Gastrointestinal stromal tumours - sunitinib: appraisal consultation document

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Sunitinib for the treatment of gastrointestinal stromal tumours

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of sunitinib for the treatment of gastrointestinal stromal tumours and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of sunitinib for the treatment of gastrointestinal stromal tumours.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).

  • The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
  • At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
  • After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
  • Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 26 March 2009

Second Appraisal Committee meeting: 8 April 2009

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 does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
1 Appraisal Committee's preliminary recommendations
1.1 The Committee is minded not to recommend sunitinib, within its marketing authorisation, as a treatment option for people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.

1.2

The Committee recommends that NICE requests further clarification from the manufacturer of sunitinib. The following information should be available for the second Appraisal Committee meeting:

  • Assessment of the impact of the costs of sunitinib on the cost-effectiveness estimate of sunitinib compared with best supportive care. Sunitinib costs in the base-case should be based on the A6181004 randomised controlled trial and should include the costs of sunitinib given to the people in the sunitinib arm of the trial who continued to receive sunitinib after disease progression.
  • An alternative scenario analysis to clarify the impact of the costs and benefits of the expanded access programme A6181036. Sunitinib costs in the scenario analysis should be based on the sunitinib treatment duration in the expanded access programme A6181036.
  • A detailed explanation of the application and methods of the rank preserved structural failure time model, which was used to derive the overall survival of people assigned to best supportive care plus placebo while accounting for crossover. The use of the model in the cost-effectiveness analysis should also be justified.
  • Assessment of the impact of the method used to control for crossover on the cost-effectiveness estimate of sunitinib compared with best supportive care. An alternative scenario analysis that must be considered should censor people who were assigned to best supportive care at the point they crossed over to receive sunitinib.
  • Complete probabilistic sensitivity analyses on the revised base case and the two scenario analyses (which use costs of sunitinib from the expanded access programme and censoring), correcting for the errors and omissions identified by the Evidence Review Group.
2 The technology
2.1 Sunitinib (Sutent, Pfizer) is one of a group of closely related tyrosine kinase inhibitors. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes, stopping the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of imatinib mesilate treatment due to resistance or intolerance.
2.2 Sunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The summary of product characteristics (SPC) lists the following conditions that may be associated with sunitinib treatment: cardiovascular events, skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC.
2.3 Sunitinib is administered orally. The recommended dosage is 50 mg once daily, for four consecutive weeks, followed by a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (within the dose range 25-75 mg). The price for a pack of 50 mg capsules (28 per pack) is £3138.80 (excluding VAT; 'British national formulary' [BNF] edition 56). The manufacturer of sunitinib has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs of subsequent treatment cycles 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 sunitinib and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1

In the submission, the manufacturer presented evidence on the clinical effectiveness of sunitinib for the treatment of unresectable and/or metastatic malignant GIST that was within the marketing authorisation for sunitinib and according to the appraisal scope. The main clinical-effectiveness evidence came from one randomised controlled trial (RCT). The RCT, A6181004, compared the effect of sunitinib plus best supportive care (n = 207) with placebo plus best supportive care (n = 105). Best supportive care was defined as the monitoring of progression, symptom control and palliative care without active treatment. The trial was conducted in people with a good performance status (Eastern Cooperative Oncology Group [ECOG] status 0 or 1). Approximately 4% of people in the trial had initial imatinib intolerance and approximately 80% had received more than 400 mg of imatinib daily before trial entry. People in the trial were stratified according to:

  • best outcome of prior imatinib treatment (progressive disease within 6 months of starting imatinib treatment [primary resistance] or progressive disease after 6 months of starting imatinib treatment [secondary resistance] or imatinib intolerance) and
  • baseline McGill pain questionnaire score (0 versus more than or equal to 1).
3.2 The primary outcome in the study was time to tumour progression, which was defined as the time from the first dose of study drug to first documentation of progressive disease. The blinded phase of the RCT was stopped early when the first planned interim analysis demonstrated that the time to tumour progression in people randomised to receive sunitinib plus best supportive care was statistically significantly longer than in people randomised to receive placebo plus best supportive care. A total of 84% of people randomised to receive placebo plus best supportive care crossed over and received sunitinib plus best supportive care. Median time to tumour progression in the intention-to-treat (ITT) population was 27.3 weeks in the sunitinib plus best supportive care arm and 6.4 weeks in the placebo plus best supportive care arm (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.23 to 0.47, p < 0.0001). The median time to tumour progression for the group that crossed over from placebo plus best supportive care to sunitinib plus best supportive care was similar to that for the group originally randomised to receive sunitinib plus best supportive care.
3.3 During the blinded phase of the study, median overall survival was not reached in either arm of the study. However, the interim ITT analysis of the RCT showed that overall survival was significantly longer for those who received sunitinib plus best supportive care compared with those who received placebo plus best supportive care (HR 0.491; 95% CI 0.290 to 0.831, p = 0.007). The ITT analysis of the entire study (that is, blinded plus open-label phase) showed that there was no statistically significant difference in overall survival for people who received sunitinib plus best supportive care (overall survival 73 weeks) compared with people who received placebo plus best supportive care (overall survival 65 weeks) (HR 0.876; 95% CI: 0.679 to 1.129, p = 0.306).
3.4 The manufacturer also presented analyses of overall survival using a rank preserved structural failure time (RPSFT) model. The RPSFT model was a 'post-hoc' approach taken by the manufacturer to control for the crossover from the placebo plus best supportive care arm to the sunitinib plus best supportive care arm. The RPSFT method estimated the overall survival of people randomised to receive placebo plus best supportive care assuming that they had not crossed over; that is, as if they had remained on placebo plus best supportive care for the duration of the trial. This method was therefore based on a comparison of the groups as they were randomised. The RPSFT method proportionally 'shrinks' the amount of additional survival conferred to people who crossed over to receive sunitinib.
3.5 The initial RPSFT analysis suggested a statistically significantly longer overall survival for people who received sunitinib plus best supportive care (overall survival 73 weeks) compared with those who received placebo plus best supportive care (overall survival 39 weeks) (HR 0.505; 95% CI 0.388 to 0.658, p < 0.0001) for the entire study. Following recommendation from an independent statistician, the manufacturer revised the 95% CI associated with the hazard ratio derived when using the RPSFT approach. The RPSFT method did not provide extra evidence against the null hypothesis and thus gives the same p value as the ITT analysis (0.306) and so the 95% confidence interval should include one. The revised 95% CI was 0.262 to 1.134.
3.6 Quality of life was measured in the RCT using the European quality of life (EuroQoL) health state questionnaire (EQ-5D). More than 75% of people completed the EQ-5D questionnaire at each time point and there were no statistically significant differences reported between the treatment groups. Treatment-related adverse events and serious adverse events were more common in the sunitinib plus best supportive care arm than in the placebo plus best supportive care arm. In the RCT, a total of 83% of people in the sunitinib plus best supportive care arm and 59% of people in the placebo plus best supportive care arm experienced treatment-related adverse events of any severity. The manufacturer stated that the adverse events reported were generally of mild to moderate intensity and were easily managed by dose reduction, dose interruption or standard supportive medical treatments. A total of 9% of people randomised to sunitinib plus best supportive care and 8% of people randomised to receive placebo plus best supportive care discontinued treatment because of adverse events.
