The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using bevacizumab in combination with paclitaxel and carboplatin for the first-line treatment of advanced ovarian cancer in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer 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)

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 race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

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 bevacizumab in combination with paclitaxel and carboplatin for the first-line treatment of ovarian cancer 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: 22 January 2013

Second Appraisal Committee meeting: 6 February 2013

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  Bevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (that is, International Federation of Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV epithelial ovarian, fallopian tube, or primary peritoneal cancer).

1.2  People currently receiving bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

2  The technology

2.1  Bevacizumab (Avastin, Roche) is a humanised monoclonal antibody that inhibits both vascular endothelial growth factor (VEGF)-induced signalling and VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. Bevacizumab in combination with carboplatin and paclitaxel has a marketing authorisation for ‘the front-line treatment of advanced (International Federation of Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer’. The licensed dose is 15 mg/kg body weight given once every 3 weeks in addition to carboplatin and paclitaxel for up to 6 cycles of treatment, followed by continued use of bevacizumab as single agent until disease progression, or for a maximum of 15 months, or until unacceptable toxicity is reached, whichever occurs earlier.

2.2  The summary of product characteristics lists the following adverse reactions that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, posterior reversible encephalopathy syndrome, hypersensitivity or infusion reactions, osteonecrosis of the jaw, ovarian failure and neutropenia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  Bevacizumab is available in 100 mg and 400 mg vials at prices of £242.66 and £924.40 respectively (excluding VAT; 'British national formulary' [BNF] edition 63). The manufacturer estimated the cost of bevacizumab (excluding VAT and assuming wastage) to be £36,078 for a patient weighing 65 kg at a dosage of 15 mg/kg every 3 weeks, amounting to an average monthly cost of £2577. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturer’s submission

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

3.1  The key evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin came from 1 randomised controlled trial (GOG-0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15 mg/kg body weight) plus paclitaxel and carboplatin in people with previously untreated stage III (incompletely resectable) or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) that assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5 mg/kg body weight) plus paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer.

3.2  GOG-0218 was a randomised, double-blind, placebo-controlled multicentre trial conducted in North America and Asia in 1873 patients with previously untreated stage III or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. The trial was for up to 15 months and patients were randomised to 1 of 3 treatment arms:

• the CPP control group (n=625) received standard chemotherapy (carboplatin at a target area under the curve of 6 mg/ml•min and paclitaxel 175 mg/m² every 3 weeks for 6 cycles),plus placebo for cycles 2 to 22
• the CPB15 group (n=625) received the same standard chemotherapy as the CPP group,plus bevacizumab (15 mg/kg) for cycles 2 to 6 and placebo as monotherapy for cycles 7 to 22
• the CPB15+ group (n=623) received the same standard chemotherapy as the CPP group, plus bevacizumab (15 mg/kg) for cycles 2 to 22.

3.3  Cycles lasted 3 weeks and treatment was discontinued at the onset of disease progression, unacceptable toxic effects, completion of all 22 cycles or withdrawal. Patients in the control arm were allowed to cross over to receive bevacizumab after disease progression. Randomisation was stratified for Gynaecologic Oncology Group (GOG) performance status (0, 1 or 2) and cancer stage (optimally debulked stage III, suboptimally debulked stage III or stage IV). The primary outcome was progression-free survival (PFS), defined as the period from randomisation to disease progression or death. Progression was assessed by the investigator based on any of the following measures: global clinical deterioration, response evaluation criteria in solid tumours (RECIST) or rising serum cancer antigen-125 (CA-125). CA-125 progression was defined as at least twice the nadir or upper limit of normal. Secondary outcomes included overall survival, objective response rate and health-related quality of life measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire, the Ovarian Cancer Subscale measure and abdominal discomfort score.

3.4  The primary efficacy analysis of PFS used censored data from September 2009 in which patients with disease progression based on rising serum CA-125 alone and patients who received non-protocol therapies before progression were excluded from the analysis. Based on an investigator assessment, the censored data showed a statistically significant improvement of 6 months in the difference between the median PFS of the CPB15+ arm and the CPP arm (CPP 12 months, CPB15+ 18 months; hazard ratio [HR] 0.645, 95% confidence interval [CI] 0.551 to 0.756, p<0.001). There was a 0.7 month difference in median PFS in favour of the CPB15 arm compared with the CPP arm (CPP 12 months, CPB15 12.7 months; HR 0.84, 95% CI 0.71 to 0.99, p=0.0204). An independent review committee assessment of these data showed similar results: 6 months difference in median PFS  infavour of the CPB15+ arm compared with the CPP arm (CPP 13.1 months, CPB15+ 19.1 months; HR 0.62, 95% CI 0.50 to 0.77, p<0.0001) but only a non-statistically significant 0.1 month difference in median PFS in the CPB15 arm compared with the CPP arm (CPP 13.1 months, CPB15 13.2 months; HR 0.93, 95% CI 0.76 to 0.1.13, p=0.222). A GOG protocol-specified analysis of PFS was undertaken in February 2010 and the results were presented without censoring CA-125 progression or use of non-protocol therapy before progression. The difference in the median PFS was 3.8 months in favour of the CPB15+ arm compared with the CPP arm (CPP 10.3 months, CPB15+ 14.1 months; HR 0.717, 95% CI 0.625 to 0.824, p<0.0001) and 0.9 months in favour of the CPB15 arm compared with the CPP arm, although the latter was not statistically significant (CPP 10.3 months, CPB15 11.2 months; HR 0.908, 95% CI 0.795 to 1.040, p=0.16).

