The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using aflibercept in combination with irinotecan and fluorouracil-based therapy 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 section 10) 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 aflibercept in combination with irinotecan and fluorouracil-based therapy in the NHS in England and Wales.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 12 July 2013

Second Appraisal Committee meeting: 23 July 2013

Details of membership of the Appraisal Committee are given in section 9, and a list of the sources of evidence used in the preparation of this document is given in section 10.

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  Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.

1.2  People currently receiving aflibercept in combination with irinotecan and fluorouracil-based therapy should be able to continue treatment until they and their clinician consider it appropriate to stop.

2  The technology

2.1  Aflibercept (Zaltrap, Sanofi) is a recombinant human fusion protein that can block the vascular endothelial growth factor (VEGF) pathway by preferentially binding to VEGF-A, VEGF-B and placental growth factor, which play an important role in the formation of new blood vessels in solid tumours (angiogenesis). By preventing these factors from activating their endogenous receptors, aflibercept interferes with the process by which blood vessels and capillaries expand into tumours (vascularisation), and so inhibits tumour growth. Aflibercept in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) (that is, in combination with irinotecan and fluorouracil-based therapy) has a UK marketing authorisation ‘for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen’. The summary of product characteristics states that aflibercept should be administered as an intravenous infusion over 1 hour at a dose of 4 mg/kg of body weight, followed by the FOLFIRI regimen, every 2 weeks until the disease progresses or unacceptable toxicity occurs.

2.2  The summary of product characteristics lists the following most common adverse reactions (according to the Common Terminology Criteria for Adverse Events v3.0) for aflibercept plus FOLFIRI in order of decreasing frequency: leukopenia, diarrhoea, neutropenia, proteinuria, increased plasma activity of aspartate aminotransferase, stomatitis, fatigue, thrombocytopenia, increased plasma activity of alanine aminotransferase, hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine and headache. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  The manufacturer states that the net price of a vial of 100 mg aflibercept is £295.65, and the net price of a vial of 200 mg aflibercept is £591.30. The cost per patient will vary with dose adjustment and treatment duration. The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturer’s submission

The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of aflibercept in combination with irinotecan and fluorouracil-based therapy and a review of this submission by the Evidence Review Group (ERG; section 10).

Clinical-effectiveness evidence

3.1  The manufacturer did a systematic literature review of studies evaluating the efficacy and safety of second-line treatments for metastatic colorectal cancer. It identified 1 relevant randomised controlled trial (RCT), the VELOUR trial, from which it obtained the key clinical evidence. The VELOUR trial was a randomised double-blind placebo-controlled phase III study that was conducted in 176 centres in 28 countries, including the UK. Eligible patients were adults who had inoperable metastatic colorectal cancer, and whose disease progressed on or after treatment with only 1 prior oxaliplatin-based chemotherapy regimen. Investigators randomised patients in a 1:1 ratio to either aflibercept plus irinotecan/5-fluorouracil/folinic acid (FOLFIRI) (n=612) or placebo plus FOLFIRI (n=614). They stratified randomisation by patients’ wellbeing and ability to perform daily activities using the Eastern Cooperative Oncology Group Performance Status (ECOG PS), and whether or not the patient had received prior therapy with bevacizumab. Patients received intravenously either aflibercept at a dose of 4 mg/kg or placebo over 1 hour on day 1, every 2 weeks, immediately followed by FOLFIRI. During the trial, patients could stop 1 study treatment (aflibercept or placebo, or FOLFIRI) but still receive the other components of the regimen. Treatment continued until disease progressed, unacceptable toxicity occurred, or the patient declined further treatment. Investigators monitored the overall survival of patients whose disease progressed during the study, and the progression-free survival of those who stopped treatment before disease progression, until the cut-off date of the study (when 863 patients had died during the trial). Investigators continued to follow some patients who had adverse events up to 9 months after that date.

3.2  The primary end point in the VELOUR trial was overall survival, defined as time from randomisation to death from any cause. One of the secondary end points was progression-free survival as assessed by an independent review committee based on radiologic progression; it was determined as time from randomisation to first observation of disease progression (at least a 20% increase in the sum of the longest diameter of target tumours, the unequivocal increase in the size of non-target tumours or the appearance of 1 or more new tumours) or death from any cause. In addition, disease progression determined by local investigators assessing lesions but also taking into account clinical progression (when the patients’ symptoms had worsened) was recorded during the trial. Other secondary end points were objective response (complete and partial responses) according to Response Evaluation Criteria In Solid Tumors criteria version 1, and adverse events and abnormal laboratory findings.

3.3  The manufacturer stated that patient characteristics and disease history at baseline were well balanced between the aflibercept and placebo groups. Of the patients randomised in the study, the median age was 61 years, 58.6% were men, 97.8% had a baseline ECOG PS of 0 or 1, and 2.2% had a baseline ECOG PS of 2. The marketing authorisation for aflibercept stipulates prior treatment with an oxaliplatin-containing regimen. In the VELOUR trial, 90.2% of patients randomised to aflibercept plus FOLFIRI and 89.4% of those randomised to placebo plus FOLFIRI had received prior oxaliplatin-based chemotherapy for locally advanced or metastatic disease. Approximately 10% of patients had received prior oxaliplatin-based chemotherapy in the adjuvant setting (that is, as an additional treatment given after the primary treatment). Oxaliplatin-based regimens were given in combination with bevacizumab in 30.4% of patients.

3.4  The manufacturer determined that it needed 863 death events to detect a statistically significant 20% risk reduction in the aflibercept group compared with the placebo group and determine the study cut-off date. To estimate time-to-event parameters, the manufacturer used survival analysis. It calculated hazard ratios and confidence intervals for the primary and subgroup analyses using a Cox proportional hazards model. It also established heterogeneity of treatment effect among subgroups using a Cox proportional hazards model, and provided an interaction test for each subgroup analysis. If a patient neither died nor had disease progression during the trial, the manufacturer censored the patient at the date when the tumour was last assessed or at the study cut-off date.

3.5  The median follow-up for the overall population at the time of the primary analysis was 22.28 months. At the study cut-off date, 403 patients (65.8%) randomised to aflibercept and 460 patients (74.9%) randomised to placebo had died. Median overall survival was 1.44 months higher for aflibercept than placebo (aflibercept 13.50 months, placebo 12.06 months), and the corresponding hazard ratio was 0.817 (95.34% confidence interval [CI] 0.713 to 0.937, p=0.0032), suggesting a reduction in the risk of death of 18.3% with aflibercept compared with placebo. The probabilities of overall survival at 6, 12, 18, 24 and 30 months were consistently higher in the aflibercept group than in the placebo group; the probability of overall survival was 4% higher at 6 months, and 85% higher at 30 months.

3.6  The manufacturer noted that the Kaplan–Meier curves for overall survival separated early and continued to separate over time, suggesting that there were patients who experienced a sustained benefit after treatment with aflibercept. Because of this, the manufacturer indicated that the difference in median overall survival of 1.44 months may underestimate the overall clinical benefit of adding aflibercept to FOLFIRI. In addition, the manufacturer calculated hazard ratios for overall survival by 6-month periods up to 18 months, and it combined all time points thereafter into a single hazard ratio. This analysis showed that hazard ratios improved over time, implying that the difference in overall survival increased in favour of aflibercept the longer patients received treatment. In response to a clarification request by the ERG, the manufacturer provided hazard ratios and the number of patients at risk of dying after 18 months by 6-month periods. These hazard ratios continued to decrease over time (suggesting that the difference in overall survival continued to increase in favour of aflibercept), but had confidence intervals that crossed 1.00 (that is, the differences were not statistically significant).

3.7  The manufacturer estimated the mean overall survival by fitting separate parametric functions to the trial data for each treatment group, and extrapolating to provide complete curves (given that calculating the mean required all patients to have died). It modelled each treatment group separately, rather than modelling treatment as a covariate, because the log-cumulative hazard plots (which are used to evaluate the validity of assuming that a hazard ratio between 2 treatments remains constant over time) were not parallel and crossed over one another. The manufacturer considered that the log-logistic function provided the best fit for overall survival for both treatment groups. The log-logistic function, however, gave a long tail (implying that some patients would live implausibly long), so the manufacturer truncated the curves at 15 years (this assumed that all patients die by 15 years). This approach estimated that aflibercept would extend mean overall survival by 4.7 months compared with placebo (aflibercept 22.8 months, placebo 18.1 months); without truncating the survival curves, the difference in mean overall survival was 6.6 months. In response to a clarification request by the ERG, the manufacturer provided estimates with the analysis truncated at 5 and 10 years. The results of this analysis are academic in confidence. The manufacturer also provided ‘restricted’ mean overall survivals for each treatment group based on actual data rather than an extrapolated model (that is, excluding patients who were alive at the end of the trial). The results of this analysis are also academic in confidence.

