Committee noted that in the economic model the survival benefit following treatment with imatinib 800 mg/day compared with best supportive care was 4.2 months. However, the Committee agreed that the evidence for this life extension could not be considered sufficiently robust, considering the uncertainty about the assumptions in the economic model, and the lack of data comparing clinical effectiveness. The Committee therefore concluded that increased doses of imatinib following disease progression at 400 mg/day imatinib did not meet the criteria for being a life-extending, end-of-life treatment.
4.3.18 In summary, the Committee agreed that clinical experience suggests that increased doses of imatinib after disease progression on 400 mg/day imatinib may offer benefit to some patients, however there is an absence of new good quality clinical and cost effectiveness data on increased doses of imatinib since the previous appraisal of imatinib (NICE technology appraisal guidance 86). Taking this into account, along with the comments from the patient experts, clinical specialists, Assessment Group, manufacturer, and those who commented on the assessment report, the Committee concluded that there was insufficient evidence to justify the use of imatinib at increased doses of 600 mg/day and 800 mg/day as an appropriate use of NHS resources for the treatment of people with unresectable and/or metastatic GISTs whose disease has progressed on treatment with 400 mg/day imatinib. The Committee also appreciated that people whose disease progresses on 400 mg/day imatinib have the option to receive sunitinib as recommended in NICE technology appraisal guidance 179.