3.5  A PFS subgroup analysis by cancer stage and debulking status using the uncensored data from February 2010 suggested that the improvement in PFS between CPB15+ and CPP was maintained across all subgroups: patients with stage III optimally debulked cancershowed 5.1 months improvement in PFS in the CPB15+ compared with the CPP arm (CPP 12.4 months, CPB15+ 17.5 months; HR 0.66, 95% CI 0.5 to 0.86); patients with stage III suboptimally debulked cancer showed 3.8 months improvement in PFS in the CPB15+ compared with the CPP arm (CPP 10.1 months, CPB15+ 13.9 months; HR 0.78, 95% CI 0.63 to 0.96); patients with stage IV cancer showed 3.3 months improvement in PFS in the CPB15+ compared with the CPP arm (CPP 9.5 months, CPB15+ 12.8 months; HR 0.64, 95% CI 0.49 to 0.82).

3.6  The overall survival analysis was calculated in August 2011 when 46.9% of patients had died. The median overall survival was 3.2 months longer in the CPB15+ arm than in the CPP arm (CPP 40.6 months, CPB15+ 43.8 months; hazard ratio 0.88, 95% CI 0.75 to 1.04, p=0.0641). However, this was not statistically significant at the p value boundary of 0.0116. The manufacturer stated that significant patient crossover from placebo after progression would have confounded the data. The manufacturer’s submission contained 2 estimates ofthe proportion of placebo patients receiving bevacizumab after progression; 27.7% and up to 40%.

3.7  ICON7 was a randomised open-label multicentre study conducted in Europe in 1528 patients with high-risk early stage or advanced stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer. The trial was for up to 12 months and patients were randomised to 1 of 2 treatment arms:

• the CP control group (n=764) received standard chemotherapy (carboplatin at a target area under the curve of 5 or 6 mg/ml•min and paclitaxel 175 mg/m² every 3 weeks for 6 cycles)
• the CPB7.5 arm (n=764) received the same standard chemotherapy as the CP group plus bevacizumab (7.5 mg/kg) every 3 weeks for 6 cycles, and continued for an additional 12 cycles or until disease progression.

3.8  Randomisation was stratified for cancer stage (category 1 – FIGO stage I–III with residual disease less than 1 cm, category 2 – FIGO stage I–III with residual disease more than 1 cm, category 3 – FIGO stage IV and inoperable FIGO stage III) and the time of initiation of chemotherapy (intention-to-start chemotherapy 4 weeks after surgery or sooner, or intention-to-start chemotherapy more than 4 weeks after surgery). Patients received treatment until disease progression, unacceptable toxicity or completion of 6 or 18 cycles of therapy as appropriate. No crossover was permitted. A pre-planned high-risk subgroup was specified and included patients with stage III cancer and more than 1 cm residual disease or stage IV cancer. The primary outcome of the trial was PFS based on RECIST on the basis of radiological, clinical and symptomatic indicators of progression. Secondary outcome measures included overall survival and quality of life. Health-related quality of life was measured using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OV28 questionnaires.

3.9  The manufacturer’s submission presented analysis of PFS from ICON7 based on a data cut-off of November 2010. For the intention-to-treat population, the difference in median PFS was 2.4 months in favour of bevacizumab (CP 17.4 months, CPB7.5 19.8 months; HR 0.87, 95% CI 0.77 to 0.99, p<0.04). The high-risk subgroup included 31% (n=462) of the trial population and there was a statistically significant difference in median PFS of 5.5 months in favour of bevacizumab in this subgroup (CP 10.5 months, CPB7.5 16.0 months; HR 0.73, 95% CI 0.60 to 0.93, p=0.002). A pre-planned exploratory analysis of PFS using subgroups defined by cancer stage and debulking status was also reported. These analyses showed that the stage III patients with optimally debulked cancer derived a smaller improvement from the treatment (difference in median PFS of1.6 months based on CP 17.7 months (n=368) and CPB7.5 19.3 months (n=383); HR 0.89, 95% CI 0.74 to 1.07) compared with stage III patients with suboptimally debulked cancer (difference in median PFS of 5.8 months based on CP 10.1 months(n=154) and CPB7.5 16.9 months (n=140); HR 0.67, 95% CI 0.52 to 0.87) or stage IV cancer (difference in median PFS of 3.4 months based on CP 10.1 months (n=97) and CPB7.5 13.5 months (n=104); HR 0.74, 95% CI 0.55 to 1.01). No statistical tests of interaction were presented by the manufacturer for thesesubgroup data.

3.10  The protocol-specified final overall survival analysis for ICON7 has not yet been reported. An exploratory overall survival analysis of the intention-to-treat population, conducted when approximately 25% of patients had died, could not calculate the median duration of overall survival because of low numbers, but gave a hazard ratio of 0.85 (95% CI 0.69 to 1.04). An interim overall survival analysis was conducted in the high-risk subgroup when approximately 47% of patients had died in the CP arm and 34% had died in the CPB7.5 arm. There was a statistically significant difference in the median overall survival of 7.8 months in favour of bevacizumabt (CP 28.8 months, CPB7.5 36.6 months; HR 0.64, 95% CI 0.48 to 0.85, p=0.002).

3.11  The manufacturer did not consider that a meta-analysis was appropriate because GOG-0218 and ICON7 used different doses and durations of bevacizumab and different study populations.

3.12  Almost all patients in GOG-0218 experienced at least 1 adverse event. Incidences of stomatitis, dysarthria, headache, epistaxis and hypertension were more than 10% higher in the bevacizumab arms than in the placebo arm. Incidences of hypertension, gastrointestinal perforation and non-central nervous system bleeding (adverse events of special interest, grade 3–5) were at least 1% higher in the CPB15+ arm than in the CPP arm.