3.8  The manufacturer found that aflibercept also prolonged progression-free survival compared with placebo; the difference in median progression-free survival was 2.23 months (aflibercept 6.90 months, placebo 4.67 months, hazard ratio 0.758 [95% CI 0.661 to 0.869]). The manufacturer provided estimates for median progression-free survival when local investigators determined disease progression. These estimates are academic in confidence. For response rate (complete and partial responses), the results favoured aflibercept, with a response rate of 19.8% (95% CI 16.4 to 23.2) in the aflibercept group and 11.1% (95% CI 8.5 to 13.8) in the placebo group.

3.9  The manufacturer performed pre-specified subgroup analyses according to the following:

• Baseline characteristics: presence of liver metastasis, location of primary tumour, number of metastatic organs (metastases in 1 organ only, or metastases in more than 1 organ), prior history of hypertension.
• Stratification variables: ECOG PS, prior bevacizumab treatment.
• Demographic characteristics: age (less than 65 years old, or 65 years or older), sex, race, geographical region.

The manufacturer focused on 2 subgroups in its submission: patients with liver metastases only (pre-specified), and a subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy (post hoc). The manufacturer stated that the subgroup of patients with liver metastases only was recognised as a relevant clinical subgroup for metastatic colorectal cancer in Bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for the treatment of metastatic colorectal cancer (NICE technology appraisal guidance 212). For the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, the manufacturer performed a post hoc analysis after the results of the VELOUR trial had been compiled. The manufacturer stated that 10% of patients in the trial had cancer that had relapsed within 6 months after starting oxaliplatin-based adjuvant therapy, which reflects patients with aggressive disease who would be unlikely to benefit from anti-vascular endothelial growth factor (VEGF) therapy.

3.10  For all the pre-specified subgroups, the manufacturer carried out an analysis of overall survival. It found no evidence of heterogeneity in treatment effect (non-significant interaction test), except in the subgroup of patients with liver metastases only (p value for interaction was 0.0899, statistically significant at the 10% level) in which there was a statistically significant difference in median overall survival. The hazard ratio for this subgroup was 0.649 (95.34% CI 0.492 to 0.855) compared with a hazard ratio of 0.868 (95.34% CI 0.742 to 1.015) in patients who had no liver metastases or in whom the cancer spread to the liver and other organs (estimates of survival times are academic in confidence). In response to a clarification request by the ERG, the manufacturer provided the difference in mean overall survival for patients using actual, rather than extrapolated, data; this estimate is academic in confidence. In the post hoc subgroup analysis, which excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy, the difference in median overall survival was 1.9 months in favour of aflibercept. In this subgroup, the unadjusted hazard ratio was 0.78 (95% CI 0.68 to 0.90) compared with 1.09 (95% CI 0.70 to 1.69) in patients whose disease had relapsed 6 months or less after starting adjuvant therapy (p value for interaction 0.1265).

3.11  For progression-free survival, the manufacturer did not find a statistically significant subgroup effect except in patients with liver metastases only (interaction test was statistically significant at the 10% level). These results and those of the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy are academic in confidence.

3.12  The incidence of adverse events of any grade (according to the Common Terminology Criteria for Adverse Events v3.0) was similar in the aflibercept and placebo groups of the VELOUR trial (99.2% and 97.9% respectively), but the incidence of some adverse events was considerably higher in the aflibercept group (for example, 41.4% of patients receiving aflibercept had hypertension [any grade] compared with 10.7% of those receiving placebo). Grade 3–4 adverse events were reported in 83.5% of patients in the aflibercept group and 62.5% of those in the placebo group. The grade 3–4 adverse events that occurred at least twice as frequently in the aflibercept group than in the placebo group, in order of decreasing relative incidence, were: hypertension (19.3% versus 1.5%), proteinuria (7.8% versus 1.2%), hand-foot syndrome (2.8% versus 0.5%), headache (1.6% versus 0.3%), arterial thromboembolic events (1.8% versus 0.5%), weight loss (2.6% versus 0.8%), stomatitis and ulceration (13.8% versus 5.0%), diarrhoea (19.3% versus 7.8%) and decreased platelet count (3.4% versus 1.6%). Typical anti-VEGF adverse reactions and adverse reactions associated with FOLFIRI were more common in the aflibercept group. The manufacturer indicated that most of the adverse events associated with aflibercept plus FOLFIRI were reversible and manageable using current clinical practice, although some (physical weakness, infections, diarrhoea and hypertension) led to permanent discontinuation of study treatment in 26.8% of patients receiving aflibercept compared with 12.1% of those receiving placebo. Furthermore, the European Public Assessment Report notes that more patients in the aflibercept than the placebo groups had their dose of FOLFIRI reduced or their treatment cycle delayed.

3.13  To further characterise the adverse effects of aflibercept, the manufacturer performed a meta-analysis by pooling safety data from 3 RCTs (VELOUR, VITAL and VANILLA). The VITAL trial evaluated aflibercept plus docetaxel compared with placebo plus docetaxel in patients with non-small cell lung cancer and, in the VANILLA trial, patients with metastatic pancreatic cancer were randomised to aflibercept plus gemcitabine or placebo plus gemcitabine. Overall, the meta-analysis included data from 2662 patients (1333 receiving aflibercept and 1329 receiving placebo). The analysis was framed so that risk ratios greater than 1 favoured placebo. The manufacturer found that, among patients treated with aflibercept, 0.4% and 0.5% had grade 4 hypertension and nephrotic syndrome respectively. It also found that adding aflibercept to concurrent chemotherapies did not increase the risk of venous thromboembolism, but it did increase the risk of grade 3–4 adverse reactions related to anti-VEGF therapy; the difference in this risk was statistically significant for hypertension (risk ratio [RR] 9.21, 95% CI 5.91 to 14.36), proteinuria (RR 8.37, 95% CI 4.37 to 16.06) and haemorrhage (RR 2.04, 95% CI 1.20 to 3.47). The incidence of adverse reactions typically associated with the background chemotherapy used in the 3 RCTs also increased with the addition of aflibercept, most notably for neutropenia (including neutropenic complications), various gastrointestinal toxicities and physical weakness.

3.14  Data on health-related quality of life were not collected in the VELOUR trial. The manufacturer conducted the ‘mCRC utilities study’, an observational, cross-sectional study to estimate utility values in patients with metastatic colorectal cancer who would be eligible for treatment with aflibercept plus FOLFIRI as per the licensed indication, or who had progressed to subsequent phases of the disease. The study took place in the Netherlands and the UK, and collected EQ-5D data. The manufacturer used these data as its main source to estimate health-related quality of life for the cost-effectiveness analysis.

ERG critique

3.15  The ERG stated that the manufacturer presented a well-conducted systematic review of clinical evidence, and used a search strategy that was unlikely to have missed any relevant studies. It also stated that the manufacturer included sufficient detail about the VELOUR trial and used appropriate criteria to assess the quality of the trial. The ERG noted, however, that the manufacturer provided minimal details of its meta‑analysis of aflibercept’s adverse events, and of the quality of the VITAL and VANILLA trials.

3.16  The ERG indicated that VELOUR was a good quality trial and directly related to the decision problem. The characteristics of patients at baseline and disease history were well balanced between the aflibercept and placebo groups in the ERG’s opinion. However, the ERG considered that patients in the trial were potentially fitter and younger than those seen in UK practice, and so patients in clinical practice may not achieve the level of benefit reported in trial. The ERG highlighted the following dissimilarities in patient characteristics:

• In the UK, patients whose disease progresses after a break in treatment during intermittent first-line palliative chemotherapy are likely to be offered repeat treatment with the first-line chemotherapy regimen. If their disease progresses while receiving this treatment, or within 6 to 8 weeks of completing it, they would then move to second-line treatment. Although the manufacturer’s submission does not state how many cycles of first-line oxaliplatin-based chemotherapy patients in the VELOUR trial received, the ERG indicated that the trial population may be healthier than patients in clinical practice who may have received several cycles of first-line treatment.
• Between 2007 and 2009, around 72% of patients diagnosed with colorectal cancer in the UK were aged 65 years or over. By contrast, in the VELOUR trial, only 33.5% of the aflibercept group and 38.9% of the placebo group were people aged 65 years or over.
• The proportion of patients with an ECOG PS of 2 in the VELOUR trial was 2.2%. According to the ERG’s clinical adviser, this is lower than the proportion reported in other trials in the second-line setting, or in UK clinical practice.
• In the VELOUR trial, 42–44% of patients had metastasis in only 1 organ, which the ERG’s clinical adviser considered higher than the proportion seen in clinical practice.