3.7 The manufacturer also provided details of an ongoing, open-label expanded access programme (EAP). This cohort study (A6181036) was set up to allow people with GIST, who might not have access to the drug because of study inclusion criteria or lack of regulatory approval where they live, to benefit from sunitinib. As of December 2007, 1126 people were enrolled in the EAP and the ITT population comprised 1117 people. People in the EAP were of ECOG performance status 0 to 4 and 68% of people had received doses of more than 400 mg of imatinib daily before joining the study. In the EAP, sunitinib treatment was given for as long as there was evidence of disease control according to the investigator. The EAP is scheduled to end in December 2009. At the time of data analysis, 50% of the ITT population were alive. The median time to tumour progression was 41 weeks (95% CI 36 to 47) and the median overall survival was 75 weeks (95% CI 68 to 84).
3.8 The manufacturer developed a Markov model to assess the cost effectiveness of sunitinib compared with best supportive care in people with unresectable and/or metastatic malignant GIST after failure of imatinib therapy because of resistance or intolerance. The model had three distinct health states: progression free, progressive disease (no active therapy) and death. All people entered the progression-free state of the model, having been assumed to have failed imatinib therapy. The model had a cycle length of 6 weeks and the time horizon was 6 years; the manufacturer stated that this reflected the maximum life expectancy of the population in the model. No subgroup analyses were conducted by the manufacturer.
3.9 The model used effectiveness data from the RCT (A6181004) described in paragraph 3.1. For progression-free survival, Weibull curves were fitted to the unadjusted ITT data from the placebo plus best supportive care and sunitinib plus best supportive care arms independently. For overall survival, Weibull curves were fitted to the unadjusted ITT data from the sunitinib plus best supportive care arm and to the RPSFT-adjusted data from the placebo plus best supportive care arm independently. In a sensitivity analysis, the manufacturer fitted a Weibull curve to the unadjusted ITT data for overall survival with placebo plus best supportive care.
3.10 The utility values used in the model were taken from the RCT, in which the EQ-5D questionnaire was used. In the progression-free health state, a utility value of 0.731 was assigned to people receiving sunitinib plus best supportive care and a utility value of 0.781 was assigned to people receiving placebo plus best supportive care. In the progressive disease health state, a utility value of 0.577 was assigned to both arms. The manufacturer did not model the effect of adverse events on utility, and stated that the reduced utility values assigned to the sunitinib plus best supportive care arm would account for disutility from adverse events.
3.11 Resource use was not measured directly in the RCT, although the drug use and relative dose intensity estimates were derived from the RCT. In the model, the manufacturer assumed a relative dose intensity of 88.6% for sunitinib and cost data were taken from the BNF 56. The manufacturer had agreed a patient access scheme with the Department of Health, in which the first cycle of sunitinib is free to the NHS.
3.12 With discounting at 3.5% per year, sunitinib compared with best supportive care produced a base-case incremental cost-effectiveness ratio (ICER) of £27,365 per QALY gained. One-way sensitivity analyses demonstrated that the ICER was most sensitive to the source of overall survival data for the best supportive care arm. When the unadjusted ITT data were used to model the placebo plus best supportive care overall survival curve, the ICER increased to £77,107 per QALY gained. Probabilistic sensitivity analyses suggested that sunitinib had a 50% probability of being cost effective compared with best supportive care at a willingness-to-pay threshold of £30,000 per QALY gained.
3.13 The ERG stated that the manufacturer's submission was generally good quality and appropriate to the decision problem. Although the clinical-effectiveness evidence was derived from only one RCT, this RCT was of good quality and demonstrated that sunitinib plus best supportive care significantly improved time to tumour progression compared with placebo plus best supportive care. The ERG stated that the economic model developed by the manufacturer was appropriate for the decision problem and appeared to contain no logical errors or internal inconsistencies.