3.13  The manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of bevacizumab plus carboplatin and paclitaxel compared with carboplatin and paclitaxel only for first-line treatment in women with stage III or IV ovarian cancer. The model was a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG-0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model are used in accordance with their marketing authorisations. The analysis was conducted from an NHS and personal social services perspective, the costs and outcomes were discounted at 3.5% per year and a 10-year time horizon was used.

3.14  PFS in the model uses the Kaplan-Meier survival curves from the GOG-0218 trial data up to the convergence of the intervention and comparator arms at month 28. The data are from the updated PFS analysis (February 2010), which includes censoring of patients who were presumed to experience progression based on rising CA-125 levels or who switched to non-protocol therapies. The manufacturer examined the fit of various parametric survival models to the progression-free data and considered a log-logistic model the best fit to extrapolate survival times beyond month 28. In the progressed disease state, the weekly probability of death was assumed to be constant and the same for both arms of the model.

3.15  The model incorporates patients’ health-related quality of life outcomes using health-state utility values for the PFS and progressed disease states. The manufacturer used the EQ-5D values from ICON7 in this model. In the PFS state a log-rank test showed that there was no difference in the utility values across the intervention and comparator arms, therefore the same utility values were used in both arms of the model. In the PFS state the values varied with time and in the progressed state a constant value was used because of the limited data available. The disutilities associated with adverse effects were assumed to have been captured in the assessment of health-related quality of life in ICON7.

3.16  Drug costs were estimated using the dose and frequency of administration in the summary of product characteristics. Data from a UK cohort study were used in the dose calculations. The base case assumed that any unused carboplatin or paclitaxel from a vial is reallocated and not wasted, whereas for bevacizumab it is assumed that any unused drug in a vial is wasted. The costs per patient per cycle were £2229 for bevacizumab, £21.80 for paclitaxel and £18.51 for carboplatin. The costs associated with pharmacy preparation of the infusion and its outpatient administration in hospital (based on NHS reference costs 2010/11) were included in the model. The weekly costs of supporting patients in the PFS and progressed health states were included in the model. Post-progression drug acquisition costs were not included in the model because this information was not available in sufficient detail from GOG-0218. Costs associated with adverse events that occurred at grade 3 or 4 severity in more than 2% of patients were incorporated into the analysis.

3.17  The base-case results estimated that adding bevacizumab to standard chemotherapy provides an additional 0.228 life years (0.188 quality-adjusted life years [QALYs], resulting from a 0.243 QALY gain in the PFS state and a 0.055 QALY loss in the progressed disease state) to patients with an expected survival of approximately 4 years. This benefit is achieved with an incremental cost of £27,089, resulting in an incremental cost-effectiveness ratio (ICER) of £144,066 per QALY gained for the licensed dose of bevacizumab plus carboplatin and paclitaxel, compared with carboplatin and paclitaxel alone. The manufacturer’s deterministic sensitivity analysis suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer’s scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment.

3.18  The manufacturer also submitted an economic model based on the ICON7 data despite the fact that the dose of bevacizumab used in that trial is unlicensed. The model is a 3-state area-under-the-curve model based on progression-free and overall survival data in an expanded high-risk subgroup. The expanded high-risk subgroup included all patients with stage III disease with sub-optimal debulking or stage IV disease or patients with unresectable disease (n=495). PFS was modelled using the Kaplan-Meier curves from the trial data until month 24, followed by extrapolation with a log-logistic parametric function. A log-logistic function was also used to model overall survival based on the fit to the ICON7 data, other published data and clinical advice that suggested that a small but significant percentage of patients with advanced ovarian cancer experience long-term survival in excess of 10 years. Utilities, resources and costs were similar to those in the GOG-0218 model. However, the manufacturer also included post-progression drug costs in the ICON7 model.

3.19  The manufacturer’s base-case results from the ICON7 model estimated that adding bevacizumab (at an unlicensed dose) to standard chemotherapy provides an additional 0.743 life years (0.561 QALYs, resulting from a 0.252 QALY gain in the PFS state and a 0.309 QALY gain in the progressed state) to patients with an expected survival of approximately 3 years. The manufacturer’s sensitivity analyses suggested that the cost-effectiveness results were influenced most by the parametric function used for overall survival, the duration of treatment and the time horizon.

3.20  The ERG considered that GOG-0218 provided evidence of the clinical effectiveness of bevacizumab plus carboplatin and paclitaxel for the first-line treatment of people in the NHS with advanced ovarian cancer, as defined in the scope. It noted that the population from the trial is generally representative of those treated in secondary care in the UK, although it may not fully represent patients with comorbidities.

3.21  The ERG was concerned that the different assessments of PFS (by investigator and independent review committee, CA-125 censored, CA-125 not censored) are not consistently reported for all time points. It commented that there may have been selective reporting of data and it is not clear what impact this may have on conclusions. In response to a request for clarification, the manufacturer stated that updated PFS data censored for CA-125 are not available; also, exploratory analyses were not updated because they were intended only to confirm the validity of investigator-assessed PFS. The ERG considered that although the direction of the evidence is consistent, the size of effect varies with the different analyses and over time. For example, thedifference in median PFS varied from 4 to 6 months; the hazard ratio varied from 0.62 (assessed by independent review committee, data censored) to 0.77 (updated investigator assessed, without data censoring). Clinical advice to the ERG suggested that CA-125 is used routinely in UK clinical practice, therefore the ERG considered that results not censored for CA-125 rises were most relevant to the UK.