3.17  The ERG noted that the hazard ratios for overall survival provided by the manufacturer by 6-month periods had wide confidence intervals at the later time points of the VELOUR trial because by this time many patients were no longer alive, leaving few patients at risk of dying (around 5% at 30 months). The ERG stated that wide confidence intervals reflect imprecise estimates, and that interpreting hazard ratios towards the end of the trial is highly uncertain, particularly at 30 months and 36 months.

3.18  To estimate mean overall survival using parametric analysis, the manufacturer assumed that the proportional hazards assumption does not hold (that is, it did not accept that the hazard ratio between the 2 treatment groups remained constant over time). The manufacturer stated that this was because the hazard ratios for overall survival decreased over time (treatment effect improved), and because the log-cumulative hazard plots were not parallel and crossed over one another. The ERG, conversely, considered that, while the hazard ratios decreased over time, they remained consistent with the proportional hazards assumption, although it acknowledged that using a proportional hazards approach is subject to judgement. In addition, the ERG noted that the log-cumulative hazard plots were very close to parallel. The ERG stated that rejecting the proportional hazards assumption and assuming a continued separation of the overall survival curves is highly uncertain given that no data were available beyond 36 months follow-up, and particularly that the progression-free survival curves separate then converge at around 12 months. The ERG suggested that it would be reasonable to assume that the survival curves converge before 5 years (that is, there is no treatment effect after 5 years), in line with clinical experience in treating metastatic colorectal cancer.

3.19  The ERG noted that the estimate of mean overall survival varied considerably depending on which parametric function the manufacturer used, making the manufacturer’s estimate of the difference in mean overall survival (4.7 months) unreliable. Because of this, the ERG requested from the manufacturer the mean estimates of overall survival for each treatment group, restricted to patients who had died before the end of the trial (that is, results based on actual data rather than an extrapolated model). The ERG indicated that the difference in restricted mean estimates provided by the manufacturer (which is academic in confidence) is likely to be an underestimate given that it does not take into account the patients with long survival times.

3.20  The manufacturer used the log-logistic function to estimate mean overall survival, and it truncated the curves at 15 years. The ERG considered that 15 years is too long for the patient population under consideration because the treatment benefit is unlikely to extend beyond 5 years. Because of this, the ERG requested that the manufacturer produce estimates with the analysis truncated at 5 years and 10 years. When the data were truncated at 5 years, the results from the different functions were more consistent with each other than when the data were truncated at 15 years. The ERG stated that it is unclear whether the mean based on extrapolating the curves and truncating the data at 5 years, or the restricted mean based on actual data, is more valid. The ERG indicated that the estimates of mean survival were longer than those of median survival because the former takes into account the few patients who live a relatively long time.

3.21  Progression-free survival in the VELOUR trial was a secondary end point assessed by an independent review committee. The ERG advised that independent review committees may miss symptoms other than tumour growth caused by disease progression, which may have an impact on treatment duration and associated costs. The ERG noted that when the manufacturer explored in a sensitivity analysis disease progression determined by investigator assessment taking into account symptomatic deterioration (as would happen in clinical practice), the results were less favourable than when disease progression was determined by the assessment of the independent review committee.

3.22  The ERG stated that, while there was no evidence of a statistically significant interaction at the 5% level between treatment groups for most of the baseline patient characteristics, the results of the subgroup analyses suggested that patients with less advanced disease in the VELOUR trial (ECOG PS equal to 0, number of organs with metastasis less than or equal to 1, and patients with liver metastases only) may be more likely to benefit from treatment with aflibercept than those with more advanced cancer.

Cost-effectiveness evidence

3.23  The manufacturer did not identify any published economic evaluations relevant to the decision problem. It submitted a de novo economic model to establish the cost effectiveness of aflibercept in patients with metastatic colorectal cancer who are eligible for second-line combination chemotherapy, and who were previously treated with an oxaliplatin-based regimen. The manufacturer performed subgroup analyses for patients with liver metastases only, and for a subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and whose disease relapsed within the following 6 months. The manufacturer conducted the analysis from the perspective of the NHS and personal social services and chose a time horizon of 15 years. It used a 2-week treatment cycle to reflect the treatment schedules of aflibercept and FOLFIRI, and applied a half-cycle correction. Costs and health effects were discounted at an annual rate of 3.5%.

3.24  The manufacturer developed a state-transition Markov cohort model simulating 3 states: stable disease, progressed disease and death. The manufacturer further split the stable-disease health state into sub-states of ‘on second-line treatment’ and ‘discontinued second-line treatment’ to distinguish between patients who receive second-line treatment until their disease progresses, and those who stop second-line treatment before their disease progresses. All simulated patients enter the model in the stable-disease health state and in the ‘on second-line treatment’ sub-state. Patients can then continue treatment and remain in the ‘on second-line treatment’ sub-state, or move to the ‘discontinued second-line treatment’ sub-state; they can instead move to the progressed-disease health state (and stop second-line treatment), or death. Patients cannot receive second-line treatment again once treatment is stopped, but they can receive further active therapy (systemic anticancer treatment, radiotherapy or surgery) or best supportive care. The manufacturer stated that the duration of second-line treatment in the model is based on the mean durations in the VELOUR trial to take into account dose delays or the discontinuation of aflibercept or FOLFIRI (for patients who were in the aflibercept group), or FOLFIRI (for patients who were in the placebo group), as observed in the trial. The manufacturer modelled adverse events as events (rather than health states) and it applied a utility decrement (disutility) for each adverse event.

3.25  The manufacturer’s model included parameters for overall survival, progression-free survival and time to discontinuing second-line treatment (before or after disease progression). To estimate the survival parameters, the manufacturer fitted alternative parametric functions (Weibull, log-normal, log-logistic and exponential) to observed Kaplan–Meier data from the VELOUR trial, and extrapolated the curves beyond the trial period for overall survival and time to discontinuing treatment, but not for progression-free survival, because the disease had progressed in all patients during the trial. In extrapolating those curves, the manufacturer assumed non-proportional hazards (that is, the hazard ratios between aflibercept plus FOLFIRI and FOLFIRI alone varied over time) so it modelled each treatment group separately. The manufacturer chose the base-case survival functions based on the results of statistical tests, visual inspection of the fit to the data and the clinical plausibility of the extrapolated portion of the curve. For overall survival, the manufacturer used the log-logistic function, and assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the 15-year time horizon, but does not cease at any point during the extrapolation period (that is, the overall survival curves start converging 12 months after starting treatment but never fully converge later in the extrapolation period). The manufacturer used the Weibull function for progression-free survival and time to treatment discontinuation. Other parametric functions were explored in scenario analyses.

3.26  The manufacturer noted that the model predicted a median overall survival and a median progression-free survival similar to those from the VELOUR trial. The largest difference was for progression-free survival in the FOLFIRI group, which the model overestimated compared with the survival time observed in the trial.

3.27  Adverse events in the model included grade 3–4 adverse events that affected more than 5% of patients in the VELOUR trial, together with 6 rarer adverse events (gastrointestinal perforation, haemorrhage, febrile neutropenia, peripheral neuropathy, urinary tract infections and hand-foot syndrome) that the manufacturer’s clinical advisory board considered important. The subgroup analyses incorporated data specific to each subgroup.

3.28  The manufacturer applied utility values in the model from its observational utility study, in which investigators assigned patients to 1 of the following 3 groups: patients with stable disease who are receiving second-line treatment, and patients who had previously received second-line treatment but stopped it because of an adverse event, or because their disease progressed. Because the sample size of the group of patients who had an adverse event and stopped treatment was very small, the manufacturer did not use the utility estimates from this group, and instead assumed that all patients with stable disease have the same utility, equal to the utility of patients with stable disease who are receiving second-line treatment. The manufacturer got descriptions of health states from patients using the EQ-5D system, and derived the utility weights by applying UK valuation of health states estimated using the time trade-off method. The utility estimates for patients with stable disease and for patients with progressed disease are academic in confidence. The manufacturer assumed that the utility in the progressed-disease health state is independent of time spent in the state. The manufacturer explained that, despite the age and health of patients, the utility values used in the model are relatively high because candidates for second-line chemotherapy must be fit enough to receive treatment.

3.29  The manufacturer also identified relevant utility studies from a systematic review of the literature. It did not use the values in those studies to source the model, but used them to compare the estimates from its utility study, and noted that they were reasonably consistent. The utility estimates in the literature that the manufacturer considered relevant ranged from 0.73 to 0.81 for stable disease, and from 0.68 to 0.69 for the progressed disease. One other study, Best et al. (2010), reported utility values of 0.51 for stable metastatic disease and 0.21 for progressed metastatic disease, but the manufacturer did not consider this study relevant because the population included patients receiving adjuvant chemotherapy and patients in remission.