Summary of Appraisal Committee’s key conclusions

TA XXX (MTA): Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours (part review of technology appraisal guidance 86)			ACD section
Key conclusion
Imatinib at 600 or 800 mg/day is not recommended for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400 mg/day imatinib. The Appraisal Committee considered that there was an absence of new good quality evidence since the previous appraisal of imatinib (NICE technology appraisal guidance 86) was published to draw conclusions about the clinical effectiveness of increased doses of imatinib after disease progression on 400 mg/day imatinib.			1 4.3.18
Current practice
Clinical need of patients including the availability of alternative treatments	Clinical specialists and patient experts highlighted the importance of providing hope to people with metastatic GISTs by offering them additional treatment options after failure of imatinib 400 mg/day.		4.3.2
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 and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)	The Committee acknowledged that despite the lack of clinical trial evidence to demonstrate the effectiveness of increased doses of imatinib treatment, there is a perception among both patient experts and clinical specialists that treatment with 800 mg/day imatinib after failure of 400 mg/day imatinib may offer some benefit.		4.3.2
What is the position of the treatment in the pathway of care for the condition?	The Committee heard from the clinical specialists that, despite the recommendations in NICE technology appraisal guidance 86, people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists noted that if a person's disease fails to respond to higher doses of imatinib, it is common practice to continue treatment with 400 mg/day imatinib (in approximately 50% of people) in addition to best supportive care if they are tolerant to imatinib.		4.3.2
Adverse effects	The clinical specialists noted that clinicians often consider increasing the dose of imatinib before offering sunitinib treatment because imatinib is considered to have a more favourable adverse event profile, even at higher doses, than sunitinib		4.3.2
Evidence for clinical effectiveness
Availability, nature and quality of evidence	No randomised controlled trials were identified on the effectiveness of an increased dose of imatinib compared with sunitinib or best supportive care, the two comparator treatments identified in the scope to this appraisal. The Committee agreed with the manufacturer and the Assessment Group that there is a paucity of robust data available to demonstrate the effectiveness of increased doses of imatinib, and that the available evidence is associated with uncertainty and potential bias. The Committee noted that the majority of available data were for people who received an increased dose of 800 mg/day imatinib after disease progression on 400 mg/day. The Committee heard from the manufacturer that there are no ongoing trials which might provide clarity to the decision problem in the appraisal. The Committee concluded that the Assessment Group had made a good effort to include all available data relevant to this appraisal but was concerned about the paucity and nature of the evidence available.		4.3.3 4.3.4
Relevance to general clinical practice in the NHS	The Committee heard from the clinical specialists that people frequently receive 800 mg/day imatinib when their disease progresses on 400 mg/day imatinib if they have tolerated previous imatinib treatment. The clinical specialists reported that 600 mg/day imatinib is rarely prescribed after disease progression on 400 mg/day. The Committee heard from the patient experts that measuring plasma concentrations of imatinib could offer a major advantage, because it might allow an individualised approach to dosing of imatinib. The Committee concluded that while measuring plasma concentrations of imatinib might potentially be of benefit, it could not base any recommendations on this because of the lack of evidence and because it was not used in routine clinical practice. The Committee heard from the clinical specialists that the criteria in NICE technology appraisal guidance 86 remained valid, that is, continuing imatinib therapy is recommended only if a response to initial treatment is achieved within 12 weeks.		4.3.2 4.3.6 4.3.9
Uncertainties generated by the evidence	See "Availability, nature and quality of evidence" above The Committee considered the data reported by the Assessment Group for the comparator treatment sunitinib. The Committee was aware that people in this study were treated with sunitinib after higher (600 or 800 mg/day) rather than lower (400 mg/day) doses of imatinib and did not necessarily reflect the population of interest in this appraisal, that is, people whose disease progresses on 400 mg/day imatinib.		4.3.8
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness	The Committee discussed whether benefits from increased doses of imatinib might be greater in certain subgroups of people. The Committee heard from the clinical specialists that there is some evidence suggesting that GISTs with certain mutations in the KIT gene are likely to be more or less sensitive to imatinib treatment. The clinical specialists suggested that the presence of an exon 9 mutation may be associated with a better outcome in people whose dose is increased to 800 mg/day imatinib. However, they explained that the clinical evidence supporting this practice is based on the experience of only a few people. The Committee also understood that mutational analysis in people with progressive disease had a limited role, if any, for clinical decision making about increasing imatinib doses.		4.3.7
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee heard that the three studies in which the dose of imatinib was increased from 400 to 800 mg/day showed that approximately one third of people had either a partial response or had stable disease. The Committee concluded that imatinib treatment at higher doses may offer some benefit to people whose disease progresses on 400 mg/day imatinib, however they were mindful that the current evidence supporting this conclusion was uncertain.		4.3.5
Evidence for cost effectiveness
Availability and nature of evidence	The Committee noted the Assessment Group's view that it had great difficulty undertaking an assessment of cost effectiveness in the absence of robust comparative clinical evidence for increased doses of imatinib. The Committee also noted that the manufacturer did not submit an economic model due to a lack of robust data comparing increased doses of imatinib with sunitinib and best supportive care.		4.3.10
Uncertainties around and plausibility of assumptions and inputs in the economic model	Key uncertainties in the clinical effectiveness evidence followed through to the economic model. A key uncertainty in the economic model was the monthly mortality rates assumed for sunitinib, best supportive care and increased doses of imatinib. The Committee concluded that taking into account the limitations of the data used to derive the monthly mortality rates, the results presented by the Assessment Group may not reflect the true value of cost effectiveness of high doses of imatinib and therefore should be interpreted with caution. The Committee considered whether any changes to the major assumptions made by the Assessment Group or further modelling may decrease the uncertainty in the cost-effectiveness estimates for high doses of imatinib. The Committee noted that any further modelling would require estimates of disease progression and mortality rates to be comparable across different treatment arms and would require the a number of changes to the assumptions in the model. The Committee noted that it was likely that these changes to the assumptions would further increase the ICERs of higher doses of imatinib presented in the current economic modelling (that is, these changes would worsen rather than improve the cost-effectiveness).		4.3.11 4.3.14
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 quality-adjusted life year (QALY) calculation? How have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible incremental cost-effectiveness ratio) ICER?	The Assessment Group did not identify any data that specifically measured the quality of life of people with GISTs who have received treatment with imatinib to use in its economic model. The Committee considered the plausibility of the utility value used in the Assessment Group's economic model for imatinib and sunitinib (0.935). The Committee thought that this value was implausibly high and noted that this value had been derived from 3 out of 9 clinicians who responded to a questionnaire. The Committee also noted that this utility value was higher than that used in NICE technology appraisal guidance 179 on sunitinib for the treatment of GISTs after disease progression on imatinib treatment. Despite sensitivity analyses performed by the Assessment Group that varied the value of utility, the Committee was not convinced that the most plausible value had been used and thought that this added further uncertainty to the model.		4.3.13
Are there specific groups of people for whom the technology is particularly cost effective?	The Committee considered data for people with exon 9 mutations and discussed whether 600 or 800 mg/day imatinib could be a cost-effective treatment option for unresectable and/or metastatic GISTs in this population. The Committee noted that the main source of evidence came from a post-hoc publication on a subgroup of people with known exon mutations who were treated with an increased dose of 800 mg/day imatinib since the start of the study. Furthermore, the Committee noted that economic modelling for this subgroup would not be considered more robust than for the entire population. Therefore, the Committee concluded that it could not make separate recommendations for for the subgroup of people with exon 9 mutations.		4.3.15
What are the key drivers of cost effectiveness?	The Committee considered the monthly mortality rates used in the Assessment Group's economic model and noted that they were key drivers of outcomes in the model.		4.3.11
Most likely cost-effectiveness estimate (given as an ICER)	With respect to the calculation of ICERs, the Committee noted that the lowest calculated ICER was £27,300 per QALY gained for 600 mg/day imatinib compared with sunitinib but recognised that this value was associated with considerable uncertainty. The Committee noted that more plausible assumptions would further increase the ICERs of increased doses of imatinib above the ICERs in the current economic modelling (that is, these changes would worsen rather than improve the cost-effectiveness). In light of this, the Committee could not justify a recommendation for 600 or 800 mg/day of imatinib as a cost-effective use of NHS resources.		4.3.14
Additional factors taken into account
Patient access schemes (Pharmaceutical Price Regulation Programme)	Not applicable.		-
End-of-life considerations	The Committee concluded that imatinib did not meet the criteria for a life-extending, end-of-life treatment.		4.3.16, 4.3.17
Equalities considerations, Social Value Judgement	No equalities issues were raised when the scope for this appraisal was developed, or during the course of the appraisal.		-