3.22  The ERG considered that the structure adopted for the economic model based on GOG-0218 was reasonable, and consistent with previous economic evaluations developed for advanced cancer. The methods of analysis were generally appropriate and conformed to NICE methodological guidelines. The ERG noted that a time horizon of 10 years was used in the model. However, the ERG considered a longer time horizon would have been more appropriate because approximately 10% of patients were still alive after 10 years. The ERG agreed that the parameters used for the model were generally appropriate.

3.23  The ERG highlighted that the clinical-effectiveness data used in the model included censoring for patients with rising CA-125 levels and for those who switched to non-protocol therapies. It considered that the hazard ratio from these data was relatively favourable compared with other PFS hazard ratios from the trial and this may have produced a more favourable cost-effectiveness estimate. The ERG also noted that the treatment duration was 1 year rather than the 15 months specified in the summary of product characteristics.

3.24  The ERG highlighted that in the trial overall survival between the arms was similar, with median values of 39.75 months for bevacizumab and 39.39 months for the chemotherapy only arm. However, in the model there is a 2-month difference in the median overall survival between the arms (bevacizumab 47 months, chemotherapy only 45 months).

3.25  The ERG also considered that the uncertainty around the model results had not been fully examined. Not all model parameters were considered in either the deterministic or probabilistic sensitivity analyses. Key parameters missing from the probabilistic sensitivity analysis included the variability in the clinical-effectiveness estimates based on the Kaplan-Meier survival data taken from the trial and variability in the cost of bevacizumab. In the deterministic sensitivity analysis input parameters that might be expected to be highly influential on the cost-effectiveness results were omitted, such as the cost of bevacizumab, treatment duration and variation in effectiveness.

3.26  The ERG undertook several exploratory deterministic sensitivity analyses that examined the impact of changes to treatment duration, treatment cost and time horizon. Using the trial discontinuation rates in GOG-0218 and with treatment for a maximum of 15 months instead of the 12 months in the base case, the ICER for bevacizumab increased from the base case of £144,066 per QALY gained to £160,788 per QALY gained. The ERG investigated the effect of changing the 10-year time horizon to the maximum permitted in the model of 25 years; this reduced the ICER to £127,701 per QALY gained. Finally, the ERG combined the analyses for treatment duration of 15 months and a time horizon of 25 years, which produced an ICER similar to the base case of £142,477 per QALY gained.

3.27  The ERG considered the ICON7 model presented by the manufacturer. It noted that this model uses an unlicensed dose of 7.5 mg/kg body weight and that treatment duration and study population differ from the licensed indication. The ICON7 data used in the model were based on a subgroup, so estimates may not be very precise because of the relatively small sample size. Overall, the ERG considered that the ICON7 model was built using appropriate data, with appropriate outcomes and was generally well described and justified in the manufacturer’s submission. The ICER appeared particularly sensitive to assumptions of parametric form for overall survival.

3.28  Full details of all the evidence are in the manufacturer’s submission and the ERG report [to be hyperlinked in final guidance].

4  Consideration of the evidence

4.1  The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab plus paclitaxel and carboplatin, having considered evidence on the nature of advanced ovarian cancer and the value placed on the benefits of bevacizumab plus paclitaxel and carboplatin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2  The Committee discussed the current management of advanced ovarian cancer. The clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. The Committee heard from the clinical specialists that 3 cycles of chemotherapy may be given before surgery for some patients expected to have residual disease left after surgery. After first-line treatment, decisions about progression are usually made using symptomatic and radiological evidence, and rises in CA-125 alone are not considered sufficient reason to consider changes in treatment. Clinical specialists also highlighted that the10-year survival rate in ovarian cancer is only 35%. This has improved in recent years, but is below the rates for many other cancers. The Committee heard from clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years. The Committee heard from the clinical specialists that bevacizumab is currently being used in the NHS in England in combination with standard chemotherapy for patients with stage IV cancer or those who have undergone surgery with more than 1 cm residual disease, followed by bevacizumab continued as maintenance therapy until progression. The Committee also heard from the clinical specialists that an unlicensed bevacizumab dose of 7.5 mg/kg (not the licensed dose of 15 mg/kg) is being used in the NHS in England. This is the dose that was used in ICON7, which was conducted across Europe and involved some centres in the UK. The commissioning representatives and patient experts also confirmed that the unlicensed dose ofbevacizumab is the one most commonly used in the NHS for advanced ovarian cancer. NICE informed the Committee that it would be unable to issue guidance on a technology used outside the terms of its marketing authorisation.

4.3  The Committee considered the evidence on bevacizumab from a patient perspective. Patient experts highlighted the limited treatment options for patients with advanced ovarian cancer and that bevacizumab provided an additional treatment option. The Committee heard from patient experts that the end of first-line treatment is a critical time for patients, when they come to terms with their prognosis, and it is important not to underestimate the impact of any extension to PFS for these patients and their families. Patient experts also highlighted the importance of patients’ belief in a treatment to their wellbeing and that patients often choose to tolerate serious side effects in the hope of gaining additional PFS.

Clinical effectiveness

4.4  The Committee considered that the main source of evidence for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin was GOG-0218. The Committee agreed this was a well-designed randomised double-blind trial. It noted the ERG’s assessment of the quality of this trial and accepted that the results of the trial are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS. The Committee noted that there were 3 arms in the trial but only the CPB15+ arm (bevacizumab given with the chemotherapy and afterwards for up to 15 months as maintenance therapy) showed a significant improvement in PFS compared with chemotherapy alone. The CPB15 arm of the trial (bevacizumab given only with the chemotherapy) showed no significant PFS benefit compared with the control arm. The Committee concluded that GOG-0218 provided relevant evidence for this appraisal and that bevacizumab was shown to be clinically effective only when it is given within its marketing authorisation, that is, at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15 months.