3.30  The manufacturer got the disutilities associated with adverse events from the published literature, and supplemented these with clinical expert opinion. It calculated the average disutility per adverse event assuming that an adverse event causes the same disutility regardless of the type of cancer. This gave an average disutility per adverse event of −0.0127 for patients receiving aflibercept plus FOLFIRI, and −0.0108 for those receiving FOLFIRI alone.

3.31  The costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. It assumed that any unused drug in a vial was discarded (wasted) for aflibercept and irinotecan (a component of FOLFIRI), but explored in scenario analyses other possibilities to model drug wastage. The cost of aflibercept in the model took into account the patient access scheme discount.

3.32  To estimate costs of caring for people with metastatic colorectal cancer (‘management costs’ including supportive medications, clinician and nurse visits [hospital and community], imaging, laboratory tests, hospitalisations, palliative care, and personal and social care), the manufacturer conducted a retrospective observational study, and undertook a questionnaire-based survey of 6 UK clinical oncologists (both unpublished studies). In the observational study, the manufacturer collected resource-use data from patients who received oxaliplatin-based chemotherapy followed by FOLFIRI as second line, and used those data to estimate total management costs per 2-week cycle for different groups of patients (the manufacturer advised that every patient would eventually receive end-of-life care regardless of prior treatment, so it did not include resource use associated with end-of-life care in the model). The clinician survey aimed to gather data on community-based care, and on personal and social care. In this, the manufacturer elicited the average treatment practices of each oncologist to get data on managing patients with metastatic colorectal cancer. It also used the results of the survey, together with NHS reference costs, to estimate the costs associated with adverse events. The manufacturer used mean resource use for adverse events, but median resource use for community-based care, and personal and social care. The cost of subsequent therapies that patients could receive after stopping second-line treatment or experiencing disease progression was calculated based on the manufacturer’s study of resource use, and was assumed to be independent of the type of second-line treatment.

3.33  The manufacturer’s deterministic base-case results estimated that the addition of aflibercept to FOLFIRI provides an additional 0.243 quality-adjusted life years (QALYs). This benefit is achieved with an additional cost of £8816, resulting in an incremental cost-effectiveness ratio (ICER) of £36,294 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone.

3.34  The manufacturer presented deterministic sensitivity analyses for the 20 parameters with the largest impact on the ICER. In these, it varied each parameter at a time above and below its base-case value. The results showed that the ICER is most sensitive to the parametric function chosen for overall survival, the utility value chosen for the progressed-disease health state, and the number of administrations assumed for second-line treatment drugs. The manufacturer explained that improving overall survival and progression-free survival increased incremental QALYs in favour of aflibercept, but also increased drug costs and the costs incurred from prolonged overall survival after disease progression.

3.35  The manufacturer carried out a probabilistic sensitivity analysis to summarise the uncertainty in the ICER. This showed that the probability of aflibercept plus FOLFIRI being cost effective when compared with FOLFIRI alone is less than 5% if the maximum acceptable ICER is £20,000 per QALY gained, and 22% at £30,000 per QALY gained.

3.36  The manufacturer investigated the structural uncertainty in the model by fitting alternative parametric functions for overall survival and progression-free survival, and by directly applying patient-level data from the VELOUR trial to model progression-free survival (given that disease had progressed in all patients during the trial). It also performed scenario analyses to test the sensitivity of the ICER to alternative assumptions around drug wastage. In these, it explored the possibility of no drug wastage, and of reducing the dose to the nearest number of whole vials for patients who would otherwise use less than 5% of the vial contents. The highest ICER from these analyses was £49,805 per QALY gained (using the Weibull function to model overall survival).

3.37  The manufacturer provided subgroup analyses to establish the cost effectiveness of aflibercept plus FOLFIRI compared with FOLFIRI alone in patients with liver metastases only, and in a subgroup that excluded those who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months. In comparison with the deterministic base-case ICER of £36,294 per QALY gained, the ICERs were £30,474 per QALY gained (incremental costs £10,974, incremental QALYs 0.360) and £32,480 per QALY gained (incremental costs £8573, incremental QALYs 0.264) respectively. At a maximum acceptable ICER of £30,000 per QALY gained, the probability of aflibercept plus FOLFIRI being cost effective compared with FOLFIRI alone in both subgroups is around 50% (numerical values not provided in the manufacturer’s submission).

ERG critique

3.38  The ERG indicated that the manufacturer’s economic evaluation is consistent with the NICE reference case. It noted that the modelled population is based on data from the VELOUR trial, which relate to patients who appear fitter and younger than those seen in clinical practice. In exploratory sensitivity analyses, the ERG investigated the effect of treating a population that better reflects patients with metastatic colorectal cancer in the UK than the VELOUR trial by modelling an older population with a lower health-related quality of life.

3.39  The ERG considered that it is uncertain whether the hazard ratio for overall survival varies over time. The ERG reported that, when assuming in the manufacturer’s model that the hazard ratio remain constant over time (that is, when applying the proportional hazards assumption), the ICER increased to £58,784 per QALY gained, with the difference being mainly driven by a reduction in incremental QALYs compared with the manufacturer’s base case. The ERG considered that even this scenario may be relatively optimistic because the progression-free survival curves separate and then converge at around 12 months, suggesting that the hazard ratio could increase over time.

3.40  In its cost-effectiveness analysis, the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI initially increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the rest of the time horizon, but does not cease at any point during the extrapolation period. The ERG noted that the difference in overall survival between aflibercept plus FOLFIRI and FOLFIRI alone decreases at a relatively slow rate after the initial 12 months and, importantly, suggests a continuing treatment effect on overall survival during the entire 15-year horizon. The ERG explained that extrapolating overall survival data from the VELOUR trial, in which the median follow-up time was just under 2 years, over a 15-year time horizon meant that the assumptions underpinning the extrapolation are key to explaining the large differences between the observed median and the extrapolated mean estimates of overall survival. The ERG stressed that extrapolating the overall survival curves beyond the trial period is highly uncertain given that no data were available for more than 3 years’ follow-up, and particularly that the progression-free survival curves separated and then converged at around 1 year. The ERG stated that the manufacturer did not explore this uncertainty sufficiently. Specifically, the manufacturer did not explore that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups may become the same from the point at which the trial ends (that is, the treatment effect of aflibercept plus FOLFIRI does not continue over the extrapolation period). Nor did the manufacturer explore that the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone may converge over the extrapolation period (that is, the treatment effect of aflibercept plus FOLFIRI gradually decreases from the point at which the trial ends) similar to the convergence observed with progression-free survival (in this scenario the risk of death may be higher in the aflibercept plus FOLFIRI group during the extrapolation period than in the FOLFIRI alone group). The ERG explored these 2 scenarios in its exploratory analyses.

3.41  Regarding the utility estimates in the model, the ERG had concerns about the generalisability of the manufacturer’s observational study because the study population appeared to be younger than UK patients, and the proportion of patients who had an ECOG PS of 2 was lower than that seen in UK clinical practice. Moreover, the ERG noted that the study was small, and produced counter-intuitive estimates in a subgroup analysis including UK patients only because the mean utility value for patients whose disease progressed was higher than for those who had stable disease and received second-line treatment.

3.42  The ERG was concerned that the utility estimates used in the model from the manufacturer’s utility study, as well as those reported in the literature, were high when compared with values used in previous appraisals of metastatic colorectal cancer, or with general UK population norms. The ERG was particularly concerned about the utility value in the model for patients whose disease had progressed. The ERG explained that, because the model predicts longer overall survival than progression-free survival, approximately three-quarters of absolute QALY increment is accrued after disease progression. Furthermore, the ERG stated that the manufacturer’s assumption that utility in the progressed-disease health state is independent of time spent in the state is clinically implausible because patients’ health-related quality of life decreases as disease progresses and patients get older.

3.43  The ERG identified an error in the manufacturer’s model in how disutilities associated with adverse events were applied, which reduced the disutilities in the model. Correcting this error increased the manufacturer’s base-case ICER from £36,294 to £37,834 per QALY gained. The ERG applied this correction in its exploratory analyses.

3.44  The costs of aflibercept plus FOLFIRI and FOLFIRI alone did not depend on the duration of second-line treatment in the model; the manufacturer calculated them separately based on data from the VELOUR trial to reflect the dose delays (for example, because of an adverse event) and dose reductions observed in the trial. The ERG, however, stated that, to reflect dose delays and reductions, it is more appropriate to apply drug cost per administration (including administration costs) directly to the proportion of patients in each health state, in line with how utility values are applied. Adjusting this increased the manufacturer’s base-case ICER from £36,294 to £37,539 per QALY gained. The ERG applied this change in its exploratory analyses.