3.14

The ERG highlighted the following key areas of concern with the manufacturer's submission:

  • the use of the RPSFT method
  • the uncertainty surrounding the cost-effectiveness estimate provided by the manufacturer
  • the cost of sunitinib for people who continued to receive sunitinib after disease progression.
3.15 The ERG stated that the RPSFT method used by the manufacturer to control for the effects of crossover was uncommon and the ERG could not determine whether the method had been applied correctly. The ERG also highlighted a number of errors and omissions in the probabilistic sensitivity analyses. In particular the ERG stated that the uncertainty in the progression-free and overall survival states was not modelled fully, as only the certainty of fit of the Weibull curves was assessed in sensitivity analyses for these parameters. The ERG also noted that the manufacturer had used standard deviations rather than standard errors for the utility values in the sensitivity analyses. The ERG was concerned, given the wide confidence interval around the estimate for the overall survival hazard ratio using the RPSFT method, that the uncertainty in the base-case ICER was substantial and likely to be higher than that presented by the manufacturer in the probabilistic sensitivity analyses. The ERG also highlighted a number of other, more minor, errors and omissions in the manufacturer's probabilistic sensitivity analyses.
3.16 The ERG noted that the economic model developed by the manufacturer assumed that sunitinib was only given until disease progression. In the RCT, from which the effectiveness of sunitinib was derived, 54 people (22%) received sunitinib after disease progression. The additional cost of sunitinib for these people, as estimated by the ERG, was £2237, which increased the base-case ICER from £27,400 to £31,800 per QALY gained. When the additional costs of sunitinib were incorporated into the sensitivity analyses that used the unadjusted ITT data, the ICER increased from £77,100 to £90,500 per QALY gained. The ERG also noted that median progression-free survival in the RCT (and thus the progression-free survival used in the manufacturer's economic model) and the EAP differed markedly. When the ERG increased the median progression-free survival to equal that of the EAP (41 weeks), the ICER increased the base-case from £27,400 to £46,300 per QALY gained. The ERG noted that the ICER increased substantially when the progression-free survival was taken from the EAP and stated that this was because people who experience longer progression-free survival receive more sunitinib and thereby incur greater sunitinib acquisition costs.
3.17 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx
4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with unresectable and/or metastatic malignant GIST, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee first considered the clinical effectiveness data presented by the manufacturer. It noted that there were statistically significant improvements in time to tumour progression and progression-free survival for people taking sunitinib plus placebo compared with people taking placebo plus best supportive care. The Committee noted that the estimates of time to tumour progression and progression-free survival were obtained at the first interim analysis and so were not confounded by any crossover. The Committee heard from clinical specialists and patient experts that the observed benefits in time to tumour progression and progression-free survival were clinically meaningful. The Committee was aware that, after the interim analysis, people were offered open-label sunitinib and that the unadjusted ITT analysis was confounded by the crossover. The Committee accepted that the observed benefits in time to tumour progression and progression-free survival were such that a substantial improvement in overall survival with sunitinib treatment was probable. The Committee therefore concluded that sunitinib was a clinically effective treatment for unresectable and/or metastatic malignant GIST which is resistant or intolerant to imatinib.
4.3 The Committee then discussed the cost-effectiveness estimate of sunitinib compared with best supportive care submitted by the manufacturer. The Committee considered the ERG comments that the model structure was appropriate for the decision problem. It also noted the concern raised by the ERG that the utility data supplied by the manufacturer in clarification could not be reconciled with data originally submitted. However, the Committee agreed that the cost-effectiveness estimate was relatively insensitive to variations in the utility values and therefore that the utility values used in the base-case were appropriate.
4.4 The Committee then discussed the best supportive care costs that were included in the economic model. The Committee noted that the base-case estimate did not include imatinib as part of best supportive care. The Committee heard from clinical specialists that in practice it may be possible that a person would benefit from imatinib as part of best supportive care because there may be newly formed tumour cells or metastases that could respond to further imatinib therapy. However, the Committee was aware that in the RCT, from which the effectiveness data were derived, no further imatinib therapy was given. The Committee therefore concluded that it was appropriate not to include imatinib as part of best supportive care and that the best supportive care costs in the base-case were appropriate.
4.5 The Committee then discussed the sunitinib costs that were included in the economic model. The Committee noted the ERG comment that 22% of people assigned to sunitinib continued to receive it after disease progression. The Committee was aware that these costs were not included in the economic model, which assumed sunitinib was given only until disease progression. The Committee acknowledged that the effectiveness data came from the RCT and that it was possible that people who received sunitinib after disease progression could have experienced additional benefits. The Committee reviewed the marketing authorisation of sunitinib and considered that treatment beyond disease progression was permissible. Therefore the Committee agreed that it was important to consider a cost-effectiveness analysis where the revised base-case included the additional costs of the sunitinib given to people in the progressive disease state in the RCT; with all other model parameters as per the original base case in the manufacturer's submission. The Committee acknowledged however that if the marketing authorisation of sunitinib did not allow sunitinib treatment beyond disease progression then investigation and discounting of any additional benefits from the sunitinib treatment received after disease progression would need to be made. It concluded that clarification about the impact of the costs of sunitinib on the cost-effectiveness estimate of sunitinib compared with best supportive care should be requested. Sunitinib costs in the base-case should be based on the A6181004 RCT, and should include the costs of sunitinib given to the people in the sunitinib arm who continued to receive sunitinib after disease progression.
4.6 The Committee then discussed the difference in the median progression-free survival in the sunitinib arm of the RCT compared with that of the EAP. The Committee understood that all people in the RCT had an ECOG performance status of 0 or 1 compared with 84% of people in the EAP. The Committee heard that the characteristics of people in the RCT and the EAP were broadly generalisable to people with GIST in the UK. The Committee also understood that radiological imaging for tumour progression was carried out uniformly and regularly in the RCT, according to the full trial protocol, whereas imaging was carried out according to individual hospital protocol in the EAP. The Committee heard from clinical specialists that this difference could account for the shorter median progression-free survival in the RCT compared with the EAP. This was because imaging in the RCT would have identified signs of progression earlier, before there were any signs of clinical progression. The Committee understood that it was possible that imaging was only conducted in the EAP after signs of clinical progression were identified. The Committee also heard from patient experts that, in practice, clinical progression was the greatest concern for patients. The Committee accepted that, in practice, sunitinib may be given until clinical, rather than radiological, evidence of disease progression; and this did not appear to be excluded from the marketing authorisation of sunitinib. The Committee therefore agreed that it was important to consider an alternative scenario analysis around the sunitinib costs, based on the increase in the median progression-free survival between the RCT and the EAP (27.3 weeks on sunitinib in the RCT compared to 41 weeks in the EAP). It concluded that an alternative scenario analysis should be requested to clarify the impact of the costs and benefits of the expanded access programme, with sunitinib costs in the scenario analysis based on sunitinib treatment duration in the EAP.
4.7 The Committee then discussed the effectiveness data that were used in the economic model. It understood that a high level of crossover had occurred in the RCT and the unadjusted ITT data for the best supportive care arm were confounded by crossover. The Committee agreed that it was appropriate to adjust the effectiveness data for the crossover that had occurred.