4.5  The Committee noted that PFS results from GOG-0218 were reported in the manufacturer’s submission using both censored (in which patients with a CA-125 rise were censored at the time of their previous scan and their results removed from further analysis), and uncensored (in which a CA-125 rise indicated progression) data. The Committee heard from clinical specialists that a rise in CA-125 alone was not used as an indication to change treatment, because this approach had not been shown to alter prognosis and also roughly a third of patients did not express CA-125. The specialists also commented that a CA-125 rise often suggested the disease was progressing but that it could take up to 6 months or so for progression to become apparent. The Committee concluded that a significant CA-125 rise is an indicator of progression and might be an early marker, but is not usually used in clinical practice in the UK as the sole indicator of progression.

4.6  The Committee discussed the most relevant PFS results for the clinical effectiveness of bevacizumab plus paclitaxel and carboplatin in the UK. The Committee noted that the results from the uncensored data of a 3.8 month difference in median PFS in favour of bevacizumab was less than the 6 month difference in median PFS obtained from the censored data. The Committee noted the ERG’s concerns about the lack of consistent reporting of the various PFS assessments at all time points. The Committee noted that clinical advice to the ERG was that the uncensored data are the most relevant to the NHS. However, the Committee heard from the clinical specialists that in their opinion the censored data were more relevant because patients in the NHS would not be treated as progressed based on a CA-125 rise alone (see section 4.5). The Committee was aware that the censored data had excluded patients with raised CA-125 from the analysis and since these patients could be regarded as at high risk of progression this could lead to bias in the results. The Committee noted that all the analyses of PFS data presented in the manufacturer’s submission taken at different time points, both censored and uncensored, showed a difference in median PFS in favour of bevacizumab of between 3.8 and 6 months. The Committee concluded that bevacizumab plus paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone, and that of the available data, the censored PFS data are more relevant to UK clinical practice but the Committee were aware of the potential bias introduced by censoring the data from those patients with raised CA-125.

4.7  The Committee considered the overall survival results from GOG-0218 and noted concerns from the ERG that switching patients in the control arm to bevacizumab after progression had confounded the overall survival analysis. The Committee noted the various estimates given in the manufacturer’s submission of the percentage of patients switching and concluded that the precise extent of switching was unclear. The Committee considered that this crossover would have an impact on the overall survival results only if second-line treatment with bevacizumab was more effective than other therapies given after progression, and the Committee did not have this information. Nevertheless the Committee accepted that the interpretation of overall survival figures from GOG-0218 was problematic, and that the non-statistically significant difference in median overall survival of 3.2 months attributed to bevacizumab should be interpreted cautiously. The Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG-0218 because of the uncertainty related to the extent and impact of patients in the control arm switching to bevacizumab after progression.

4.8  The Committee noted the adverse events reported in GOG-0218. It understood that these events were as predicted from other studies with bevacizumab and did not raise new safety concerns. The Committee considered the adverse events of special interest for which the incidence was more than 1% higher in the CPB15+ arm than in the CPP arm. These were hypertension, gastrointestinal perforation and non-central nervous system bleeding. The Committee heard from the clinical specialists that most adverse events could be satisfactorily managed. The Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that the adverse events were manageable.

4.9  The Committee discussed the evidence from the supporting ICON7 trial. It heard from the clinical specialists that the strengths of this trial were that it included some UK patients, and that patterns of practice were based on the most appropriate definitions of progression, disease staging and surgical debulking. The clinical specialists stated that patients in the optimal debulking subgroups differed between the GOG-0218 and ICON7 trials. The specialists considered that this is shown by fewer patients in the group with optimally debulked cancer in GOG-0218 having complete resection (that is, no visible disease) than in ICON7. The Committee also heard from the clinical specialists that this might be because another trial, conducted at the same time as GOG-0218, may have enrolled the patients who had complete resection. The Committee noted that the information on the proportion of patients in ICON7 who had completely resected disease was not supplied, and that the marketing authorisation for bevacizumab did not specify complete or incomplete resection. The Committee also noted that in ICON7 no patient crossover was allowed after disease progression. The Committee was aware of the disadvantages of ICON7 relative to the NICE decision problem, including its open-label design and inclusion of some patients with stage I and II cancer, which is not covered by the marketing authorisation for bevacizumab. In addition, the trial used a lower dose and shorter duration of bevacizumab treatment than is now licensed. Nevertheless, 81% of the patients were covered by the marketing authorisation and the Committee considered that the results from the trial contributed to the body of knowledge about the efficacy of bevacizumab plus paclitaxel and carboplatin for advanced ovarian cancer.

4.10  The Committee considered the PFS results from ICON7. It noted that the overall difference between the PFS medians in the intention-to-treat population was 2.4 months, which was less than the 6 months in the intention-to-treat population in GOG-0218 using the censored data. The clinical specialists emphasised that professional opinion was that this difference was related to patient selection and patient characteristics, not to the lower dose and duration of treatment in ICON7. The Committee also noted that PFS in the chemotherapy comparator arm was worse in ICON7 than in GOG-0218, which could affect interpretation of the results. The Committee concluded that the trials were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking and differing baseline factors between the trials.