3.45  The manufacturer assumed that, because aflibercept is administered at the same time as FOLFIRI, no extra costs in terms of additional staff or inpatient admissions would be incurred. The ERG indicated that, even if given simultaneously, administering aflibercept involves preparing an additional infusion, which incurs an extra cost compared with FOLFIRI alone. The ERG highlighted that, in Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy (NICE technology appraisal guidance 242), the pharmacy preparation of cetuximab and bevacizumab was estimated to be £15 per infusion. In addition, the ERG stated that, if aflibercept is given before or after FOLFIRI, instead of at the same time, administering aflibercept will include an additional hour of infusion time compared with administering FOLFIRI alone. The ERG noted that the model is sensitive to the assumptions underlying the administration costs of aflibercept plus FOLFIRI, and it explored these assumptions in sensitivity analyses.

3.46  Regarding resource use for community, and personal and social care, the manufacturer modelled the median estimate from its survey of clinical oncologists, instead of the mean. The ERG indicated that mean values are more commonly used in cost-effectiveness analyses, and that the use of medians may underestimate expected costs. The ERG noted that, when the manufacturer used the mean value in a sensitivity analysis, the base-case ICER increased from £36,294 to £41,222 per QALY gained. The ERG stated that it is unclear in this case whether the median is a better estimate than the mean because there was a small number of survey responders (n=6) and the data were skewed. The ERG noted that the model is sensitive to this parameter and it further explored this in sensitivity analyses.

3.47  The ERG advised that the results of the analysis of the liver metastases only subgroup should be interpreted cautiously. Because the parametric curves for overall survival and progression-free survival were fitted independently for each treatment group based on data for this subgroup from the VELOUR trial, and the subgroup corresponded to approximately 25% of the trial population, the ERG highlighted that the analysis may not have been powered to demonstrate a difference in treatment effect in this subgroup. For the analysis of the subgroup that excluded adjuvant chemotherapy, the ERG indicated that this analysis was performed post hoc, and so its results may be biased. The ERG’s clinical advisers also stated that patients who receive adjuvant chemotherapy and relapse quickly afterwards would not be treated differently to other patients in UK clinical practice.

ERG exploratory analyses

3.48  The ERG investigated the uncertainty around how the manufacturer had chosen to extrapolate overall survival by considering other scenarios for the magnitude and duration of the overall survival benefit associated with second-line treatments. The ERG modelled the following scenarios by assuming that:

• The risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same after 30 months of starting treatment.
• The risk of death in aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same after 36 months of starting treatment.

The ERG implemented the following scenarios to mimic the converging progression-free survival curves.

• The survival curves begin converging after 30 months of starting treatment, and come together after a further 12 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.
• The survival curves begin converging after 30 months of starting treatment, and come together after a further 18 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.
• The survival curves begin converging after 36 months of starting treatment, and come together after a further 12 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.
• The survival curves begin converging after 36 months of starting treatment, and come together after a further 18 months, after which point the risk of death in both treatment groups becomes the same until the end of the time horizon.

In all of the above scenarios, the ERG assumed that the treatment effect of aflibercept plus FOLFIRI continues until either 30 months or 36 months. The ERG chose these time points because it identified them as particularly uncertain from the hazard ratios for overall survival by 6‑month periods presented by the manufacturer. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICER was £45,570 and £42,718 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30 months or 36 months respectively. In the scenario in which the ERG assumed that the survival curves begin converging after 30 months or 36 months of starting treatment over a period of 12 months or 18 months, the ICERs ranged from £55,424 per QALY gained (when curves begin converging after 36 months over 18 months) to £66,377 per QALY gained (when curves begin converging after 30 months over 12 months). The ERG explained that, in this scenario, when the curves begin converging over 12 months, the magnitude of the additional survival benefit from treatment with aflibercept plus FOLFIRI is assumed to taper at a higher rate than when the curves begin converging over 18 months, and so convergence over 12 months results in higher ICERs.

3.49  To address its concerns about some of the parameters used in the manufacturer’s base-case model, the ERG performed the following sensitivity analyses, varying 1 parameter at a time:

• Applying 2 alternative utility values for patients whose disease progressed: 0.21 from Best et al. (2010) and 0.60 from Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer (NICE technology appraisal guidance 118). The ERG stated that the latter may better reflect the values reported in the literature.
• Including a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI compared with administering FOLFIRI alone. For the preparation cost, the ERG applied a cost of £15, in line with NICE technology appraisal guidance 242 and, for the extra time for infusion, it applied £45, based on NHS reference costs. The ERG explored the impact of these 2 assumptions separately and jointly.

When the ERG used the lower utility values of 0.21 and 0.6, the ICER increased from £36,294 per QALY gained (base-case ICER) to £71,143 and £40,608 per QALY gained respectively. Including a cost for preparing an additional infusion of aflibercept, and a cost for an additional hour of infusion time for aflibercept plus FOLFIRI, together increased the ICER to £39,258 per QALY gained.

3.50  The ERG applied its preferred adjustments and model inputs to the manufacturer’s base-case model (hereafter the ‘ERG base case’). In this, the ERG corrected the error it identified in the manufacturer’s model (section 3.43), and applied the acquisition and administration costs to all patients in the second-line treatment health state of the model (section 3.44). In addition, the ERG assumed that patients entered the model at the age of 70 years and accounted for the impact of age on health-related quality of life by applying a utility decrement for aging. The ICER resulting from the above 3 changes was £41,653 per QALY gained. The ERG then applied its preferred model inputs for the parameters it varied in one-way sensitivity analyses:

• an additional administration cost for aflibercept of £15
• mean instead of median resource use estimates (section 3.46).

The ERG applied the above with or without:

• a utility value of 0.60 for patients whose disease had progressed.

When the ERG applied the 0.60 utility value, the analysis gave an ICER of £54,368 per QALY gained for aflibercept plus FOLFIRI compared with FOLFIRI alone. Without this modification (that is, using the same value in the manufacturer’s base case), the ICER was £47,965 per QALY gained.

3.51  The ERG presented deterministic results for the scenario analyses (section 3.48) within its base case, and using the utility value of 0.60 for patients whose disease had progressed. It presented results for the overall population, and separately for each subgroup the manufacturer had identified. When the ERG assumed that the risk of death in the aflibercept plus FOLFIRI and FOLFIRI alone groups becomes the same beyond the trial period, the ICERs were £66,506 and £62,894 per QALY gained for a treatment effect of aflibercept plus FOLFIRI lasting until 30 months or 36 months respectively. In the scenario in which the ERG assumed that the survival curves begin converging after 30 months or 36 months of starting treatment over a period of 12 months or 18 months, the ICERs ranged from £78,226 per QALY gained (when the curves begin converging after 36 months over 18 months) to £92,089 per QALY gained (when the curves begin converging after 30 months over 12 months). The ERG found that, using median resource-use estimates from the manufacturer’s survey of UK oncologists (that is, as per the manufacturer’s base case), instead of mean, consistently decreased the ICERs for the scenario analyses within the ERG base case by approximately £5000 per QALY gained.

3.52  The ERG also presented results based on the probabilistic sensitivity analysis for selected scenario analyses. These suggested that the deterministic results (section 3.51) underestimated the ICER by £5000 to £14,000 per QALY gained.

3.53  For the subgroup analyses combining the ERG’s assumptions of overall survival and the ERG’s alternative base case, the ICER for aflibercept plus FOLFIRI compared with FOLFIRI ranged from £46,576 to £58,257 per QALY gained for the liver metastases only subgroup, and from £57,224 to £80,187 per QALY gained for the subgroup that excluded patients who had received adjuvant oxaliplatin-based therapy and relapsed within the following 6 months.

3.54  Full details of all the evidence are in the manufacturer’s submission and the ERG report.

4  Consideration of the evidence

4.1  The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aflibercept in combination with irinotecan and fluorouracil-based therapy, having considered evidence on the nature of metastatic colorectal cancer and the value placed on the benefits of aflibercept in combination with irinotecan and fluorouracil-based therapy by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2  The Committee heard from the clinical specialists and patient experts about the nature of the condition. It heard that metastatic colorectal cancer can be debilitating, can affect a person’s ability to work and lead a normal life, and can lead to premature death. The Committee noted that the illness also brings about a burden on relatives and friends. The Committee understood that the course of the disease varies, with some people’s health deteriorating quickly and others’ slowly. The Committee heard from patient experts that quality of life in people with the disease may be bad when it is first diagnosed because patients are usually very weak and may have many metastases, but that with treatment the quality of life may improve, as may the ability to work and socialise. The Committee understood that, in clinical practice, disease progression (in patients who already have metastatic disease) would be detected using radiological imaging, although symptoms would also be taken into account. It heard from patient experts that disease progression usually affects quality of life, but it may take a long time before it affects daily activities. The Committee heard further from patient experts that, although people would appreciate small extensions of life, they value quality of life more than length of life. The Committee noted that treatment is generally associated with unpleasant side effects, particularly high blood pressure and diarrhoea and that, while some people may be willing to tolerate the side effects, others may not. The Committee understood that clinicians are now more experienced in managing these side effects and ‘optimising’ treatment, although it heard from patient experts that the treatments for the side effects may themselves have side effects.