4.8

The Committee then discussed the RPSFT method used by the manufacturer. The Committee understood that the RPSFT method was used as it preserved the randomisation of the RCT when crossover had occurred. However, the Committee had the following concerns with the method:

  • The method is rarely used and had never been used in a cost-effectiveness analysis before, despite crossover being a common issue in many trials and the method being available for many years.
  • The method and its application were opaque. The original paper detailing the method used a parametric model; however it was not clear to the Committee whether a parametric or non-parametric model had been used by the manufacturer.
  • It was not clear whether the 'shrinking' of values had been applied only to time on sunitinib before progression, time on sunitinib both before and after progression or time from starting sunitinib until death. The manufacturer had not presented any calculations or disaggregated figures for time in progressive disease for people who were assigned to best supportive care.
  • It was not clear whether the manufacturer had applied the correct methods, as suggested by an independent statistician, and this concern was reflected by the ERG.
  • The method for calculating the original confidence interval appeared incorrect and advice from an independent statistician produced a much wider confidence interval. The calculations for confidence intervals were not submitted by the manufacturer and could not be verified by the ERG.
  • Additional concerns were raised by the Committee about the RPSFT method, which appeared to assume that proportionate increase in survival with sunitinib would be the same, irrespective of when sunitinib was given. The Committee heard from clinical specialists that only people who were of ECOG performance status 0 or 1 were permitted to cross over to receive open-label sunitinib in the RCT and that the ITT median overall survival demonstrated that sunitinib given after best supportive care was not significantly different from sunitinib given from the start of the RCT. However, the Committee agreed that this assumption had not been addressed by the manufacturer.
  • The Committee was also concerned about the face validity of the economic model. The Committee heard from clinical specialists that the time spent in progressive disease produced by the model was much longer than expected in clinical practice. In the model, the time in progressive disease for people randomised to sunitinib was 1.38 years with a total of 1.98 life years gained and for those randomised to best supportive care the time in progressive disease was 1.02 years with a total of 1.21 life years gained. The Committee heard that, in clinical practice, time in progressive disease would be expected to constitute approximately half of the overall life years gained.
  • The Committee noted that in the economic analysis, the survival curves were modelled with independent Weibull curves because the application of a constant hazard ratio to the best supportive care curve gave a poor fit to the sunitinib data. However, the Committee was concerned that the RPSFT method assumes a proportionate treatment effect and it was unclear whether this would further affect the face validity of the economic model.

Therefore, the Committee agreed that clarification about the RPSFT model should be requested from the manufacturer. The application and methods of the RPSFT model, which was used to derive the overall survival of people assigned to best supportive care plus placebo while accounting for crossover should be explained in detail. The use of the RPSFT model in the cost-effectiveness analysis should be justified.