4.11  The Committee considered the results presented for the ICON7 high-risk subgroup. This was a pre-specified, but not stratified subgroup that included 31% of patients with high-risk disease (defined as stage III suboptimally debulked or stage IV debulked ovarian cancer). This subgroup was broadly comparable with 2 of the 3 stratified groups in GOG-0218 but did not represent the whole population covered by the marketing authorisation, which does not specify debulking status. Separate analysis of the high-risk subgroup showed a difference in median PFS of 5.4 months in favour of bevacizumab. This was higher than the 2.4 months difference in the ICON7 intention-to-treat population, and was comparable to the gain in the intention-to-treat GOG-0218 population using the censored data (6 months; see section 3.4). Hazard ratios were not provided for the non-high-risk subgroup (that is, the intention-to-treat population minus the high-risk subgroup) but the Committee assumed that they would have shown little or no benefit. The Committee also considered the PFS results by cancer stage and debulking status in the population of ICON7 covered by the marketing authorisation. It noted there was an apparent differential response, with little benefit shown in the stage III population with optimally debulked cancer (difference in median PFS 1.6 months in favour of bevacizumab) compared with the population with stage III suboptimally debulked cancer (difference in median PFS 5.8 months) or stage IV cancer (difference in median PFS 3.4 months). The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation, whereas GOG-0218 results indicated a benefit not dependent on debulking status in stage III and IV cancer with the greatest PFS benefit shown in the optimally debulked subgroup (based on uncensored data from GOG-0218, corresponding censored subgroup data not supplied by manufacturer, see section 3.5). The Committee agreed that results of the open-label ICON7 trial indicated a smaller PFS benefit in the intention-to-treat population than was seen in GOG-0218, and also suggested a different benefit based on cancer stage and debulking status that had not been shown in GOG-0218. The Committee was aware that several hypotheses could explain these differences. The Committee concluded that the ICON7 data contributed to confidence that treatment with bevacizumabcould delay progression, but that the reasons for the apparent differential response and differences in PFS suggested by the ICON7 subgroup analysis compared with the analysis of GOG-0218 censored dataremained uncertain.

4.12  The Committee examined the overall survival data from ICON7 and noted that mature data on the intention-to-treat population were not yet available but an interim analysis of the high-risk subgroup showed a difference in median overall survival of 7.8 months in favour of bevacizumab. The Committee noted that taking into account the shape of the Kaplan-Meier curve from the interim analysis of the high-risk patients, it is likely the mean overall survival benefit would be much less than the median. The Committee concluded that the interim data for a subgroup in the trial suggested a difference in overall survival in favour of bevacizumab, but this should be interpreted with caution.

Cost effectiveness

4.13  The Committee discussed the cost-effectiveness estimates and the assumptions on which these were based from the manufacturer’s economic model based on GOG-0218. The Committee concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer.

4.14  The Committee considered the model inputs including clinical effectiveness, patient outcomes, resource use and costs. The Committee noted that PFS was based on the Kaplan-Meier curve from the censored data of GOG-0218 until month 28, after which PFS is represented by a log-logistic parametric function. The Committee also noted that the model used an equal post-progression death rate between the arms. The Committee understood the ERG’s concerns about the treatment duration of 12 months instead of the15 months specified in the marketing authorisation and the time horizon of 10 years. The ERG did not consider this time horizon to be long enough, although the Committee heard from the clinical specialists that 10 years was probably appropriate, given that only a small number of patients survive longer than 10 years. The Committee noted that the EQ-5D utilities from the expanded high-risk subgroup of ICON7(see 3.18) were used in the model and that the same utilities were assumed in both arms of the model. The Committee also noted that no disutilities associated with adverse events had been incorporated into the model. The Committee concluded that the model inputs used by the manufacturer were reasonable.

4.15  The Committee considered the most plausible ICERs from the model based on the GOG-0218 trial presented by the manufacturer and by the ERG in their exploratory analyses. It noted that the manufacturer’s base-case ICER was approximately £144,000 per QALY gained. The Committee considered the ERG’s exploratory analyses, which examined the changes in the ICER with a treatment duration of 15 months or a time horizon of 25 years or both, and gave a range of ICERs from £128,000 to £161,000 per QALY gained. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus paclitaxel and carboplatin would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.

4.16  The Committee also considered the cost-effectiveness model presented by the manufacturer based on ICON7 using the unlicensed dose of bevacizumab. The Committee noted the large difference in incremental QALYs between the GOG-0218 model results using the intention-to-treat population and the ICON7 model results based on a sub-group (0.299 for GOG-0218 and 0.516 for ICON7), which contributed to the lower ICER in the ICON7 model. The manufacturer’s analysis of the incremental QALYs by health state indicated that most of this difference was caused by the difference in QALYs gained or lost in the progressed disease state of the models (0.309 QALYs gained in ICON7 compared with 0.055 QALYs lost in GOG-0218). The Committee understood that the modelling of overall survival differed between the models, but questioned whether these QALY gains in the progressed disease state in the ICON7 model were plausible. The Committee also noted an underlying difference in the overall survival of the control groups from the trials on which the models were based (approximately 28 months in ICON7 compared with 39 months in GOG-0218). The Committee noted that the manufacturer’s ICON7 model included more patients than those in the pre-specified high-risk subgroup from the trial. In addition, sensitivity analysis examining alternative extrapolation functions for overall survival in the ICON7 model demonstrated that use of a gamma or Weibull parametric function increased the manufacturer’s base-case ICER. The Committee was concerned that post-progression survival and overall survival could be overestimated in the ICON7 model, and QALY gains could be overestimated in the manufacturer’s ICON7 base case. However, the Committee was aware that the ERG had not evaluated the ICON7 model in detail because it used bevacizumab at an unlicensed dose. The Committee concluded that the ICON7 model was not relevant to the decision problem, but noted that there were several features of the model it would otherwise have questioned and examined in detail.