4.3  The Committee discussed the management of metastatic colorectal cancer, noting the licensed indication for aflibercept. The Committee heard from clinical specialists that the current treatment options for this patient population are limited, and that treatment is determined on an individual basis. The Committee was aware that, in Colorectal cancer: the diagnosis and management of colorectal cancer (NICE clinical guideline 131), NICE recommends, as second-line treatment options, single-agent irinotecan or FOLFIRI after first-line FOLFOX (folinic acid plus fluorouracil plus oxaliplatin), and single-agent irinotecan after first-line XELOX (capecitabine plus oxaliplatin). The Committee heard from the clinical specialists that surgical resection of tumours may be a treatment option in some patients with metastatic disease, and it understood that the proportion of patients with metastatic colorectal cancer who survive over 5 years has now increased to 10–15% because of successful tumour resection. The Committee noted that patient experts considered it important to give clinicians treatment choices because chemotherapy can make resection possible in some patients. It also noted that patients consider that biologic therapies such as aflibercept improve quality of life compared with chemotherapy.

Clinical effectiveness

4.4  The Committee considered the evidence on the clinical effectiveness of aflibercept, noting that it was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem; however, it considered that the trial had limitations. The Committee, echoing comments from a patient expert, would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life. The Committee would also have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee discussed the Evidence Review Group’s (ERG) concern that patients in the VELOUR trial appeared to have been fitter and younger than those seen in UK clinical practice. The Committee heard from clinical specialists that the disease and demographic characteristics seen in patients in the VELOUR trial were not the same as those treated in UK clinical practice, in which patients are older; however, evidence from the VELOUR trial suggested there would be no difference in response to treatment in older patients. The Committee agreed that, apart from this, the patient population in the VELOUR trial was reasonably representative of patients seen in the NHS and therefore concluded that the results from the VELOUR trial are generalisable to UK clinical practice.

4.5  The Committee discussed the results for overall survival from the VELOUR trial. The Committee noted that, in its submission and in response to clarification requests by the ERG, the manufacturer produced a range of estimates for the difference in overall survival between the aflibercept and placebo groups of the trial. The Committee agreed that the manufacturer’s median overall survival estimate of 1.44 months reflects a statistically significant but clinically small benefit. The Committee noted the marked difference between this estimate and the calculated mean overall survival of 4.7 months. The Committee noted that the manufacturer considered the difference in mean overall survival to better represent the magnitude of the clinical benefit than the difference in median because there were a few patients who appeared to experience a sustained benefit after treatment with aflibercept. The Committee was aware that, to estimate mean overall survival, the manufacturer extrapolated the survival curves over 15 years. The Committee discussed whether the manufacturer’s estimate of the difference in mean overall survival was robust noting that, during the VELOUR trial most patients had died (66% and 75% of patients in the aflibercept and placebo groups respectively). The Committee heard from the ERG that, because few patients were at risk of dying late in the trial, the hazard ratios by 6-month periods late in the trial had wide confidence intervals, reflecting imprecise and uncertain estimates. The Committee agreed that extrapolating the survival curves over 15 years, when most patients had lived for less than 3 years, results in highly uncertain estimates for overall survival. The Committee accepted that the true difference in overall survival might be underestimated by the estimate of 1.44 months calculated from median values, when accounting for patients who were alive after the end of the trial. However, it concluded that, given the uncertainty around the manufacturer’s extrapolation, the difference in mean overall survival of 4.7 months was not plausible.

4.6  The Committee considered the Kaplan–Meier curves reflecting the trial data for overall survival and progression-free survival. The Committee noted that the principal difference between the overall survival and progression-free survival curves was that the area between the aflibercept plus FOLFIRI and placebo plus FOLFIRI curves continued to widen across the trial period for overall survival whereas, for progression-free survival, the curves converged at around 12 months. The Committee heard from the clinical specialists that, because the overall survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease-modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped (that is, survival post disease progression was increased more than progression-free survival). The Committee discussed how the disease-modifying effect may manifest clinically. It heard that aflibercept may have delayed death by shrinking tumours, and so extended the period before the tumour grew again. The Committee, however, was aware that the evidence from the VELOUR trial does not support this theory because the disease had progressed in all patients during the trial. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the differences between the overall survival and progression-free survival curves. The Committee concluded that it would be appropriate to capture the treatment effect on progression-free survival in the estimate of health-related quality of life, but was aware that the VELOUR trial provided no such data.

4.7  The Committee considered the subgroup analysis presented by the manufacturer for patients with liver metastases only. The Committee noted that, in this subgroup, there was a statistically significant difference in overall survival in favour of aflibercept compared with the rest of the trial population, with a statistically significant interaction test at the 10% level. The Committee was aware that the 10% significance level was less specific (that is, a higher chance of a positive finding) than the more conventional 5% level. The Committee agreed that there is no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs, or patients with metastases at multiple sites in the body. The Committee was aware that patients with liver metastases only are more likely to be considered for surgical resection of the metastases and possibly live longer than those with widespread metastases. The Committee therefore discussed whether aflibercept can make liver metastases operable in patients with metastatic colorectal cancer. The Committee noted that only a very small minority of patients in the VELOUR trial proceeded to have surgical resection of liver metastases after treatment with aflibercept. The Committee heard from the clinical specialist that in approximately 20–30% of patients who undergo surgery to remove the liver metastases, metastatic colorectal cancer can be cured. The Committee, however, was not presented with evidence about resection and cure rates with aflibercept in the subgroup of patients with liver metastases only. The Committee also considered that liver resection for curative purposes was more appropriate in the first line setting than in the second line setting. Furthermore, it heard from the manufacturer that the modelling of the liver metastases only subgroup did not include the cost of surgical resection. The Committee concluded that it would be appropriate to include this cost and that this is likely to affect the ICER. The Committee agreed that, given the lack of evidence, aflibercept cannot be considered an effective treatment option for the purpose of making liver metastases resectable. The Committee therefore concluded that this subgroup should not be considered further.

4.8  The Committee considered the subgroup that excluded patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months. The Committee heard from the clinical specialists that, in clinical practice, patients in this subgroup would not be treated differently to the overall trial population. In addition, the Committee noted that the manufacturer acknowledged that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup was differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy.

4.9  The Committee discussed the adverse reactions associated with aflibercept. The Committee noted that more patients in the aflibercept group (27%) stopped treatment because of adverse events than in the placebo group (12%). The Committee also noted that adding aflibercept to FOLFIRI increased the adverse events typically associated with FOLFIRI, most notably neutropenia, although it heard from clinical specialists that neutropenia would not routinely be treated in clinical practice. The Committee heard from the manufacturer that the dose of FOLFIRI used in the trial was higher than the dose that is routinely used in clinical practice and might have caused some of the adverse events. The Committee was also aware that aflibercept increased the risk of hypertension, as would other anti-vascular endothelial growth factor therapies. The Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse reactions, but these were broadly similar to those related to other chemotherapeutic regimens.

Cost effectiveness

4.10   The Committee considered the structure of the model submitted by the manufacturer, and how it captured the main aspects of the condition. The Committee noted that the manufacturer chose to split the stable-disease health state into 2 sub-states to capture the costs and health benefits for patients with stable disease who either receive second-line treatment with aflibercept plus FOLFIRI or FOLFIRI alone, or who have stable disease but have stopped second-line treatment for reasons other than disease progression. The Committee heard from the ERG that the manufacturer applied the same utility value to the 2 sub-states of the stable-disease health state. It further heard that the acquisition and administration costs of second-line treatments in the model did not depend on the proportion of patients in each state, and that they were calculated outside the model. The Committee agreed that the costs and quality-adjusted life years (QALYs) in the stable-disease health state were not specific to the 2 sub-states (‘on second-line treatment’ and ‘post second-line treatment’). The Committee concluded that overall the model adhered to the NICE reference case for assessing cost effectiveness.