4.9 The Committee then discussed whether there were any, more conventional, methods for controlling for crossover that could have been used by the manufacturer. The Committee accepted that an uncommon method may be appropriate, but felt that comparison with a more standard method, such as censoring of the data from the time of crossover, would be useful. The Committee acknowledged that a large number of people crossed over from the placebo plus best supportive care arm. However the Committee still agreed that it was important to compare the cost-effectiveness estimate, derived using the RPSFT method to calculate the overall survival of the best supportive care arm, with an estimate derived by censoring people assigned to best supportive care who received open-label sunitinib. It concluded that clarification about the impact of the method used to control for crossover on the cost-effectiveness estimate of sunitinib compared with best supportive care should be requested. An alternative scenario analysis that must be considered should censor people who were assigned to best supportive care at the point they crossed over to receive sunitinib.
4.10 The Committee then discussed the uncertainty surrounding the cost-effectiveness estimates. The Committee acknowledged the concerns highlighted by the ERG that there were a number of errors and omissions in the original probabilistic sensitivity analysis carried out by the manufacturer. The Committee agreed that it was important to consider complete probabilistic sensitivity analyses for the revised base-case and the two scenario analyses (which use costs of sunitinib from the EAP and censoring) using a more conventional method of censoring for crossover, including correction of the errors and omissions as detailed by the ERG in paragraph 3.15. It concluded that these data should be requested from the manufacturer.
4.11 In summary, the Committee concluded that it was minded not to recommend sunitinib, within its marketing authorisation, as a treatment option for people with unresectable and/or metastatic malignant GIST after failure of imatinib treatment because of resistance or intolerance. It recommended that further clarification and analyses should be requested from the manufacturer to address the various areas of uncertainty in the economic analysis.
5 Implementation
5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
5.2 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

5.3

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/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 which support this locally.
  • Audit support for monitoring local practice.
6 Proposed recommendations for further research
6.1 There is a trial comparing 37.5 mg sunitinib with 800 mg of imatinib that is currently recruiting participants.
6.2 The Committee made no recommendations for further research.
7 Related NICE guidance

Published

  • Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. NICE technology appraisal guidance 86 (2004). Available from www.nice.org.uk/TA86
8 Proposed date for review of guidance
8.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
8.2 It is proposed that the guidance on this technology is considered for review in February 2012. The Institute would particularly welcome comment on this proposed date.
Andrew Stevens
Chair, Appraisal Committee
February 2009
Appendix A: Appraisal Committee members and NICE project team

A. Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

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

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

Professor David Barnett
Professor of Clinical Pharmacology, University of Leicester

Dr David W Black
Director of Public Health, Derbyshire County PCT

Mr Mark Campbell
Director of Standards, Bury PCT

Professor Mike Campbell
Professor of Medical Statistics, University of Sheffield

Mr David Chandler
Lay Member

Mr Peter Clarke
Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Merseyside

Dr Christine Davey
Senior Researcher, North Yorkshire Alliance R & D Unit

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

Dr Catherine Jackson
Professor of Primary Care Medicine, University of St Andrews

Dr Peter Jackson
Clinical Pharmacologist, the University of Sheffield

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority

Dr Simon Mitchell
Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester

Dr Richard Alexander Nakielny
Consultant Radiologist, Royal Hallamshire Hospital, Sheffield

Mrs Ruth Oliver-Williams
Head of Nursing / Quality Improvement Lead Surgical Services, Royal Derby Hospital, Derby

Dr Katherine Payne
Health Economics Research Fellow, The University of Manchester

Dr Danielle Preedy
Lay Member

Dr Martin J Price
Head of Outcomes Research, Janssen-Cilag Ltd

Dr Philip Rutledge
Consultant in Medicines Management, NHS Lothian

Mr Miles Scott
Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens (Chair)
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

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

Dr Cathryn Thomas
Associate Professor and General Practitioner, University of Birmingham

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.

Rebecca Trowman
Technical Lead

Joanna Richardson
Technical Adviser

Christopher Feinmann
Project Manager

Appendix B. Sources of evidence considered by the Committee
A

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

  • Bond M, et al, The clinical and cost effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer, January 2009.
B The following organisations accepted the invitation to participate in this appraisal. 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:

  • Pfizer (sunitinib)
II

Professional/specialist and patient/carer groups:

  • Association of Upper GI Surgeons
  • Rarer Cancers Forum
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians, Medical Oncology Joint Special Committee
  • Royal College of Radiologists
  • Sarcoma UK
III

Other consultees

  • Department of Health
  • Plymouth Teaching PCT
  • Welsh Assembly Government
IV

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

  • Department of Health,†Social Services and Public Safety for Northern Ireland
  • National Collaborating Centre for Cancer
  • NHS Quality Improvement Scotland
  • Peninsula Technology Assessment Group, University of Exeter (PenTAG)
C

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

  • Professor Ian Judson, nominated by Royal College of Physicians – clinical specialist
  • Professor Marco Novelli, nominated by Royal College of Pathologists – clinical specialist
  • Ms Stella Pendleton, nominated by Rarer Cancers Forum – patient expert
  • Mrs Judith Robinson, nominated by GIST Support UK – patient expert

This page was last updated: 30 March 2010

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Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.