 

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer		Section
Key conclusion
Bevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer (that is, International Federation of Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV epithelial ovarian, fallopian tube, or primary peritoneal cancer). The Committee concluded that bevacizumab was shown to be clinically effective only when it is given at the same time as paclitaxel and carboplatin and then as a maintenance treatment for up to 15 months. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus paclitaxel and carboplatin would not be a cost-effective use of NHS resources for first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.			1.1 4.4 4.15
Current practice
Clinical need of patients, including the availability of alternative treatments		The clinical specialists confirmed that chemotherapy with paclitaxel and carboplatin was current standard clinical practice in the NHS in England and Wales for first-line treatment of advanced ovarian cancer after debulking surgery. They also highlighted that 10-year survival rate in ovarian cancer is only 35%. This has improved in recent years, but is below the rates for many other cancers. Patient experts highlighted the limited treatment options available for patients with advanced ovarian cancer and that bevacizumab provided an additional treatment option.	4.2, 4.3
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from patient experts that the end of first-line treatment time is a critical time for patients, when they come to terms with their prognosis, and it is important not to underestimate the impact of any extension to progression-free survival for these patients and their families. The Committee heard from clinical specialists that they considered bevacizumab to be an innovative technology because there have been few new beneficial developments in ovarian cancer for several years.	4.3, 4.2
What is the position of the treatment in the pathway of care for the condition?		Bevacizumab in combination with carboplatin and paclitaxel has a UK marketing authorisation for ‘the front-line treatment of advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer’.	2.1
Adverse reactions		The Committee concluded that adding bevacizumab to a paclitaxel and carboplatin regimen did not lead to unacceptable toxicity compared with paclitaxel and carboplatin alone and that adverse events were manageable.	4.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The key evidence for the clinical effectiveness of bevacizumab in combination with paclitaxel and carboplatin came from 1 randomised controlled trial (GOG-0218). The trial assessed the efficacy and safety of bevacizumab (at its licensed dose of 15 mg/kg body weight) in combination with paclitaxel and carboplatin in people with previously untreated stage III (incompletely resectable) or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer who had undergone debulking surgery. This evidence was supported by results from a randomised open-label trial (ICON7) which assessed the efficacy and safety of bevacizumab at an unlicensed dose (7.5 mg/kg body weight) in combination with paclitaxel and carboplatin in people with high-risk early stage or advanced epithelial ovarian, fallopian tube or primary peritoneal cancer.	3.1
Relevance to general clinical practice in the NHS		The Committee accepted that the results of GOG-0218 are relevant to the first-line treatment of patients with advanced ovarian cancer in the NHS.	4.4
Uncertainties generated by the evidence		The Committee noted the ERG concerns about the lack of consistent reporting of the different PFS assessments at all time points in GOG-0218. There was also some uncertainty about which set of PFS results (censored or uncensored) from GOG-0218 is most appropriate for the NHS. The Committee concluded the censored PFS data are more relevant to UK clinical practice. The Committee concluded that the overall survival benefit of bevacizumab plus carboplatin and paclitaxel is uncertain from the results of GOG-0218 because of the uncertainty related to the extent and impact of patients in the control arm switching to bevacizumab after progression. The Committee concluded that GOG-0218 and ICON7 were difficult to compare because of different inclusion criteria, bevacizumab dose and duration of treatment, definitions of progression and optimal debulking and differing baseline factors between the trials.	4.6 4.7 4.10
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted there was a differential response, with little benefit shown in the stage III population with optimally debulked cancer (difference in median PFS 1.6 months in favour of bevacizumab) compared with the population with stage III suboptimally debulked cancer (difference in median PFS 5.8 months) or stage IV cancer (difference in median PFS 3.4 months. The Committee heard from the clinical specialists that these PFS analyses from ICON7 showed benefit in only a proportion of the population covered by the marketing authorisation, whereas GOG-0218 results indicated a benefit not dependent on debulking status in stage III and IV cancer (see section 3.5). The Committee was aware that several hypotheses could explain these differences.	4.11
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that bevacizumab in combination with paclitaxel and carboplatin improved PFS compared with paclitaxel and carboplatin alone, and that of the available data, the censored PFS data are more relevant to UK clinical practice. The difference in median PFS in favour of bevacizumab using the censored data from GOG-0218 was 6 months.	4.6
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer submitted a 3-state semi-Markov model with health states consisting of PFS, progressed disease and death. Data from GOG-0218 were used to inform model inputs for dosing, survival and safety. Both the intervention and comparator in the model are used in accordance with their marketing authorisations. The Committee concluded that the GOG-0218 model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of bevacizumab plus paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. The Committee concluded that the ICON7 model was not relevant to the decision problem, but noted that there were several features of the model it would otherwise have questioned and examined in detail.	3.13 4.13 4.16
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee considered the model inputs including clinical effectiveness, patient outcomes, resource use and costs and concluded that they were reasonable. The Committee understood the ERG concerns about the treatment duration of 12 months instead of the15 months specified in the marketing authorisation and a time horizon of 10 years. The ERG did not consider this time horizon was long enough, although the Committee heard from the clinical specialists that 10 years was probably appropriate.	4.14
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 economic model, and how have they been considered?		The Committee noted that the EQ-5D utilities from the expanded high-risk subgroup of ICON7 were used in the model and that the same utilities were assumed in both arms of the model.	4.14
Are there specific groups of people for whom the technology is particularly cost effective?		No. The Committee agreed that the range of ICERs obtained from the cost-effectiveness model of bevacizumab plus paclitaxel and carboplatin were outside the range normally considered as a cost-effective use of NHS resources. It therefore concluded that bevacizumab plus paclitaxel and carboplatin would not be a cost-effective use of NHS resources for the first-line treatment of advanced ovarian cancer compared with paclitaxel and carboplatin alone.	4.15
What are the key drivers of cost effectiveness?		The manufacturer’s deterministic sensitivity analysis for GOG-0218 suggested that the cost-effectiveness results are influenced by the parametric functions used for the PFS extrapolation and the time horizon used in the model. The manufacturer’s scenario analyses identified the key drivers of the cost-effectiveness results as the dose and duration of bevacizumab treatment. The manufacturer’s sensitivity analyses for the ICON7 trial suggested that the cost-effectiveness results were influenced most by the parametric function used for overall survival, the duration of treatment and the time horizon.	3.17 3.19
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the manufacturer’s base-case ICER was approximately £144,000 per QALY gained. The Committee considered the ERG’s exploratory analyses, which examined the changes in the ICER with a treatment duration of 15 months or a time horizon of 25 years or both, and the associated range of ICERs from £128,000 to £161,000 per QALY gained.	4.15
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable
End-of-life considerations		Not applicable
Equalities considerations and social value judgements		No issues relating to equality considerations were raised in the submissions or the Committee meeting.