4.11  The Committee discussed whether or not the 15-year time horizon used by the manufacturer in the model was appropriate. The Committee recognised that that the choice of the time horizon is a sensitive parameter in the model given the uncertainty associated with extrapolating overall survival. The Committee was aware that the time horizon should be sufficiently long to capture all the costs and health benefits in the full population (that is, a lifetime horizon should be used), and concluded that it was therefore appropriate for the manufacturer to have chosen a time horizon of 15 years. However, the Committee agreed that when the time horizon is much longer than the duration of the trial, it is particularly important to explore the assumptions underlying how overall survival is extrapolated, and the impact of using alternative survival functions on the estimates.

4.12  The Committee discussed how the manufacturer extrapolated overall survival, and the alternative assumptions considered by the ERG in its exploratory analyses. The Committee noted that the manufacturer assumed that the survival benefit from treatment with aflibercept plus FOLFIRI increases relative to treatment with FOLFIRI alone until around 12 months after starting treatment, and then decreases over the 15-year time horizon, but does not cease at any point during the extrapolation period (that is, the hazard ratio decreases until around 12 months then increases over the time horizon but never reaches 1.0). The Committee noted that the ERG explored 2 alternative scenarios: the first assumed that the risk of death becomes the same in both treatment groups at the point at which the trial ends and continues to be the same across the extrapolation period (that is, the hazard ratio becomes 1.0 during the extrapolation period, and the survival curves become parallel); and the second assumed that the overall survival curves for aflibercept plus FOLFIRI and FOLFIRI alone converge over the extrapolation period (that is, the hazard ratio gradually increases from the point at which the trial ends until the survival curves come together, then the hazard ratio becomes 1.0 thereafter). The Committee understood that, in the ERG’s second scenario, it may be possible that patients receiving aflibercept plus FOLFIRI have a higher risk of death than those receiving FOLFIRI alone (that is, the hazard ratio may be greater than 1). The Committee considered that the manufacturer’s assumption that the treatment benefit continues beyond the trial period and until 15 years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial, and given that the hazard ratios towards the end of the trial had wide confidence intervals. The Committee considered that the ERG’s analysis that allows the hazard ratio to become greater than 1 could be considered implausible. The Committee agreed that the ERG’s first scenario which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0) represents an acceptable compromise between the 2 extremes of assuming continuing treatment effect (manufacturer’s base case) and allowing for a reversed treatment effect (ERG’s second scenario). However, the Committee concluded that, although this was considered the most plausible assumption for extrapolating overall survival, it still considered that great uncertainty exists.

4.13  The Committee considered the estimates of health-related quality of life used in the manufacturer’s model, noting it would have preferred to have seen health-related quality-of-life data collected in the trial used for the model. The Committee also considered utility values used in previous metastatic colorectal cancer technology appraisals and the ERG’s critique of these estimates. The Committee was aware that the manufacturer used 2 utility values in the model: 1 for patients in the stable-disease health state (regardless of whether or not they were receiving second-line treatment); and the other for those in the progressed-disease health state (both values are academic in confidence). The Committee noted that the ERG considered that the value in the progressed-disease health state was particularly high, and explored an alternative lower value of 0.60 in sensitivity analyses. The Committee understood from the ERG that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to this parameter at this stage in the model. The Committee discussed the alternative utility values for the progressed disease state, and agreed that the value used by the manufacturer appears too high, and possibly overestimates the QALY benefit in the subpopulation in which disease progressed; the Committee considered that the value of 0.60 used by the ERG better reflected patients whose disease had progressed. In addition, the Committee noted that many QALYs in the model accrued after 5 years of treatment but, because the life expectancy of most people with metastatic colorectal cancer is shorter than 2 years, the Committee did not accept that the modelling of QALYs was in line with clinical experience of treating metastatic colorectal cancer. The Committee also agreed that adjusting the utility values for age was appropriate to reflect the natural deterioration in health-related quality of life in patients with the disease. The Committee concluded that it would be appropriate to use a value of 0.60 in the model for the progressed-disease health state and adjust it for age.

4.14  The Committee discussed the costs of administering aflibercept plus FOLFIRI in the model, noting that the manufacturer assumed no extra cost for administering aflibercept in the model. The Committee was aware that aflibercept would normally be prepared in a sterile compartment, and would therefore incur an extra cost; the Committee estimated that this cost is likely to be higher than the £15 used by the ERG. The Committee was also aware that the marketing authorisation for aflibercept stipulates that aflibercept should be administered separately over 1 hour, but that the cost for an additional hour of infusion time (£45) was not included in the ERG base case. The Committee concluded that the cost-effectiveness analysis should account for a more realistic extra preparation cost and a cost for an additional infusion time for aflibercept plus FOLFIRI compared with FOLFIRI alone.

4.15  The Committee discussed the costs in the model derived from the manufacturer’s survey of clinical oncologists. The Committee noted that the manufacturer’s model incorporated median estimates from the survey, whereas the ERG argued that the mean is more appropriate. The Committee heard from the manufacturer that the estimates used in the model relate to median responses elicited from the clinicians, and not median costs. The Committee agreed that, if the sample of clinicians was appropriately homogenous, and reflected similar practices, the distribution of the data collected from the survey would be largely uniform, and it would be more appropriate to use mean estimates than median. The Committee concluded that the model should include the mean estimates from the manufacturer’s survey of UK oncologists.

4.16  The Committee discussed the most plausible incremental cost-effectiveness ratios (ICERs) for aflibercept in combination with irinotecan and fluorouracil-based therapy for metastatic colorectal cancer. The Committee agreed that the cost-effectiveness analysis should assume equal risk of death for all patients beyond the trial period. It also agreed that the analysis should incorporate an age-adjusted utility value of 0.60 for the progressed disease state, an extra preparation cost for aflibercept, a cost for an additional infusion time for aflibercept plus FOLFIRI compared with FOLFIRI alone, and the mean estimates from the manufacturer’s survey of UK oncologists. The Committee therefore did not consider that the manufacturer’s cost-effectiveness base-case estimate of £36,500 appropriately reflected the true cost effectiveness of the treatment. The Committee instead considered the ICERs from the ERG’s exploratory analyses, which mirrored its favoured parameters and assumptions in the model, as more appropriate. It noted that the resulting ICERs ranged from £62,900 per QALY gained to £66,500 per QALY gained, depending on whether the treatment benefits of aflibercept plus FOLFIRI and FOLFIRI alone became the same after 30 or 36 months of starting treatment. The Committee agreed that these ICERs would be higher when accounting for an extra preparation cost for aflibercept of more than £15 (cost used by the ERG), and a cost for an additional hour of infusion time of £45. The Committee also considered that the ICERs may be higher when modelling treatments that patients may receive further down the treatment pathway, for example, surgery to remove secondary tumours. The Committee concluded that, because the most plausible ICERs were higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained, aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost-effective use of NHS resources for patients with metastatic colorectal cancer.

4.17  The Committee discussed whether aflibercept should be considered an innovative treatment. The Committee acknowledged that aflibercept represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.

4.18  The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.

• The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
• There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
• The treatment is licensed or otherwise indicated for small patient populations.

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

4.19  The Committee considered the criterion for short life expectancy and the evidence for life expectancy in this group of patients. The Committee noted the overall survival estimates presented by the manufacturer from the VELOUR trial with the observed median survival in the placebo group of VELOUR of 12.1 months and the estimated mean overall survival of 18.1 months. The Committee also noted the ERG’s preferred estimate of 10.5 months from the literature. The Committee concluded that patients receiving current standard NHS treatment would have an expected survival of less than 24 months from the point at which they would be considered for second-line therapy and that therefore the criterion for short life expectancy was fulfilled in this appraisal.

4.20  The Committee considered the second criterion that treatment offers an extension to life of at least 3 additional months. The Committee considered that, in the absence of a robust estimate of the difference in mean overall survival, and an estimate of overall survival of 1.44 months (section 4.5) calculated from median values, no robust evidence had been presented to indicate that aflibercept plus FOLFIRI compared with FOLFIRI alone offered a 3-month survival gain and therefore aflibercept plus FOLFIRI did not meet this criterion.