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 Proposed recommendations for further research

6.1 The Committee concluded that there were substantial gaps in the evidence and that research into the following areas should be considered:

• A national register of all people being treated with imatinib, sunitinib and best supportive care should be maintained. Details could include patient characteristics, dose and duration of treatment, tumour response rates and survival both with and after discontinuation of treatment.
• The use of mutational analysis to predict individual response to treatment.
• The use of plasma level measurement to individualise treatments for patients.

7 Related NICE guidance

Published

• Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours. NICE technology appraisal guidance 86 (2004). Available from www.nice.org.uk/guidance/TA86
• Sunitinib for the treatment of gastrointestinal stromal tumours. NICE technology appraisal guidance 179 (2009). Available from www.nice.org.uk/guidance/TA179

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 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.

Amanda Adler
Chair, Appraisal Committee
June 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 Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

Professor John Cairns
Professor of Health Economics, Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty
External Relations Director - Pharmaceuticals and Personal Health, Oral Care Europe

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Sally Gooch
Independent Nursing and Healthcare Consultant

Eleanor Grey
Lay member

Sanjay Gupta
YPD Service Case Manager, Southwark Health and Social Care, Southwark PCT

Dr Neil Iosson
General Practitioner

Dr Rosa Legood
Lecturer, London School of Hygiene and Tropical Medicine

Terence Lewis
Lay member

Dr Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the NIHR Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Stephen Palmer
Senior Research Fellow, Centre for Health Economics, University of York

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Roderick Smith
Finance Director, West Kent Primary Care Trust

Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Nathalie Verin
Health Economics Manager, Boston Scientific UK and Ireland

Dr Colin Watts
Consultant Neurosurgeon, Addenbrookes Hospital

Tom Wilson
Director of Contracting and Performance, NHS Tameside and Glossop

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.

João Vieira, Sally Doss
Technical Lead(s)

Fiona Rinaldi
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The assessment report for this appraisal was prepared by Aberdeen Health Technology Assessment Group:

• Hislop J, Quayyum Z et al. Systematic review of the clinical and cost effectiveness of imatinib at escalated doses of 600 mg/day or 800 mg/day for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours which have progressed on treatment at a dose of 400 mg/day, March 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, assessment report and the appraisal consultation document (ACD). Organisations listed in I ,II and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturers/sponsors:

• Novartis Pharmaceuticals UK

II Professional/specialist and patient/carer groups:

• Beating Bowel Cancer
• Bowel Cancer UK
• Cancer Research UK
• GIST Support UK
• Macmillan Cancer Support
• Rarer Cancers Forum
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• Sarcoma UK
• United Kingdom Oncology Nursing Society

III Other consultees:

• Department of Health
• Welsh Assembly Government

IV Commentator organisations (without the right of appeal):

• Department of Health, Social Services and Public Safety for Northern Ireland
• National Cancer Research Institute
• National Collaborating Centre for Cancer
• NHS Quality Improvement Scotland
• Pfizer

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on imatinib by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Robin Reid, Consultant Pathologist, nominated by NHS Quality Improvement Scotland - clinical specialist
• Professor Ian Judson, Consultant, nominated by Royal College of Physicians - clinical specialist
• Dr David Cook, Retired, nominated by GIST Support UK - patient expert
• Judith Robinson, Chair of GIST Support UK, nominated by GIST Support UK - patient expert

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

• Novartis Pharmaceuticals UK