 

5  Implementation

5.1  The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

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

5.3  NICE has developed tools [hyperlink to be added before publication] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

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

6  Related NICE guidance

Published

• Ovarian cancer. NICE clinical guideline 122 (2011).
• Trabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal guidance 222 (2011).
• Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer. NICE technology appraisal guidance 91 (2005).
• Review of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. NICE technology appraisal 55 (2003).

Under development

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

Bevacizumab for the treatment of platinum-sensitive or partially platinum-sensitive recurrent advanced ovarian cancer (including fallopian tube and primary peritoneal cancer). NICE technology appraisal guidance. Publication expected June 2013.

• Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for the treatment of recurrent ovarian cancer (including review of technology appraisal no. 91 and technology appraisal no. 222).NICE technology appraisal guidance. Publication expected February 2014.
• Vintafolide in combination with pegylated liposomal doxorubicin hydrochloride for the treatment of folate receptor positive, platinum-resistant ovarian cancer. NICE technology appraisal guidance. Publication expected July 2014.

7  Proposed date for review of guidance

7.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in April 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Jane Adam
Chair, Appraisal Committee
December 2012

Appendix A: Appraisal Committee members, and NICE project team

A  Appraisal Committee members

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

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

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

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

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

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

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

Dr Gerardine Bryant
GP, Swadlincote, Derbyshire

Mr Andrew England
Lecturer in Medical Imaging, NIHR Fellow, University of Liverpool

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

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

Dr Brian Hawkins
Chief Pharmacist, Cwm Taf Health Board, South Wales

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital, Bristol

Dr Sharon Saint Lamont
Head of Quality and Innovation, North East Strategic Health Authority

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

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

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

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

Ms Sarah Parry
CNS Paediatric Pain Management, Bristol Royal Hospital for Children

Ms Pamela Rees
Lay Member

Dr Ann Richardson
Lay Member

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

Ms Ellen Rule
Programme Director, NHS Bristol

Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Dr Peter Sims
GP, Devon

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

Mr David Thomson
Lay Member

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

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

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.

Bernice Dillon
Technical Lead

Joanna Richardson
Technical Adviser

Bijal Joshi
Project Manager

 Appendix B: Sources of evidence considered by the Committee

A      The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessments Centre:

• Cooper K, Pickett K, Frampton GK et al. Bevacizumab in combination with carboplatin and paclitaxel for the first-line treatment of ovarian cancer. A single technology appraisal. October 2012

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

 I            Manufacturer/sponsor:

• Roche Products (bevacizumab)

 II           Professional/specialist and patient/carer groups:

• Macmillan Cancer Support
• Ovacome
• Ovarian Cancer Action
• Rarer Cancers Foundation
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Obstetricians & Gynaecologists
• Royal College of Pathologists
• Royal College of Physicians (NCRI/RCP/RCR/ACP/JCCO)
• Target Ovarian Cancer
• United Kingdom Clinical Pharmacy Association

 III        Other consultees:

• Department of Health
• Outer North East London PCT Cluster
• Welsh Government

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

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Health Care Improvement Scotland
• MRC Clinical Trials Unit
• National Collaborating Centre for Cancer
• National Institute for Health Research Health Technology Assessment Programme
• Southampton Health Technology Assessments Centre

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

• Dr Marcia Hall, Consultant in Medical Oncology, nominated by organisation representing NCRI/RCP/RCR/ACP/JCCO – clinical specialist
• Dr Sarah Blagden, Clinical Senior Lecturer/Honorary Consultant in Medical Oncology, nominated by organisation representing Ovarian Cancer Action – clinical specialist
• Ms Louise Bayne, CEO, nominated by organisation representing Ovacome – patient expert
• Dr Sharon Tate, Public Affairs Manager, nominated by organisation representing Target Ovarian Cancer – patient expert

D      The following individuals were nominated as NHS Commissioning experts by the selected PCT Cluster located to this appraisal. They gave their expert/NHS commissioning personal view on bevacizumab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Mrs Oge Chesa, Commissioning and Interface Pharmacist Advisor, NHS Waltham Forest, selected by Outer North East London PCT Cluster – NHS commissioning expert
• Ms Rajinder Nijjar, Lead Cancer Pharmacist, North East London Cancer Network, selected by Outer North East London PCT Cluster – NHS commissioning expert

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

• Roche Products