4.21  On the basis of these discussions (sections 4.19–4.20) the Committee concluded that treatment with aflibercept plus FOLFIRI does not fulfil the criteria for special consideration under the supplementary advice from NICE, and decided that it was not necessary to make a decision on the remaining criterion. The Committee noted the manufacturer’s suggestion that approximately 4000 patients in England and Wales would receive second-line treatment for metastatic colorectal cancer. It understood that aflibercept holds a marketing authorisation for treatment of a much larger population with neovascular (wet) age-related macular degeneration, but that this was a different formulation of aflibercept marketed by another company. The Committee also considered that, even if aflibercept had satisfied all 3 criteria, the additional weight that would need to be assigned to the QALY benefits would be too great to justify it as an appropriate use of limited NHS resources.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title:		Section
Key conclusion
Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. This is because the analyses that used the Committee’s preferred assumptions resulted in ICERs of at least £62,900 to £66,500 per QALY gained.			1.1 4.16
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from clinical specialists that the current treatment options for patients with metastatic colorectal cancer are limited, and that treatment is determined on an individual basis. The Committee heard from the clinical specialists that surgical resection of tumours may be a treatment option in some patients with metastatic disease. The Committee noted that patient experts considered it important to give clinicians treatment choices because chemotherapy can make resection possible in some patients.	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 noted that patients consider that biologic therapies such as aflibercept improve quality of life compared with chemotherapy. The Committee heard that the differences between the overall survival and progression-free survival curves might reflect a disease-modifying effect in that aflibercept might have altered the natural course of the disease so that patients lived longer even after treatment stopped and despite the disease progressing. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the differences between the curves. The Committee acknowledged that aflibercept represented a novel recombinant fusion protein.	4.3 4.6 4.17
What is the position of the treatment in the pathway of care for the condition?		Aflibercept plus FOLFIRI has a UK marketing authorisation for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.	2.1
Adverse reactions		The Committee concluded that treatment with aflibercept plus FOLFIRI was associated with a considerable burden of adverse reactions, but these were broadly similar to those related to other chemotherapeutic regimens.	4.9
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted that the evidence on the clinical effectiveness of aflibercept was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem. However, the Committee would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life, and would have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee concluded that the results from the VELOUR trial are generalisable to UK clinical practice.	4.4
Relevance to general clinical practice in the NHS		No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated by the evidence		The Committee noted the marked difference between the manufacturer’s estimate calculated from median overall survivals and that calculated from mean overall survivals. The Committee was aware that, to estimate mean overall survival, the manufacturer extrapolated the survival curves over 15 years. The Committee agreed that extrapolating the survival curves over 15 years, when most patients had lived for less than 3 years, and when the hazard ratios by 6-month periods late in the trial had wide confidence intervals, results in highly uncertain estimates for overall survival.	4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted that in the liver metastases only subgroup there was a statistically significant difference in overall survival in favour of aflibercept compared with the rest of the trial population. The Committee noted that only a very small minority of patients in the VELOUR trial proceeded to have surgical resection of liver metastases after treatment with aflibercept. The Committee heard from the clinical specialist that in approximately 20–30% of patients who undergo surgery to remove the liver metastases, metastatic colorectal cancer can be cured. The Committee, however, was not presented with evidence about resection and cure rates with aflibercept in the subgroup of patients with liver metastases only. The Committee also considered that liver resection for curative purposes was more appropriate in the first line setting than in the second line setting. The Committee agreed that, given the lack of evidence, aflibercept cannot be considered an effective treatment option for the purpose of making liver metastases resectable and did not consider this subgroup further. The Committee heard from the clinical specialists that, in clinical practice, patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months would not be treated differently to the overall trial population. In addition, the Committee noted that the manufacturer acknowledged that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup was differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy.	4.7 4.8
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that, given the uncertainty around the manufacturer’s extrapolation, the difference in mean overall survival of 4.7 months was not plausible. The Committee agreed that the manufacturer’s estimate of 1.44 months calculated from median overall survivals reflects a statistically significant but clinically small benefit.	4.5
Evidence for cost effectiveness
Availability and nature of evidence		The Committee agreed that the costs and quality-adjusted life years (QALYs) in the stable disease health state were not specific to the 2 sub-states (‘on second-line treatment’ and ‘post second-line treatment’). The Committee concluded that overall the model adhered to the NICE reference case for assessing cost effectiveness.	4.10
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee discussed how the manufacturer extrapolated overall survival, and the alternative assumptions considered by the ERG in its exploratory analyses. The Committee considered that the manufacturer’s assumption that the treatment effect of aflibercept plus FOLFIRI continues during the extrapolation period is highly uncertain given that most patients had died during the 3-year follow-up period of the trial, and given that the hazard ratios towards the end of the trial had wide confidence intervals. The Committee considered that the ERG’s scenario, in which the treatment effect of aflibercept plus FOLFIRI gradually decreases over the extrapolation period, could be considered implausible because it allows the hazard ratio to become greater than 1. The Committee agreed that the ERG’s scenario, which assumes no treatment effect from aflibercept plus FOLFIRI from the point at which the trial ends onwards, represents an acceptable compromise between these 2 extremes. However, the Committee concluded that, although this was considered the most plausible assumption for extrapolating overall survival, it still considered that great uncertainty exists.	4.12
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 agreed that the utility value used by the manufacturer for the progressed-disease health state appears too high. The Committee concluded that it would be appropriate to use a value of 0.60 in the model for the progressed-disease health state and adjust it for age. The Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.	4.13 4.17
Are there specific groups of people for whom the technology is particularly cost effective?		Having considered the clinical evidence presented by the manufacturer for the 2 subgroups, the Committee concluded that it did not need to consider the cost effectiveness of the technology for any of the subgroups.	4.7 4.8
What are the key drivers of cost effectiveness?		The Committee agreed that, when the time horizon is much longer than the duration of a trial, it is particularly important to explore the assumptions underlying how overall survival is extrapolated, and the impact of using alternative survival functions on the estimates. The Committee understood from the ERG that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to the utility value in the progressed-disease health state.	4.11 4.13
Most likely cost-effectiveness estimate (given as an ICER)		The Committee considered that the ICERs from the ERG’s exploratory analyses, which mirrored its favoured parameters and assumptions in the model, were more appropriate than the manufacturer’s estimate of cost effectiveness. It noted that the resulting ICERs ranged from £62,900 per QALY gained to £66,500 per QALY gained (depending on whether the risk of death in both treatment groups became the same after 30 or 36 months of starting treatment). The Committee agreed that these ICERs would be higher when accounting for an extra preparation cost for aflibercept of more than £15 (cost used by the ERG), and a cost for an additional hour of infusion time of £45.	4.16
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.	2.3
End-of-life considerations		The Committee concluded that no robust evidence had been presented to indicate that aflibercept plus FOLFIRI compared with FOLFIRI alone offered a 3-month survival gain and that therefore aflibercept plus FOLFIRI does not fulfil the criteria for special consideration under the supplementary advice from NICE.	4.20 4.21
Equalities considerations and social value judgements		No equality issues relevant to the Committee’s preliminary recommendations were raised.

5  Implementation

5.1  NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] 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

Details are correct at the time of consultation. Further information is available on the NICE website.

Published

• Colorectal cancer, the diagnosis and management of colorectal cancer. NICE clinical guideline 131(2011).
• Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of TA150 and part review of TA118). NICE technology appraisal guidance 242 (2012).
• Panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 240 (2011).

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 August 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.

Amanda Adler
Chair, Appraisal Committee
June 2013

8  Appraisal Committee members, guideline representatives and NICE project team

8.1  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 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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

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

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

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

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

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

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

Mark Chapman
Health Economics and Market Access Manager, Medtronic UK

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Robert Hinchliffe
HEFCE Clinical Senior Lecturer in Vascular Surgery and Honorary Consultant Vascular Surgeon, St George's Vascular Institute

Professor Daniel Hochhauser
Consultant in Medical Oncology, UCL Cancer Institute

Dr Neil Iosson
General Practitioner

Anne Joshua
Associate Director of Pharmacy, NHS Direct

Dr Rebecca Kearney
Clinical Lecturer, University of Warwick

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Elizabeth Murray
Reader in Primary Care, University College London

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

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

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Roderick Smith
Chief Finance Officer, Coastal West Sussex Clinical Commissioning Group

Cliff Snelling
Lay Member

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

Dr Nicky Welton
Senior Lecturer in Biostatistics/Health Technology Assessment, University of Bristol

8.2  NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Ahmed Elsada
Technical Lead(s)

Joanna Richardson
Technical Adviser

Jeremy Powell
Project Manager

9  Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by the CRD and CHE Technology Assessment Group, University of York:

• Wade R, Duarte A et al. Aflibercept in combination with irinotecan and fluorouracil-based therapy for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, April 2013

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:

• Sanofi

II. Professional/specialist and patient/carer groups:

• Beating Bowel Cancer
• Cancer Research UK
• Royal College of Nursing

III. Other consultees:

• Department of Health
• Welsh Government

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

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Medicines and Healthcare products Regulatory Agency
• Pfizer
• Roche

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

• Dr Richard Adams, Senior Lecturer and Consultant Oncologist, Velindre Cancer Centre and Cardiff University, nominated by Sanofi - clinical specialist
• Jacqueline Fraser, nominated by Beating Bowel Cancer - patient expert
• Helen Minnery, nominated by Beating Bowel Cancer - patient expert

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

• Sanofi